Clinical review for the USMLE Step 1 by Surgisphere

Clinical Review for the USMLE Step 1

Also from Catalyst Publishers Clinical Review for the USMLE Step 1 Clinical Review for the USMLE Step 2 Clinical Review for the USMLE Step 3 Clinical Review of Surgery Clinical Review of Vascular Surgery Clinical Review of Medicine General Surgery Q&A Vascular Surgery Q&A

Available online at www.ClinicalReview.com Join the comprehensive vascular surgery review trusted by residents and program directors all around the country. This multidisciplinary, peerreviewed course includes hundreds of practice questions, audio and video reviews, videos of major vascular surgery procedures, and online textbooks. This is the only review course of its kind to follow the Association of Program Directors in Vascular Surgery curriculum.

Clinical Review for the USMLE Step 1 EDITORS Sapan S. Desai, M.D., Ph.D. Assistant Professor Department of Surgery Duke University Medical Center Durham, North Carolina

Danny O. Jacobs, M.D., M.P.H. Professor and Chair Department of Surgery Duke University Medical Center Durham, North Carolina

Clinical Review for the USMLE Step 1 Edited by Sapan S. Desai, MD, PhD and Danny O. Jacobs, MD, MPH Copyright ÂŠ 2012 Surgisphere Corporation, All Rights Reserved. www.ClinicalReview.com | www.CatalystPublishers.com | www.Surgisphere.com Prepared in the United States of America

This title is published by Catalyst Publishers in association with the Surgisphere Corporation, 4706 Carmen Lane, Durham, NC 27707. No part of this book may be reproduced in any form or by any means, mechanical or electronic, including photocopying, recording, electronic storage, virtual or actual without written permission from the Surgisphere Corporation. You may not alter or remove any notice of copyright or ownership from this content. Surgisphere and the Surgisphere logo are trademarks of the Surgisphere Corporation. The Catalyst Publishers logo is a trademark of Catalyst Publishers. Various images within this text are used under various versions of the Creative Commons license. Credit is provided in all instances the original author can be identified. Images contained are used with permission; if a particular image is not referenced or used appropriately, please contact us so that the appropriate arrangements can be made. While every precaution has been taken in the preparation of this textbook, the authors, editors, Catalyst Publishers, and the Surgisphere Corporation assume no responsibility for errors, omissions, or damages arising from the use of the information contained herein.

Third Edition

Cataloging-In-Publication Data

Surgisphere Corporation

Clinical Review for the USMLE Step 1

1. Medicine 2. Exam Preparation

I. Surgisphere Corporation

01 / 10 9 8 7 6 5 4 3 2

II. Clinical Review for the USMLE Step 1

For Eashan Desai

FOREWORD

There is a single light of science, and to brighten it anywhere is to brighten it everywhere. Isaac Asimov

he United States Medical Licensing Examination is taken throughout the year by medical students and residents around the country. It is used by residency programs as one measure of the caliber of potential candidates and is required to become a physician eligible to practice medicine.1 Poor performance on the USMLE is likely to adversely affect your application for residency, may limit the opportunities available for you in career selection, and jeopardizes your medical career.

This textbook and its accompanying online course were created to improve the quality of medical education and thereby help to improve the quality of care our patients receive. While there can be no substitute for studying the reference textbooks in the field, there are numerous moments during medical school and residency to quickly review and understand high-yield topics. The focus of this program is to provide a high-yield review of topics commonly tested on the USMLE. This material is derived from the major medical reference textbooks and covers topics that have appeared on recent USMLE examinations. The overall organization of this textbook reflects the content outline produced by the FSMB and NBME to ensure that every subject area is given due consideration. Students and residents who have used this program in recent years have reported scores in the top 1% across the world. The online program available last year was used by medical students from nearly every medical school around the world, and residents from nearly every residency program across the nation.2 Based on their feedback and our proven approach to education, this is our solution for preparing for the USMLE.

Sapan S. Desai, MD, PhD

Assistant Professor of Surgery Duke University Medical Center Executive Editor Journal of Surgical Radiology Chief Executive Officer Surgisphere Corporation

1 2

Residency programs use the USMLE score as one element in selecting residents during the match. Poor scores mitigate the opportunity for competitive specialties and for joining top-tier residency programs. Poor performance may even prevent the ability to become a certified medical practitioner. Students around the world and residents around the United States used this review program from 20062011 to prepare for the USMLE.

CONTENTS

Copyright MedicalRf.com. Used with permission. I will pass over the other arts in silence and direct my words for a while to that which is responsible for the health of mankind; certainly of all the arts that human genius has discovered, this is by far the most useful, indispensible, difficult, and laborious. Andreas Vesalius De Humani Corporus Fabrica, 1543

Foreword..................................................................... vi Contents..................................................................... viii Contributors................................................................ xx Introduction.............................................................. xxiv 1. Overview of Topics.............................................................................. 1 2. Organization of Text............................................................................ 1 3. Study Plan.......................................................................................... 1 4. Feedback........................................................................................... 2

General Principles........................................................... 4 1. Introduction......................................................................................... 5 2. Biochemistry and Molecular Biology....................................................... 5 2.1.

Gene Expression..................................................................... 5

2.2.

Protein and Enzyme Structure and Function............................... 13

2.3.

Energy Metabolism................................................................ 15

2.4. Biochemical Disorders............................................................ 20

3. Biology of Cells................................................................................. 24 3.1.

Adaptive Cell Responses and Cellular Homeostasis.................... 24

3.2.

Mechanisms of Injury and Necrosis.......................................... 25

3.3. Apoptosis............................................................................. 26 3.4.

Mechanisms of Dysregulation.................................................. 26

3.5.

Cell Structure and Function..................................................... 31

3.6.

Growth Factors..................................................................... 37

4. Human Development and Genetics.......................................................38 4.1.

Pedigree Analysis.................................................................. 38

4.2.

Population Genetics............................................................... 39

4.3.

Gene Therapy....................................................................... 40

4.4. Genetic Testing and Counseling............................................... 40

5. Inflammation and Repair......................................................................42 5.1. Fever................................................................................... 42 5.2.

Systemic Inflammatory Response Syndrome............................... 43

5.3. Sepsis.................................................................................. 44 ix

Clinical Review for the USMLE Step 1 5.4. Shock.................................................................................. 45 5.5. Wound Healing.................................................................... 46

6. Psychology........................................................................................47 6.1.

Life Cycle............................................................................. 47

6.2.

Theories of Development........................................................ 50

6.3.

Coping Mechanisms.............................................................. 53

6.4. Conditioning and Patient Adherence........................................ 57 6.5.

Patient Interviewing and Challenging Situations.......................... 59

6.6. Medical Ethics...................................................................... 61

7. Fluid, Electrolytes, Nutrition, and Acid-Base........................................... 66 7.1.

Electrolyte Disturbances.......................................................... 66

7.2. Nutrition............................................................................... 70 7.3. Acid-Base............................................................................. 75 7.4. Fluids................................................................................... 77 7.5.

Metabolic Disorders............................................................... 78

8. Pharmacology................................................................................... 80 8.1. Pharmacokinetics................................................................... 80 8.2. Pharmacodynamics................................................................ 81 8.3.

Efficacy and Potency.............................................................. 82

8.4. Drug Development................................................................. 82

9. Microbiology.....................................................................................82 9.1. Bacteria............................................................................... 82 9.2. Organisms............................................................................ 86 9.3. Antimicrobials....................................................................... 90 9.4. Fungus................................................................................. 94 9.5. Virus.................................................................................... 96 9.6. Parasites............................................................................... 99 9.7.

Common Infections.............................................................. 100

9.8. Prions.................................................................................101

10. Biostatistics.....................................................................................102 10.1. Introduction........................................................................ 102 10.2. Descriptive Statistics............................................................. 102 10.3. Measures of Central Tendency: Mean, Median, and Mode....... 103 10.4. Measures of Spread: Range, variance and Standard Deviation.. 103 10.5. Normal Distributions............................................................ 104 x

10.6. Skewed Distributions............................................................ 104 10.7. Estimation and Bias.............................................................. 105 10.8. Hypothesis Testing............................................................... 107 10.9. Tests of Significance............................................................. 109 10.10. Study Designs and Measures of Association............................. 111 10.11. Measures of Associations Between Two Binary Variables ..........112 10.12. Diagnostic Tests....................................................................114

Hematology. ..............................................................116 1. Basic Science................................................................................... 117 1.1. Embryology.........................................................................117 1.2.

Developmental Structure and Function.....................................117

1.3. Erythrocytes.........................................................................117 1.4. Platelets............................................................................. 120 1.5. Coagulation....................................................................... 120 1.6.

Overview of Hemostasis ...................................................... 124

2. Hematologic Disorders...................................................................... 126 2.1.

Preoperative Assessment....................................................... 126

2.2.

Approach to The Bleeding Patient.......................................... 126

2.3.

Acquired Bleeding Disorders................................................. 127

2.4. Dilutional Coagulopathy .......................................................131 2.5.

Hypercoagulable States........................................................131

2.6.

Venous Thromboembolism..................................................... 132

2.7. Anemias............................................................................. 133 2.8.

Transfusion Reactions........................................................... 139

2.9.

Other Red Blood Cell Conditions........................................... 140

2.10. Platelets and Coagulation......................................................141

3. Pharmacology and Treatment.............................................................143 3.1.

Anticoagulants and Hemostatic Agents................................... 143

3.2.

Blood Products.................................................................... 143

3.3.

Jehovah’s Witnesses............................................................ 146

4. References.......................................................................................146

CNS & PNS............................................................. 148 1. Introduction......................................................................................149 xi

Clinical Review for the USMLE Step 1 2. Embryology.....................................................................................149 2.1. Embryogenesis.................................................................... 149 2.2.

Embryologic Tissue Derivatives.............................................. 150

2.3.

Branchial Apparatus............................................................ 150

2.4. Twins................................................................................. 152 2.5.

Neural Plate and Neural Tube............................................... 152

2.6.

Development of the Inner Ear................................................ 154

2.7.

Development of the Eye........................................................ 155

3. Anatomy.........................................................................................155 3.1.

Vascular Supply to the Head and Neck.................................. 155

3.2.

Vascular Supply to the Upper Extremity.................................. 158

3.3.

Vascular Supply to the Abdomen and Pelvis............................ 160

3.4.

Vascular Supply to the Lower Extremity....................................161

3.5. Cranial Nerves................................................................... 163 3.6.

Brain Nuclei....................................................................... 169

3.7.

Triangles of the Neck........................................................... 177

3.8. Innervation......................................................................... 179

4. Physiology.......................................................................................184 4.1. Neurons............................................................................. 184 4.2.

Supporting Cells.................................................................. 186

4.3.

Brain Death........................................................................ 186

4.4. Peripheral Vascular Resistance............................................... 186 4.5. Autoregulation.................................................................... 187 4.6.

Venous Hemodynamics........................................................ 187

4.7.

Respiratory Flow Variation.................................................... 187

4.8. Vasoactive Mediators........................................................... 188 4.9.

Cerebral Perfusion Pressure................................................... 188

5. CNS and PNS Pathology...................................................................189 5.1.

Spinal Cord Pathology......................................................... 189

5.2.

Brain Pathology....................................................................191

5.3.

Sensory Disturbances........................................................... 199

5.4.

Infectious Diseases............................................................... 201

5.5.

Neurodegenerative Disorders................................................ 203

5.6.

Sleep Disorders................................................................... 207

5.7. Epilepsy............................................................................. 208 5.8. Cancer.............................................................................. 209 xii

5.9.

Salivary Gland Tumors..........................................................210

6. Psychopathology.............................................................................. 211 6.1.

Psychotic Disorders...............................................................211

6.2.

Mood Disorders...................................................................213

6.3.

Anxiety Disorders.................................................................215

6.4. Cognitive Disorders...............................................................217 6.5.

Amnestic Disorders...............................................................219

6.6.

Somatoform Disorders.......................................................... 220

6.7.

Malingering and Factitious Disorders...................................... 221

6.8.

Personality Disorders............................................................ 221

6.9.

Substance Abuse Disorders................................................... 224

7. Pharmacology..................................................................................230 7.1.

Cholinergic Agents.............................................................. 230

7.2.

Adrenergic Agents............................................................... 231

7.3.

Serotoninergic Agents.......................................................... 233

7.4. Toxicology.......................................................................... 233 7.5. Anticonvulsants................................................................... 236 7.6.

Cognitive Agents................................................................. 236

7.7. Anesthetics......................................................................... 237 7.8. Analgesics.......................................................................... 238 7.9. Antipsychotics..................................................................... 239 7.10. Antidepressants................................................................... 242 7.11. Mood Stabilizers................................................................. 246 7.12. Anxiolytics.......................................................................... 249 7.13. Other Medications............................................................... 251 7.14. Major Adverse Drug Effects.................................................. 251

Skin & Soft Tissue...................................................... 254 1. Introduction......................................................................................255 2. Basic Science...................................................................................255 2.1. Anatomy............................................................................ 255 2.2. Embryology........................................................................ 256 2.3.

Repair and Regeneration...................................................... 256

2.4. Scar Formation.................................................................... 258

3. Pathology........................................................................................258 xiii

Clinical Review for the USMLE Step 1 3.1.

Infectious and Inflammatory Disorders.................................... 258

3.2. Trauma.............................................................................. 270 3.3. Cancer.............................................................................. 275 3.4.

Soft Tissue Tumors............................................................... 278

Musculoskeletal. ........................................................ 280 1. Basic Science................................................................................... 281 1.1.

Embryology and Histology.................................................... 281

1.2. Physiology.......................................................................... 281

2. Pathology........................................................................................284 2.1.

Anatomic Disorders............................................................. 284

2.2.

Metabolic Bone Diseases...................................................... 290

2.3.

Inflammatory and Infectious Disorders.................................... 292

2.4. Cancer.............................................................................. 300

3. Pharmacology..................................................................................302

Respiratory. ............................................................... 304 1. Basic Science...................................................................................305 1.1. Anatomy............................................................................ 305 1.2. Physiology.......................................................................... 305

2. Pathology........................................................................................307 2.1.

Congenital and Structural..................................................... 307

2.2.

Inflammatory and Infectious...................................................319

2.3. Vascular............................................................................. 326 2.4. Trauma.............................................................................. 327 2.5. Cancer.............................................................................. 329

3. Pharmacology..................................................................................334 3.1.

Endotracheal Intubation........................................................ 335

Cardiovascular.......................................................... 340 1. Introduction......................................................................................341 2. Epidemiology...................................................................................341 2.1.

Causes of Death.................................................................. 341

2.2. Preventive Medicine............................................................. 341 2.3. xiv

Use of Tests........................................................................ 342

2.4. Routine Screening................................................................ 342 2.5.

Cancer Screening................................................................ 342

3. Basic Science.................................................................................. 344 3.1. Embryology........................................................................ 344 3.2. Anatomy............................................................................ 344 3.3. Physiology.......................................................................... 346 3.4.

Vasoactive Mediators........................................................... 350

4. Pathology........................................................................................351 4.1.

Basic Topics........................................................................ 351

4.2.

Congenital Heart Defects...................................................... 353

4.3.

Coronary Heart Disease....................................................... 354

4.4. Valvular Heart Disease......................................................... 365 4.5. Cardiomyopathy................................................................. 371 4.6. Pericardial Disease...............................................................374 4.7. Arrhythmia......................................................................... 378 4.8.

Aortic Diseases................................................................... 382

4.9.

Vascular Disorders............................................................... 385

5. Pharmacology..................................................................................389 5.1. Nitrates.............................................................................. 389 5.2.

Adrenergic Agents and Antihypertensives............................... 389

5.3. ACE-Inhibitors..................................................................... 392 5.4. Aspirin............................................................................... 392 5.5. Heparin............................................................................. 392 5.6.

Streptokinase and Alteplase.................................................. 393

5.7. Digoxin.............................................................................. 393 5.8. Antihyperlipidemics.............................................................. 393 5.9. Antiarrhythmics................................................................... 395 5.10. Pressors and Inotropes......................................................... 396 5.11. Studies and Procedures........................................................ 397

Gastrointestinal......................................................... 400 1. Basic Science...................................................................................401 1.1. Embryology........................................................................ 401 1.2. Anatomy............................................................................ 401 1.3. Physiology...........................................................................412 xv

Clinical Review for the USMLE Step 1 2. Pathology........................................................................................ 421 2.1. Esophagus.......................................................................... 421 2.2. Stomach............................................................................. 430 2.3.

Small Intestine..................................................................... 437

2.4. Large Intestine..................................................................... 447 2.5.

Rectum and Anus................................................................. 466

2.6.

Abdominal Wall.................................................................. 470

2.7. Liver.................................................................................. 475 2.8.

Biliary Disease.................................................................... 485

2.9.

Pancreatic Disorders............................................................ 490

2.10. Spleen............................................................................... 495

3. Pharmacology..................................................................................498

Genitourinary............................................................ 500 1. Basic Science...................................................................................501 1.1. Embryology........................................................................ 501 1.2. Anatomy............................................................................ 502 1.3. Histology............................................................................ 502 1.4. Physiology.......................................................................... 502

2. Pathology........................................................................................507 2.1.

Renal Failure....................................................................... 507

2.2.

Structural and Metabolic Disorders......................................... 508

2.3.

Vascular Disease..................................................................513

2.4. Inflammatory and Metabolic Disorders....................................515 2.5.

Glomerular and Nephrotic Disease.........................................516

2.6.

Infectious Diseases............................................................... 520

2.7.

Sexually-Transmitted Diseases................................................ 523

2.8. Trauma.............................................................................. 528 2.9. Cancer.............................................................................. 528

3. Pharmacology..................................................................................532

Reproductive.............................................................. 534 1. Basic Science...................................................................................535 1.1. Embryology........................................................................ 535 1.2. Gametogenesis................................................................... 535 1.3. Anatomy............................................................................ 536 xvi

1.4. Physiology.......................................................................... 537

2. Fetal / Neonatal Pathology................................................................553 2.1.

General Concepts............................................................... 553

2.2.

Genetic Disorders................................................................ 554

2.3.

Disorders of the Chest.......................................................... 557

2.4. Disorders of the Abdomen.................................................... 561 2.5.

Hepatobiliary Disease.......................................................... 565

2.6.

Pediatric Tumors.................................................................. 566

3. Breast Pathology...............................................................................567 3.1.

Diagnostic Imaging.............................................................. 567

3.2.

Benign Breast Disease.......................................................... 569

3.3.

Malignant Breast Disease..................................................... 570

4. Gynecology.....................................................................................573 4.1.

Ovarian Disease................................................................. 573

4.2.

Cervical, Uterine, and Vaginal Disease................................... 577

5. Pharmacology..................................................................................582 5.1.

Steroid Hormones................................................................ 582

Endocrine................................................................. 584 1. Basic Science...................................................................................585 1.1. Anatomy............................................................................ 585 1.2. Physiology.......................................................................... 588 1.3.

Diagnostic Studies............................................................... 590

2. Pathology........................................................................................ 591 2.1.

Hypothalamus and Pituitary.................................................. 591

2.2. Thyroid.............................................................................. 593 2.3. Parathyroid......................................................................... 598 2.4. Adrenal Gland.................................................................... 601 2.5. Pancreas............................................................................ 606 2.6.

Metabolic Disorders..............................................................610

2.7.

Multiple Endocrine Neoplasia................................................612

3. Pharmacology.................................................................................. 613 3.1. Diabetes.............................................................................613 3.2.

Hormonal Agents and Corticosteroids.....................................614

xvii

Clinical Review for the USMLE Step 1

Immune System............................................................616 1. Basic Science................................................................................... 617 1.1. Immunization.......................................................................617 1.2.

General Concepts in Immunology...........................................618

1.3.

Immune-Mediated Pathology................................................. 631

2. Oncology........................................................................................637 2.1. Pathology........................................................................... 637 2.2. Pharmacology..................................................................... 645

xviii

xix

CONTRIBUTORS

Surgisphere is grateful for the contributions of more than 40 authors to the Clinical Review Series over the past several years. Adaptations of their contributions are used in this textbook.

Gowthami Arepally, MD, PhD

William Eward, DVM, MD

Associate Professor of Hematology Department of Medicine Duke University Medical Center

Resident Department of Surgery Duke University Medical Center

Ali Azizzadeh, MD

Jackie Garonzik, MD

Associate Professor Department of Surgery University of Texas at Houston

Resident Department of Surgery Johns Hopkins University

Tara Brennan, MD

Prateek K. Gupta, MD

Resident Department of Ophthalmology University of Illinois

Resident Department of Surgery Creighton University

Johnny T. Chang, MD

John W. Hallett, MD

Resident Department of Surgery Brown University

Professor Department of Surgery University of South Carolina

Mani Daneshmand, MD

Joseph P. Hart, MD

Resident Department of Surgery Duke University Medical Center

Assistant Professor Department of Surgery University of South Carolina

Melissa Danko, MD

Jeff Hoehner, MD, PhD

Resident Department of Surgery Duke University Medical Center

Associate Professor Department of Surgery Duke University Medical Center

Niketa Desai, PharmD

G. Chad Hughes, MD

Pharmacist Department of Pharmacology Long Island University

Associate Professor Department of Surgery Duke University Medical Center

Sapan S. Desai, MD, PhD

Danny O. Jacobs, MD, MPH

Assistant Professor Department of Surgery Duke University Medical Center

Professor and Chair Department of Surgery Duke University Medical Center

Amahuaro Edebiri, MD

Issam Koleilat, MD

Professor and Chair Department of Obstetrics & Gynecology Bayero University

Resident Department of Surgery Albany Medical College

xxi

Clinical Review for the USMLE Step 1

xxii

Michael Lidsky, MD

Leontine Narcisse, MD, PhD

Resident Department of Surgery Duke University Medical Center

Fellow Department of Surgery Westchester Medical Center

Keri E. Lunsford, MD, PhD

Theodore Pappas, MD

Resident Department of Surgery Duke University Medical Center

Professor Department of Surgery Duke University Medical Center

Alice D. Ma, MD

Luigi Pascarella, MD

Associate Professor of Hematology Department of Medicine Duke University Medical Center

Resident Department of Surgery Duke University Medical Center

Jerimiah Mason, MD

David A. Peterson, MD

Resident Department of Surgery Baptist Medical Center

Fellow Department of Surgery Duke University Medical Center

Stephanie Mayer, MD

Scott K. Pruitt, MD, PhD

Resident Department of Surgery Duke University Medical Center

Associate Professor Department of Surgery Duke University Medical Center

Richard L. McCann, MD

Elaheh Rahbar, PhD

Professor Department of Surgery Duke University Medical Center

Professor Department of Surgery University of Texas at Houston

Eric Mowatt-Larssen, MD

Mohammad Hossein Rahbar, PhD

Assistant Professor Department of Surgery Duke University Medical Center

Professor and Director Dept of Epidemiology & Biostatistics University of Texas at Houston

Daniel Murariu, MD

Randall Scheri, MD

Resident Department of Surgery University of Hawaii

Assistant Professor Department of Surgery Duke University Medical Center

Charles Murphy, MD

Mark Shapiro, MD

Assistant Professor Department of Surgery Duke University Medical Center

Associate Professor Department of Surgery Duke University Medical Center

Tamarah Westmoreland, MD, PhD

Professor Department of Surgery Duke University Medical Center

Resident Department of Surgery Duke University Medical Center

Suzanne Stewart, MD

Judson Williams, MD

Resident Department of Surgery Duke University Medical Center

Elisabeth Tracy, MD

Mark D. Williams, MD

Resident Department of Surgery Duke University Medical Center

Professor Department of Surgery St. Elizabeth Medical Center

Immanuel Turner, MD

Jocelyn Wittstein, MD

Resident Department of Surgery Duke University Medical Center

Cynthia Shortell, MD

xxiii

INTRODUCTION

Copyright MedicalRf.com. Used with permission. The matter is already quite difficult enough, and I have no wish to make it even more obscure. Andreas Vesalius De Humani Corporus Fabrica, 1543

1. Overview

Topics

The United States Medical Licensing Examination Step 1 must be successfully passed in order to complete medical school and be eligible for a residency program. This examination tests your ability to apply basic medical and clinical topics to the practice of medicine. It covers a broad variety of topics from every major field of medicine with an emphasis on concepts that pertain to the practice of medicine. The Step 1 examination seeks to measure your basic science and clinical acumen, and ability to identify key principles regarding common medical diseases.

2. Organization

Text

This textbook and the Comprehensive Review Course faithfully follow the content outline for the USMLE Step 1 Examination. This course covers essential topics in the clinical sciences that you are expected to master. High-yield topics are covered with an emphasis on understanding the key information. Every attempt is made to highlight material that is particularly important for the practice of medicine, and therefore more likely to appear on the boards. A subject-based approach is used in this textbook, with the first half of the book focused on basic science principles and the latter half focused on clinical principles. Appropriate emphasis is placed on basic science topics and clinical medicine topics, and this series is formulated specifically for the basic science and clinical topics that you are expected to master for the Step 1. Following most sections are pertinent questions to help you further your knowledge in additional areas while practicing what you have learned.

3. Study Plan How you study for the USMLE depends on how much time you have available. Motivated students and residents who prepare in advance will benefit the most from the online review program and the enormous body of information available on the website. Regardless of how much time you have available, this entire review program is designed to be done piecemeal using the short periods of time you have available on call nights and down time. Each topic is designed to be covered in just a few minutes, and many students report making good progress on the question bank by doing a few questions over lunch each day. Based on student feedback, our recommendation is to keep this book with you at all times. It is a handy book to go through whenever a few minutes are available. While each individual study plan will be different, there are a few trends that we have noticed with high scorers: 1.

Use this book in conjunction with the online questions and your existing reference books

Do questions and read through several topics every night starting at least a month in advance

Review the high-yield PowerPoint presentations at least a week in advance of your exam

Take note of your strengths and weaknesses and focus on them accordingly

Complete the entire Comprehensive Review Course

We recommend going through this resource in its entirety. Topics that have appeared on recent exams or more than once are marked by a star. In addition, topics that the reviewers have deemed to be particularly worthwhile are also highlighted. It is important to reiterate that the purpose of this book is to 1

Clinical Review for the USMLE Step 1 help you become a better doctor â&#x20AC;&#x201C; your score on this exam should reflect your mastery of basic science and clinical medicine. Students that are more pressed for time may want to take advantage of the High-Yield Topic section at the back of the textbook. This section highlights the most frequently tested material and is a good review of key facts. Organizing your study around this is a good way to start, but no comprehensive study plan is complete without a thorough review of practice questions and a chance to reinforce what you have learned. Take advantage of our Comprehensive Review Course to maximize your score and truly get closer to your potential. Use this textbook in conjunction with the Comprehensive Review Course at www.ClinicalReview.com. This will permit you to practice nearly 10,000 questions, review explanations, go through a detailed high-yield PowerPoint slide presentation, watch audio/video lectures, and access all of our textbooks online.

4. Feedback We are always searching for ways to improve our products. If you have any comments or suggestions, we would love to hear from you. Contact us at Support@ClinicalReview.com any time.

Sapan S. Desai, MD, PhD Assistant Professor of Surgery Duke University Medical Center Executive Editor Journal of Surgical Radiology Chief Executive Officer Surgisphere Corporation

Feedback

GENERAL PRINCIPLES

Section Editors Sapan S. Desai, MD, PhD

Danny O. Jacobs, MD, MPH

Assistant Professor Department of Surgery Duke University Medical Center

Professor and Chair Department of Surgery Duke University Medical Center

Contributors Mohammad Hossein Rahbar, PhD

Elaheh Rahbar, PhD

Professor and Director Dept of Epidemiology & Biostatistics University of Texas at Houston

Professor Department of Surgery University of Texas at Houston

Eric Mowatt-Larssen, MD Assistant Professor Department of Surgery Duke University Medical Center Biostatistics (adapted from the Clinical Review of Phlebology and Venous Ultrasound)

Sapan S. Desai, MD, PhD

Mark D. Williams, MD

Assistant Professor Professor Department of Surgery Department of Surgery Duke University Medical Center St. Elizabeth Medical Center Surgical Critical Care (adapted from the Clinical Review of Surgery)

Scott K. Pruitt, MD, PhD

Tara Brennan, MD

Associate Professor Resident Department of Surgery Department of Ophthalmology Duke University Medical Center University of Illinois

Leontine Narcisse, MD, PhD

Jerimiah Mason, MD

Fellow Resident Department of Surgery Department of Surgery Westchester Medical Center Baptist Medical Center

Niketa Desai, PharmD Pharmacist Department of Pharmacology Long Island University Surgical Principles (adapted from the Clinical Review of Surgery)

1. Introduction The content outline produced by the National Board of Medical Examiners and Federation of State Medical Boards includes a hodgepodge of 10 topics under General Principles. Some of the topics are straightforward, such as the Biology of Cells and the Biology of Tissue Response to Disease. Others are more complex topics typically covered over a full year course in medical school, such as Biochemistry and Molecular Biology, Pharmacology, and Microbiology. The content outline serves as a rough basis for what the board deems is a topic that may appear on the USMLE. It is impossible for any review course to cover every topic that could appear on the exam - that is the purpose for reading the large textbooks and going to medical school. What we will focus on in this section are the high-yield topics loosely organized according to the USMLE content outline.

2. Biochemistry

and

Molecular Biology

2.1. Gene Expression 2.1.1

DNA Structure

As you have had repeatedly instilled within you since high school, DNA is a double helix composed of nucleotides. These four nucleotide bases are divided into purines (adenine and guanine) and pyrimidines (cytosine and thymine). Hydrogen bonds connect A to T and C to G - base pairs that are anchored along a 2-deoxyribose pentose sugar backbone that relies on phosphodiester bonds. DNA is transcribed into RNA (discussed below). If the sequence on the DNA strand is the same as the resulting mRNA copy that is created, that strand is called the â&#x20AC;&#x153;senseâ&#x20AC;? strand. The other strand then becomes the antisense strand. Sequences along a long strand of DNA that can be used to transcribe RNA are known as genes. There are more than 3 billion DNA base pairs in the human genome. Extensive supercoiling occurs to help condense these strands of DNA into a more manageable structure - these are known as chromosomes when they become hypercondensed. There are 23 pairs of chromosomes and approximately 23,000 protein-coding genes in the human genome, with only about 1.5% of the total genome used to code for proteins.

2.1.2

DNA Replication

DNA replication begins at specific protein complexes that facilitate separating the DNA into Figure 1. Copyright Madeleine Price Ball. Used with two strands and create a replication fork. A permission. 5

Clinical Review for the USMLE Step 1 protein complex forms at the fork and RNA primers attach to the leading strand and lagging strand. The leading strand typically receives a single RNA primer as it will be created in one piece from start to finish (3’ to 5’). The lagging strand receives several RNA primers as it will be created in short sequences known as Okazaki fragments (5’ to 3’). The RNA primers will eventually be removed by RNase and replaced with DNA-appropriate nucleotides. As the replication fork causes the DNA strands to separate and unwind, DNA gyrase helps to create negative rotations in the DNA to reduce the rotational tension that would otherwise occur. There are also a variety of DNA polymerases that assist with DNA replication. Polymerase alpha helps to synthesize RNA primer and initiate polymerization. Polymerase beta plays a role in DNA repair. Polymerase gamma is used for mitochondrial DNA replication and also has proofreading capability. Polymerase delta helps to fill gaps following RNA primer excision and also plays major role in polymerization; it also has proofreading capability. Finally, polymerase epsilon plays a role in proofreading as well and helps to assist polymerase delta. Proofreading on the completed strand occurs in a 3’ to 5’ direction.

2.1.3

DNA Exchange

DNA exchange takes the form of genetic recombination, of which there are several different types. Recombination can occur between similar molecules of DNA, known as homologous recombination; it can also occur among dissimilar DNA molecules and is Figure 2. Copyright Madeleine Price Ball. Used termed non-homologous recombination. Recombinawith permission. tion plays an important role in two scenarios: first, it is an important method of DNA repair; second, recombination is an important part of chromosomal crossover in meiosis and is responsible for the genetic variation we see in our offspring. Additional genetic recombination occurs in B cells as part of antibody production. Homologous recombination occurs when the damaged portion of a DNA strand is resected and the remaining strand attached to its complimentary strand on its sister chromosome. In the case of damaged DNA, crossover does not occur and there is no genetic rearrangement. In meiosis, crossover does occur with reassortment of genes. Homologous recombination occurs in the S and G2 phases of the cell cycle due to the availability of sister chromatids. Non-homologous recombination, more precisely termed non-homologous end joining, is used when there is a double-strand break in DNA. When a break typically occurs, there is some overlap in the complimentary strands that can be processed by various repair proteins to facilitate accurate ligation. Defects in non-homologous end joining can occur if there is insufficient overlap or the ligation does not 6

Biochemistry and Molecular Biology occur correctly; in the worst case, this can lead to truncation of a protein product and the creation of a tumorgenic focus. Over 3 billion exposed nucleotides, at least 100,000 mutations occur pay day secondary to endogenous factors such as free radicals and exogenous factors like UV radiation and toxins. Disorders in DNA repair are well known and lead to a variety of syndromes. Ataxia-telangiectasia is characterized by radiation and chemical sensitivity leading to early aging. Bloom syndrome is sensitivity to UV radiation leading to leukemia and other cancers. Cockayne syndrome is sensitivity to UV radiation and chemicals leading to carcinogenesis and mental retardation. Fanconi anemia is a defect in DNA repair leading to pancytopenia. Trichothiodystrophy is characterized by sensitive nails, hair, and skin leading to their early destruction. Werner syndrome leads to early senescence and growth retardation. Xeroderma pigmentosum is UV radiation sensitivity that leads to early senescence and skin cancer. Breast cancer and colon cancer are also related to defects in DNA repair. A variety of other mutations can also occur. Among the most common are point mutations, in which a Figure 3. Copyright Wikimedia. Used with permalfunction of DNA repair or direct toxic damage mission. leads to one nucleotide being exchanged for another. Point mutations may have one of three effects. A silent mutation occurs when the same amino acid is coded due to tRNA wobble and degeneracy of the DNA code. A missense mutation occurs when a different amino acid is coded. Phenotypic effects may or may not be present depending on changes to protein folding and post-translational modification. Finally, nonsense mutations occur when a truncated protein product is formed due to early stop sequence. Deletions occur when a nucleotide is excised from the DNA. This may lead to the same effects as insertion. Deletions are most commonly due to the effect of transposable elements. Insertions occur when an additional nucleotide is added to the DNA code. If one or two nucleotides are added, a frameshift mutation occurs in which the reading frame is shifted and the protein that is created is different. This most often results in a nonsense mutation. Transitions occur when an adenine to guanine or cytosine to thymine shift occurs. Transversions occur when adenine is changed to thymine or guanine changed to cytosine. Interstitial deletions occur when distant genes on the same chromosome are juxtaposed due to loss of genetic material in between. Interstitial deletions may lead to linkage disequilibrium, in which nonmendelian inheritance occurs because two genes are very close to each other and thus prone to be inherited together due to a lower chance of reassortment independent of each other. All of these mutations can lead to one of two phenotypically-significant effects. A gain of function mutation occurs when a new protein product is formed that has new and typically abnormal function. Gain of function mutations commonly have dominant effects. Loss of function mutations occur with the 7

Clinical Review for the USMLE Step 1 formation of a gene product with no function. Loss of function mutations are also known as amorphic mutation and commonly have recessive effects, unless there is a dominant negative mutation. Dominant negative mutation lead to an altered gene product that inhibits normal protein production by the intact allele leading to a partially-dominant phenotype. This is seen in osteogenesis imperfecta. Additional genetic effects also occur. Anticipation occurs when the severity of inherited disorder worsens with successive generations due to the accumulation of trinucleotide repeat sequences, as seen in Huntingtonâ&#x20AC;&#x2122;s disease, myotonic dystrophy, and fragile X. Imprinting is when genetic reprogramming occurs based on whether gene is inherited from father or mother. Imprinting leads to changes in clonal DNA and is seen in Prader-Willi and Angelman syndrome (chromosome 15). In Prader-Willi syndrome, 2 chromosomes are inherited from the mother and it presents with hyperphagia, mental retardation, and large, offset ears. Angelman syndrome occurs when 2 chromosomes are inherited from the father. Angelman syndrome presents with memory defects, poor feeding, absent speech, and seizures. Loss of heterozygosity occurs when one unique allele is lost, leading to only one functional allele. Mosaicism, as seen in calico cats, occurs when a gene is penetrant in different tissues. Mosaicism may be due to alterations in methylation of DNA, leading to staggered inactivation and incomplete penetrance. Penetrance relates to the expression of genes that occurs if the gene Figure 4. Copyright Yassine Mrabet. Used with per- is present (highly penetrant) or one that is reliant on environmental effects and other genes mission. (low penetrance). Variable expression of genes is seen when the expression of genes in a similar inheritance leads to different phenotypes from one person to another. A gene may also be completely penetrant and fully expressed in certain people. Finally, pleiotropy is seen when one gene that functions on several targets leads to several distinct phenotypic traits. This is seen in phenylketonurea.

2.1.4

Epigenetics

Epigenetics is the study of modifications to gene expression or the phenotype that occur from non-DNArelated causes. For example, methylation of the DNA may lead to inactivation of certain transcription pathways and plays a role in inactivation of one of the paired X chromosomes in women. Modification 8

Figure 5. Copyright Mikael Haggstrom. Used with permission.

Biochemistry and Molecular Biology

Clinical Review for the USMLE Step 1

Figure 7. DNA replication. Copyright Mariana Ruiz. Used with permission. of DNA histones via acetylation, methylation, ubiquination, or other methods can also lead to changes in activity. In 2011, epigenetics was demonstrated to play a role in RNA activity.

2.1.5

DNA Transcription

DNA transcription creates a messenger RNA sequence based off a DNA sequence. The chief difference between the DNA and RNA sequences is that the thymine found in DNA is replaced with a uracil nucleotide in RNA. Transcription proceeds with unwinding of the DNA similar to what occurs in DNA replication; this action is facilitated by RNA polymerase. The RNA nucleotides then pair with their complimentary DNA nucleotides (A with T, U with A, C with G, and G with C). An anchoring platform forms for the RNA nucleotides in the form of a sugar backbone, and the RNA strand is separated from its complimentary DNA strand. The RNA undergoes modification by the addition of a 3’ poly-adenylation tail and a 5’ methyl cap. The 5’ methyl cap permits binding of the mRNA to ribosomes, while the 3’ poly-A tail increases stability and prevents early breakdown by exonucleases. The poly-A tail also facilitates transport out of the nucleus and into the rough endoplasmic reticulum (rER), where translation into proteins will occur. Prior to this transport, additional modification to the mRNA will occur where non-coding introns are excised, leaving only the coding exons. Alternative splicing can also occur on the mature transcript to generate different protein products. The mRNA will eventually be degraded by RNases.

Figure 6. DNA transcription with RNA polymerase. Copyright Forluvoft. Used with permission. 10

Biochemistry and Molecular Biology A variety of proteins and domains are involved in DNA transcription. The promoter enables gene transcription after being recognized by RNA polymerase. The TATA box, located near transcriptional site, binds to transcription factors and helps to position them for transcription. Enhancers are protein-binding regions within DNA that help to increase the efficiency and speed of transcription; they are not necessarily located near transcriptional site. Repressors decrease the transcription rate by preventing the formation of mRNA. There are three major RNA polymerases. RNA polymerase I forms rRNA and does not need a TATA box to function. RNA polymerase I uses upstream binding factors and various transcription factors to bind to the upstream control sequence. RNA polymerase II forms mRNA and snRNA. RNA polymerase II requires a TATA box. RNA polymerase III forms tRNA and 5S rRNA and also uses a TATA box. Of the three major products created, rRNA is the most common, mRNA is the largest, and tRNA is the smallest. The function of these RNA fragments will be discussed in â&#x20AC;&#x153;2.1.6 DNA Translation and Protein Synthesisâ&#x20AC;? on page 12. Reverse transcription is found with certain virus such as HIV, where an RNA product can be converted into DNA using an enzyme called reverse transcriptase. Ribonuclease H then generates a complimentary DNA strand and forms a double helix. Integrase can then be used to integrate this DNA sequence into the primary genome. Thereafter, further transcription will generate the RNA products and eventually the protein machinery for the virus. This technology has been used to develop protein products that can replace defective hormones, such as insulin in type I diabetics.

Figure 8. RNA translation. Copyright Mariana Ruiz. Used with permission. 11

Clinical Review for the USMLE Step 1 2.1.6

DNA Translation and Protein Synthesis

Translation uses the mRNA template to construct proteins in the cytoplasm after nuclear modification of the mRNA sequence is complete. Protein formation occurs over four phases, starting with activation. Activation relies on the appropriate amino acid binding to transfer RNA (tRNA), a process that relies on ATP. tRNA transfers the amino acid to the growing polypeptide chain at the ribosome to help produce proteins translated from the mRNA sequence. The anticodon region recognizes codon sequence in the reading frame on mRNA. The mRNA codon specifies only one amino acid, and so is unambiguous. However, other codons may also specify that amino acid (degeneracy). There is no pause between reading frames â&#x20AC;&#x201C; they are all continuous (commaless). The sequences that specify amino acids are used by other species; the only exceptions are mitochondria and certain primitive species (universal). tRNA is approximately 90 nucleotides in length and is able to permit one amino acid to bind to more than one codon sequence due to wobble. Wobble requires recognition of the first two nucleotides. In certain circumstances, the third nucleotide may vary and the same amino acid will still bind. This contributes to degeneracy. Initiation, the second step in the process, occurs when the ribosomal RNA (rRNA) binds to the 5â&#x20AC;&#x2122; side of the mRNA to promote elongation of the polypeptide sequence. Methionine, the start codon, binds first. Elongation, the third step in the process, occurs when additional amino acids are added by tRNAs that recognize the codon sequence on the mRNA. After binding the tRNA and translocating to the next amino acid in the polypeptide, the growing sequence is done. After creation of the polypeptide, the final step in the process is termination at a UAA, UAG, or UGA codon. These three sequences do not code for amino acids and halt further development of the polypeptide. Ribosomal RNA is composed of four separate molecules, including a 5S (large subunit), 5.8S (large subunit), 18S (small subunit), and 28S (large subunit) subunits. rRNA is generally made in the nucleolus. The counterparts to rRNA in the mitochondria are the 16S and 23S subunits. Small RNA Proteins, or snRNPs, are used for RNA splicing, transcription factor regulation, maintaining telomeres, and to serve as RNA polymerase II. When complexed with small nuclear ribonucleoproteins, these proteins excise introns to develop the mature mRNA transcript. Small nucleolar RNAs are also used to methylate RNA. Other small RNA proteins are used to modify the transcript and increase RNA functionality. Protein synthesis can also take other forms. The process of translation can be time-consuming and an inefficient way to deliver proteins that are needed urgently by the cell. In this instance, precursors can be generated via translation and made available to the cell. Post-translational modification or enzymatic cleavage can lead to the generation of the active form of the protein.

2.1.7

Post-Translational Processing and Protein Modifications

Post-translational processing and modification of proteins occurs in rER and Golgi complex. This process involves numerous modifications individualized to the protein. A variety of modifications can occur, including acetylation of the N-terminus, biotinylation on lysine residues, glutamylation on glutamic acid residues, glycylation on the C-terminal, glycosylation on asparagine, hydroxylysine, serine, or threonine, phosphorylation on serine, tyrosine, threonine, or histidine groups, sulfur groups added to tyrosine, disulfide bridges added to cysteine groups, and ubiquitin added if proteins need to be marked for proteolysis. These processes are disrupted in Angelman syndrome and Von Hippel-Lindau syndrome, leading to defects in protein function. Antibodies to ubiquitin are present as neurofibrillary tangles in Alzheimer disease, Lewy bodies in Parkinson disease, Pick bodies in Pick disease, Mallory bodies in 12

Biochemistry and Molecular Biology alcoholic hepatitis, and Rosenthal fibers in astrocytes, leading to accumulation of malfunctioning protein products. The Golgi apparatus (“Golgi Apparatus” on page 32), rough endoplasmic reticulum (“Rough Endoplasmic Reticulum” on page 31), and smooth endoplasmic reticulum each play a unique role in posttranslational processing of proteins.

2.1.8

Protein Sorting

Following creation of a protein product, it must be appropriately guided to the organelle or extracellular destination. This is often done by embedding a targeting signal in the polypeptide chain. Post-translational modification such as glycosylation also helps to guide proteins to their final destination. Two additional forms of protein translocation exist - cotranslational translocation occurs while the protein is still being manufactured. A signal recognition particle initiates translocation of the protein molecule via a receptor on the rER and eventually transported to the Golgi apparatus. Posttranslational translocation occurs after all of the protein processing by the rER and Golgi apparatus are completed. This occurs in proteins intended for the mitochondria and nucleus.

2.1.9

Protein Degradation

Proteolysis can lead to additional modification of proteins, or even lead to their complete breakdown into their constituent amino acids. Examples of modification via proteolysis include removal of methionine residues after translation and deletion of signaling sequences that help navigate proteins throughout and out of the cell. Total degradation can occur with digested proteins using enzymes such as trypsin, chymotrypsin, and others created by the pancreas. A form of proteolysis occurs when the pro-form of the digestive enzymes are cleaved to generate their active form.

2.2. Protein and Enzyme Structure and Function 2.2.1

Protein Structure

Protein structure comes in one of four forms. Primary structure is based off the amino acid sequence only and has no fold- Figure 9. Copyright Mariana Ruiz. Used with permission. ing or three dimensional changes. Second13

Clinical Review for the USMLE Step 1 ary structure has alpha helices and beta-pleated sheets. Tertiary structure coalesces the molecule into a three-dimensional manifold that can have complex interactions with other proteins and molecules. Finally, quaternary structure creates complex protein superstructures through interaction of various subunits and other proteins.

2.2.2

Enzyme Function

Enzyme regulation typically occurs in one of three forms. Competitive inhibitors bind to active sites and prevent the activator of the enzyme from binding. This leads to a dose-dependent effect which can be overcome by adding more activator. Allosteric inhibitors bind to the ectopic portion of enzymes to cause a conformational change in the binding site. This leads to non-competitive inhibition.

Figure 10. Hexose monophosphate shunt. Copyright Mike Jones. Used with permission. 14

Biochemistry and Molecular Biology Irreversible inhibitors bind covalently to the active site of the enzyme and lead to its inactivation. This leads to non-competitive inhibition and is a common mode of function for various poisons. Enzyme function is dependent on the kinetics of its activity, which is measured by Km and Vmax. Km is a measure of affinity and refers to the affinity of substrate to enzyme at Â˝ Vmax. Low numbers indicate increased affinity. Vmax is the maximum velocity at which reaction can proceed. Competitive inhibitors increase Km and do not change Vmax, while non-competitive inhibitors decrease Vmax but do not change Km. A third type of inhibitor, uncompetitive inhibitors, decrease Km and increase Vmax.

2.3. Energy Metabolism 2.3.1

Hexose Monophosphate Shunt

Nucleotides are generated by the hexose monophosphate (HMP) shunt, an anabolic pathway that uses glucose to form 5 carbon sugars. The HMP shunt generates NADPH for reduction reactions and forms ribose-5-phosphate for use in nucleotide synthesis. The HMP shunt plays a major role especially in the liver, lipocytes, adrenal cortex, testis, and mammary gland where high production of proteins and a high level of translation occurs. The HMP shunt operates in the cytoplasm. The key enzymes include transketolase, which rearranges 2-carbon groups and requires thiamine; transaldolase, which rearranges 3-carbon groups; glucose6-phosphate dehydrogenase (G6PD) which is required in NADPH formation and regeneration of glutathione. Deficiency of G6PD provides immunity against malaria.

2.3.2

ATP Generation

Overview The majority of ATP is made through aerobic metabolism, yielding between 36-38 ATP molecules per glucose. Anaerobic metabolism yields 2 ATP per glucose, and if glucose is formed to produce ATP, there is a net loss of 2 ATP. Glycolysis will produce pyruvate, yielding 4 NADH and 2 ATP. Pyruvate Figure 11. ATP molecule. will generate acetyl CoA and 2 NADH. The citric acid cycle will use the Copyright Ben Mills. Used acetyl CoA and generate 6 NADH, 2 FADH 2, and 2 GTP. with permission.

Glycolysis Glycolysis can be distilled into approximately 11 major steps with a variety of reversible and irreversible components. The exam tests your knowledge of both (see Figure 12 on page 16). 1.

Glucose is converted to glucose-6-phosphate by hexokinase (most tissues) or glucokinase (liver). This is irreversible.

G-6-P is converted to fructose-6-phosphate by phosphoglucose isomerase.

F-6-P is converted to fructose-1,6-bisphosphate by phosphofructokinase-1 (irreversible).

F-1,6-BP is converted to dihydroxyacetone phosphate by aldolase. 15

Clinical Review for the USMLE Step 1

Figure 12. Glycolysis. Copyright Yassine Mrabet. Used with permission.

Biochemistry and Molecular Biology 5.

DHAP is converted to glyceraldehyde-3-phosphate by triose phosphate isomerase.

G-3-P is converted to 1,3-bisphosphoglycerate by glyceraldehyde 3-phosphate dehydrogenase.

1,3-BP is converted to 3-phosphoglycerate by phosphoglycerate kinase.

3-PG is converted to 2-phosphoglycerate by phosphoglyceromutase.

2-PG is converted to phosphoenolpyruvate by enolase.

10. PEP is converted to pyruvate by pyruvate kinase (irreversible). 11. Pyruvate is converted to acetyl-CoA by pyruvate dehydrogenase (irreversible). The net production of glycolysis is 4 NADH, 2 ATP, and pyruvate. The essential cofactors include pyruvate dehydrogenase, vitamin B1 (thiamine), B2 (riboflavin), B3 (niacin), B5 (pantothenate), and lipoic acid. A deficiency in pyruvate dehydrogenase can be treated with a high fat diet to increase content of ketogenic nutrients. Enzymatic control during glycolysis occurs at four key places. Hexokinase is inhibited by G6P; glucokinase is not inhibited by G6P. PFK-1 is inhibited by ATP and citrate and stimulated by AMP and

Figure 13. Citric acid cycle. Copyright Yassine Mrabet. Used with permission. 17

Clinical Review for the USMLE Step 1 F-2,6-BP. Pyruvate kinase is inhibited by ATP and alanine; it is stimulated by F-1,6-BP. Finally, pyruvate dehydrogenase is inhibited by ATP, NADH, acetyl-CoA.

Citric Acid Cycle The citric acid cycle can also be condensed into a number of steps. The key reaction starts with citrate, which is converted to succinyl-CoA, then alpha-ketoglutarate, followed by citrate, oxaloacetate, malate, fumarate, and succinate. 1.

Citrate is converted to cis-aconitate, then isocitrate by aconitase

Isocitrate is converted to oxalosuccinate then alpha-ketoglutarate by isocitrate dehydrogenase

Alpha-ketoglutarate is converted to succinyl-CoA by alpha-ketoglutarate dehydrogenase

Succinyl-CoA is converted to succinate by succinyl-CoA synthetase

Succinate is converted to fumarate by succinate dehydrogenase

Fumarate is converted to L-malate by fumarase

Malate is converted to oxaloacetate by malate dehydrogenase

Oxaloacetate is used to reform citrate with citrate synthase

From citrate to succinyl-CoA, a total of 2 NADH and 2 CO足2 are produced by molecule of acetyl-CoA. From succinylCoA to oxaloacetate a total of 1 NADH, 1 FADH 2, 1 GTP, and 1 CoA are produced per molecule of acetyl-CoA. A net of 12 ATP per acetyl-CoA are produced with these byproducts (24 per glucose). In summary: Acetyl-CoA + 3 NAD+ + FAD + GDP + Pi + 3 H2O --> CoASH + 3 NADH + H+ + FADH 2 + GTP + 2 CO2 + 3 H+ The end result is 2 ATP, 6 NADH, and 2 FADH 2.

Electron Transport Chain The electron transport chain is a series of redox reactions Figure 14. Electron transport chain. Copyright Tim Vickers. Used with that occurs in the inner mem- permission. brane of mitochondria to gen18

Biochemistry and Molecular Biology erate a proton-gradient used to produce ATP. It uses four complexes which generally use NADH and a proton pump to generate the necessary gradient. Complex I is NADH dehydrogenase (proton pump), which can be inhibited by amytal and rotenone. Complex II is succinate dehydrogenase. Complex III is cytochrome bc1 (proton pump) and is inhibited by antimycin A. Complex IV is cytochrome c (proton pump) and is inhibited by cyanide, carbon monoxide, and azide. The electron transport chain culminates in a proton pump which mitochondrial F-ATPase uses to generate ATP; this ATPase can be inhibited by oligomycin. Uncoupling agents such as 2,4-dinitrophenol increase membrane permeability to lead to malignant hyperpyrexia through futile proton gradient activity.

NADH and NADPH Generation

Figure 15. Copyright with permission.

Wikimedia.

Used

NADH is the reduced form of NAD, and NAD+ is the oxidized form of NAD. NADH is generated in glycolysis and citric acid cycle to help form ATP. NADPH is generated by adding a phosphate group to NAD followed by reduction. NADPH plays a role in anabolic reactions to generate fat and nucleic acids. NADPH also plays a vital role in the oxygen-dependent respiratory burst and is used with NADPH oxidase to form oxygen free radicals. These free radicals are used to generate hydrogen peroxide with superoxide dismutase. H 2O2 is converted to bleach (HOCl) by myeloperoxidase. Excess H 2O2 is deactivated along with oxygen free radicals by catalase, which forms water. NADPH is reconstituted by this reaction. Glutathione reductase plays a vital role in this reaction, and is regenerated through the action of glucose6-phosphate dehydrogenase (which forms more G6P, used in this reaction).

Amino Acid Pathways Amino acids can be divided into essential and nonessential. Typically, the essential amino acids are precursors for other amino acids or cannot otherwise be manufactured de novo by the body. Examples

Figure 16. The Cori cycle. Copyright Eyal Bairey. Used with permission. 19

Clinical Review for the USMLE Step 1 include phenylalanine, tryptophan, histidine, glycine, and arginine. Phenylalanine is converted to tyrosine, which is converted to L-dopa; L-dopa is converted to dopamine, which is converted to norepinephrine by the adrenal gland. Norepinephrine is used to manufacture epinephrine. Tyrosine is used to manufacture thyroxine. Dopamine is used to produce melanin. Tryptophan is an important precursor to niacin, serotonin, and melatonin. Histidine helps to form histamine. Glycine is used to produce porphyrin, which is a component of heme. Arginine is used to produce creatine, urea, and nitric oxide.

Cori Cycle The Cori cycle, also known as the lactic acid cycle, is a mechanism through which lactate production by the muscle is converted to glucose in the liver. This is a direct consequence of the inability of muscles to produce glucose through their lack of glucose-6-phosphatase. The Cori cycle prevents lactic acidosis within the muscle during anaerobic conditions while maintaining the ability to produce ATP.

Irreversible Enzymes We had a brief discussion of irreversible enzymes above in â&#x20AC;&#x153;Glycolysisâ&#x20AC;? on page 15. However, the following is a list of the major enzymes by organelle; this is provided in a single place for your reference and also to highlight their relative importance on the USMLE. 1.

Pyruvate carboxylase converts pyruvate to oxaloacetate; this reaction occurs in the mitochondria.

PEP carboxykinase converts oxaloacetate to PEP; this reaction occurs in the cytosol.

Fructose 1,6-bisphosphatase converts F-1,6-BP to F-6-P; this reaction also occurs in the cytosol.

Glucose-6-phosphatase converts G-6-P to glucose in the cytosol. This enzyme is found in the liver, kidney, and intestines, but not in the muscle. Defect in any of these enzymes will lead to hypoglycemia.

2.4. Biochemical Disorders There are a variety of high-yield disorders covered in this section. All of these are exam-worthy in that they test important biochemical pathways. Knowledge of their enzymatic defect, presentation, and management is important.

2.4.1

Iron Pathway Defects

Acute Intermittent Porphyria Acute intermittent porphyria is a deficiency in uroporphyrinogen I synthase leading to deltaALA accumulation. It leads to excess porphobilinogen in urine and CNS changes.

Lead Poisoning

Figure 17. Heme synthesis. Copyright Piemmea. Used Lead poisoning leads to inhibition of ferroche- with permission. latase and ALA dehydratase, leading to excess ALA and coproporphyrin in urine. It presents with anemia, stippled RBCs, and lead lines in bone. 20

Biochemistry and Molecular Biology Porphyria Cutanea Tarda Porphyria cutanea tarda is a deficiency in uroporphyrinogen decarboxylase that leads to uroporphyrin in urine. It is one of the most common enzyme defects and is treated with hemin to inhibit ALA synthase.

2.4.2

Amino Acid Diseases

Phenylketonuria PKU is caused by a lack of phenylalanine hydroxylase, lack of tetrahydrobiopterin cofactor, and a defect in dihydropterine reductase. It leads to the build up of phenylalanine, making tyrosine an essential amino acid in these patients. PKU presents with progressive mental retardation, fair skin with eczema, and a particular body odor.

Alkaptonuria Alkaptonuria is a defect in homogentisic acid oxidase that leads to an inability to degrade tyrosine. Alkaptonuria presents with dark urine and arthralgias. It is typically a benign disorder.

Albinism Albinism is due a defect in tyrosinase that leads to the inability to make melanin from tyrosine. This results in the lack of neural crest migration to skin and subsequent lack of melanin. This increases the risk of skin cancer.

Homocystinuria Homocystinuria should not be confused with homocysteinemia. Homocystinuria is due to a defect in cystathionine synthase and methionine synthase leading to the inability to reabsorb homocysteine. Cysteine becomes an essential amino acid with this disorder. Homocystinuria presents with a Marfanoid habitus, lens dislocation, mental retardation, and osteoporosis. Treatment is with having a low protein diet, particularly in methionine.

Cystinuria Cystinuria is a defect in tubular amino acid transporter leading to a defect in the transportation of cystine, ornithine, lysine, and arginine in the kidneys. It presents with cystine kidney stones and can be treated with acetazolamide.

Maple Syrup Urine Disease Maple syrup urine disease is a defect in alpha-ketoacid dehydrogenase that leads to the inability to degrade branched amino acids, including isoleucine, leucine, and valine. It presents with mental retardation and leads to death.

2.4.3

Purine and Pyrimidine Salvage Diseases

Adenosine Deaminase Deficiency Adenosine deaminase deficiency leads to excess ATP and dATP with the inability to make ribonucleo21

Clinical Review for the USMLE Step 1 tide reductase, leading to a defect in DNA synthesis and a decrease in lymphocyte count. It presents with severe combined immunodeficiency syndrome.

Lesch-Nyhan Disease Lesch-Nyhan disease is an X-linked recessive disorder due to a defect in HGPRTase leading to a defect in purine salvage pathway. Patients have an inability to convert hypoxanthine to inosine monophosphate and an inability to convert guanine to guanosine monophosphate. Lesch-Nyhan disease presents with excess uric acid production with deposition throughout brain, leading to self-mutilation, significant aggression, hyperuricemia, and gout. Renal failure occurs in the 20â&#x20AC;&#x2122;s.

2.4.4

Lysosomal Storage Diseases

Fabry Disease Fabry disease is an X-linked recessive sphingolipidosis that leads to a defect in alpha-glactosidase A and subsequent accumulation of ceramide trihexoside. Fabry disease presents with renal failure, neuropathy, corneal opacity, nodules, angiokeratomas, and hypertension.

Krabbe Disease Krabbe disease is an autosomal recessive sphingolipidosis that leads to a defect in glactosylceramide beta-glactosidase and the accumulation of galactocerebroside. It presents with neural degeneration, optic atrophy, spasticity, and death by age 2.

Gaucher Disease Gaucher disease is a sphingolipidosis that has a defect in beta-glucocerebrosidase, leading to the accumulation of glucocerebroside. It causes damage to CNS, hepatomegaly, splenomegaly, and bone marrow atrophy but has a normal lifespan. Macrophages have a fibrillary appearance in this autosomal recessive disorder.

Niemann-Pick Disease Niemann-Pick disease is a sphingolipidosis with a defect in sphingomyelinase, leading to the build up of sphingomyelin. It causes failure to thrive, deafness, blindness, hepatosplenomegaly, and has a characteristic red spot on fundoscopy. Patients die by age 3 in this autosomal recessive disease.

Tay-Sachs Disease Tay-Sachs is a sphingolipidosis that has a lack of hexosaminidase A, leading to the accumulation of GM2 ganglioside. It presents with progressive blindness, deafness, seizures, and death by age 3. TaySachs also has a cherry red spot on fundoscopy. This is an autosomal recessive disease that primarily affects the Ashkenazi Jewish population.

Metachromatic Leukodystrophy Metachromatic leukodystrophy is a sphingolipidosis that has a deficiency of arylsulfatase A, leading to the accumulation of sulfatide in brain. This causes abnormalities within myelin, presenting with mental retardation, neuropathy, and metachromasia. This is an autosomal recessive disorder. 22

Biochemistry and Molecular Biology Hurler Syndrome Hurler syndrome is a mucopolysaccharidosis that has a defect in alpha-L-iduronidase. It presents with corneal clouding and mental retardation. It is an autosomal recessive disease.

Hunter Syndrome Hunter syndrome is a mucopolysaccharidosis with a defect in L-iduronosulfate sulfatase, leading to the accumulation of heparan sulfate and dermatan sulfate. It is a milder form of Hurlerâ&#x20AC;&#x2122;s syndrome and lacks corneal clouding with only mild mental retardation. It is an X-linked recessive disorder.

2.4.5

Glycogen Storage Diseases

Von Gierke Disease Von Gierke disease is a glycogen storage disease that has a defect in glucose-6-phosphatase. It leads to the inability to remove phosphate, keeping glucose trapped in liver. Glycogen structure is normal, but the disease is characterized by severe hypoglycemia, lactic acidosis, hepatomegaly, hyperlipidemia, hyperuricemia, short stature, increase in VLDLs, and xanthomas.

Pompe Disease Pompe disease is a glycogen storage disease with a defect in alpha 1,4-glucosidase in the lysosome. It leads to glycogen accumulation in inclusion bodies, presenting with cardiomegaly, muscle weakness, and death by age 2.

Cori Disease Cori disease is a glycogen storage disease with a defect in glycogen debranching enzyme. The glycogen in this disease is characterized by short outer branches and single glucose residues at outer branches due to a lack of alpha 1,6 branch breakdown. It presents with mild hypoglycemia and hepatomegaly.

Anderson Disease Anderson disease is a glycogen storage disease with amylopectinosis, a defect in a branching enzyme, and a subsequent paucity of branches in glycogen edges. It presents with hypotonia, cirrhosis, and death by age 2.

McArdle Disease McArdle disease is a glycogen storage disease with a defect in muscle glycogen phosphorylase. It leads to the accumulation of glycogen, a decrease in glucose, and an increase in lactic acid formation. It presents with muscle cramps and weakness on exercise. McArdle disease is diagnosed via muscle biopsy and a normal glycogen structure.

Hers Disease Hers disease is a glycogen storage disease with a defect in hepatic glycogen phosphorylase. It leads to a mild fasting hypoglycemia with hepatomegaly and cirrhosis. Glycogen structure is normal.

Clinical Review for the USMLE Step 1

3. Biology

Cells

3.1. Adaptive Cell Responses 3.1.1

and

Cellular Homeostasis

Cell Cycle

The cell cycle begins with interphase. The first growth phase occurs during interphase and is when the cell prepares nucleoside kinases for DNA transcription. The cell is currently 2N. S phase starts when DNA synthesis begins. The genetic material is now 4N. S phase is also a part of interphase. Failure of DNA repair in this stage may lead to G0 and cessation of cell duplication. The second growth phase is the final part of interphase and is the final opportunity for the cell to ensure that all enzymes and proteins necessary to complete mitosis are prepared and available. G0 phase is a stop phase that occurs due to several reasons. The inability to progress through cell division is often due to missing enzymes or insufficient nutrients / minerals. G0 is a quiescent state for neuronal population, and a resting state for most cells in the body until a growth factor signal is received Figure 18. Copyright Richard Wheeler. Used with indicating cell duplication. permission. Mitosis is composed of prophase, prometaphase, metaphase, anaphase, telophase, and cytokinesis. Prophase has heterochromatin and is marked by the start of mitotic spindle. Prometaphase has dissolution of the nuclear envelope. Metaphase occurs when the kinetochores move to opposite sides of the cell. Anaphase has separation of sister chromatids. Telophase has separation of genetic material to opposite poles of the cell. Finally, cytokinesis is marked by a cleavage furrow and cell separation.

Figure 19. Adapted from the NIH. Used with permission.

Biology of Cells

3.2. Mechanisms Necrosis 3.2.1

Injury

and

Cell Necrosis

Cell necrosis is unprogrammed cell death, and it occurs due to direct injury to cells leading to disordered destruction. There is no organized pattern of chromatin condensation, karyorrhexis, or signaling to phagocytes. With cell necrosis, there is damage to nearby cells due to release of toxic byproducts, such as lysosomal enzymes. Figure 20. Coagulative necrosis in the heart followMorphologic features of necrosis can be catego- ing myocardial infarction. Copyright Wikimedia. rized as coagulative necrosis, liquefactive necro- Used with permission. sis, caseous necrosis, fatty necrosis, and fibrinoid necrosis.

3.2.2

Coagulative Necrosis

Coagulative necrosis is a cellular necrosis that maintains outlines of the cells. It leads to a homogenous, eosinophilic mass due to protein coagulation, and is typically the result of ischemic infarcts. Coagulative necrosis is commonly found in myocardial infarcts, but may occur in most tissues that suffer from ischemic infarction.

3.2.3

Liquefactive Necrosis

3.2.4

Caseous Necrosis

Figure 21. Liquefactive necrosis in the brain following a CVA. Copyright Wikimedia. Used with perLiquefactive necrosis occurs due to significant mission. cellular destruction mediated by the immune system. It is often found with significant pus production due to neutrophil phagocytosis and later destruction. Liquefactive necrosis occurs in pneumonia and with severe pancreatitis due to the action of pancreatic enzymes.

Caseous necrosis is the combination of coagulation of proteins and liquefactive cellular destruction leading to a cheese-like appearance. It is most prominent in tuberculosis.

3.2.5

Fatty Necrosis

Figure 22. Caseous necrosis in the lung in a patient with tuberculosis. Copyright Wikimedia. Used with Fatty necrosis leads to the destruction of lipo- permission. cytes due to the action of various enzymes. It 25

Clinical Review for the USMLE Step 1 is commonly the result of pancreatitis leading to pancreatic enzyme-mediated lipocyte destruction. It also occurs following breast surgery due to inflammation.

3.2.6

Fibrinoid Necrosis

Fibrinoid necrosis is the result of vascular damage leading to fibrin deposition within arterial walls leading to thickening. It is an immune-mediated disease.

3.3. Apoptosis

Figure 23. Fat necrosis following trauma. Copyright Wikimedia. Used with permission.

Apoptosis is programmed cell death and occurs as part of normal development. It is a normal response to cell damage, infection, stress, or DNA damage and is a necessary part of normal tissue turnover. The morphologic features include rounding of the cell, condensation and degradation of chromatin, karyorrhexis, blebbing of plasma membrane, and the formation of apoptotic bodies with subsequent phagocytosis. Mediators of apoptosis include PARP-1 (poly-ADP ribose polymerase-1), a number of caspases, and Fas-associated death do- Figure 24. Fibrinoid necrosis of an artery. Copymains (FADD). right Wikimedia. Used with permission.

3.4. Mechanisms of Dysregulation 3.4.1

Aplasia, Hypoplasia, Atrophy, and Atresia

Aplasia is the failure of organ development and is an original defect, not an acquired defect. One exception to this rule is aplastic anemia, which is a misnomer as this is an acquired defect. Hypoplasia refers to an organ that does not grow to its intended size, while atrophy refers to a decrease in cellular size and is reversible (vs. apoptosis, which is irreversible). Atresia is the failure of luminal development, whether inherited or acquired. This occurs with biliary atresia.

3.4.2

Stenosis

Stenosis is the narrowing of a lumen, which is seen in coronary artery stenosis in unstable angina. It should not be confused with occlusion, which is total elimination of the lumen of a vessel.

3.4.3

Malformation, Deformation, and Hamartoma

Congenital deformity in a structure are known as malformations. Acquired defects in a structure are known as deformations. Hamartomas are disarrangements of normal organ components.

Biology of Cells 3.4.4

Fistula

Fistulas are abnormal connection between two regions, which can be seen in Crohn’s disease. In Crohn’s, fistulas form between the GI tract and other organs due to transluminal inflammation.

3.4.5

Hypertrophy and Hyperplasia

Hypertrophy is an increase in the size of a cell. This occurs in muscles (hypertrophic cardiomyopathy). Hyperplasia is an increase in the number of cells and can be seen in the prostate with benign prostatic hyperplasia.

3.4.6

Metaplasia, Dysplasia, and Anaplasia

Metaplasia is the replacement of one cell type by another as part of an adaptive response. This is a reversible process and is not cancerous. Metaplasia occurs in Barrett’s esophagus in GERD. Dysplasia is the loss of cell polarity with hyperplastic changes leading to carcinoma in-situ. This is a pre-cancerous change. It is marked by changes in cellular size from one to another. There are dark-staining nucleus with increased nucleus to cytoplasm (N:C) ratio, and numerous mitotic spindles. Dysplasia is due to underlying accumulated genetic mutations.

Figure 25. Various signal transduction pathways used in apoptosis, including the FADD pathway. Copyright Boghog2. Used with permission. 27

Clinical Review for the USMLE Step 1 Anaplasia is characterized by the loss of apical/basolateral cell polarity with cells able to survive without being anchored to a basement membrane. There is significant variability in cell size, regression to immature-looking cells, and a significantly increased N:C ratio. There are also multiple, odd-looking mitotic spindles, multiple genetic abnormalities and mutations.

3.4.7

Cancer Genetics

Tumor Suppressor Genes Tumor suppressor genes include p53 and RB (retinoblastoma gene). Tumor suppressor genes serve to modulate differentiation of cells and play a role in limiting cellular proliferation. Defects in tumor suppressor genes eliminates this inhibitory effect and permits cells to differentiate and proliferate at will. This is known as a loss of function mutation.

Oncogenes Oncogenes also regulate cell growth and proliferation, but there are strict controls on their function. Mutations in oncogenes lead to amplification and over-expression of the gene, eliminating the effect of their controls. A fusion gene or other alterations of the gene can lead to the production of oncogene proteins that no longer respond to their traditional controls. Examples of oncogenes include the ras and myc family of proto-oncogenes. Oncogenes can be classified into growth factors (discussed further in section “3.6. Growth Factors” on page 37), receptor tyrosine kinases, cytoplasmic tyrosine kinases, serine/threonine kinases, GTP proteins, and transcription factors (discussed below in section “3.5.4 Cell Receptors” on page 36).

Hereditary Tumors There are a variety of hereditary tumors that have a basis in genetics. Often, the defect can be isolated to a particular part of the chromosome. However, it is important to note that cancer occurs as a result of multiple mutations in a variety of tumor suppressor genes and oncogenes. Table 1. Hereditary tumors. Type

Etiology

Pathophysiology

Defect

Notes

Li-Fraumeni Syndrome

P53 TSR

Cell cycle regulation, apoptosis.

17p13 defect

Brain tumor, sarcoma, leukemia, breast cancer.

Familial retinoblastoma

RB1 TSR

Cell cycle regulation.

13q14

Retinoblastoma, osteogenic sarcoma.

Wilms tumor

WT1 TSR

Transcriptional regulation.

11p13

Pediatric kidney CA.

Neurofibromatosis 1

NF1 TSR

RAS inactivation promoter.

17q11

Neurofibromas, sarcomas, gliomas.

Neurofibromatosis 2

NF2 TSR

Cell membrane to cytoskeleton linker.

22q12

Vestibulocochlear schwannomas, meningiomas, astrocytomas, Ependymomas.

Familial adenomatous polyposis

APC TSR

Adhesion molecule signaling.

5q21

Colon CA.

Tuberous sclerosis 1

TSC1 TSR

9q34

Facial angiofibromas + tubers

Tuberous sclerosis 2

TSC2 TSR

GTPase activator.

Hamartomas throughout, rhabdomyosarcomas.

Deleted in pancreatic carcinoma

DPC4 / SMAD4 TSR

TGF-B/BMP signal transduction regulator.

18q21

Pancreatic CA, colon CA.

Biology of Cells Deleted in colorectal carcinoma

DCC TSR

Transmembrane receptor for axonal guidance.

18q21

Colorectal CA.

Familial breast CA 1

BRCA1 TSR

Double strand breakage repair w/ Rad51.

17q21

Breast and ovarian CA; more common in women.

Familial breast CA 2

BRCA2 TSR

Double strand breakage repair.

13q12

Breast and ovarian CA; more common in men â&#x20AC;&#x201C; also causes pancreatic CA and prostate CA.

Peutz-Jeghers syndrome

STK11 TSR (STK)

VEGF regulator.

19p13

Hyperpigmentation, hamartoma polyps, colorectal CA, breast CA, ovarian CA.

DNA mismatch repair enzyme.

2p22

Colorectal CA.

Hereditary nonpolyposis colorectal CA type 1

MSH2 TSR

Hereditary nonpolyposis colorectal CA type 2

MLH1 TSR

DNA mismatch repair enzyme.

3p21

Colorectal CA.

Von Hippel-Lindau syndrome

VHL TSR

Transcription elongation regulator.

3p26

Renal CA, Hemangioblastoma, pheochromocytoma.

Familial melanoma

CDKN2A TSR

Inhibits CDK4/6.

9p21

Melanoma, pancreatic CA.

Basal cell carcinoma

PTCH TSR

Hedgehog signal regulator.

9p22

Basal cell CA.

MEN1

MEN1 TSR

11q13

Parathyroid, pituitary, islet cell, carcinoid

MEN2

RET, MEN2

TK for GDNF.

10q11

Medullary thyroid, pheochromocytoma, mucosal hamartomas.

Beckwith-Wiedmann

p57, KIP2

Cell cycle regulator.

11p15

Wilms tumor, adrenocortical CA, hepatoblastoma.

Ataxia telangiectasia

Multiple, ATM gene

Failure to halt cell cycle after damage to DNA.

11q22

Lymphoma, ataxia, immunodeficiency.

Bloom syndrome

BLM

DNA helicase.

15q26

Solid tumors, immunodeficiency.

Table 2. Carcinogens. Type

Tumor

Afltatoxin

Hepatocellular carcinoma

Vinyl chloride

Hepatocellular carcinoma

Nitrosamines

Esophageal CA and stomach CA

Asbestos

Mesothelioma, bronchogenic CA

Arsenic

SCC

CCl4

Centrilobular necrosis of liver

Aniline dyes

Bladder CA (TCC)

HTLV1

Adult T-cell leukemia

HBV

Hepatocellular carcinoma

HCV

Hepatocellular carcinoma

EBV

Burkittâ&#x20AC;&#x2122;s lymphoma, nasopharyngeal CA

HPV 16, 18, 31, 33

Cervical CA

HHV8

Kaposi sarcoma, B cell lymphoma

Clinical Review for the USMLE Step 1 Table 3. Tumors markers. Type

Location

Notes

AFP

Hepatocellular CA, embryonal cell tumors of the Follow after Dx. testes, yolk sac tumors, mixed germ cell tumors.

Beta-2-microglobulin

Multiple myeloma, CLL, lymphomas.

Prognostic indicator.

B-hCG

Germ cell tumors, choriocarcinoma, mediastinal tumors.

Follow levels.

Bladder tumor antigen

Bladder CA, used w/ NMP22.

Recurrence of tumor indicator.

CA 15 -3

Breast cancer.

Elevated in advanced disease.

CA 27.29

Breast cancer.

Prognostic marker.

CA 125

Ovarian CA; positive in fibroids, endometriosis, lung CA.

Possible screening test, but would miss many early CA (hence why many are not used as screening tests).

CA 72-4

Ovarian CA, stomach CA.

CA 19 -9

Pancreatic CA +/- colorectal CA.

CEA better for colorectal CA; highly sensitive for pancreatic CA.

Calcitonin

Medullary thyroid CA (parafollicular C cells).

Early detection of CA.

CEA

Colorectal CA; also elevated in lung CA and breast CA.

Chromogranin A

Carcinoid, neuroblastoma, SCLC.

Estrogen receptors / progesterone receptors

Breast cancer.

Tamoxifen (raloxifene for osteoporosis).

HER-2/neu / c-erbB-2

Breast cancer.

Positive in 1 in 3 patients; prognostic indicator â&#x20AC;&#x201C; use trastuzumab in patients w/ positive result.

Neuron-specific enolase

SCLC, neuroblastoma, carcinoid.

Follow-up testing.

NMP22

Bladder CA.

Prognostic.

PSA

Prostate CA, BPH.

NOT for use as a screening test; prognostic; not 100%.

Prostate acid phosphatase

Prostate cancer.

PSA is more sensitive.

S-100

Melanoma, Histiocytosis X.

Metastatic disease.

3.4.8

Metastasis and Cancer Staging

Metastasis Metastasis occurs when cancer spreads from one part of the body to another. Metastasis can occur hematogenously, via lymphatics, via body cavities (such as peritoneal carcinomatosis), and iatrogenically during cancer operations. Metastatic cancer has mutated sufficiently for it to no longer require basic signalling molecules to control its proliferation and spread. Cells no longer respond to signals from the basement membrane and are free to grow in any direction. Signals that control apoptosis, proliferation, and control differentiation no longer affect the mutated cells.

Cancer Staging Each type of cancer is divided into four stages, I through IV. The specific characteristics of each stage de30

Biology of Cells pend on the particular type of tumor. Generally, stage I cancers are highly amenable to surgical or medical management and can be treated successfully with the appropriate therapy. Most patients with stage I cancer will have a five year survival between 75 and 100%. Stage II cancers tend to be larger and may have involvement of lymph nodes. They are also generally amenable to surgical management, although some types of cancers may also be treated with chemotherapy. Five year survival varies by cancer, but generally ranges between 50-75%. Stage III cancers typically have lymph node involvement and may even involve proximal structures through direct growth. Due to their large size and extensive involvement, they are often pre-treated with chemotherapeutic agents, followed by surgery in selected individuals. Many patients will often have chemotherapy following surgical resection. Five year survival typically ranges between 25-50%. Stage IV cancers are commonly metastatic to distant sites, involve lymph nodes, and are large in size. Their metastatic nature implies Figure 26. Rough endoplasmic reticulum photomicrothat they no longer respond to common sig- graph. Copyright Louisa Howard. Used with permisnalling mechanisms. Treatment is difficult sion. and often simply palliative. Chemotherapy is often the mainstay of management, although selected patients may benefit from surgery to relieve pain. Exceptions to this rule exist for certain cancers; colon cancer metastatic to the liver may be treated with liver resection and colectomy in conjunction with chemotherapy. Survival in this particular case may be as high as 40% over several years. However, most stage IV cancers tend to have dismal survival, ranging from a few months for pancreatic cancer to a couple of years for melanomas. Due to the toxic effects of the chemotherapy, the rapid proliferation of the cancer, and the cachectic effects of the cancer, survival more than a few years is uncommon.

3.5. Cell Structure 3.5.1

and

Function

Organelles

Rough Endoplasmic Reticulum The rough endoplasmic reticulum (rER) plays a role in protein synthesis, sequesters calcium and thereby serves as an intracellular store, produces steroids, helps to synthesize and store glycogen, and helps to create membrane proteins. The rER is studded with ribosomes and is directly connected to the outer nuclear membrane. It permits proteins to be targeted for the cell membrane or secreted from the cell and has the ability to add N-linked oligosaccharides to proteins to as- Figure 27. Photomicrograph of the Golgi apparatus. sist with signaling. The rER is found in large Copyright Louisa Howard. Used with permission. 31

Clinical Review for the USMLE Step 1 amounts in tissues that synthesize numerous secretory proteins, including neurons (Nissl substance), the small intestine (Goblet cells), plasma cells (antibody production), and endocrine glands (hormone production).

Smooth Endoplasmic Reticulum The smooth endoplasmic reticulum (sER) plays a role in lipophilic substance generation, forms steroid hormones, and detoxifies many substances. It plays a major role in drug and toxin detoxification. The sER is found in large amounts in areas that synthesize lipophilic substances or break down toxins or drugs, including the liver (P-450 system for drug conversion and detoxification), adrenal cortex (steroid hormones), testes and ovaries (steroid hormones), and thyroid (steroid hormones). The steroid hormones include progesterone, estrogen, testosterone, cortisol, aldosterone, and thyroid hormone.

Golgi Apparatus The Golgi apparatus has three distinct tiers of function. The first tier serves as an extension of the rER and receives proteins from the rER to start early processing of proteins. The second tier is the modification complex and modifies the N-oligosaccharide group on asparagine that was added in rER. It also adds an O-oligosaccharide group on serine and threonine. Glycosylation permits proper protein folding and increases protein stability. It also prevents early protein degradation. This part of the Golgi apparatus also adds disulfide bonds on glycoproteins and tyrosine groups, O-N-acetylglucosamine groups to serine and threonine to prevent activation by phosphorylation, and a GPI anchor to keep proteins anchored to the membrane. This anchor permits controlled release of proteins from the cell when the anchor is cleaved. Failure of these processes may play a role in oncogenesis and diabetes. Tier three of the Golgi functions as the export complex. It sends proteins to the rER, lysosomes, cytosol, cell membrane, or secretes them from the cell. Proteins destined for the lysosome have a mannose6-phosphate group added here. A defect in this protein is involved in I-cell disease and leads to the inability to target lysosomal enzymes properly, leading to their secretion from cell.

Nucleolus The nucleolus is created by chromosomes and is composed of ribosomal RNA segments that are being formed. It is separated into the pars fibrosa (newly transcribed rRNA) and pars granulosa (large and small ribosomal subunits / ribonucleoproteins).

Mitochondria The mitochondria are composed of an outer membrane and inner membrane. The inner membrane contains cardiolipin, which permits only proteins with an NH 2 sequence to enter. The inner membrane requires the action of hsp70 to promote protein unfolding prior to entry. The oxidation reactions of the electron transport chain and ATP synthesis takes place within the inner membrane. The matrix is the innermost part of the mitochondrion and permits pyruvate and fatty acid oxidation. This is where the citric acid cycle takes place. Other roles of the mitochondria include heme synthesis, steroid synthesis, and heat production. Mitochondria undergo clonal replication. They are inherited as a haplotype from the mother and generally unchanged across generations. Mitochondria provides history of human derivation but only in terms of females.

Biology of Cells Lysosomes Lysosomes contain acid hydrolases to digest large molecules, along with lipase, carbohydrases, proteases, and nucleases. Their internal pH is 4.8. Lysosomes play an important role in the initiation of apoptosis. A side effect of ischemia and cell damage is that rupturing lysosomes will contribute to damage in the penumbra region following local ischemia to some cells, such as what occurs after a myocardial infarction or stroke. Lysosomes are involved in a variety of diseases, including mucopolysaccharidoses, gangliosidoses, lipid storage diseases, glycoproteinoses, mucolipidoses, and leukodystrophies (see ““2.4.4 Lysosomal Storage Diseases” on page 22).

3.5.2 Cytoskeleton, Plasma Membrane, and Extracellular Matrix

Figure 28. Microtubules stained in green and actin filaments in red. Copyright Wikimedia. Used with permission.

Cilia and Microtubules The cytoskeleton is composed of microtubules arranged as nine pairs of doublets (9+2). The axoneme, or core of the cilium, is anchored to a basal body, also known as a microtubule organizing center (MTOC). The basal body is made from the centriole, which has a 9+0 organization (no central doublet). Microtubules within the cell are used to transport substances. Kinesin provides the energy for anterograde transport, while dynein provides the energy for retrograde transport. Dynein also provides energy for ciliary motion. Kinesin and dynein are both ATPases. Cilia are commonly found in the trachea, oviducts, and inner ear. Microtubular transport is essential in neurons for the transport of neurotransmitters from the Nissl substance to the axon terminal.

Stereocilia Stereocilia are cilia are found in the form of a large kinocilium that imparts polarity to the mechanosensory hair cells of the vestibular and Figure 29. Cell junctions. Copyright Mariana Ruiz. auditory system. Stereocilia do not contain mi- Used with permission. crotubules (“false cilia”). They are composed of actin, myosin, and cadherins. Stereocilia bear a similarity to microvilli. 33

Clinical Review for the USMLE Step 1

Figure 30. Stereocilia found in type I and type II hair cells of the vestibular system. The single large structure in the center is a kinocilium. Copyright Sapan Desai. Used with permission.

Plasma Membrane The plasma membrane is a fluid membrane anchored to a cytoskeleton to provide apical and basolateral polarity to a cell as the cell is anchored on its basement membrane. Its semipermeable nature permits small carbohydrates and water to penetrate readily. Ion channels permit selective transport of electro34

Biology of Cells lytes, which generates an electric potential to the cell. Signal transduction molecules permit activation of cell processes via binding of protein hormones. Steroid hormones readily pass through the cell membrane and directly affect nuclear messengers and DNA transcription.

3.5.3

Channels, Transporters, and Gap Junctions

Membrane Ports Membrane ports function via a variety of transport mechanisms. With active transport, ATP mediates the transport of solutes across the plasma membrane, typically against the concentration gradient. In facilitated transport, an ion that moves along its concentration gradient is used to drive passage of another ion against its concentration gradient. The ion flowing along its concentration gradient was previously transported against its concentration gradient by active transport. Facilitated transport indirectly uses ATP. Passive transport provides a passageway for an ion or solute to move across a plasma membrane and does not directly or indirectly use ATP. Symports permit two ions to move across the membrane together, while antiports permit two ions to move in opposite directions across the membrane.

Active Transporters The Na-K ATPase (P-type ATPase) is the primary mediator of cell potential and is found on all cells. It pumps sodium out of the cell and potassium into the cell in a 3:2 ratio (3 sodium, 2 potassium). The Na-K ATPase relies on ATP to phosphorylate the pump to permit release of sodium once the ions travel to the outside surface of the cell. The H-K ATPase (P-type ATPase) is found in parietal cells of the stomach to acidify gastric contents. V-type ATPases are found on many intracellular organelles and are used to modulate hydrogen concentration; sometimes paired with calcium or other ions. F-type ATPases are found in bacteria and mitochondrial inner membranes to drive ATP synthesis.

Ion Channels Voltage-gated ion channels are commonly Na, K, Cl, or Ca channels that open or close depending on the membrane potential of the cell to permit s elective transport of ions down their concentration gradients. Ligand-gated channels provide selective transport of various ions following binding of a ligand to the ion channel. A common example is the nicotininc acetylcholine receptor.

Figure 31. Nicotinic acetylcholine receptor with labeled subStretch receptors are potassium units. Copyright Sapan Desai. Used with permission. channels found in the tip links of 35

Clinical Review for the USMLE Step 1 the stereocilia and kinocilium of the hair cells in the vestibular and auditory system. G-protein-gated open in response to binding of G-proteins. Inward-rectifier K channels are found in the pacemaker cells of the heart, beta cells in pancreas. Funny currents are spontaneously depolarizing sodium channels found in the pacemaker cells of the heart. Various toxins can bind to these channels and inhibit their action. Tetrodotoxin binds to sodium channels and prevents their function. Lidocaine also binds to sodium channels. Dendrotoxin binds to potassium channels. Various rare genetic conditions can lead to malfunction of these channels, including episodic ataxia, generalized epilepsy with febrile seizures, paramyotonia congenital, potassium-aggravated myotonias, and hyperkalemic periodic paralysis. Mutations are also found in various types of ion channels.

3.5.4

Cell Receptors

G-Proteins G-proteins are embedded within the plasma membrane and play a role in activating cell signaling pathways. G-proteins are made up of alpha, beta, and gamma subunits. Proteins bind to G-proteins in order to modulate their activity, such as ras. G-protein activation influences pathways in many cells with the end result leading to modulation of DNA synthesis and other cell activity. Gs proteins stimulate cAMP and PKA formation, Gi proteins inhibit cAMP and PKA formation, and Gq proteins stimulate IP3 and DAG formation to increase Ca and PKC, respectively. Gs proteins are activated by B1, B2, D1, D5, H2, and V2 receptors. Gi proteins are activated by A2, M2, M4, D2, D4 receptors. Gq proteins are activated by A1, M1, M3, M5, D3, H1, and V1 receptors.

Receptor Subtypes Table 4. List of receptors, their signaling pathway, and their general function in the body. Receptor

Pathway

→ IP3, DAG

Function Vasoconstriction

α1

α2

→ cAMP

Decrease SNS activity

β1

→ cAMP

Increase SNS activity

β2

→ cAMP

Bronchodilation, vasodilation

→ IP3, DAG

Cortex and hippocampus (memory)

→ IP3, DAG

Substantia nigra (Parkinson’s disease)

→ cAMP

Renal vasodilation, psychosis

→ cAMP

Caudate, putamen, nucleus accumbens, olfactory tubercle, septum, hypothalamus, and cortex; also plays a role in psychosis

→ cAMP

Limbic structures (cognitive and emotional traits), psychosis

→ IP3, DAG

Limbic structures (cognitive and emotional traits), psychosis

→ cAMP

Hippocampus, hypothalamus (pain and affect)

→ cAMP → IP3, DAG

→ cAMP

Decrease heart rate (increase PNS) Increase exocrine gland and GI activity Neostriatum

Biology of Cells Receptor

Pathway

Function

→ IP3, DAG

Bronchoconstriction, mucus production in respiratory tract, and pruritus

→ cAMP

Increase GI activity

→ IP3, DAG

Vasoconstriction (via ADH)

→ cAMP

Increase water absorption by the kidney (via ADH)

3.6. Growth Factors 3.6.1

PDGF

Platelet-derived growth factor (PDGF) comes from multiple sources, including platelets, macrophages, and neurons. It serves to regulate cell growth, cell migration, angiogenesis, and embryonic signaling. Pathology related to PDGF leads to atherosclerosis, fibrosis, and malignancy. PDGF functions via the tyrosine kinase receptor.

3.6.2

EGF

Epidermal growth factor (EGF) is derived from macrophages, neurons, and the skin. It leads to elevations in calcium, glycolysis, and protein synthesis leading to cell proliferation. Defects lead to tumorigenesis. EGF works via the tyrosine kinase receptor.

3.6.3

TGF-α

Transforming growth factor alpha (TGF-α) is derived from macrophages, neurons, and skin. It serves a role in epithelial development, neuronal proliferation, and stem cell development. Defects lead to cancer. TGF-α works via the tyrosine kinase receptor.

3.6.4

TGF-b

TGF-β has numerous sources. It plays a role in inflammation modulation, tissue regeneration, differentiation, and embryonal signaling. Pathological conditions with this growth factor lead to renal fibrosis following damage and diabetes (treated by ACE-inhibitors). It functions via the serine, threonine kinase receptor.

3.6.5

NGF

Neuronal growth factor is derived from neurons and helps to maintain neuronal survival through feedback activation. It plays a role in some degenerative conditions, such as Alzheimer disease. It functions on neurons via TrkA receptors.

3.6.6

EPO

Erythropoiein is derived from mesangial cells of the kidney. It is essential for the development of erythrocytes in bone marrow. Defects in EPO can lead to polycythemia vera, primary and secondary erythropoiesis. It functions via EpoR receptors in RBC precursors.

Clinical Review for the USMLE Step 1 3.6.7

IGF-1

Insulin growth factor 1 (IGF-1) is derived from the liver and is released in significant amounts after stimulation by growth hormone. IGF-1, also known as somatomedin C, stimulates cell growth, differentiation, and development via a system-wide response. Pathology associated with IGF-1 leads to acromegaly, tumorigenesis, hypoglycemia, lipohypertrophy, and tonsillar hypertrophy. IGF-1 works via the tyrosine kinase receptor. It can play a therapeutic role in patients with IGF / GH deficiency and ALS.

3.6.8

IGF-2

IGF-2 is derived from the brain, kidney, pancreas, muscle. IGF-2 has more specific sources and targets compared to IGF-1. It is important in fetal development, development of brain, kidney, and liver. Defects lead to hypoglycemia. It leads to activation of the IGF-1 receptor; the IGF-2 receptor is not paired with a cell-signaling pathway.

4. Human Development

and

Genetics

4.1. Pedigree Analysis 4.1.1

Inheritance Patterns and Risk Determination

Pedigrees are diagrams that delineate genetic relationships between related people. Pedigrees can be used to determine inheritance patterns, such as autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, and mitochondrial. Several conventions are used for pedigrees: squares are used to represent males, while circles represent females. A couple that has mated is shown at the same level and are connected by horizontal lines. Children are represented by vertical lines emanating from their parents. Shaded squares and circles represent individuals with a particular trait.

Autosomal Dominant Figure 32. Example of an autosomal Autosomal dominant conditions are phenotypically-evident if dominant condition. Copyright Wikithe individual has at least one allele for the condition. Passing media. Used with permission. on the allele to their children occurs 50% of the time. Rarely, individuals may be â&#x20AC;&#x153;double positiveâ&#x20AC;? and have both alleles for an autosomal dominant condition; for most diseases, this leads to severe problems that are incompatible with life. Examples include Huntington disease and polycystic kidney disease.

Autosomal Recessive Autosomal recessive traits, such as albinism, are passed on only if two affected individuals each pass on the allele that codes for the disease. These individuals do not need to have the phenotype for the disease, as the trait is recessive by definiFigure 33. Example of an autosomal tion. For example, in the figure to the right, the father is a carrecessive trait. Copyright Wikimedia. rier for the trait while the mother has both alleles for the trait. Used with permission. Roughly 50% of her children will also have the trait. Their son 38

Human Development and Genetics on the far right marries a woman who also has both alleles for the trait; given that at least one of their children then has the phenotype, that son must be a carrier for the trait. Were this inheritance pattern autosomal dominant, all children would have been positive. Had it been X-linked recessive, all of her male children would have been positive. Finally, had this pattern been mitochondrial, all of her children would again had the trait. Other examples of autosomal recessive diseases include sickle cell disease, Tay-Sachs disease, and cystic fibro- Figure 34. X-linked dominant trait. sis. It is common to skip generations with autosomal recessive Copyright Wikimedia. Used with permission. disorders.

X-Linked Dominant X-linked dominant traits are passed on to all females of affected fathers as they will donate their only X chromosome to their daughters. Their sons will all be negative as their X chromosome will come from the mother. For affected mothers, their children have a 50% chance of inheriting the disease depending on which of the two alleles they receive. Figure 35. X-linked recessive trait shown skipping generations. CopyX-linked recessive traits are evident in the sons of phenotypi- right Wikimedia. Used with permiscally-affected mothers given that the mother has two positive sion. alleles and that the son will receive one of these X chromosomes. Daughters have a 50% chance of becoming a carrier. It is common to skip generations with X-linked recessive disorders. Examples include color blindness, hemophila A and B, and various muscular dystrophies.

X-Linked Recessive

Mitochondrial Inheritance Mitochondrial inheritance affects all children of the mother, and her daughters continue to pass along the trait. Sons will not pass the trait along to their children unless they marry a Figure 36. Example of a mitochondrial woman who is afflicted. Examples include diseases related to inheritance pedigree. The motherâ&#x20AC;&#x2122;s son exercise intolerance and dysfunction of the muscles. does not pass it on to his children on the far right of the diagram. Copyright Wikimedia. Used with permission. 4.2. Population Genetics

Hardy-Weinberg Equilibrium The Hardy-Weinberg equilibrium is used to estimate number of carriers and risk to the population. The ideal terms of use require perfect Mendelian inheritance with random mating and no population effects. Deviation from the Hardy-Weinberg theorem occurs in a variety of cases, including confounding from the founder effect, small population size, genetic drift, population bottlenecks, and selection. The founder effect occurs when a small number of generally similar individuals found a population with significant inbreeding. It leads to a predisposition towards having certain genetic diseases, such as 39

Clinical Review for the USMLE Step 1 seen with the Ashkenazi Jew population. Small population sizes lead to increased predisposition toward genetic disease. Genetic drift has a greater chance for deleterious mutations leading to negative effects due to random mutations. Genetic diversity minimizes the effects of negative mutations. Population bottlenecks lead to a dramatic reduction in population and increased genetic drift and founder-effect type effects. Selection occurs when adaptive traits impart Figure 37. Illustration of gene therapy. Copyright Terese Winslow / advantage and thus are transmitted more readily through NIH. Used with permission. the population.

4.3. Gene Therapy Gene therapy offers the potential to use adenovirus vectors to insert beneficial sequences into the hostâ&#x20AC;&#x2122;s DNA, thereby leading to a change in a phenotype. For example, patients with loss of function mutations can have a gene inserted that produces the relevant protein product. If the sperm or egg cells are affected, the changes will be passed along to their progeny. A second method for transmitting beneficial sequences is to use stem cells. These totipotent cells can be implanted into the brain or marrow and allowed to proliferate and replace abnormally functioning cells. Long term studies using these two techniques are pending in the form of clinical trials at major institutions.

4.4. Genetic Testing 4.4.1

and

Counseling

DNA Sequencing

DNA sequencing involves determining the entire nucleotide structure of a particular gene. Various methods exist to determine the precise nucleotide sequence of DNA. The negative aspect is that it is difficult to tell the differences between introns and exons. Sequencing is important to identify where various genes are located in chromosomes and to better understand the human genetic code. The human genome project completed a map of the entire human genome at the nucleotide level and used this map to identify the location of approximately 25,000-30,000 human genes. Approximately 3 billion nucleotides were sequenced and used to provide genetic testing to identify the presence of potentially deleterious genes.

Human Development and Genetics 4.4.2

PCR

Polymerase chain reaction (PCR) permits amplification of a particular DNA sequence for additional testing or analysis. It uses a DNA template that binds to the target and isolates it for amplification. Primers bind to the target and begin transcription, which is performed by heat-stable taq polymerase. A series of deoxynucleotides provides the nucleic acids for transcription. Exponential amplification occurs so as few as 20 cycles can yield over a million copies

4.4.3

RFLP

Restriction fragment length polymorphisms (RFLPs) are used on purified DNA that has been amplified using PCR. The DNA is cut into restriction fragments by endonucleases and separated on an agarose gel through electrophoresis. The separated fragments provide a unique DNA fingerprint for an individual due to differences in where the enzymes cut. This is the result of random mutations. The fragments can be used to positively identify an individual or make judgments regarding relationships between individuals (paternity testing).

4.4.4

DNA Microarrays

DNA chips contain thousands of organized probes in a known configuration. The microarray can be used to quickly identify whether a person has a particular gene for a disease using tissue collected from that person. Microarrays lead to the issue of information analysis given the sheer amount of data they generate. Careful statistical analysis is necessary to avoid issues with confounding and incidental findings.

4.4.5

Southern Blot

4.4.6

Northern Blot

Figure 38. Western blot. Copyright Ernst Hempelmann. Used Southern blots use DNA probes to identify specific DNA sequencwith permission. es. They can be used to verify that a particular DNA sequence exists.

Northern blots use a DNA probe to bind to an RNA sequence. A reverse procedure can be used to bind DNA on a gel with probes made from cell RNA. This permits gene expression profiling on an ongoing basis for various cells.

4.4.7

Western Blot

Western blots are used to detect protein within a homogenous tissue extract. Western blots initially separate proteins denatured proteins by gel electrophoresis. Proteins are probed using antibodies to determine whether the protein is present. Western blots can be used as a confirmatory test due to its high specificity; examples include HIV, bovine spongiform encephalopathy, and lyme disease. 41

Clinical Review for the USMLE Step 1 4.4.8

Immunohistochemistry

Immunohistochemistry uses antibodies to precisely locate various proteins on intact tissue mounted to slides. Direct immunofluorescence has an antibody bind to tissue that also fluoresces upon binding. Indirect immunofluorescence works by having an antibody bind to tissue, which is then bound to a secondary antibody. A color reaction occurs upon application of an enzyme.

4.4.9

ELISA

Enzyme-linked immunosorbent assay (ELISA) is used to detect an antibody in a sample. Generating quantitative information is possible, a benefit difficult to realize with other techniques. ELISA may be used to ascertain competitive binding of various proteins.

4.4.10

Genetic Counseling

Genetic counseling relies on completing a targeted analysis of a patientâ&#x20AC;&#x2122;s DNA to determine if they have risk factors for a particular disease. For example, the presence of BRCA 1 in a woman with a strong family history of breast cancer is likely to develop breast cancer at a young age. An appropriate analysis of both genetic and environmental risk factors can help patientâ&#x20AC;&#x2122;s make decisions for future care. For example, a young woman with BRCA 1 may elect to undergo prophylactic bilateral mastectomy to minimize the risk of breast cancer.

5. Inflammation

and

Repair

5.1. Fever 5.1.1

Overview

Fever can be generated from endogenous, exogenous, and toxic causes. Endogenous mediators include IL-1, IL-6, and TNF-alpha. Exogenous causes include endotoxin. Toxic injury from products like 2,4DNP can also lead to fever. Fever is never normal and is not compensation for hypothermia. Fever following surgery is a common occurrence; the cause can often be narrowed down by postoperative day and the presentation of the patient.

5.1.2

Postoperative Days 1 and 2

Fevers that occur by postoperative day two are typically due to atelectasis. Atelectasis can be minimized with the use of an incentive spirometer and facilitating deep breathing and cough. This is particular important in patients who undergo open chest procedures or those with multiple rib fractures; an epidural to manage postoperative chest pain may be particularly beneficial.

5.1.3

Postoperative Days 3 Through 5

The most common cause of postoperative fever between postoperative days three and five is due to urinary tract infection. Prophylactic measures can be taken in patients who are more susceptible than normal for developing UTIs. This population includes patients who have indwelling Foley catheters, and who have a historical predilection for developing UTI.

Inflammation and Repair 5.1.4

Postoperative Days 4 Through 6

Deep vein thrombosis is the most common cause of postoperative fever on days four through six. DVT is a serious issue than can lead to sudden death due to a massive pulmonary embolism, and astute surgeons and health care providers take steps to minimize this potentially disastrous outcome. Low-dose heparin given subcutaneously and the use of sequential compressed devices (SCD) have been shown to reduce the incidence of DVT. The best way to reduce the chances of DVT occurring is to have the patient ambulate as soon as possible following surgery. Patients most at risk for DVT/PE are trauma patients, and those who have undergone pelvic procedures, orthopedic surgery, or a general surgery procedure.

5.1.5

Postoperative Days 5 Through 7

Infections of the surgical wound are most common postoperative days five through seven. Prophylactic antibiotics dosed during surgery and continued for 24 hours are an important part of any surgical procedure, even in some clean cases. Finally, fevers that occur after postoperative day seven are often iatrogenic, often from medications.

5.2. Systemic Inflammatory Response Syndrome Systemic inflammatory response syndrome (SIRS) is the presence of two or more of the following: •

Fever / Chills: > 38°C or < 36°C

•

Tachycardia: > 90 bpm

•

Tachypnea: > 20 breaths per minute or a PaCO2 < 32 mmHg

•

Leukocytosis: > 12,000/µL or < 4,000/µL or > 10% bands

SIRS can be due to bacteremia (sepsis) and can progress to end-organ damage (severe sepsis). SIRS should be thought of as a global inflammatory state with a pronounced cytokine cascade activation leading to multiple organ dysfunction syndrome (MODS). The proinflammatory state includes numerous acute phase reactants and release of vasoactive cytokines. The more end organs affected, the higher the risk of mortality. With lactic acidosis, change in mental status, decreased urine production, or other signs of organ dysfunction, MODS develops with SIRS. If the etiology is bacteremia, the sepsis becomes severe sepsis. The addition of hypotension to sepsis (SIRS due to bacteremia) is septic shock. Systolic BP < 90 mmHg or a need for vasopressors is septic shock. SIRS is treated with admission to the ICU, antibiotics if infection is suspected, and supportive therapy. Fluid sequestration and third space fluid losses can be large; thus fluid resuscitation is necessary. A pulmonary artery catheter (PAC) can be used to monitor cardiac function, however their use for monitoring resuscitation is becoming rare as there is little clinical data showing that their use leads to a better clinical outcome. There are newer technologies now becoming available that can monitor cardiac function noninvasively. Activated protein C (Xigris) leads to fibrinolysis and reduces inflammation but can lead to bleeding. Aggressive fluid resuscitation with correction of central venous PO2, serum lactate, base excess, urine output, and blood pressure must be done. Intravenous steroids are often used not only in patients with adrenal dysfunction but also in septic shock patients who are not responding. Patients in septic shock 43

Clinical Review for the USMLE Step 1 who otherwise do not have adrenal dysfunction cannot mount the massive adrenal response necessary and steroids need to be added. Tight glucose control has been shown to be beneficial. If the etiology of SIRS (usually infection) is not discovered and treated, the patient will progress to severe sepsis, MODS, and septic shock.

5.3. Sepsis Sepsis is SIRS with bacteremia. The most common cause of sepsis is from gram negative bacteremia. The most common source is genitourinary, followed by respiratory and abdomen. Diversion of blood flow from the central circulation to the peripheral vessels occurs due to increased heat production from hypermetabolism. Without fluid repletion, ischemia of central tissues occurs. Further, there is a diffuse increase in microvascular permeability secondary to the inflammatory response taking place. Left uncontrolled, the end result is decreased urine output from renal hypoperfusion, hypotension from diversion of intravascular volume, and warming of the extremities from decreased systemic vascular resistance (SVR). Cardiac output increases to compensate for the hypotension. Sepsis causes decreased oxygen consumption and exerts its effects on the mitochondria of cells. In sepsis with a pronounced inflammatory response and cytokine activation, no matter how much oxygen is delivered to the cells, they do not use it well. Sepsis also causes microthrombosis at the capillary level which produces shunting of oxygenated blood from the pre-capillary arterioles to post-capillary venules without the oxygen being used by the tissue. APC works by preventing this microthrombosis. This decreased oxygen consumption produces an increase in mixed venous oxygen content. Proof that infection is the etiology of the SIRS can be elusive, but sepsis has a source of infection. If organ dysfunction is evident, the sepsis is severe sepsis. Numerous general symptoms are often present. Fever and mental status changes are common. The source of infection must be diligently sought. IV lines should be immediately tested and changed, especially central lines. A complete physical exam should be done to identify any source of infection. If tachypnea is one of the features of the SIRS, respiratory alkalosis is often present. Virtually any uncontrolled infection or significant disease process can lead to SIRS. Almost anything can cause SIRS: an amusement part thrill ride often makes people tachycardic and tachypneic. Many disease processes can cause SIRS and organ dysfunction yet that is not sepsis unless an infection is involved. For instance, sterile fulminant pancreatitis can cause SIRS, MODS and even death without sepsis. Glucocorticoid release in shock leads to insulin resistance. The resulting hyperglycemia is the earliest sign of impending sepsis and may occur up to 24 hours preceding hypotension, low SVR, high CO, and warm extremities. Respiratory alkalosis, hyperventilation, and altered mental status are other early signs of sepsis. Sepsis is associated with an increase in IL 6. Late sepsis will progress with worsening hypotension, a decrease in cardiac output from poor filling pressures (low CVP and BV), increased PVR, cold extremities, conversion to lactic acidosis with metabolic acidosis, and hypoventilation. Supportive therapy and maintaining organ perfusion are essential to decrease morbidity and mortality. Infection by IV lines may be treated with imipenem, meropenem, cefoperazone, cefepime, or vancomycin. APC (Xigris) used in the treatment of sepsis leads to fibrinolysis, but has strict criteria for use.

Inflammation and Repair

5.4. Shock 5.4.1

Septic Shock

Septic shock is sepsis with shock and causes hypoperfusion of end organs. Tachypnea and abnormalities in the WBC are typically present. Distributive shock is the early stage of septic shock and results with uneven fluid distribution (third space fluid sequestration and diversion of blood from central organs to the periphery) throughout the body. This is secondary to release of acute phase reactants and a gross systemic inflammatory reaction. This inflammation is commonly secondary to infection by gram negative organisms and subsequent production of endotoxins. Unopposed activation of TNF commonly occurs as the initiator of this inflammatory cascade. With continued hypoperfusion, the period of warm septic shock with shunting of blood to the periphery is replaced with late shock and leads to a state of global hypoperfusion and imminent cardiovascular collapse. Treatment for septic shock requires correction of the underlying septic source, fluid resuscitation, and the use of pressors. End organ dysfunction must be corrected as quickly as possible to avoid long term damage. Steroids may have some role to help mitigate the immune response. Septic patients with end organ failure who meet APACHE II criteria may be candidates for APC (Xigris).

5.4.2

Hypovolemic Shock

Severe hypovolemia can overwhelm the bodyâ&#x20AC;&#x2122;s ability to generate sufficient vasoconstriction and cardiac output. Hypovolemic shock is the most common type of shock and can occur secondary to hemorrhage, burns, dehydration, abuse of diuretics, vomiting, and diarrhea. The initial response is increased peripheral vasoconstriction and cardiac contractility, tachycardia and cool extremities. The renin-angiotensinaldosterone axis is stimulated, ANP release by the heart is inhibited to decrease diuresis, and the desire to drink fluid is stimulated. Hypovolemia requires replacement of the intravascular volume. Typically, lactated ringers is given as a bolus. In the adult when hemorrhage is thought to be the etiology of the shock, if two liters of ringers lactact does not correct the shock or if the hemorrhage continues, packed red blood cells should be infused. Correction of the inciting events leading to the hypovolemia (stop the hemorrhage!) is the first priority. Admission to an ICU and use of invasive pressure monitoring may be required.

5.4.3

Cardiogenic Shock

Cardiogenic shock is due to compromised function of the heart, such as with heart failure following a myocardial infarction, arrhythmia, cardiomyopathy, or high-grade congestive heart failure. Sustained hypotension leading to hypoperfusion is the result even with satisfactory filling pressure of the left ventricle. Cardiogenic shock therefore presents with prerenal failure, mental status changes, and cool extremities. Jugular venous distention and pulmonary edema are other findings. Pericardial tamponade, saddle pulmonary embolus, and tension pneumothorax must be ruled out as they can produce symptoms similar to cardiogenic shock. Following diagnosis, most practitioners will consider the use of a pulmonary artery catheter to help guide resuscitation and tailor therapy according to the available cardiac function. Inotropic agents such as dobutamine are often necessary to augment cardiac function. If the left heart failure is poignant, an intra-aortic balloon pump may be necessary to reduce afterload and augment cardiac function. Failing this, a left ventricular assist device or heart transplantation may be required. 45

Clinical Review for the USMLE Step 1 5.4.4

Anaphylactic Shock

Widespread vasodilation in response to excess histamine release leads to anaphylactic shock. It is secondary to a severe type I hypersensitivity reaction. Systemic vasodilation occurs and overwhelms the ability of the heart to generate sufficient output. There are a variety of causes, including bee stings and allergic reaction to various medications. Anaphylactic shock is induced by IgE. Severe swelling of the face and throat can occur and lead to obstruction of the airway. Anaphylactic shock requires immediate supportive therapy due to the risk of respiratory arrest. Epinephrine is used to forestall the collapse of the airway and stimulate the cardiovascular system.

5.4.5

Neurogenic Shock

Neurogenic shock occurs secondary to acute disruption of central nervous system pathways, typically at the level of the spinal cord from acute trauma. Loss of background sympathetic activity leads to hypotension, bradycardia, and peripheral vasodilation. Treatment of neurogenic shock requires supportive therapy and stabilization of any fractures leading to compromise of the spinal cord. A significant amount of fluid resuscitation may be necessary. Atropine may be used for symptomatic bradycardia. Pressors may be required. If the neurogenic shock is due to trauma, hemorrhagic shock must first be ruled out (stop the bleeding!) as the source of the shock.

5.4.6

Endocrine Shock

Endocrine shock may occur secondary to profound hypothyroidism, thyrotoxicosis, or adrenal insufficiency. A combination of hypovolemic and cardiogenic shock may occur. Treatment is to support the endocrine function. Endocrine shock may contribute to septic shock as an inadequate adrenal response to septic shock has been recognized and steroid supplementation may be needed.

5.5. Wound Healing 5.5.1

Phases of Wound Healing

Psychology By the end of the first week, the proliferative phase has begun (days 5 through 21). Fibroblasts become the dominant cell type and rapidly synthesize collagen as well as matrix material such as GAGs (glycosaminoglycans). Although wound tensile strength begins to increase as a result, the collagen is predominantly type III, whereas in normal skin there is a 4:1 ratio between type I and type III collagen. Wound contraction occurs with the appearance of myofibroblasts, specialized fibroblasts with contractile cytoplasmic microfilaments. Angiogenesis begins during the proliferative phase under the influence of factors such as VEGF (vascular endothelial growth factor) secreted by platelets and other cells. The maturation or remodeling phase (week 4 up to 1 year) begins as the rate of collagen breakdown mediated by metalloproteases increases to match the rate of collagen synthesis. Type III collagen is replaced by type I, reestablishing the normal 4:1 ratio. The collagen also becomes more organized and better cross linked, and the tissue becomes less cellular. The wound reaches its peak strength, about 80% of baseline, after about 60 days. Type I collagen is the predominant collagen in mature scars. Type II collagen is the primary constituent of cartilage. Type III collagen is found in embryonic tissue, vasculature, uterus, and gastrointestinal tract; it is the predominant collagen in immature scars. Type IV collagen is found in basement membrane. Wound healing may be negatively affected by increasing age, systemic disease, immunosuppression, steroids (which can be reversed by vitamin A), malnutrition, smoking, infection, foreign bodies, radiation, and scar formation. Abnormal scarring may occur in the form of widened, hypertrophic, or keloid scars. Widened scars are marked by normal quantities of collagen spread over a larger area, whereas the histology of hypertrophic and keloid scars are similar and involve excessive collagen deposition. Keloid scars differ from hypertrophic in that keloids grow beyond the normal wound borders. Widened and hypertrophic scars both result largely from excessive tension on the wound, whereas the etiology of keloids is unclear but may be influenced by autoimmune and endocrine factors. Keloids also differ from widened and hypertrophic scars in that the latter generally respond well to treatment (primarily excision and closure), but keloids often worsen and require combination therapy with multiple modalities. In addition, keloids show a much higher correlation with genetic, familial, and racial factors.

6. Psychology 6.1. Life Cycle 6.1.1

The Neonate

The neonate is born with excellent sensory skills, including the ability to distinguish between various tastes, mimick a parentâ&#x20AC;&#x2122;s expressions, respond to loud noises, follow an object with his eyes, and being comforted by a voice or being picked up. Basic reflexes present at birth include the palmar grasp reflex (the child automatically holds onto an object placed in his palm), the rooting reflex, (the child turns in the direction of stroking of his cheek), the stepping reflex (the child moves as if he is walking when held upright), the Moro reflex (the neonate extends his limbs when startled), and the Babinski reflex (the child moves his great toe upwards and fans his toes outward when the plantar surface is stroked). The palmar grasp reflex remains until 2 months of age, the rooting reflex remains until 3 months of age, and the stepping reflex, Moro reflex, and Babinski reflex remain for about 1 year. Continuation of these reflexes several months after they should have rescinded may indicate an underlying pathology.

Clinical Review for the USMLE Step 1 6.1.2

Infancy

During infancy (from birth to 18 months) the baby begins to spontaneously smile. Spontaneous smiling begins at approximately 1 week and disappears by 3 months. The infant begins to develop a social smile (smiling at a face) by 2 months. At three months, the infant begins to use facial expressions to show underlying emotions. Laughing begins at four months. The infant begins to exhibit stranger anxiety at 7 months and is oriented to the voice of his mother and father. Stranger anxiety typically resolves in a few months. At 15 months of age, the infant develops separation anxiety when kept from his mother and this separation may cause great distress. These ranges are inexact and vary child to child. Motor development progresses to the point where the infant is able to roll over at 3 months. Around 6 months, the infant begins to crawl, and at 7 months, the infant is able to sit unsupported. At one year of age, the infant is able to stand without support, can walk if given assistance, and says his first word. By 15 months, the child is able to walk independently. Language development begins at 3 months with babbling. The first words are usually echoes of what is spoken to the infant (echolalia). It is no wonder that the first words are typically something repeatedly said to the infant, such as mama or papa. During visits to the physician, guidance to the parents should center on childproofing the house, because the infant begins to move from place to place and is now at risk of numerous environmental dangers.

6.1.3

The Toddler

From 18 months to 3 years is the toddler period. During this time, the toddler is going through the anal period (Freud), autonomy versus shame and doubt (Erikson), and the perioperational phase (Piaget). Autonomy is manifest during this time by the child saying “no” to simple parental requests, even when the child would ordinarily say “yes.” Language continues to develop with simple two-word sentences at age 2, three-word sentences at age 3, four-word sentences at age 4, and five-word sentences at age 5. Vocabulary extends to several hundred words at age 2, even though only several dozen words make up the spoken vocabulary. Some stuttering may occur at this early age, as the motor pathways continue to develop. Control over bowel movements is typically completed by age 3, and control over micturition is controlled by age 4. Toilet training should typically not be attempted until cues are given by the child, including curiosity about the bathroom, squatting to expel feces, and displeasure after urination or defecation. At 1 year of age, the child is able to stack three blocks, throw a ball, scribble on paper, run, and climb stairs using one foot at a time. The child moves to and fro from his mother, which is known as rapprochement. At age 2, the child can stack six blocks, kick a ball, undress himself, and use utensils. The child plays alongside other children (parallel play), and can name body parts. This is also the time that autonomy becomes most noticeable with frequent use of the word “No.” Counseling by the physician during this time should include management of tantrums. Techniques that the parents should be educated on include ignoring the toddler’s outburst completely, shifting the child’s attention to something else, and using “time out” periods to teach the child that tantrums are unacceptable. The most significant task during the second year of life is resolving separation anxiety and alleviating the distress in the child caused by removing him from his mother. In children who are hospitalized at this age, their most significant concern is separation from their parents, which supersedes even their fear of bodily harm or pain. The child’s height at age 2 should be noted, as this is typically half their height as an adult.

Psychology 6.1.4

Preschoolers

Development by Age 3 Preschool aged children (ages 3-6) have significantly larger vocabularies, numbering in the thousands of words. Pronouns, age, gender, and name are articulated by age 3, prepositions are complete by age 4, and an understanding of the concept of time is complete by age 5, including the use of the future tense. At age 3, the child can stack 9 blocks, can ride a tricycle, use scissors, partially dress himself, and can climb stairs using alternate feet. At this point, the child is typically able to spend a portion of the day away from his mother, and can also identify colors. At this time there is no evidence that daily separation from his mother has long-term sequelae, and a good day care setting may be recommended by the physician.

Development by Age 4 At age 4, the child is able to create simple drawings of people, button her clothes, and brush her teeth. She can hop on one foot and copy a cross. Social development continues at this age with interest in sexual identity, having nightmares, developing imaginary companions, and being overly concerned about disease and injury. Preschool-aged children typically can play cooperatively with other children, and have good self-expression.

Development by Age 5 At age 5, the preschooler can draw a person in detail, play hopscotch, and copy a square. Freudâ&#x20AC;&#x2122;s Oedipal stage reaches its climax at this age, as the child begins to have a rivalry with the same-sex parent, and the child is unable to understand the meaning of death. The loss of friends, relatives, or pets is typically not understood to be permanent and the child may expect them to return at any given moment.

6.1.5

School-Age

As school-aged children (ages 6-12), they become more mature and cooperative and tend to start becoming more involved with people other than their parents. As they begin to develop role models, these children tend to identify with the same sex parent, and psychosocial issues tend to be dormant at this age. Children at this age have well-developed motor skills and a strong moral sense. They are able to tie shoelaces, ride a bicycle, copy a triangle, print letters, and learns to read. By age 6, the child understands that the death of others is permanent. Due to a well-developing superego, this is often considered the best time for elective surgery. With regard to the ability to draw shapes, a three year old can draw a circle, a four year old can draw a cross and a rectangle, a five year old can draw a square, a six year old can draw a triangle, and a seven year old can draw a diamond. Note that one way to remember this progression is to note that circle, cross, rectangle, square, and triangle are in alphabetical order.

6.1.6

Teenagers

Puberty begins in these years and is hallmarked by the onset of menarche in females (between ages 9-12) and ejaculation in males (between the ages of 10-13). Physical development at this age, in addition to side effects such as acne, lead to a number of psychosocial issues for this age group. These issues often include a preoccupation with body image and gender roles. They now begin to deeply explore their sexuality and solidify their sense of identity. 49

Clinical Review for the USMLE Step 1 Homosexual experiences may occur at this age as role confusion develops. Some element of risk-taking behavior is typically present. This hazardous behavior may be minimized by using short-term consequences. Both the parents and physician should serve as mentors and role models as teenagers experiment with their sexuality. In their counseling role, birth control and education regarding sexually transmitted diseases should be discussed. The first age of sexual intercourse is typically around 16, but less than 1/3 of teenagers regularly use birth control. This has led to a serious problem with teenage pregnancy, leading to over one million United States pregnancies in this age group yearly. Of that number of pregnancies, nearly 400,000 end in abortion, and often require parental consent depending on state law. Risk factors for teenage pregnancy include divorced parents, lack of planning for the future, psychosocial issues leading to depression, and poor performance in school.

6.1.7

Early Adulthood

With early adulthood spanning the ages of 20 to 40, typical concerns include marriage and having children. Nearly 75% of Americans have been married and with children by age 30, but only 25% of families have two parents living in the home. It is also at this age that a reappraisal of one’s life starts and the adult’s role in society is more clearly defined.

6.1.8

Middle Age

Middle adulthood, from 40 to 65, leads to more concern over power and authority. Failures in this stage often lead to a change in profession, a change in lifestyle, divorce or infidelity, use of illicit drugs, and depression. This is what is often termed as a “midlife crisis,” and it is widely believed to be caused by one’s increased awareness of their mortality. This is typically punctuated by menopause in women and diminished strength, stamina, and sexual performance in both genders. However, it is important to note that hormone levels stay the same and there is no evidence of decreased “sexual drive.”

6.1.9

The Elderly

The average life expectancy in the United States is 76 years, and the fastest growing age group in the population is adults over age 85. African American men have the lowest life expectancy at 66 years of age, followed by white men and black women at 74, and white women at 80. Physical changes at this age make independent living more difficult due to decreased vision and hearing, incontinence, diminished immune responses, a general decrease in body system functioning and reserve, diminished strength, and decreased bone mass. Decreased cerebral blood flow and age-related mental function changes lead to some memory lapses, but any change in intelligence should be considered pathological. There are also changes in sleep patterns leading to a loss of sleep and decreased quality.

6.2. Theories 6.2.1

Development

Overview

Child development covers the maturation of a child from birth through the teenage years. There are three major theories that attempt to describe the various stages a child goes through. Sigmund Freud breaks down the developmental process as falling into the oral period, anal period, oedipal period, latency, and intensification of sexual activity. Erik Erikson breaks the stages down into a time of basic trust versus mistrust, autonomy versus shame and doubt, initiative versus guilt, industry versus inferiority, and identity versus role confusion. Finally, Jean Piaget breaks down these stages into a period of 50

Psychology sensorimotor development, perioperational development, preoperational development, concrete operations, and formal operations. Table 5. Theories of development. Theories of Development Sigmund Freud

Erik Erikson

Jean Piaget

Oral period

Basic trust versus mistrust

Sensorimotor development

Anal period

Autonomy versus shame and doubt

Perioperational development

Oedipal period

Initiative versus guilt

Preoperational development

Latency

Industry versus inferiority

Concrete operations

Intensification of sexual activity

Identity versus role confusion

Formal operations

6.2.2

Freud’s Stages

Freud’s stages are centered on the erotogenic zones. He believes that the first period is the oral phase, as this is the stage in which the child derives pleasure from suckling. If the child is able to successfully meet his needs through suckling, Freud says he will later be able to meet the needs of other stages. The oral stage begins at birth and continues until about 18 months of age. The anal period is when the child is able to exert readiness and self control through activities such as toilet training. During this period of time, the conflicts in the child’s life center on self-control versus parental demands. With too much control by the parents during this time, Freud believes that the child will become stubborn and compulsive as an adult. This period spans the time from 18 months to 3 years. The Oedipal period is when the child develops feelings for the opposite-sex parent. The child is fearful of retaliation by the opposite sex parent at this time, and resolves this conflict by identifying with the same-sex parent. This occurs during the preschool years, from 3 years to 6 years of age. The latent period is next. During this stage the child is able to translate his sexual drive into schoolwork and play. This stage occurs during the early schooling years, from 6 to 12 years of age. Finally, Freud believes that the last period occurs during the teenage years and is a time of increased sexuality. Table 6. Freud’s stages. Freud’s Stages Birth to 18 months

Oral period

18 months to 3 years

Anal period

3 years to 6 years

Oedipal period

6 years to 12 years

Latent period

12 years to adulthood

Intensification of sexual activity

6.2.3

Erikson’s Stages

Erikson’s stages are similar in concept to Freud’s, without the focus on human sexuality. The first period is the development of basic trust versus mistrust, and occurs from birth to 18 months. It is during this time that the child learns to rely upon his parents, especially his mother as he forms a bond through suckling and intimate care. From 18 months to 3 years, the child begins to focus on autonomy versus 51

Clinical Review for the USMLE Step 1 shame and doubt, learning to take care of tasks on his own and continuing to take on additional responsibilities. Initiative versus guilt follows in the preschool years, from age 3 to 6. This is the time that the child begins to communicate more with the outside world; positive feedback at this stage is important as the child develops language abilities. From 6 years of age to 12, the child begins to take pride in his education and takes part in various hobbies and sports. This is the development of industry versus inferiority. The teenage years hallmark the development of identity versus role confusion as the child learns who he is and how he fits into the world. Various social, physical, and emotional strengths and weaknesses are explored during these years. From age 12 to 20, teenagers undergo identity versus role confusion. They explore their sexuality more and try to understand their role as they experiment with various relationships. Experimentation with the same sex at this point is not uncommon. For young adults from age 20 to 40, intimacy versus isolation becomes the predominant phase. Relationships with their life partner and children begin to form at this point. In middle aged adults (age 40-65), additional maturation, creativity, and productivity takes place in the generativity versus stagnation period. In the elderly, Erikson’s ego integrity versus despair stage is dominant. Pride over one’s accomplishments at this age typically prevents depression, anxiety, and worsening of any underlying abuse of alcohol or drugs. The combination of continued physical and occupational activity, in addition to higher education, a strong social support system, and a beneficial family history are all contributors to increased longevity. Table 7. Erikson’s stages. Erikson’s Stages Birth to 18 months

Basic trust versus mistrust

18 months to 3 years

Autonomy versus shame and doubt

3 years to 6 years

Initiative versus guilt

6 years to 12 years

Industry versus inferiority

12 years to 20 years

Identity versus role confusion

20 years to 40 years

Intimacy versus isolation

40 years to 65 years

Generativity versus stagnation

65 years +

Ego integrity versus despair

6.2.4

Piaget’s Stages

Piaget hallmarks the period from birth to 18 months as the sensorimotor period, during which the child learns basic interactions with the outside world. This includes both sensory and motor stimulation, as the child initially learns through direct interactions with the environment, followed by out of sight, then out of mind, and finally learning object permanence. The next phase, spanning 18 months to 3 years, is the perioperational phase. The child’s intuition is the main source of decision-making, not logic, during this phase. From 3 years to 6 years, the preoperational phase appears and the child believes that moving objects are alive and have feelings (animism); the child is egocentric and so believes that the world exists for only them, and assigns meaning to events around themselves that do not have a foundation in reality (artificialism). 52

Psychology In the school age years, from 6 to 12, the child develops concrete operations and learns about conservatism and reversibility. The child begins to realize that water poured from a large, thin glass into a short, wide glass is still the same amount of water. Reversibility occurs when the child learns that taking 3 blocks from 10 yields 7 blocks, and adding 3 blocks to 7 gives 10 blocks. During the teenage years, formal operations are developed where the adolescent learns abstract reasoning and post conventional morality. During this stage, the teen becomes aware that exceptions to rules exist and should be exercised when ethically permissible. Table 8. Piagetâ&#x20AC;&#x2122;s stages. Piagetâ&#x20AC;&#x2122;s Stages Birth to 18 months

Sensorimotor period

18 months to 3 years

Perioperational period

3 years to 6 years

Preoperational period

6 years to 12 years

Concrete operations

12 years to adulthood

Abstract reasoning and post conventional morality

6.2.5

Progression of Stages

It is important to realize that subsequent stages cannot proceed until the stage before it is completed successfully. For example, it is difficult to develop abstract reasoning when basic logic skills are not in place. Circumstances that prevent maturation into the next stage can include brain injury, prolonged neglect, prolonged hospitalization, and a variety of developmental disorders. There are also a number of influences on child development, including genetic factors, prenatal care, socioeconomic status, gender, temperament, parental attachment, and the quality of the parental relationships. If development proceeds without significant delay or interference, the child begins to develop basic skills by a certain age. Failure to develop these abilities leads to developmental retardation with sequelae that can continue all the way through adulthood.

6.3. Coping Mechanisms 6.3.1

Overview

Ego defenses are techniques that people use to cope with stresses presented to them by their environment. These defenses are unconscious reactions to this stress. Over time, a personâ&#x20AC;&#x2122;s ego defenses typically mature as a function of age and experience. There are four mature ego defenses, including altruism, humor, sublimation, and suppression; these are adaptive behavioral responses to external stressors and illness. There are a number of immature ego defenses, including acting out, blocking, denial, displacement, dissociation, fixation, identification, isolation of affect, passive-aggressive behavior, projection, rationalization, reaction formation, regression, repression, somatization, splitting, and undoing; generally, these are maladaptive responses to stress and illness.

Clinical Review for the USMLE Step 1 Table 9. Ego defenses. Mature Ego Defenses

Immature Ego Defenses

Sublimation

Acting out

Projection

Altruism

Blocking

Rationalization

Suppression

Denial

Reaction formation

Humor

Displacement

Regression

Dissociation

Repression

Fixation

Somatization

Identification

Splitting

Isolation of affect

Transference

Passive-aggressive

Undoing

6.3.2

Mature Ego Defenses

Altruism Altruism is a mature ego defense in which the person gives to others without expecting anything in return. Altruistic behavior is typically preformed to alleviate guilty feelings. Large donations during the holidays by anonymous individuals may be done to reduce guilty feelings regarding the amount of wealth they have (“share the wealth”).

Humor Humor is a mature ego defense that individuals use to reduce anxiety in a difficult situation. Making jokes helps to alleviate tension in an otherwise intractable situation; for example, humor is especially common in anatomy labs where it is sometimes the only way to deal with the macabre nature of what medical students have to confront.

Sublimation Sublimation is the replacement of thoughts or actions that are unacceptable with a more desirable action. The new action is consistent with the person’s ethics and morals, whereas the previous action was more impulsive and less responsible. Art and literature are prime examples of sublimation, where one artist’s feelings may be transformed into an attractive painting.

Suppression Suppression is a voluntary ego mechanism and so is different from the other mature ego defenses in that it is not automatic. Suppression involves temporarily removing a thought from the consciousness in order to continue to cope with the outside world. A mature application of this is to temporarily stop thinking about various appointments that one must go to until the day after your wedding (“take it one step at a time”). Suppression should be differentiated from repression in that removing a thought from the consciousness is temporary in suppression; in repression, the thought is removed from memory and the person forgets that the thought was removed. Repression is an immature ego defense.

Psychology 6.3.3

Immature Ego Defenses

Acting Out Immature ego defenses deal with the outside world in ways that only forestall dealing with a difficult situation. They typically do not lead to resolution of events. Acting out is an example of an immature ego defense in which a person will express undesirable feelings with equally undesirable actions. An example of acting out is throwing a temper tantrum. In this behavior a child’s frustration with a parent may lead to an immature emotional outburst. Acting out covers the real emotion (the child’s frustration) and so is different than displacement.

Blocking Blocking is an immature defense mechanism in which a person will transiently stop thinking about a particular thought. It is different than suppression in that the conflict is never resolved, and the person continues to stop thinking about the thought whenever it occurs. For example, a homosexual male embarrassed about being attracted to other men may block his libidinous thoughts instead of coming to terms with his sexual orientation.

Denial Denial is an immature ego defense in which the person contradicts a fact to avoid pain. Denial is typically the first stage in dealing with death in which a person will believe that the results of accurate medical tests are false. Denial can best be treated by explaining the situation in terms that the patient can comprehend and helping them become aware that there may be a more responsible or mature method of dealing with the situation at hand (“you can’t argue with the facts”).

Displacement Displacement is an immature way to transfer unacceptable feelings towards one person onto another person. A person who has a bad day at work and yells at his wife when he comes home is displacing his negative feelings towards his boss onto his wife. There is no change in the unacceptable feelings – fear in one situation is expressed as fear in another situation; anger with anger. Dealing with displacement may be helping the person to realize where the underlying feelings are coming from and helping them to deal with the adverse situation in a more constructive manner (“face the truth”).

Dissociation Dissociation is a method of changing one’s identity to avoid a stressful situation. In its more extreme presentation, a stressful situation may lead to dissociative identity disorder or multiple personality disorder. A person may deal with a stressful situation by packing up his things and creating an entirely different life elsewhere. More common presentations involve changing aspects of one’s personality, actions, memory, or consciousness.

Fixation Fixation is having a preoccupation with a certain event. An obsession with the sports channel or with cooking shows on television may be an egosyntonic method (albeit immature way) of avoiding other obligations. Dealing with fixation may be done by empowering a person with other methods of dealing with their stressful obligations. 55

Clinical Review for the USMLE Step 1 Identification Identification is an immature ego defense of believing that the averse actions one person has experienced makes it acceptable for the patient to employ those same actions on another. This is common in abused children who later become the abusers. Assisting a person involves helping them realize where their negative tendencies originated from, and transforming those tendencies into more positive actions that do not harm others (also known as sublimation).

Isolation of Affect Isolation of affect results in separating one’s feelings from an idea or event. Separating one’s feelings prevents a person from being hurt while dealing with an otherwise stressful event. This may be common in cold-blooded murders, in which the person does not demonstrate remorse when conducting a distressing and despicable action. If the process is more cognitive, isolation of affect is termed intellectualization. This is common in patients with obsessive-compulsive disorder in which the patient ruminates about actions that they cannot help conducting. Schizophrenics sometimes demonstrate isolation of affect.

Passive-Aggressive Passive-aggressive ego defenses are an immature method of being unconsciously hostile towards others in order to relieve negative feelings toward them. A person may demonstrate passive-aggressive behavior towards his boss by not alerting him that his vehicle is parked in a tow-away zone. Passive-aggressive behavior is common in patients with borderline personality disorder and in children. A person behaving badly towards another is an intentional act, and is by definition not a manifestation of passiveaggressiveness.

Projection Projection is attributing an unacceptable thought or impulse as being due to another source. For example, a person who is angry with another person may believe that others are angry towards him. Another example is where a man who hates dogs believes that dogs hate him when they urinate on his property. Projection is especially common in patients with paranoid delusions (“everyone is against me”). The belief that the world exists for the individual, for example, the sports fan that believes that the event is being held for her benefit, is known as introjection. Projection is often tested on the USMLE.

Rationalization Rationalization is a method to relieve guilt and shame by creating a faulty logical reasoning for why the action is somehow beneficial. For example, spending money on toys instead of spending it to provide food and shelter can be rationalized by believing that one needs the toys for her survival. Rationalization is the method that obsessive-compulsives use to alleviate their remorse over their actions and thoughts.

Reaction Formation Reaction formation is an immature method of taking a negative impulse and doing the opposite action. A person who wants to destroy another person’s career but instead takes steps to help them gain a promotion is engaging in reaction formation. It is an immature ego defense since the underlying negative impulse is never resolved. Reaction formation may underlie the behavior of long-time hostages when they illogically take steps to protect their abuser. 56

Psychology Regression Regression is common in stressed children, such as those hospitalized or confronted with the birth of a new sibling. Regression is returning to a previous level of functioning, such as suddenly becoming incontinent after years of successful toilet training. Regression also occurs in severely ill adults, who suddenly require all of their needs to be taken care of when they are capable of being somewhat independent.

Repression Repression, as discussed above, is an immature ego defense whereby the person takes an untenable idea, forgets it, and then forgets that they forgot it. Repressed memories are common in sexually abused patients who attempt to move on with their lives by forgetting all details of the event. Repression is an immature mechanism because stimuli later in life may lead to a sudden and dramatic recall of events leading to sudden collapse of the ego. One way to deal with repression is to gradually bring memories to the forefront in an egosyntonic method, best resolved by creating a permissible and egosyntonic atmosphere.

Somatization Somatization is an immature method of having physical symptoms to escape an otherwise stressful event. For example, developing a headache to avoid a disturbing conversation is an immature ego defense. Somatization is common in somatoform disorder.

Splitting Splitting is the belief that things are either one way or the opposite way. There is no middle ground. For example, the belief that all things are either good or evil is splitting (“black of white, no shades of gray”). Splitting is especially common in borderline personality disorder and in people with prejudices and stereotypes.

Undoing and Transference Undoing is an attempt to prevent an unacceptable impulse or event from occurring without taking any concrete and logical actions. An example of this is knocking on wood after saying that one has never been in a car accident in an attempt to magically avoid future car accidents. Transference is projection of one’s feelings, due to ideas or events in their life, onto another person. Patients often transfer their anger with a disease onto the physician. In this case, the physician may also be guilty of countertransference. In this situation the physician’s resentment of the patient being angry with him and causes him to become angry with his patient.

6.4. Conditioning 6.4.1

and

Patient Adherence

Introduction

Conditioning is a topic that is worth a careful but brief review for the USMLE. The topics are easily tested and it is important not to confuse the various types of conditioning. Reinforcement schedules are confusing to remember, but it is important to have a clear understanding of this so you can successfully answer a simple recall-type question on the boards. Knowing the basic information and being comfortable in applying it to the exam and in clinical practice is vital. These mechanisms also serve to help 57

Clinical Review for the USMLE Step 1 motivate patients to make lifestyle changes and improve their health.

6.4.2

Classical Conditioning

Conditioning pairs a stimulus with a response. The unconditioned response is the automatic response we make to a certain stimulus. For example, we salivate when presented with a tasty meal. Salivating is the unconditioned response to the meal, which acts as the stimulus. Since we are biologically programmed to respond to food, food is the unconditioned stimulus – unconditioned because it does not require any learning on our part. Pavlov conducted these experiments in dogs, where he realized that if he paired ringing the bell with providing the dogs food that they would begin to associate the ringing of the bell with the unconditioned response, salivation. Eventually, he was able to simply ring the bell and cause the dogs to salivate. The ringing of the bell became the conditioned stimulus – conditioned because it required the development of a learned behavior in the dogs, and the salivation the conditioned response – because the bell now caused the salivation (which is not a normal response) Table 10. Classical conditioning. Classical Conditioning Unconditioned response

Automatic response to a particular stimulus

Unconditioned stimulus

An item that produces an automatic response

Conditioned stimulus

An action that replaces the unconditioned stimulus to produce the conditioned response

Conditioned response

Automatic response to a conditioned stimulus

6.4.3

Operant Conditioning

Operant conditioning is eliciting a particular response in order for the experimental subject to receive a reward. For example, giving a dog a treat when she responds to an oral command is an example of operant conditioning – operant because the reward is operating to create a particular response. Operant conditioning is different from classical conditioning because it does not involve innate responses to innate stimuli in order to cause a change.

6.4.4

Reinforcement

Operant conditioning is broken into positive and negative reinforcement, and positive and negative punishment. Positive reinforcement is giving a reward once a desired action is performed. In the example above, giving the dog a treat once it obeys a command is an example of positive reinforcement – positive because something is given, reinforcement because it strengthens the chance of a particular behavior occurring. Negative reinforcement is removing something negative if a desired behavior occurs. Read this example carefully – an example of negative reinforcement is taking away the leash of a dog that obeys a command to sit (assuming the leash serves as something the dog dislikes). The dog learns to sit (reinforcement of an action), and learns that if it obeys that command, the leash will be removed (a negative stimulus). Negative reinforcement is often confused with punishment. Negative reinforcement is taking something negative away. Positive punishment is taking a negative action to suppress an undesired behavior. For example, spanking a child when they throw a tantrum is positive punishment – positive because an action is taken (spanking), and punishment because something negative is done to avoid a behavior. Negative punishment is taking away something positive in order to stop a particular behavior. An ex58

Psychology ample of negative punishment is taking away a child’s favorite toy when they are misbehaving. Negative punishment is different than negative reinforcement in that negative reinforcement involves taking away something negative (the leash), while negative punishment involves taking away something positive (the toy). Punishment is typically ineffective in removing a negative behavior as the unwanted behavior quickly returns once the punishment stops. Long lasting changes tend to occur only with reinforcement.

6.4.5

Reinforcement Schedules

Reinforcement schedules also influence the speed at which a wanted behavior is learned or an unwanted behavior extinguished. Continuous reinforcement, or providing a reward every time a particular action is desired, leads to rapid extinction of the desired action once the reward is stopped. One way to think about this is that the person learns to associate the desired action with the reward, and that there is no reason to continue the desired action once there is no reward coming. Variable ratio reinforcement has the slowest extinction once the reward is stopped; the next most successful reinforcement schedule is fixed ratio reinforcement. Slot machines demonstrate variable ratio reinforcement due to their payoff at seemingly random times. Vending machines demonstrate continuous reinforcement since they reward the user every time money is spent. These disparate reinforcement schedules explain why people get angry when vending machines malfunction, but do not get angry when they do not win in a casino on their first attempt. To complete this section, it should be noted that money is an example of a tool that provides secondary reinforcement as accumulation of wealth through hard work assists in obtaining additional rewards. Finally, studies have demonstrated that an increase in GABA is necessary to prevent learned helplessness. For example, mice may simply accept that they will be shocked if they do not pull a lever to prevent the negative stimulus. Table 11. Reinforcement schedules. Reinforcement Schedules Variable ratio reinforcement

Giving a reward at variable times that a desired action is completed

Fixed ratio reinforcement

Giving a reward at a predetermined interval that a desired action is completed

Continuous reinforcement

Providing a reward every time a desired action is done

6.5. Patient Interviewing 6.5.1

and

Challenging Situations

Introduction

There are a number of disorders that take place primarily in children. These psychiatric illnesses are traditionally placed along axis II disorders and may be present from birth or develop spontaneously during the formative years. A majority of these disorders are present throughout the lifespan, and can often lead to severe psychosocial dysfunction. It should also be noted that the majority of illnesses that occur in adults can also present in children, and the astute clinician should be wary of these developments.

6.5.2

Interview Strategy

Structuring interviews with children requires investigators to be more concrete with their questions. For example, the questions posed to children should be both precise and accurate – “Do you hit your younger brother when you get mad?” is preferable to “How do you react when you get angry?” It is also important to observe children in their interactions with others and to be cognizant that this younger age group often presents with comorbid mental illnesses. 59

Clinical Review for the USMLE Step 1 6.5.3

Psychological Tests

Child psychiatry often makes use of various psychological tests. The most common tests of general intelligence are the Stanford- Binet Intelligence Scale and the revised Wechsler Intelligence Scale for Children (WISC-R). The latter is the most commonly used test in children who attend school. The WISC-R yields a comprehensive performance score including verbal and performance scores that can be used to gauge a childâ&#x20AC;&#x2122;s intelligence quotient (IQ). A number of other tests also exist to measure personality traits, behavior, motor skills, perceptual skills, etc.

6.5.4

Mental Retardation

Definition Mental retardation is defined as having an intelligence quotient of less than 70. According to the WISCR examination, IQ can be quantified as the mental age (defined by the test) divided by the chronologic age of the child, multiplied by 100. For example, if a five-year old child scores a 10 on the WISC-R, the childâ&#x20AC;&#x2122;s IQ is 200. A mentally retarded child would score an IQ of less than 70. A diagnosis of mild mental retardation is made if the IQ of the child is between 50 and 70 (85% of the mentally-retarded population); moderate mental retardation has an IQ between 35 and 50 (10%); severe mental retardation has an IQ between 20 and 35, and profound mental retardation has an IQ less than 20.

Epidemiology Mental retardation affects approximately 2% of the population, and is more common in males. Mental retardation has positive predictors, including low socioeconomic status (SES), which can lead to mild mental retardation (but is most likely a side effect of the poorer education and poor nutrition and therefore poorer performance on intelligence tests). More severe forms of mental retardation are independent of socioeconomic status.

Etiology The most common causes of mental retardation are Down syndrome (Trisomy 21), fragile X syndrome (the most common cause of heritable mental retardation), inborn errors of metabolism, maternal diabetes, substance abuse, rubella, and perinatal or early childhood injuries. Approximately one-third of all patients do not have a clear cause of the retardation.

Presentation Mental retardation typically manifests with physical malformations, such as the moon faces of Down syndrome. Infants are eventually identified by their inability to meet developmental milestones including delayed speech, inability to care for self, and poor social skills.

Diagnosis In order for mental retardation to be diagnosed, symptoms must be present prior to age 18, and the childâ&#x20AC;&#x2122;s IQ must be less than 70 with congruent deficits in functioning. Mental retardation has a long differential diagnosis, but some of the more common etiologies include attention deficit hyperactivity disorder (ADHD), learning disorders, depression, and schizophrenia. Tests to rule out some of these etiologies include EEGs for seizure disorder, an MRI or CT of the brain to rule out organic brain diseases, IQ testing, and a thorough medical, neurologic, and psychiatric work-up. 60

Psychology Prognosis The majority of children with mental retardation progress through the normal developmental milestones, but at a slower pace. These children often require supplemental resources at school and occasionally a more structured environment to help them manage their resources and stay focused on task. Children with mild mental retardation can be educated so that they can read, write, and perform basic mathematical tasks. Many of these children can live with their parents and become productive citizens in society by holding a job. Children with moderate mental retardation typically can only be trained to perform basic tasks and to perform basic self-care, thereby enabling them to live in a structured group home. Children with profound mental retardation invariably require institutionalized care starting in early life. Many of these children often have a severe inborn error of metabolism such as Tay-Sachs disease, leading to progressive decline and early death.

6.6. Medical Ethics 6.6.1

Introduction

A number of concepts dealing with medical ethics are tested. You can expect up to a dozen questions asking you to use your clinical decision making capability to arrive at the best course of action available to the physician in response to a particular case scenario. Concepts on autonomy, informed consent, and advanced directives are virtually guaranteed to be tested, as these are encountered on a regular basis in clinical practice. The physician’s response to a particular ethical situation is also common on the exam. This section on medical ethics will start with a definition of common terms, followed by discussions of informed consent, advanced directives, confidentiality, and malpractice. The last section delineates the appropriate response of a physician to various hypothetical patient case presentations.

6.6.2

General Concepts

Autonomy Autonomy is defined as the recognition that patients are individuals with their own preferences, and that the physician should make efforts to honor the patient’s right to request or refuse medical care whenever possible. Autonomy is tested on the USMLE by testing the limits of when it is appropriate to listen to a patient and follow their requests or when ancillary measures must be taken, such as receiving parental permission or a court order in order to take action. For example, minors (those less than eighteen years of age) have autonomy in treatment for sexually transmitted diseases. No parental consent is required, and minors have the right to refuse care for their illness. Minors also have autonomy in treatment for substance abuse, birth control, and prenatal care. However, parental permission must be obtained before conducting an abortion. Discussing illnesses with children should always be done after a thorough discussion with the parent. The physician must first understand what the parent has told the child, and inform the child in accordance with the parent’s wishes.

Nonmaleficence Nonmaleficence is more colloquially known as “do no harm.” This is a relative consideration, as certain therapies for cancer may cause a number of dangerous treatment-related side effects, but the therapy should proceed as scheduled as not treating the patient at all is almost certainly going to lead to death.

Clinical Review for the USMLE Step 1 Beneficence Beneficence is a related concept in which physicians are required to act in the patient’s best interest when no contradictory decision otherwise exists. This is the default action a physician should always take in the absence of other information. In this manner, the physician is acting as a fiduciary for the patient. Patient autonomy supersedes beneficence in almost every situation and it is very difficult ethically and legally to institute positive treatment for a patient against her will. The few exceptions to this are when the patient is a danger to themselves or to others.

6.6.3

Ethical Decision-Making

Overview The USMLE may present you with a number of situations where you are required to use your clinical judgment to decide what the appropriate response would be. The question writers follow very specific guidelines regarding the appropriate ethical and moral conduct of a physician. Keeping the concepts of autonomy, informed consent, decision-making capacity, nonmaleficence, beneficence, confidentiality, and malpractice in mind should clarify what the appropriate decision should be in a particular case.

Noncompliance In situations where the patient is noncompliant with his medical care, such as not taking a necessary prescription, the best course of action is to identify the basic issue that prevents compliance. In response to most case-scenarios, the best way to proceed is to work to improve the trust in the physician-patient relationship. In situations where the patient is attempting to be compliant but has difficulty with maintaining the proper schedule, written directions should be provided to the patient. If appropriate, and within the patient’s wishes, additional help may be solicited with family members and other health caretakers.

Demanding Patients Patients may occasionally make uncomfortable demands on the physician. Patients who request unnecessary procedures that are not medically indicated, or refuse to undertake a necessary procedure deserve to have an honest discussion with the physician. Understanding the patient’s thinking is the key to resolving these types of problems. A common course of action with patient’s requiring unnecessary cosmetic surgery is to alleviate the underlying psychological insecurity issues. Unnecessary procedures should not be performed in the interest of nonmaleficence. Physician-assisted suicide (euthanasia) is not medically acceptable. However, in the interest of beneficence, the physician may provide strong pain relieving medications when medically indicated, even though their administration will coincidentally lead to a decreased life span.

Angry Patients Patients also get angry for a number of reasons in a health care setting. Anger over the amount of time spent waiting to see the doctor should be handled by apologizing to the patient for the wait. The physician is not obligated (and should not) attempt to explain the reasons for the delay. A patient upset with another physician or the level of care she has received elsewhere should be handled carefully. It is not professionally appropriate to discuss this situation with the patient; instead, the patient should be encouraged to speak directly with the individual that caused his grievance. In cases where the patient is upset with a member of your staff, the patient should be told that you will personally speak with that 62

Psychology individual and address the patientâ&#x20AC;&#x2122;s concerns.

Patient-Physician Relationships Finally, patients may state that they find you attractive and that they are interested in a romantic relationship with you. While standards on this vary from place to place (and are often left to the discretion of the physician but never advisable from a legal standpoint), for the purposes of the USMLE, romantic relationships are never appropriate between a physician and patient. In this situation, direct, closeended questions should be used and the presence of a chaperone may be indicated. Another situation in which a chaperone is indicated is when a male physician does a breast or pelvic exam on a female.

Impaired Physicians It is not uncommon to encounter questions related to impaired physicians on the USMLE. If a colleague is under the influence of alcohol or drugs, has impaired judgment from sleep deprivation, or can no longer adequately function due to age-related issues, it is the responsibility of the physician to relieve themselves of duty. If this is not done in a responsibile manner, colleagues should ensure that a high level of patient care continues to be provided and take steps to have the impaired physician removed from duty. This can initially take the form of having a frank discussion with the physician, then escalating it to the administrative level with appropriate documentation.

Communicating Bad News Discussing complications or untimely death can be a difficult situation for most physicians. Adverse events are best handled in an open and honest manner. It may also be advisable to alert the hospitalâ&#x20AC;&#x2122;s risk management team so that they can also assist with any medicolegal aspects of the adverse event. Discussing these complex issues is best done in the presence of the responsible members of the family. Accept responsibility where it is appropriate, apologize where it is relevant, and assist the family in any manner you can as they navigate the challenges they have ahead.

6.6.4

Informed Consent

Medicolegal Definition Informed consent is the practice of obtaining permission in order to perform an invasive procedure. Informed consent is traditionally in the written form and can serve as a legal document. Most procedures require informed consent except when the procedure must be performed on an emergency basis and consent cannot be acquired or is impractical (treat the latter situation carefully). In order for informed consent to be successfully obtained, the patient must be educated in a clear and simple manner regarding the benefits of the procedure, the risks of the procedure, alternatives to the procedure, and the consequences of not having any procedure performed. The legal standards are further met by obtaining this consent with a discussion of the pertinent information, establishing written consent stating the patientâ&#x20AC;&#x2122;s agreement to the procedure offered, and gaining this consent in a manner free from coercion.

Exceptions to Informed Consent Informed consent is not practically obtained in a number of circumstances, and familiarity with the exceptions to this rule are likely to be tested. Informed consent does not need to be obtained in cases where emergency treatment is required to alleviate a life-threatening condition and there is no time to discuss the benefits and alternatives; in cases where therapeutic privilege is instituted, in which information must be withheld from the patient to prevent even greater harm than would occur with the 63

Clinical Review for the USMLE Step 1 therapy (but make this decision very carefully, as therapeutic privilege is often successfully challenged in a court); when the patient lacks the cognitive or physical ability to competently make an informed decision; and in cases where the patient signs a waiver to obtaining informed consent. It is important to note that family members cannot require that a physician not inform the patient regarding their illness. In this case, the appropriate course of action is to discuss the situation in a private room with the family members first, determine whether informing the patient would create even greater harm, and if it does not, then moving forward to inform the patient regarding their illness.

Competency A patientâ&#x20AC;&#x2122;s competence is established through their sound decision-making capability. Elements of a good decision-making ability include informing the patient regarding the intervention, the patientâ&#x20AC;&#x2122;s decision does not repeatedly change over time, the decision appears to be consistent with other choices the patient would make, the patient does not have any psychosocial issues that complicate their ability to make an informed decision, and if the patient communicates a clear choice to the physician.

6.6.5

Advanced Directives

Oral Advanced Directives Advanced directives are a guide to providing treatment to a patient when she is otherwise unable to make a choice due to an intervening medical illness. In this case, a patientâ&#x20AC;&#x2122;s prior oral directives take precedence, especially if the patient was able to make an informed, clear choice and communicate this lucidly to the physician ahead of time. The decision is considered valid if it is repeated over time.

Written Advanced Directives Written advanced directives are used in cases where an oral directive was not established. There are two major types of written advanced directives, including living wills and durable power of attorney. Living wills direct the physician to employ only certain life-saving measures and dictate if and when they can be withheld or withdrawn. Living wills take precedence only when there is no prior oral directive. Living wills are not flexible and are being replaced with durable power of attorney, in many cases.

Durable Power of Attorney Durable power of attorney is the designation of a surrogate, usually a spouse or other family member, who makes the judgment on behalf of the patient regarding medical decisions. The legality of durable power of attorney is predicated on the designated person making a decision similar to what the patient would choose if she were competent. A durable power of attorney incorporates elements of a living will in that the patient can designate that certain measures be taken in various clinical situations. Written advanced directives can be revoked at any time by the patient.

6.6.6

Confidentiality

HIPPA Guidelines As discussed previously, information flow between patients, family members, and health care team members should follow HIPPA guidelines. The health care issues involved with a patient should not be discussed with anybody except health care personnel immediately involved with care of that patient. With permission from the patient, information can be provided to family members. According to HIP64

Psychology PA guidelines, this discussion should take place in a private place that protects the privacy of the information; hence, discussions regarding specific patients should be undertaken only if their privacy can be protected. Identifying information should be avoided, and discussion in public places should be limited.

HIPPA Provisions Confidentiality is an important cornerstone to providing medical care in a secure environment while protecting the privacy of patients. Recent regulations instituted via the Health Information Privacy Protection Act (HIPPA) dictate when and how confidentiality should operate. Generally, disclosing information about the patient to anybody except members of the health care team directly involved with the patient is disallowed. Information can be disclosed only on a need to know basis, although family members can be informed regarding the patientâ&#x20AC;&#x2122;s condition if it is compatible with what the physician believes the patient would desire. Waivers to confidentiality can be signed by the patient.

Exceptions to Confidentiality Confidentiality also has its own exceptions. Informing others regarding a patientâ&#x20AC;&#x2122;s condition is allowed in situations where the potential harm to others is serious, as can occur if the patient is a danger to society. Confidentiality is also waived in situations where the patient is a danger to himself and the physician may make decisions to protect the patient from himself or others as deemed medically necessary. Physicians are required by law to inform people who may be harmed by the patient, thus breaching confidentiality. Other exceptions to confidentiality include informing health officials and people at risk for infectious diseases, situations involving abuse of children or elders, patients who are at risk of harming others due to inability to operate a motor vehicle or operate in a safe manner in their vocation, and in patients prone to suicide or homicide.

6.6.7

Health Organizations

HMO Health maintenance organizations (HMOs) force patients to see providers within the network and do not cover outside provider expenses. With an HMO, providers contract with outside organization to receive more patients, which they serve at a discount. Patients must see their primary care physician before any specialists can be consulted; this physician plays a gatekeeper role to the more expensive specialists. HMOs have an utilization review that seeks to ensure that the proper amount of care is being delivered without ordering too many or too few lab tests and studies.

PPO Patient provider organizations (PPOs) allow patients to see any provider within or out of the network. There is decreased reimbursement for out of network expenses, leading to greater personal expense for the patient if they go out of network to see another doctor. Older insurance plans incorporated capitation into their plans, where they gave a single lump payment for the total number of patients under a physicianâ&#x20AC;&#x2122;s care. This has fallen out of favor as physicians were less likely to order needed studies or laboratory tests as this led to decreased net profit.

Medicare Medicare is a federal program to provide assistance to the elderly and certain disabled persons. It has three major components, or parts. Part A covers hospital expenses, part B covers physician expenses, and part D covers certain medicine expenses. Medicare traditionally covers ambulance, dialysis, speech 65

Clinical Review for the USMLE Step 1 and occupational therapy costs, but does not cover the cost of a physical exam or nursing home care after a certain amount of time.

Medicaid Medicaid is a federal and state assistance program to those unable to pay for their own health care. It offers basic access to healthcare and is similar to public aid programs.

7. Fluid, Electrolytes, Nutrition,

and

Acid -Base

7.1. Electrolyte Disturbances 7.1.1 Hyponatremia Hyponatremia = serum Na+ < 135 mEq/L Hypotonic Hypovolemic • Diuretics, salt wasting syndromes, vomiting, diarrhea, burns • Third-space losses (pancreatitis, peritonitis) Isovolemic • Renal failure, SIADH, glucocorticoid deficiency, hypothyroidism, various medications Hypervolemic • Cirrhosis, CHF, nephrotic syndrome Isotonic • Excessive isotonic infusions with glucose or mannitol, pseudohyponatremia Hypertonic • Hyperglycemia 100 mL/dL > normal causes Na+ decrease of 1.6 mEq/L • Hypertonic infusions of glucose or mannitol

Figure 39. The three major types of hyponatremia. Copyright Surgisphere Corporation. Used with permission. The severity of symptoms depends for a large part on how quickly the sodium level drops. Minor hyponatremia is typically asymptomatic. Moderate hyponatremia can lead to confusion, lethargy, anorexia, and myalgia. Severe hyponatremia can lead to coma or seizures. The diagnosis is made by examining the osmolarity, carefully assessing the patient for objective signs and symptoms (i.e. tachycardia, dehydration), and measuring serum glucose. Pseudohyponatremia is diagnosed with normal or elevated osmolarity that does not match the calculated osmolarity; common causes include multiple myeloma and hypertriglyceridemia that increase the protein or lipid fraction in the plasma. The sodium deficit can be calculated because 60% of body weigh is fluid and 140 mEq/L is the normal Na+ concentration: 0.6 x (weight in kg) x (desired sodium - actual sodium) The treatment for hyponatremia is to slowly correct the serum sodium with half corrected in the first 24 hours. A rate no faster than 1 mEq/hr should be used to avoid central pontine myelinolysis (CPM), 66

Fluid, Electrolytes, Nutrition, and Acid-Base seizure, and increased intracranial pressure (ICP). Hypovolemic hyponatremia is corrected with 0.9% normal saline (NS); hypervolemic hyponatremia is corrected with sodium and water restriction and ACE-inhibitors may be beneficial. CPM tends to occur in severe hyponatremia and presents with stupor, confusion, lethargy, and quadriparesis. Some patients recover from CPM over a period of weeks. Conservation of sodium is done through an ADH-independent reabsorption.

7.1.2

Hypernatremia Hypernatremia, Na+ > 145 mEq/L Hypovolemic • Water loss from diuretics, GI, respiratory, and skin Isovolemic • Decreased TBW with decreased ECF, DI, skin losses, central defects in osmolarity Hypervolemic • Increased TBW with increased Na+, hypertonic fluid, excess salt intake, Conn or Cushing syndrome

Figure 40. Hypernatremia is divided into hypovolemic, isovolemic, and hypervolemic. Copyright Surgisphere Corporation. Used with permission. Just as in hyponatremia, the severity of symptoms is due largely to how quickly the hypernatremia develops. Hypernatremia presents with fatigue, confusion, and lethargy that can progress to seizures and coma. Hypovolemic hypernatremia is treated with NS given at 2 mOsm/kg/hr. Isovolemic hypernatremia is treated with 0.45% NaCl (½ NS) with half the water deficit corrected over the first day. No more than 1 mEq/L/hr should be given in an acute setting. DI is treated with vasopressin. Hypervolemic hypernatremia is treated with ½ NS and loop diuretics.

7.1.3

Hypochloremia

Hypochloremic alkalosis should be treated with potassium. Vomiting will lead to hypochloremic metabolic alkalosis.

7.1.4

Hypokalemia

Hypokalemia is K+ < 3.5 mEq/L Decreased intake • Especially in the elderly or in those receiving total parenteral nutrition Increased losses • Diuretics, mineralocorticoids, hyperaldosteronism, osmotic diuresis, excess urine flow, and gastrointestinal losses from diarrhea) • Vomiting: loss of volume and gastric acid causes extracellular Na+ shift (volume) in exchange for K+ plus renal reabsorption of Na+ with loss of K+ Intracellular shift • Acute insulin therapy for hyperglycemia • B12, ß-blockers, digibind, and alkalosis (each 0.1 pH increase leads to a shift of 0.5 mEq/L of K+).

Figure 41. Various causes of hypokalemia. Copyright Surgisphere Corporation. Used with permission. 67

Clinical Review for the USMLE Step 1 Hypokalemia presents with hypertension if the underlying cause is primary hyperaldosteronism or licorice ingestion, while hypotension may suggest laxative abuse, Bartter syndrome, or bulimia. Hypokalemia may also present with flaccidity, muscle weakness, and loss of deep tendon reflexes (DTRs). Arrhythmia can also occur. Prevent further potassium loss and replenish the stores to treat hypokalemia. Most K+ is intracellular so serum K+ may underestimate the replenishment needed. No more than 10 mEq/hr can be infused via peripheral lines due to venous irritation. A maximum of 40 mEq/hr can be infused through central lines in emergent situations.

7.1.5

Hyperkalemia

Hyperkalemia is the result of increased intake of potassium, impaired excretion of potassium, or a shift from the intracellular to extracellular space. Decreased excretion is commonly due to potassiumsparing diuretics, ACE-inhibitors, NSAIDs, type IV RTA, and renal failure. Hyperkalemia is common in hospitalized patients, rhabdomyolysis, and diabetes. The adrenocortical syndromes pertaining to 21-hydroxylase deficiency and 11-beta hydroxylase deficiency are other causes. Mortality occurs with the development of fatal arrhythmias in very high potassium titers. Identifying the etiology of hyperkalemia is done by renal function tests to identify renal insufficiency. Obtain: urine K+ urine osmolality, serum K+, serum osmolality, and EKG. Hyperkalemia causes EKG changes including peaked T waves, PR interval prolongation, QRS widening, disappearance of the P wave, and sinus arrest. Bradycardia may also be present. Treatment involves correcting toxicity caused by the hyperkalemia, removing excess sources of potassium, and shifting potassium intracellularly with glucose and insulin administration. Bicarbonate and Ă&#x;-blockers can be used to correct the metabolic acidosis and to decrease extracellular potassium. Potassium excretion can be facilitated with fluorohydrocortisone and stopping potassium-sparing diuretics and ACE-inhibitors. GI excretion can be increased with potassium-binding resins such as Kayexalate. Dialysis is an option in emergency situations.

7.1.6

Hypocalcemia

Hypocalcemia occurs with serum calcium level less than 8.5 mg/dL. Loss of calcium regulation by vitamin D, parathyroid hormone (PTH), calcitonin, hypomagnesemia, and hyperphosphatemia account for the majority of hypocalcemic presentations. Other causes include pancreatitis, sepsis, rhabdomyolysis, and exposure to toxins such as fluoride, ethanol, phenytoin, citrate, and cimetidine. Since 50% of the calcium is bound to albumin, hypoalbuminemia produces a low serum calcium but the ionized calcium concentration (the physiologically active form) remains normal. Symptomatic hypocalcemia may lead to circumoral paresthesia, Chvostek sign (facial spasm after tapping on the facial nerve anterior to the tragus), and Trousseau sign (spasm of the wrist after stopping forearm blood flow with a blood pressure cuff). Diagnosis is made by electrolyte panels and EKG findings positive for a prolonged QT interval. Albumin levels should be checked and the Ca2+ value corrected: Corrected Ca2+ = Ca2+ â&#x20AC;&#x201C; albumin + 4. The ionized Ca2+ can be measured instead. Treatment of hypocalcemia includes identifying PTH deficits, giving vitamin D or calcitriol along with thiazide diuretics to prevent excess Ca2+ excretion, correcting hypomagnesemia, restricting phosphate, oral Ca2+ supplementation, and infusion in emergent situations. Calcium carbonate is useful as an oral 68

Fluid, Electrolytes, Nutrition, and Acid-Base supplement. Calcium chloride infusion requires a central line, while calcium gluconate can be given via a peripheral line.

7.1.7

Hypercalcemia

Hypercalcemia is diagnosed with a serum Ca2+ level more than 10.5 mg/dL. Half of the Ca2+ is bound to albumin, which must be measured in order to determine the amount of free ionized calcium, unless the lab can provide free ionized Ca2+ concentrations. Hypercalcemia primarily affects the kidneys and CNS and leads to fatigue, depression, personality changes, confusion, somnolence, and even coma and death. Nephrolithiasis, positive inotropy, arrhythmia, constipation, and anorexia are other manifestations. The vast majority of cases are due to hyperparathyroidism or malignancy from metastatic cancer to the bone or parathyroid hormone related peptide (PTHrP) secretion by lung cancer. Other conditions include vitamin A or D excess and renal failure. Dehydration is common in hypercalcemia, and metastatic calcifications in other tissues are common in more severe cases (termed calciphylaxis), particularly if phosphorus is also high. PTH levels should be measured and a search for malignancy should be undertaken. A shortened QT interval may be present on EKG. Always check albumin levels. Treatment involves volume repletion, mobilization, reducing GI Ca2+ absorption with prednisone and oral phosphate, preventing bone resorption with biphosphonates such as pamidronate, etidronate, risedronate, and alendronate, and administering calcitonin. Dialysis may also be used in more serious cases. A surgical option includes a partial parathyroidectomy. Hypercalcemia with diarrhea should begin a search for MEN syndrome; gastrin levels should be measured as the diarrhea may be a sign of a gastrinoma.

7.1.8

Hypophosphatemia

Phosphate levels less than 2.5 mg/dL qualify as hypophosphatemia. Causes for hypophosphatemia include poor intake, increased excretion, or a shift from the extracellular to intracellular space. Alcoholics, patients with eating disorders, Crohn disease, vitamin D deficiency, RTA, antacids that bind to phosphate, hyperparathyroidism, hypokalemia, hypomagnesemia, volume expansion, respiratory alkalosis, and acetazolamide are other causes for hypophosphatemia. Hypophosphatemia presents with rhabdomyolysis, seizures, coma, hemolytic anemia, and platelet dysfunction. The urine phosphate content is measured. Deficits less than 100 mg/d imply gastrointestinal loss or redistribution of phosphate; greater deficits are due to Fanconi syndrome. High Ca2+ with hypophosphatemia implies primary hyperparathyroidism or malignancy as the chief cause. Low Ca2+ with hypophosphatemia indicates 2o hyperparathyroidism, rickets, renal failure, and familial causes. Hypophosphatemia leads to decreased cardiac output, increased RBC destruction, depletion of 2,3 DPG, and left shift in the oxygen-hemoglobin curve. There is also increased difficulty weaning from a ventilator. Treatment for hypophosphatemia includes oral repletion in minor cases or IV administration if severe. Vitamin D supplementation is given. Primary or secondary hyperparathyroidism may require a parathyroidectomy. Hypophosphatemia following refeeding presents as respiratory failure and prolonged dependence on a mechanical ventilator. Refeeding syndrome is due to phosphorylation of glucose intermediaries and leads to decreased phosphate available for ATP generation. Failure of ATP production occurs. The most appropriate therapy is to replete phosphate. 69

Clinical Review for the USMLE Step 1 7.1.9

Hyperphosphatemia

Hyperphosphatemia is defined as phosphate greater than 5 mg/dL in the serum. Excess intake can occur with vitamin D intoxication. Decreased clearance can occur with hypoparathyroidism or renal failure. A shift from the intracellular to extracellular space occurs in rhabdomyolysis and tumor lysis syndrome. Hyperphosphatemia presents with hypocalcemia and calciphylaxis. Most patients are asymptomatic, but muscle cramps, perioral paresthesia, uremic symptoms, and general malaise can occur. Hyperphosphatemia is treated by temporizing renal failure, dietary restriction of phosphate, binders such as calcium carbonate, insulin and glucose infusion as a temporary measure, and dialysis in more serious cases.

7.1.10

Hypomagnesemia

Hypomagnesemia is magnesium less than 1.8 mg/dL. It is commonly due to malabsorption, poor dietary intake, excess excretion, or redistribution within the body. Causes of excess excretion include diarrhea, diuretic abuse, ATN, hypokalemia, hypercalciuria, or endocrine disturbances. Redistribution in the body can occur with hypoalbuminemia, pancreatitis, glucose and insulin administration. Hypomagnesemia presents with weakness, hyperreflexia, seizures, hypokalemia, and hypocalcemia. EKG changes include prolonged QT and PR, flattened T waves, atrial fibrillation, and torsade de pointes. Treatment of hypomagnesemia is by oral magnesium oxide supplements or IV magnesium sulfate. Cardiac dysfunction must be addressed.

7.1.11

Hypermagnesemia

Hypermagnesemia is magnesium greater than 2.5 mg/dL. It is due to renal failure with decreased excretion, abuse of antacids, tumor lysis syndrome, rhabdomyolysis, DKA, pheochromocytoma, and toxicity from lithium. Hypermagnesemia presents with decreased DTR, hypotension, paresthesia, coma, and specific EKG changes. EKG changes are opposite of those found with hypomagnesemia. Reverse EKG changes in hypermagnesemia with IV calcium. If necessary, dialysis may be used to regain normal magnesium homeostasis.

7.2. Nutrition 7.2.1

Nutritional Requirements

Familiarity with nutritional requirements and energy content of various sources of intake are an important component of providing appropriate nutritional care to the surgical patient. The major source of protein turnover is skeletal muscle, which becomes especially significant in prolonged starvation and acute injury. Table 12. Energy content for carbohydrates, proteins, and lipids. Carbohydrate Protein Lipid 70

3.4 kcal / g 4 kcal / g 9 kcal / g

Fluid, Electrolytes, Nutrition, and Acid-Base The Harris-Benedict equation is used to determine basal energy expenditure. Various modifications are used to determine the estimated caloric needs for patients. The equation varies for men and women. The average caloric need for a 70 kg male is about 1700 kcal/day. The average caloric need for a 70 kg female is slightly less. The metabolic cart can also be used to calculate overall nutritional status and the respiratory quotient. Indirect calorimetry works by calculating CO2 production. The respiratory quotient is calculated as the ratio between CO2 produced to O2 consumed. The respiratory quotient is a unitless number calculated as the ratio between the amount of carbon dioxide produced and the amount of oxygen consumed. This value typically correlates to the caloric value for each liter of carbon dioxide produced. Table 13. Respiratory quotient for various metabolic processes. Carbohydrate oxidation Fat oxidation Protein breakdown Lipogenesis Normal

7.2.2

1 0.7 0.8 > 1.0 0.8

Enteral and Parenteral Nutrition

Enteral Nutrition Enteral feeding provides the advantage of a decreased risk of sepsis through line infection, induction of the immune system through small intestine production of IgA, and maintenance of the gastrointestinal tract. This leads to increased integrity of the GI tract with decreased spontaneous bacterial translocation across the cell wall. Gastrin induction increases insulin release and anabolism. Enteral nutrition, however, has a decreased rate of absorption in the immediate postoperative period. Tube feeding does not improve longevity or quality of life in nursing home residents. Nonocclusive bowel necrosis may occur within two weeks of starting enteral feeds and present with pneumatosis and necrosis. Treatment is reversion to TPN.

Parenteral Nutrition Parenteral nutrition has specific indications due to the significant morbidity and mortality associated with TPN. TPN has a proven benefit with enterocutaneous fistulae and improves their closure rate, decreases the incidence of renal failure in ARF, improves morbidity with short gut syndrome and severe burn patients when enteral feeding would be insufficient, and may induce remission of Crohn disease. TPN has also been used to mitigate symptomatic pneumatosis intestinalis when surgery is not indicated. The essential minerals that should be included with long term TPN include acetate, gluconate, calcium, chloride, chromium, copper, iodine, magnesium, manganese, phosphorus, potassium, selenium, sodium, and zinc.

7.2.3

Essential Amino Acids

Arginine is an essential amino acid that augments the immune system. Glutamine is the amino acid most abundant in circulation. Glutamine levels following intestinal surgery are decreased due to an increase in utilization by the intestinal cells. 71

Clinical Review for the USMLE Step 1 7.2.4

Malnutrition and Obesity

Obesity Obesity is an epidemic in the United States, affecting over a quarter of the population. It is especially common in American Indians, Hawaiians, Hispanics, and African Americans. Obesity is defined as having a body mass index (BMI) over the 85th percentile or more than 30 kg/m2, calculated as weight (kg) divided by height (m2). Obesity has a genetic inheritance, but changes in society, poor diet, and lack of exercise all contribute. Complications of obesity include obstructive sleep apnea (OSA), pseudotumor cerebri, liver dysfunction, cardiovascular disease, hypertension, hypertriglyceridemia, arthritis, diabetes, and cancer. Other factors that can contribute to obesity include Prader-Willi syndrome, Down syndrome, Turner syndrome, growth hormone deficiencies, pseudohypoparathyroidism, hypothyroidism, polycystic ovarian syndrome, and medications such as antidepressants and oral contraceptives. Treatment of obesity requires major lifestyle changes; thus treatment is multifaceted and must include reducing other risk factors (such as smoking or alcohol abuse), and treating any concomitant disorders such as DM, HTN, CVA, and heart disease. The last resort is surgical intervention in the form of bariatric surgery â&#x20AC;&#x201C; this is typically used in patients with a BMI exceeding 40. Expanded criteria for surgery are used at centers of excellence due to experience.

Malnutrition Malnutrition may present as kwashiorkor with protein starvation and edema, and marasmus with both protein and caloric starvation leading to cachexia. Deficiencies in multiple vitamins and significantly poor diet are commonly implicated for malnutrition. There are systemic effects with significant cognitive and physical retardation, and diminished immune activity. Severe malnutrition is rare in the United States; nearly 150 million children worldwide are affected by malnutrition. Malnutrition presents with weight loss, trailing off the normal growth curves, and behavioral/cognitive changes. Physical exam detects anasarca with kwashiorkor. Cheilosis, angular stomatitis, fatty hepatomegaly, and skin hyperpigmentation with peeling are present. Thin and brittle hair is commonly found. Iron deficiency presents with constitutional symptoms, anemia, decreased cognition, headache, glossitis, and koilonychia. Iodine deficiency presents with goiter and physical and mental retardation. Albumin is not recommended for acute monitoring due to its long half-life; pre-albumin and transferrin are better markers for nutrition due to their shorter half-lives.

7.2.5

Vitamin Deficits

Vitamin A Deficiency Retinol deficiency is primarily due to poor diet and excessive rice consumption, and secondarily due to malabsorption syndromes and malnutrition syndromes. Vitamin A deficiency presents with growth retardation, night blindness, xerophthalmia, hair changes, keratomalacia, follicular hyperkeratosis, and Bitot spots with foamy patches in the conjunctiva.

Fluid, Electrolytes, Nutrition, and Acid-Base Vitamin C Deficiency Vitamin C deficiency is due to poor diet, pregnancy, thyrotoxicosis, inflammatory disease, after surgery, burns, and diarrhea. Scurvy presents with splinter hemorrhages in the nail bed, swollen and friable gums, loss of teeth, breakdown of old scars, poor healing, spontaneous hemorrhage, petechiae, and hyperkeratotic hair follicles. A dietary deficiency as the etiology of scurvy amongst their sailors was proven by a surgeon in the British Navy. The British are referred to as ‘limeys’ as they carried and consumed limes (a good source of vitamin C) on their long sea voyages by sail and prevented their sailors from becoming ‘scurvy dogs.’

Vitamin D Deficiency Vitamin D deficiency is primarily due to poor sunlight exposure or poor intake of calcium or phosphorus. Secondary causes include hypoparathyroidism, hereditary diseases, and poor absorption. The effect of vitamin D deficiency is rickets in children and osteomalacia in adults. Treatment is adequate intake of calcium, phosphorus, and vitamin D supplements.

Vitamin E Deficiency Tocopherol deficiency is a natural state in infants but may present later in life with poor intake, malabsorption syndromes, or genetic causes. Vitamin E deficiency presents with hemolytic anemia, reticulocytosis, hyperbilirubinemia, abetalipoproteinemia, neuropathy such as spinocerebellar ataxia and loss of DTRs, and retinopathy.

Vitamin K Deficiency Vitamin K is a lipid soluble vitamin essential for the formation of clotting factors. It is produced by colonic bacteria. Terminal ileum disease or resection prevents normal vitamin K production and absorption as there is an enterohepatic circulaton of vitamin K from intestine, ileal absorption, portal venous system, liver, bile back to intestine. Deficiency may occur from cirrhosis, malabsorption syndromes, biliary disease, various medications (coumadin, INH, rifampin, barbiturates, and others), lupus, DIC, polycythemia vera, cystic fibrosis, and leukemia. Vitamin K helps to form coagulation factor II (prothrombin), factor VII (proconvertin), factor IX (Christmas factor), and factor X (Stuart factor). Protein C, protein S, Protein Z, and several bone matrix proteins reliant on glutamic acid residue conversion by vitamin K are also modified by vitamin K. Coumadin is used as a therapeutic anticoagulant because it interferes with vitamin K metabolism which causes a deficiency in the vitamin K dependent clotting factors Vitamin K deficiency presents as hemorrhagic disease of newborns (HDN) or as a bleeding diathesis in adults. Vitamin K deficiency, if severe enough, presents as complaints of significant hemorrhage following mild trauma. Ecchymoses, petechiae, hematomas, and oozing of blood are common. GI bleeds, hematuria, menorrhagia, epistaxis, and mucosal bleeds occur frequently. PT and aPTT are elevated. Des-gamma-carboxy prothrombin is present in the absence of vitamin K. Treatment for vitamin K deficiency involves correcting the cause of the underlying deficit and providing vitamin K supplements. FFP is necessary in severe disease to prevent hemorrhage. Subcutaneous injections of phylloquinone (vitamin K1) can be given; menadione (vitamin K3) can be given orally in malabsorption syndromes. Phytonadione can also be directly injected in severe disease. Green leafy vegetables and oils provide a good source of vitamin K. 73

Clinical Review for the USMLE Step 1 Vitamin B1 Deficiency Primary thiamine deficiency is due to decreased intake especially in a high-rice diet. Secondary deficiency is due to hyperthyroidism, pregnancy, fever, malabsorption syndromes, diarrhea, and liver disease. Alcoholism impairs utilization. Thiamine deficiency presents as dry beriberi with peripheral neurologic symptoms including distal extremity paresthesias, cramps, and pain, CNS symptoms including Wernicke-Korsakoff syndrome, and cardiovascular symptoms including high output cardiac failure with tachycardia, diaphoresis, warm skin, and lactic acidosis. Korsakoff syndrome presents first with confusion and confabulations, Wernicke encephalopathy happens last and consists of nystagmus, ophthalmoplegia, and coma. Shock can occur and death ensues rapidly if treatment is not started in time. Magnesium sulfate is given with thiamine to reduce peripheral resistance to thiamine. Electrolyte replacement is also be necessary.

Vitamin B2 Deficiency Riboflavin deficiency is due to decreased intake of milk and animal products; secondary deficiency is due to malabsorption syndromes, diarrhea, liver disease, and alcoholism. Riboflavin deficiency presents with pallor, mucosal ulceration such as angular stomatitis and cheilosis, and linear fissures in the skin commonly infected by Candida. A red tongue is present, and cutaneous lesions leading to erythema and acanthosis may occur. Keratitis may lead to lacrimation and photophobia.

Nicotinic Acid Deficiency Niacin, vitamin B3, deficiency is due to excessive maize consumption, amino acid imbalances, malabsorption syndromes, cirrhosis, and alcoholism. Pellagra may occur and present with a photosensitive rash, red stomatitis, glossitis, bloody diarrhea, and CNS changes. Desquamation, keratosis, edema of the tongue and other mucous membranes, GI discomfort, confabulations, cogwheel rigidity, and psychiatric changes occur in severe cases. Tryptophan deficiency may present in a similar manner. Deficiency is treated with niacinamide along with replenishment of other lacking vitamins.

Vitamin B6 Deficiency Pyridoxine deficiency is rarely a primary deficiency; secondary causes include oral contraceptive use, use of hydralazine, cycloserine, or penicillamine, and increased metabolic activity. Seborrheic dermatosis, cheilosis, glossitis, peripheral neuropathy, lymphopenia, seizures, and anemia develop with worsening deficiency.

Biotin Deficiency Biotin deficiency occurs in raw egg consumption or long term total parenteral nutrition (TPN). Biotin deficiency presents with alopecia, keratoconjunctivitis, immunologic deficiencies, and retardation of development.

Mineral Deficiency Chromium deficiency leads to hyperglycemia after prolonged TPN. Selenium deficiency leads to myalgia and cardiomyopathy. Like most mineral nutrients, iron from digested food or supplements is almost entirely absorbed in the duodenum. Iron deficiency may occur following a pancreaticoduodenectomy.

Fluid, Electrolytes, Nutrition, and Acid-Base 7.2.6

Vitamin Toxicity

Vitamin A Toxicity Excessive vitamin A causes thickening of hair and increased hair loss throughout the body. As the toxicity worsens, pseudotumor cerebri, headache, and weakness may develop. Hepatosplenomegaly is also seen.

Vitamin D Toxicity Vitamin D toxicity leads to anorexia, nausea, vomiting, polyuria, polydipsia, pruritus, azotemia, proteinuria, metastatic calcifications from hypercalcemia, and anxiety. Acidifying the urine and administering corticosteroids are treatment options.

Vitamin E Toxicity Tocopherol toxicity can decrease the effectiveness of vitamin K, which may lead to spontaneous hemorrhage in patients on warfarin.

Vitamin K Toxicity Vitamin K toxicity is rare, but very high doses of its precursor, menadione, may lead to hemolytic anemia and kernicterus.

Vitamin B6 Toxicity Excessive vitamin B6 consumption may lead to sensory ataxia and decreased lower extremity proprioception.

7.3. Acid -Base 7.3.1

Arterial Blood Gas

The ABG is used to measure oxygenation of the blood and to determine the nature of hypoxia. ABG measures five values: pH, PaCO2, PaO2, HCO3 –, and O2 saturation, while the base excess is automatically calculated. Acidosis or alkalosis is determined by the pH. Hypoxemia is determined by the PaO2. Compensation for any potential metabolic acidosis or alkalosis is measured by PaCO2 and HCO3 –. The change is pH due to a change in the PCO2 (hyper or hypoventilation) can be calculated: Corrected HCO3 – = measured HCO3 – + (anion gap – 12) Anion gap = (Na+ + K+) - (Cl– + HCO3 –) Expected PaCO2 = (1.5 x HCO3 –) + (8±2) Acute respiratory acidosis: pH = 0.08 x [(PaCO2 – 40) / 10] Chronic respiratory acidosis: pH = 0.03 x [(PaCO2 – 40) / 10] Acute respiratory alkalosis: pH = 0.08 x [(40 – PaCO2) / 10] Chronic respiratory alkalosis: pH = 0.03 x [(40 – PaCO2) / 10] 75

Clinical Review for the USMLE Step 1 A corrected HCO3– is calculated to determine whether there is also a metabolic acidosis or alkalosis. Because the measured bicarbonate may be normal due to a changed anion gap. This correction is relatively straightforward: The normal corrected HCO3 – should be approximately 24. Significant variation indicates a complex metabolic disturbance – HCO3 – more than 24 indicates a coexisting metabolic alkalosis, while an HCO3– less than 24 indicates a coexisting non-anion gap metabolic acidosis. The expected respiratory compensation for a metabolic acidosis can be calculated with Winter’s formula. This is due to a linear relationship between changes in HCO3 - and compensation by the lung to change in PaCO2. Metabolic acidosis causes hyperventilation and a drop in PaCO2 as respiratory compensation. Variation outside of the range specified by Winter’s formula indicates a concurrent respiratory disturbance and not just compensation for a metabolic acidosis. Winter’s formula can only be used for metabolic acidosis; it does not predict the respiratory compensation in response to a metabolic alkalosis. With metabolic alkalosis, the respiratory response is hypoventilation and a PaCO2 above 40 but less than 50, and alkalotic pH above 7.42.

7.3.2

Metabolic Acidosis

Anion Gap Metabolic Acidosis An anion gap metabolic acidosis means that the metabolic acidosis is due to hydrogen ions not measured by the laboratory standard chem 7. It is commonly due to lactic acidosis (commnly from hypoperfusion of end organs, shock) ketoacidosis (but not ketone bodies), uremia in chronic renal failure, and ingestion of toxins such as aspirin, ethylene glycol, methanol, and paraldehyde. Anion gap metabolic acidosis is diagnosed by the presence of ketoacids (as in alcoholic ketoacidosis, diabetic ketoacidosis, paraldehyde poisoning, starvation, high-fat diet, and isopropyl alcohol poisoning) or ketoacids being absent (as in renal failure, lactic acidosis, methanol poisoning, ethylene glycol poisoning, and aspirin poisoning). The indications for dialysis include acidosis, hyperkalemia, symptomatic uremia, drug filtration, and fluid overload.

Non-Anion Gap Metabolic Acidosis A non-anion gap metabolic acidosis means that the metabolic acidosis is due to hydrogen ions measured by the chem 7. It is a disturbance common in renal tubular acidosis (RTA), diarrhea, GI tract fistulas, pancreatic disease, use of carbonic anhydrase inhibitors, acid ingestion, dilution of alkali, ileostomy, and various medications (beta-blockers, spironolactone). Treatment is to correct the underlying etiology but to avoid hypernatremia, fluid overload, and excessive bicarbonate infusion.

Renal Tubular Acidosis RTA type I is known as distal RTA, and occurs with medications such as amphotericin, lithium, and NSAIDs, and in diseases such as nephrolithiasis, sickle cell anemia, infection, and autoimmune disorders. RTA type I presents with inability to acidify urine with secondary hyperaldosteronism, hypokalemia, nephrolithiasis, and nephrocalcinosis. RTA type II is known as proximal RTA, and occurs with Wilson disease, Fanconi syndrome, amyloidosis, vitamin D deficiency, hypocalcemia, hepatitis, and autoimmune diseases. RTA type II leads to basic urine in the early stage until the bicarbonate is lost, then subsequent urine acidification. RTA type II 76

Fluid, Electrolytes, Nutrition, and Acid-Base also leads to hypokalemia, osteomalacia and rickets. RTA type IV is known as hypoaldosteronism RTA, and occurs from a decrease in aldosterone or insensitivity to angiotensin II, diabetes, Addison disease, sickle cell disease, and renal insufficiency. RTA type IV presents with hyperkalemia and hyperchloremic non-anion gap metabolic acidosis. RTA type I is treated with oral bicarbonate and potassium replacement. RTA type II is treated with potassium replacement and volume depletion to enhance bicarbonate reabsorption. Thiazide diuretics are also useful. RTA type IV is treated with fludrocortisone, a mineralocorticoid.

7.3.3

Metabolic Alkalosis

Metabolic alkalosis is an increase in pH, increased bicarbonate, and compensatory hypoventilation with an increase in PaCO2 (the opposite of metabolic acidosis). Chloride-responsive metabolic alkalosis has a urine chloride of less than 15, and is commonly due to vomiting, pyloric stenosis, laxative abuse, diuretics, and hypercapnia. Chloride-resistant forms have a urine chloride more than 15, and are commonly a result of severe potassium or magnesium deficiency (as in diuretic abuse), increased mineralocorticoids, Bartterâ&#x20AC;&#x2122;s syndrome, chewing tobacco, and licorice consumption. Neuromuscular excitability, hypokalemia, and hypovolemia are commonly found on exam, and treatment involves correcting the underlying disorder. KCl is sometimes given to correct significant electrolyte abnormalities. Potassium must be corrected first in chloride-resistant metabolic alkalosis.

7.3.4

Respiratory Acidosis

Respiratory acidosis is due to hypoventilation and produces a compensatory increased bicarbonate. Causes of respiratory suppression include COPD, airway obstruction, pneumothorax, myasthenia gravis, muscular dystrophy, nervous system disorders (such as Guillain-BarrĂŠ syndrome), botulism, tetanus, organophosphate poisoning, and central depression of the respiratory system (as in narcotic abuse or general endotracheal anesthesia). Presenting signs include confusion leading to stupor and coma, and encephalopathy. Respiratory acidosis is managed by treating the underlying cause, and using artificial ventilation to decrease CO2 retention. Oxygenation of COPD patients who are chronically hypoxic and depend on hypoxia for respiratory stimulation, may lead to depression of the respiratory drive, so only the minimum amount of oxygen via nasal cannula should be provided to maintain oxygenation of the blood.

7.3.5

Respiratory Alkalosis

Respiratory alkalosis is elevated pH, because of hyperventilation (decrease PCO2), and a compensatory decrease in bicarbonate. It is commonly a result of anxiety causing hyperventilation but may also be a consequence of shock, pulmonary disease, pregnancy, cirrhosis, hyperthyroidism, and aspirin poisoning. Presentation is with rapid, deep breathing, anxiety, chest pain, and circumoral paresthesia. Treat respiratory alkalosis by minimizing anxiety in the patient, breathing into a paper bag to increase PCO2, and decreasing minute volume if the patient is artificially ventilated.

7.4. Fluids The SAFE study and Australian ICU study, two of the best studies of the plethora of research over 77

Clinical Review for the USMLE Step 1 decades that have compared crystalloid to colloid, have indicated that crystalloid administration for hypotensive patients is as effective as colloids or blood unless the patient is anemic and has a specific indication for transfusion.

7.5. Metabolic Disorders A variety of metabolic disorders were discussed in “2.4.1 Iron Pathway Defects” on page 20, “2.4.2 Amino Acid Diseases” on page 21, “2.4.3 Purine and Pyrimidine Salvage Diseases” on page 21, “2.4.4 Lysosomal Storage Diseases” on page 22, and “2.4.5 Glycogen Storage Diseases” on page 23.

7.5.1 Cholesterol Cholesterol is formed from acetyl-CoA through the HMG-CoA reductase pathway. About ¼ of all production occurs in liver, but there is significant production by intestines, adrenal glands, testes, and ovaries as well. Approximately 50% of all intestinal cholesterol content is reabFigure 42. Cholesterol synthesis pathway. Copyright Ku- sorbed; levels are regulated by existing cholesterol concentrations. This pathway pirijo. Used with permission. is mediated by the sterol regulatory element binding protein and others, which transcribes genes for the LDL receptor and HMG-CoA reductase (rate-limiting step). Cholesterol is excreted via bile. Chylomicrons are made by intestinal epithelial cells, and transport triglycerides to tissues. They also transport cholesterol to the liver, and may lead to pancreatitis if in excess. VLDLs transport triglycerides from the liver to tissues and are made by the liver. If they are in excess, VLDLs may contribute to acute pancreatitis. LDLs transport cholesterol from the liver to tissues and are made by VLDL conversion. They are regulated by receptor-mediated endocytosis uptake; excess leads to atherosclerosis, xanthomas, xanthelesmas. Most circulating cholesterol is bound to LDL. HDL transports cholesterol from tissues back to liver for processing and excretion. HDLs are made by the liver and intestines. HDLs use scavenger receptors to enter hepatocytes, ovaries, testes, and adrenal glands. HDLs carry significant amounts of cholesterol. There are four major apolipoproteins for USMLE purposes. A-1 activates lecithin-cholesterol acyltrans-

Fluid, Electrolytes, Nutrition, and Acid-Base ferase, and high levels decrease the risk of coronary artery disease. A-1 is known as lecithin in liver and transfers fatty acids from lecithin to cholesterol and traps it in HDL. A-1 prevents plaque formation. B-100 binds to the LDL receptor and is upregulated in hypercholesterolemia. C-II is a cofactor to lipoprotein lipase, which mediates fatty acid uptake into cells from chylomicrons and VLDLs. Finally, apolipoprotein E mediates the uptake of remnants.

7.5.2

Hypercholesterolemia

Type I hypercholesterolemia is an autosomal recessive disorder that leads to increased chylomicrons and elevated triglycerides. It is due to a lipoprotein lipase deficiency and subsequent failure of ApoC-II to function. Type IIa hypercholesterolemia is an autosomal dominant disorder that leads to increased LDL and cholesterol. It is due to a decrease in LDL receptors.

Figure 43. Cholesterol pathways. Copyright Jag123 and Wikimedia. Used with permission.

Clinical Review for the USMLE Step 1 Type IIb is a combined hyperlipidemia with increased LDL and VLDL leading to increased triglycerides and cholesterol. It is due to increased liver synthesis of VLDLs. Type III hypercholesterolemia is a dysbetalipoproteinemia hallmarked by an increased IDL, VLDL, and chylomicron remnants. It causes elevated triglycerides and cholesterol and is due to altered ApoE function. Type IV is a hypertriglyceridemia leading to increased VLDLs and triglycerides. It is due to overproduction of VLDL by the liver. Type V hypercholesterolemia is a mixed hypertriglyceridemia that leads to increased VLDL and chylomicrons, with subsequently increased triglycerides and cholesterol. There is increased production of VLDL and decreased clearance of VLDLs and chylomicrons.

8. Pharmacology 8.1. Pharmacokinetics The Michaelis-Menten reaction is used to model enzyme behavior. A free enzyme binds to a free substrate to form an enzyme-substrate complex. The enzyme-substrate complex is catalyzed to reform the enzyme and generate a product. Steady state is reached when the addition of new substrate equals formation of new product. The enzyme is always conserved in reactions. The velocity of product formation is directly dependent on the maximum velocity of the reaction and inversely dependent on the affinity of the enzyme and amount of substrate. The volume of distribution (V D) quantifies the amount of drug Figure 44. Saturation curve showing rate vs. concentration. found in the body. High lipid solubil- Copyright Wikimedia. Used with permission. ity means high volume of distribution. This is similar with drugs that have a low plasma protein binding and high tissue binding affinities. V D = total drug in body / drug concentration in blood Clearance refers to the rate of elimination of a drug from the body as compared to its plasma concentration. CL = drug elimination / plasma drug concentration Half-life is the time it takes to clear the body of half of the current amount of drug. Approximately 4 tÂ˝ are required to achieve 95% clearance. t1/2 = (0.7 x V D) / CL = 0. / k 80

Pharmacology Zero-order elimination proceeds linearly with a fixed amount of drug eliminated per unit time. It is typically due to saturation of the elimination enzymes. First-order elimination proceeds as exponential decay with fixed ratio of drug eliminated per unit time. Enzymes are functioning below saturation levels. The loading dose is the amount of drug that may be given initially to reach a target plasma concentration more quickly. LD = Cp x (V D/F) LD = Loading Dose

Figure 45. Effect of a partial agonist. Copyright Wikimedia. Used with permission.

Cp = Plasma Concentration V D = Volume of Distribution F = Bioavailability The maintenance dose is the amount of drug that is given to achieve a steady-state concentration between drug plasma concentration and drug elimination. Figure 46. Dose response curve showing efficacy and potency. MD = Cp x (CL/F) Copyright Wikimedia. Used with permission. MD = Maintenance Dose

8.2. Pharmacodynamics Competitive antagonist lead to a rightward shift in the amount of enzyme needed to achieve the same level of activity. Such a shift also occurs when a patient has become tolerant to the effects of a particular drug, such as where increasing amounts of narcotic are needed to maintain a low pain level. Partial agonists decrease the efficacy of a particular medication, as seen in the figure. Even with increasing drug concentrations, the overall response remains lower than the baseline. Noncompetitive antagonists are similar to the partial agonist in the graph to the right. At ED50 (effective dose) for the drug, Figure 47. Drug development process. Produced by the FDA half of all patients will respond. As the / public domain. dose is increased, more and more pa81

Clinical Review for the USMLE Step 1 tients will enter the range of the lethal dose and risk succumbing to the lethal side effects of the drug.

8.3. Efficacy

and

Potency

Efficacy is when two drugs that reach the same maximum desired effect have similar clinical outcomes. Heroin and morphine have approximately the same efficacy in that both can lead to 100% analgesia. Codeine is less efficacious than either of these drugs. Potency refers to the minimum dose needed to achieve a desirable therapeutic effect. Heroin is more potent than morphine in that a lower dose is needed to achieve 100% analgesia.

8.4. Drug Development Drug development involves hundreds of millions of dollars in capital with dozens of potential drug candidates. After extensive testing, a few prototypic drugs are chosen for further analysis. Based on early trials in patients, the number of potential drugs is narrowed. Approval is submitted for the best drugs, a process that takes nearly 10 years.

9. Microbiology 9.1. Bacteria 9.1.1

Bacterial Classification

Microbiology

Clinical Review for the USMLE Step 1

Microbiology 9.1.2 Anatomy

Bacterial

The peptidoglycan capsule is an osmotic pressure protection mechanism and provides protection from phagocytosis. The cell wall is found in gram positives and is a significant antigen; it also contains teichoic acid in gram positive bacteria. The outer and inner membranes have an endotoxin component from lipopolysaccharide layer in gram negative bacteria. The fimbria play a role in sexual reproduction, plasmid transmission, and adherence to cell surface. Plasmids have a resistance mechanism that can be transferred between bacteria. Figure 48. Bacterial anatomy. Copyright Mariana Ruiz. Used with permission. Gram positive bugs have teichoic acid, which play a role in adherence and virulence. They are characterized by a large cell wall with a peptidoglycan layer. Gram negative bugs have endotoxin within a lipopolysaccharide layer.

9.1.3

Bacterial Physiology

Exotoxins are found in both gram-positive and gram-negative bugs. Examples include C. diphtheriae, C. tetani, C. botulinum, C. perfringens, B. anthracis, S. aureus, S. pyogenes, E. coli, V. cholerae, and B. pertussis. Exotoxins are preformed, secreted, and highly toxic. They are also heat-labile. Endotoxins are found in all gram-negative bugs with a lipopolysaccharide layer. It is a component of the bacterial membrane. There is a low lethal index but induces significant acute phase reaction with fever. Endotoxins are heat-stable.

9.1.4

Bacterial Genetics

Prokaryotic DNA replication relies on primase, which forms the RNA primer; DNA ligase, which seals nicks; and DNA topoisom85

Clinical Review for the USMLE Step 1 erase I, which creates a single nick to relieve supercoils. DNA topoisomerase II and DNA gyrase nick both strands to relieve supercoils. DNA polymerase I excises RNA primer, DNA repair, 3’ à 5’ 3’ nick translation à proofreading, 5’. DNA polymerase II is involved in damaged DNA replication with 5’ à 3’ and 5’ activity à 3’. DNA polymerase III is involved in 3’ à 5’ exonuclease proofreading. DNA polymerase IV functions as a DNA polymerase. DNA polymerase V bypasses damaged DNA. Bacteria have a circular plasmid genome with multiple start sites and alternative protein formation with offset reading frames (not commaless). Prokaryotic RNA translation uses a single RNA polymerase.

9.1.5

Laboratory Tests

Bacteria have a variety of pigments. Blue-green is found with Pseudomonas, yellow with S. aureus, and red with S. marcescens. Agars can be used to separate various bacteria. Blood agar is used to separate GAS, GBS, and GDS based on hemolysis. Alpha-hemolytic bacteria will undergo partial hemolysis (green); examples include S. pneumonia and S. viridans. Beta-hemolytic bacteria undergo complete hemolysis (clear); examples include S. pyogenes and S. agalactiae. Gamma-hemolytic bacteria undergo no hemolysis (red); examples include E. fecalis and S. bovis. Chocolate agar can be used to grow N. meningitidis, N. gonorrhea, H. influenza, and H. ducreyi. Thayer-Martin agar can be used to grow N. gonorrhea. Bile esculin agar (BEA) grows Group D streptococci (S. bovis, E. fecalis) and enterococci. Hektoen enteric agar (HEA) isolates the Enterobacteriaceae group (especially shigella and salmonella). MacConkey agar (MAC) inhibits gram positive bacteria. Mannitol salt agar (MSA) permits mannitol fermentation. Phenylethyl alcohol agar (PEA) grows Staphylococcus spp.. Trypticase soy agar (TSA) grows Brucella spp., Corynebacterium spp., Listeria spp., Neisseria spp., and Vibrio spp. Xylose-lysin-deoxycholate agar (XLD) grows gram-negative bacteria from stool. Sabouraud agar grows fungus. Hay infusion agar grows mold.

9.2. Organisms 9.2.1

Gram Positive Cocci

Staphylococcus Staphylococcus spp. form a biofilm that protects bacteria from antibiotics. Table 14. Gram Positive Cocci: Staphylococcus Etiology

Features

Pathophysiology Superantigen with IL-1/IL-2 synthesis.

Staphylococcus aureus

Exotoxin

Toxic shock syndrome from TSS toxin-1 that leads to cytokine release. Scaled skin syndrome from exfoliative toxin release – exotoxins ET-A and ET-B that breakdown tight junctions. Preformed toxin.

Presentation Toxic shock syndrome – fever, hypotension, hyperemia. Scalded skin syndrome Acute bacterial endocarditis. Osteomyelitis

Treatment Methicillin Vancomycin Clindamycin TMP-SMX Linezolid

Streptococcus IgA protease permits organisms to colonize mucosal surfaces and cause infection. Encapsulated bugs that cause infection following splenectomy: S. pneumoniae, N. meningitidis, H. influenzae B., and K. pneumoniae. 86

Microbiology Table 15. Gram Positive Cocci: Streptococcus Etiology

Features

Streptococcus pneumoniae

IgA protease. Encapsulated.

Pathophysiology

Presentation

#1 cause of meningitis in children and elderly, otitis media, and pneumonia.

Meningitis Neonatal conjunctivitis. Otitis media, Pneumonia

Treatment Penicillin Ampicillin

Pharyngitis Erythrogenic toxin (superantigen) and streptolysin O (ASO titers; hemolysin). M protein antibody.

GAS Streptococcus pyogenes

Bacitracin sensitive. Exotoxin

Gas production in necrotizing fasciitis (other causes include C. perfringens and Vibrio). Superantigen SSA expression may lead to systemic symptoms.

Cellulitis / Necrotizing fasciitis Impetigo / Erysipelas Scarlet fever â&#x20AC;&#x201C; erythema, fever, strawberry tongue, desquamation Toxic shock syndrome Rheumatic fever â&#x20AC;&#x201C; erythema marginatum, mitral valve damage

Penicillin Ampicillin

Clindamycin and vancomycin for necrotizing fasciitis

Acute glomerulonephritis (PSGN)

9.2.2

Gram Negative Cocci

Neisseria Table 16. Gram Negative Cocci: Neisseria Etiology

Features IgA protease.

Neisseria meningitidis

9.2.3

Maltose and glucose fermenter. Encapsulated.

Pathophysiology Common cause of meningitis.

Presentation Meningitis Waterhouse-Friderichsen syndrome.

Treatment Vaccination available. Ceftriaxone

Gram Positive Rods

Non-Spore Formers Table 17. Gram Positive Rods: Non-Spore Formers Etiology

Features Obligate anaerobe.

Actinomyces israelii

Draining sulfur granules (yellow flecks).

Pathophysiology

Presentation Oral / facial abscess. IUD infection.

Treatment Penicillin (SNAP)

Clinical Review for the USMLE Step 1 Spore Formers Table 18. Gram Positive Rods: Spore Formers Etiology

Features

Clostridium difficile

Obligate anaerobe

Clostridium perfringens

Pathophysiology

Presentation

Caused by clindamycin, neomycin, and broad-spectrum antibiotics.

Exotoxin Obligate anaerobe.

Lecithinase with gas production.

Treatment

Pseudomembranous colitis â&#x20AC;&#x201C; diarrhea, fever, sepsis. Myonecrosis â&#x20AC;&#x201C; gas gangrene with severe infection. Food poisoning from reheated meat.

Vancomycin. Metronidazole.

Surgical debridement and IV antibiotics

Serious exotoxin production occurs with Clostridial spp., which can lead to the development of necrotizing fasciitis as soon as six hours following an operation. The clostridial group functions as gram positive rods, and is obligate anaerobes. C. perfringens in particular produces several toxins, including a necrotizing, hemolytic Lecithinase (alpha toxin), a hemolysin (theta toxin), a collagenase (kappa toxin), a hyaluronidase (mu toxin), and a deoxyribonuclease (nu toxin). An endotoxin is also produced by this potent bacterium. Rapid spread requiring surgical intervention and serial debridement may be required in the worst cases, and may lead to death even with aggressive therapy. C. difficile produces a potent exotoxin that leads to pseudomembranous colitis leading to diarrhea. Metronidazole or vancomycin is orally given with infection. Cholestyramine can be given to bind toxin. C. tetani produces a neurotoxin that leads to rigidity and muscular spasms, culminating in asphyxiation and death. Treatment is wound debridement and penicillin. C. botulinum produces a neurotoxin leading to GI symptoms, diplopia, and finally paralysis.

9.2.4

Gram Negative Rods

Aerobes Table 19. Gram Negative Rods: Aerobes Etiology Pseudomonas aeruginosa

Features Blue-green pigment. Lactose nonfermenter. Oxidase positive. Encapsulated

Pathophysiology

Presentation

Treatment

Burn infections, pneumonia in CF, sepsis, otitis externa, and UTI

Ampicillin and gentamicin

Eschar formation in burn patients with secondary infection.

Ceftazidime Ciprofloxacin

Facultative Anaerobes Table 20. Gram Negative Rods: Facultative Anaerobes Etiology Helicobacter pylori

Features Spirals

Pathophysiology Uses urease to breakdown mucus layer and lead to ulcer formation in stomach and duodenum

Presentation Gastritis, duodenal ulcer, gastric ulcer

Treatment Bismuth, metronidazole, amoxicillin, clarithromycin, omeprazole.

Microbiology 9.2.5

Enterobacteriaceae

Primary antigen is a polysaccharide of endotoxin. The K antigen is a capsular antigen (virulence factor); the H antigen is found in motile varieties. Enterobacteriaceae are glucose fermenters. Table 21. Gram Negative Rods: Enterobacteriaceae Etiology

Pathophysiology

Presentation

Treatment

Bacteremia, lower respiratory tract infecImipenem, cilastatin, Meropetion. Most common cause of liver abscess in nem, Cefepime, Ciprofloxacin. a patient with diverticulitis

Enterobacter Heat-labile toxin with adenylate cyclase production through ADP ribosylation of Gs protein; heat-stable works on guanylate cyclase.

Escherichia coli

Klebsiella pneumoniae Ammonium magnesium phosphate stones.

Proteus mirabilis

Invasive.

Salmonella enteritidis

10,000 required for disease.

9.2.6

Food poisoning from undercooked meat; watery diarrhea (ETEC). Bloody diarrhea (EIEC, EHEC, EHEC O157:H7). Meningitis in elderly. Bacteremia in biliary tract (most common)

Ampicillin and gentamicin Meropenem Ciprofloxacin

Pneumonia with currant jelly sputum. Cholecystitis (uncommon).

Cefotaxime, Ceftriaxone, Gentamicin, Amikacin, Piperacillin / tazobactam.

Struvite stones in UTI.

Ceftriaxone, Gentamicin, Imipenem / cilastatin. Surgical stone removal.

Food poisoning from poultry, meat, eggs with bloody diarrhea

Permit natural course as antibiotics will worsen disease. Consider TMP-SMX for systemic disease.

Anaerobes

Obligate anaerobes lack catalase and are foul smelling gas formers. B. fragilis is the most common bacterium within the intestine. Table 22. Gram Negative Rods: Anaerobes Etiology

Features

Pathophysiology

Bacteroides fragilis

9.2.7

Presentation Normal bowel flora

Treatment Neomycin, Clindamycin.

Atypical Bacteria

Table 23. Atypical Bacteria Etiology

Pathophysiology

Presentation

Treatment

Mycobacterium tuberculosis

Found in the apex of the lung due to the highest PO2.

Tuberculosis â&#x20AC;&#x201C; night sweats, fever, anorexia, hemoptysis. Primary: Ghon complex in lower nodes with fibrotic healing and caseating granulomas, progressive disease, bacteremia, or allergic reaction. Secondary: Fibrocaseous cavitation with secondary spread in body.

Rifampin, Isoniazid, Streptomycin, Pyrazinamide, Ethambutol, Cycloserine

Clinical Review for the USMLE Step 1

9.3. Antimicrobials 9.3.1

Penicillins

Resistance to penicillins comes from beta-lactamases that cleave the penicillins to make them impotent. Penicillins bind to PBPs with subsequent inhibition of the transpeptidase step leading to cell lysis. It will not affect organisms that do not have a cell wall. Penicillins are cleared by the kidneys, which can be slowed with the administration of probenecid. Table 24. Antimicrobials: Penicillin Drug

Indications

Mechanism of Action

Penicillin G

GPC (Streptococcus, meningococcus, enterococcus), GPR

Inhibits cross-linking of cell wall leading to bacterial lysis Ă bactericidal

Amoxicillin

GPC, GPR, GNR, E. coli, H. influenzae, L. monocytogenes

Piperacillin

Extended spectrum. Pseudomonas and GNR.

9.3.2

Complications

Contraindications

Notes

Hypersensitivity (anaphylaxis), hemolytic anemia

Do not use in bacteria with beta-lactamases or w/ known hypersensitivity (common rxn is skin rash)

Effective against Neisseria spp., C. perfringens, Fusobacteria, and Treponema

Inhibits cross-linking of cell wall leading to bacterial lysis

As above plus pseudomembranous colitis. Seizures at high doses.

Do not use if hypersensitivity to penicillins.

Use with clavulanic acid or sulbactam to block beta-lactamases. Wide spectrum. Oral.

Inhibits cross-linking of cell wall leading to bacterial lysis

Hypersensitivity, Do not use if hypersensitivity to penicillins. Sodium hemolytic anemia, platelet dysfunction. loading.

Cephalosporins â&#x20AC;&#x201C; First Generation

Resistance to cephalosporins comes from beta-lactamases that cleave the penicillins to make them impotent. Cephalosporins have a hexagonal ring with two functional groups. Penicillins have a pentagonal ring with one functional group. Both are susceptible to beta-lactamases. Table 25. Antimicrobials: First Generation Cephalosporins Drug

Indications

Mechanism of Action

GPC Cefazolin

E. coli K. pneumoniae P. mirabilis

Inhibit cell wall synthesis by preventing cross-linking. Bactericidal.

Complications

Contraindications

Hypersensitivity (rash).

Aminoglycosides (nephrotoxicity).

10% penicillin cross hypersensitivity

Alcohol (disulfiram reaction)

Notes

Less susceptible to beta-lactamases.

Microbiology 9.3.3

Cephalosporins â&#x20AC;&#x201C; Second Generation

Table 26. Antimicrobials: Second Generation Cephalosporins Drug

Indications

Mechanism of Action

Complications

Contraindications

Notes

Avoid with aminoglycosides (nephrotoxicity).

Less susceptible to beta-lactamases.

Avoid with alcohol (disulfiram reaction)

Broader range compared to first generation.

GPC, E. coli Enterobacter

Inhibit cell wall synthesis by preventing crosslinking.

H. influenzae Cefoxitin

K. pneumoniae Neisseria spp.

Hypersensitivity (rash).

Bactericidal.

P. mirabilis Serratia spp.

9.3.4

Cephalosporins â&#x20AC;&#x201C; Third Generation

Table 27. Antimicrobials: Third Generation Cephalosporins Drug

Indications

Mechanism of Action

Gram-negatives.

Inhibit cell wall synthesis by preventing crosslinking.

Meningitis Resistant organisms Ceftriaxone

Serious infections

Bactericidal.

Broad range. Low activity against gram positives.

9.3.5

Complications

Contraindications

Avoid with aminoglycosides (nephrotoxicity). Hypersensitivity (rash). Avoid with alcohol (disulfiram reaction)

Broadest range.

Notes Cross blood-brain barrier.

Ceftazidime is especially good against Pseudomonas.

Monobactams / Carbapenems

Table 28. Antimicrobials: Monobactams and Carbapenems Drug

Aztreonam

Indications

Mechanism of Action

GNR, Klebsiella spp., Pseudomonas spp., Serratia spp.

Prevents synthesis of cell wall. Bactericidal.

GPC, GNR Imipenem

Anaerobes Enterobacter

Improved activity with aminoglycosides Beta-lactamase resistant cell wall synthesis inhibitor. Bactericidal.

Complications

GI Sx.

GI Sx. Rash. CNS toxicity leading to seizures at high doses. Nephrotoxic. Eosinophilia.

Contraindications

Notes

No effect against anaerobes or grampositive bacteria.

No cross-sensitivity with penicillins. Especially recommended in renal disease.

Renal disease.

Imipenem is always given with cilastatin to avoid inactivation in kidney. Synthetic.

Clinical Review for the USMLE Step 1 9.3.6

Aminoglycosides

R-factor resistance leads to drug inactivation and decreased uptake. May also be modified through acetylation, adenylation, or phosphorylation of the compound. Excreted unchanged by kidney. Table 29. Antimicrobials: Aminoglycosides Drug

Gentamicin

Indications Severe gramnegative infections. Aerobes only. Pseudomonas.

9.3.7

Mechanism of Action

Complications

Contraindications

30S inhibitor.

Nephrotoxic.

Bacteriostatic.

Ototoxic.

Do not use with cephalosporins.

Cause mRNA misreading by preventing formation of initiation complex à bactericidal.

Cause NMJ blockade after surgery.

Do not use with loop diuretics.

Possible superinfection.

Renal clearance – avoid in renal disease.

Notes Require O2 for use – no effect against anaerobes.

Given IV.

Tetracyclines

R-factor resistance leads to drug inactivation and decreased uptake. Also has increased removal from cell. Avoid dairy foods, iron-containing preparations, and antacids with use of tetracyclines. Table 30. Antimicrobials: Tetracyclines Drug

Indications

9.3.8

Complications

B. burgdorferi

GI Sx.

Chlamydia

Tooth discoloration and stunted growth in children.

Mycoplasma Doxycycline

Mechanism of Action

Rickettsia

30S inhibitor prevents tRNA attachment.

Tularemia

Bacteriostatic.

Fanconi syndrome.

Ureaplasma

Photosensitivity (common).

V. cholerae

Possible superinfection.

Contraindications

Avoid in renal patients. Avoid in children.

Notes

Do not use in CNS infections.

Macrolides

Resistance by rRNA methylation leading to prevention of binding to 50S unit. Table 31. Antimicrobials: Macrolides

Drug

Indications

Azithromycin

Pneumonia and URTI., GPC, Mycoplasma, Legionella, Chlamydia, Neisseria

Mechanism of Action 50S inhibitor prevents translocation and inhibits protein synthesis. Bacteriostatic.

Complications

Contraindications

GI Sx (common). Hepatitis. Eosinophilia. Skin rashes.

Avoid in hepatic patients. Macrolides are excreted in bile.

Notes

Microbiology 9.3.9

Fluoroquinolones

Resistance by change in DNA gyrase. Drug penetration may also change. No plasmid-resistance. Table 32. Antimicrobials: Fluoroquinolones Drug

Indications

Ciprofloxacin

GNR, Pseudomonas, Neisseria spp., Gram-positives (MRSA), UTI, TB

9.3.10

Mechanism of Action Prevents action of topoisomerase II. Bactericidal.

Complications GI Sx. Tendon rupture. Theophylline levels increase in plasma.

Contraindications Avoid in pregnancy and children due to cartilage damage. Avoid in renal patients.

Notes Very potent drugs. Broad spectrum except against anaerobes and some GPC. Renal secretion.

Sulfonamides / Trimethoprims

Resistance by modification of DHP synthase, increased synthesis of PABA, or decreased uptake of drug. Table 33. Antimicrobials: Sulfonamides and Trimethoprims Drug

Indications

Sulfamethoxazole

Gram-positives, gram-negatives, Nocardia, Chlamydia, recurrent otitis media, UTI

Trimethoprim

9.3.11

UTI, prostatitis, Shigella, Salmonella, P. carinii, Nocardiosis, and HIB

Mechanism of Action Inhibits DHP synthase by PABA metabolites. Bacteriostatic.

Prevents the use of DHFR in bacteria. Bacteriostatic. Additive with SMX.

Complications Allergic reactions. Nephrotoxicity, kernicterus, changes volume of other medications. Rash, anemia, crystalluria.

Megaloblastic anemia, pancytopenia. BMS.

Contraindications G6PD deficiency, avoid in infants, use with care with other drugs. Avoid in pregnancy.

Notes Combined with TMP. Resembles PABA. Penetrate CNS. Give with folate to avoid anemia. Used for recurrent UTIs. TMP-SMX used for P. carinii pneumonia.

Other Antimicrobials

Resistance to vancomycin comes from mutation of D-ala D-ala to D-ala D-lac. Plasmid-mediated. Rfactor resistance for chloramphenicol leads to drug inactivation by acetyltransferase inactivation and decreased uptake.

Clinical Review for the USMLE Step 1 Table 34. Antimicrobials: Other Drugs Drug

Indications

Mechanism of Action

Contraindications

Notes

Chloramphenicol

Meningitis

50S inhibitor to decrease tRNA binding to A site. Bacteriostatic.

Metronidazole

Protozoa. G. vaginalis. Anaerobes. Bacteroides. Clostridium spp.

Formation of toxic products. Bactericidal.

GI sx

Avoid with alcohol due to disulfiram reaction.

Used for numerous STDs.

Vancomycin

Resistant GPRs, S. aureus / MRSA / PRSP, C. difficile

Prevents cell wall formation through D-ala D-ala binding and sequestration.

Nephrotoxic. Ototoxic (deafness). DVTs. Red man syndrome.

Renal disease. Renally cleared agent.

Avoid red man syndrome with antihistamines and gradual administration.

Clindamycin

Anaerobic infections. B. fragilis. C. perfringens.

50S inhibitor. Bacteriostatic.

Pseudomembranous colitis

Renal and hepatic clearance.

PO. Treat pseudomembranous colitis with flagyl. A lincosamide.

9.4. Fungus 9.4.1

Complications

Fungal Classification

Aplastic anemia, gray baby syndrome.

Avoid in pregnancy and infants (low UDPglucuronyl transferase).

Crosses BBB.

Microbiology 9.4.2

Fungal Anatomy

Fungi are single or multicellular heterotrophs. Multicellular fungi have hyphae that aggregate to form a mycelium. Fungi can reproduce asexually via budding. Yeast are a unicellular fungus that use asexual reproduction or ascospores. Dimorphism permits switching between a yeast-like form to multicellular filamentous form (as in Candida).

9.4.3

Laboratory Tests

Sabouraud agar is used to grow fungus. Hay infusion agar grows mold.

9.4.4

Fungology

Topical Infections Table 35. Cutaneous Fungal Infections Etiology Candida albicans

Pathophysiology

Presentation

Budding yeast with pseudohyphae and germ tube formation. Water soluble toxin leads to pain.

Treatment

Oral thrush. Infectious Nystatin topical therapy. Fluconesophagitis. Diaper rash. azole or amphotericin B for sysVaginal infection. temic infection or vaginal infection.

Systemic Infections Table 36. Systemic Fungal Infections Etiology

Presentation

Treatment

Aspergillus fumigatus

Lung cavitary lesions with fungus balls followed by disseminated cutaneous infection. Papules, ulcers, eschars.

Coccidioidomycosis

Primary â&#x20AC;&#x201C; flu-like illness and erythema nodosum common in kids and travelers. Systemic â&#x20AC;&#x201C; African Americans and other groups with an HLA predisposition leading to skin, tissue, bone, and meningeal infection.

Systemic: amphotericin B

Cryptococcus neoformans

Meningitis or acute pulmonary infection in IC.

Amphotericin B

Pneumocystis carinii

Diffuse pneumonia in IC.

Pentamidine, TMP-SMX, Dapsone

Amphotericin B Local: fluconazole

Mold form outside body. Yeast form, in warmer temperatures, inside body.

Clinical Review for the USMLE Step 1 9.4.5

Antifungals

Table 37. Antifungals Drug

Indications

Mechanism of Action

Complications

Contraindications

Notes

Meningitis Cryptococcus Amphotericin B

Aspergillus Histoplasma Candida

Sequesters ergosterol and has detergentlike effect on cell wall. Fungicidal at high doses.

F/C. Hypotension. Nephrotoxicity.

Avoid in renal disease.

Does not cross BBB. Must be given intrathecally for meningitis. Given slowly via IV.

Arrhythmias.

Mucor Nystatin

Candida

Sequesters ergosterol, disrupts cell wall.

Oral candidiasis. Topical only.

Systemic infections. Fluconazole

Cryptococcal meningitis.

Block formation of ergosterol by lanosterol. Fungistatic.

Candida.

9.5. Virus 9.5.1

Viral Classification

Gynecomastia, hepatitis, F/C.

Avoid in hepatic disease.

Good absorption and CNS penetration.

Microbiology

Clinical Review for the USMLE Step 1

9.5.2

Viral Anatomy

Viruses use either DNA or RNA for transcription. A capsid serves as an enclosure for nucleic acid that serves to protect nucleic acid from digestion, permits binding to host cells, and permits penetration into host cell. The envelope is a lipid bilayer that surrounds capsid, typically obtained from the cell membrane itself. Used to attach to the host cell and to evade host defenses. dsDNA viral nucleic acids are infectious, along with positive strand ssRNA nucleic acids. Negative strand virus nucleic acids by themselves are not infectious. Only retroviruses are diploid. Of the DNA viruses, only poxvirus replicates in the cytoplasm, and of the RNA viruses, only influenza virus and retroviruses replicate in the nucleus. Reassortment involves rearrangement of segments that may occur in orthomyxoviruses, bunyaviruses, arenaviruses, and reoviruses. Oncogenic viruses include the papillomavirus family, herpesvirus family, hepadnavirus family, flaviviruses, adenoviruses, poxviruses, and retroviruses. HPV 6 and 11 typically form genital warts, but may progress to form epidermodysplasia verruciformis. HPV 16, 18, 31, 33, and 45 can lead to cervical, penile, and vulvar cancer. Herpesviruses that can lead to cancer include EBV, which typically causes infectious mononucleosis, but may also cause Burkittâ&#x20AC;&#x2122;s lymphoma, nasopharyngeal carcinoma, and contribute to Hodgkin disease. Hepadnavirus that can lead to cancer include HBV, which typically causes infectious hepatitis, but may progress to hepatocellular carcinoma. Flaviviridae such as HCV may lead to hepatocellular carcinoma through p53 effects.

Microbiology Adenoviridae typically causes the common cold, but may lead to adenocarcinoma of the upper respiratory tract. Poxviridae typically causes small pox, but may contribute to various malignancies. Retroviridae such as HTLV cause adult T-cell leukemia and contribute to lymphoma.

9.5.3

Antivirals

Phosphorylation by the virus of DNA polymerase permits DNA polymerase binding and subsequent inhibition of DNA synthesis. Table 38. Antivirals Drug

Indications HSV

Acyclovir

VZV EBV

Ganciclovir

CMV in IC EBV in IC

Mechanism of Action

Complications

Contraindications

Notes

Inhibits viral DNA polymerase, guanine analog.

Tremor, nephrotoxicity.

Avoid in renal patients.

Also treated with vidarabine (adenosine analog)

Inhibits viral DNA polymerase.

Pancytopenia, especially with WBCs.

Use with care due to BMS.

Like ACV.

9.6. Parasites 9.6.1

Parasite Classification

Clinical Review for the USMLE Step 1 9.6.2

Antiparasitics

Table 39. Antiparasitics Drug Metronidazole

Indications Giardia, Entaboeba histolytica, Gardnerella vaginalis, Trichomonas

Mechanism of Action Targets DNA.

Complications Disulfiram-like reaction.

Contraindications

Notes Does not eliminate cysts.

9.7. Common Infections 9.7.1

Toxic Shock Syndrome

Toxic shock syndrome (TSS) is erythema leading to systemic manifestations of shock due to S. aureus. Superantigen known as TSS toxin-1 (TSST-1) leading to cytokine release throughout the body leads to the diffuse injury and systemic symptoms. TSS presents with symptoms include fever, hypotension, organ involvement, and distal extremity desquamation. Erythema is present with a scarlatiniform eruption. The tongue is cherry red, and hyperemia of mucous membranes is common. Several organs may be involved leading to serious systemwide damage and complications. Diagnosis is made by culture. Supportive therapy is used with TSS, including IVF, pressors, antibiotics, and draining the affected regions. Silver sulfadiazine cream is contraindicated; mupirocin ointment is used instead. Standard antistaphylococcus antibiotics are used as previously discussed.

9.7.2

Toxic Epidermal Necrolysis / Stevens Johnson Syndrome

Causes of toxic epidermal necrolysis include dilantin and bactrim. Biopsy of the skin will indicate nondisjunction of the dermal and epidermal interface. Treatment includes steroid therapy and stopping the offending agent.

9.7.3

Bites

Following a human bite, an incision and drainage should be done. Augmentin should be given to the patient. Tetanus vaccination should also be verified and IgG should be considered. Human bites lead to infection with S. aureus and Eikenella corrodens. Wounds are typically left open following irrigation and debridement. Bites from animals are treated in a similar fashion. Cat bites are more likely to be infected than dog bites due to the presence of Pasteurella multocida. Bites from most animals (and humans) can be safely treated with Augmentin or Bactrim. A bite from a brown recluse spider can be treated with dapsone.

9.7.4

Tetanus

Tetanus is caused by neurotoxin release by C. tetani, leading to a 30% mortality rate if not treated early. Tetanus infection must be especially considered in the presence of dirty wounds contaminated by soil or feces, puncture wounds, burns, and frostbite. For clean, minor wounds, children under 7 should be treated with a DPT (Diphtheriae, Pertussis, and Tetanus) vaccination as prophylaxis. Children over 7 100

Microbiology can be treated with the Td (tetanus toxoid) vaccination for similar wounds. Adults should receive a Td if the most recent vaccination is over 10 years ago. All dirty or major wounds receive a Td unless the full immunization schedule has been followed and the most recent vaccination is less than 5 years ago.

9.7.5

Sexually Transmitted Diseases

Urethritis, cervicitis, and prostatitis due to N. gonorrhea or Chlamydia are treated with ceftriaxone, ciprofloxacin with doxycycline, or ciprofloxacin with azithromycin. Disseminated gonococcal infection is treated with ceftriaxone followed by ciprofloxacin. PID is treated with ceftriaxone with doxycycline or cefotetan with doxycycline. HSV receives ACV or VCV. Haemophilus ducreyi leading to chancroid is treated with ceftriaxone, erythromycin, or azithromycin. LGV due to Chlamydia is treated with doxycycline. Syphilis due to Treponema pallidum is treated with benzathine penicillin or penicillin G if neurosyphilis is present. Table 40. STDs STD

Treatment

Urethritis, cervicitis, and prostatitis due to N. gonorrhea or Chlamydia

Ceftriaxone, ciprofloxacin with doxycycline, or ciprofloxacin with azithromycin

Disseminated gonococcal infection

Ceftriaxone followed by Cipro.

PID

Ceftriaxone with doxycycline or cefotetan with doxycycline.

HSV

ACV or VCV.

Haemophilus ducreyi

Ceftriaxone, erythromycin, or azithromycin.

LGV due to Chlamydia

Doxycyline

9.7.6

Reportable Diseases

Diseases that may lead to outbreaks or signify an underlying quality control defect must be reported to the state department of public health. These include AIDS (but not necessarily HIV), measles, mumps, rubella, pertussis, chickenpox, smallpox, shigella, salmonella, hepatitis A-E, syphilis, rabies, tuberculosis, gonorrhea, chlamydia, lyme disease, and Legionaireâ&#x20AC;&#x2122;s.

9.8. Prions Prions are misfolded proteins that catalyze changes in other proteins to cause structural and physiological malformations. This process infects other cells and leads to aggregations of proteins that cannot be broken down by the body. Such aggregations accumulate until they lead to cell death, then become a nexus for infecting other nearby cells. Normal proteins serve as the basis for a prion-based infection. These are known as PrPC (common); the prion form is known as PrPSc (scrapie). Infectious prion proteins reproduce by one of two methods. In the het- Figure 49. The fibril model for prion replicaerodimer model, one prion protein binds to a normal tion. Copyright Wikimedia. Used with permisprotein and causes a structural shift. This catalyzes sion. 101

Clinical Review for the USMLE Step 1 structural changes in other proteins and propagates the prion. In the heterodimer model, there is exponential growth in the rate of infection. In the fibril model, expanding linear chains of proteins occur, with prion-based structural changes occurring only at the tips of the fibrils. Unless the fibrils break off, growth is linear. There are several prion diseases that affect humans, including Creutzfeldt-Jakob disease, fatal familial insomnia, and kuru. Creutzfeldt-Jakob disease is a fatal, degenerative neurological disorder that leads to progressive breakdown of the brain. Fatal familial insomnia is an autosomal dominant prion disorder that leads to progressive insomnia and eventually death, with initial presentation in middle-aged adults. Figure 50. The heterodimer model of prion replication. Finally, kuru is a disease once spread via Copyright Wikimedia. Used with permission. cannabalism that presents with progressive neurological degeneration and seizures. Infection is typically via ingestion of the prion protein such as consuming a meat product. However, spread via feces (fecal-oral spread) and airborne methods can also occur. As in the case of fatal familial insomnia, genetic spread is also possible. Sterilization is difficult as typical denaturization processes via heat, acids, radiation, and proteases are not 100% effective.

10. Biostatistics 10.1. Introduction Biostatistics is a branch of statistics that applies statistical methods to medical and biological problems. It is of essential importance in the successful conduct of clinical and translational studies. An understanding of biostatistics enables the critical analysis of scholarly articles and their proper assimilation into oneâ&#x20AC;&#x2122;s own practice. In recent years, as a result of extraordinary advancement in computational capabilities, there have been significant improvements in statistical techniques and research design methodologies, including adaptive designs, randomization and Bayesian methods in clinical trials. However, clinical and translational investigators are often unaware of these new statistical methods. The lack of awareness is compounded by the tendency for individual clinical and translational studies to have either too few study subjects (Levin & Danesh-Meyer, 2010), too much random noise in the study data (Baggerly, Morris, Edmonson, & Coombes, 2005), or too much potential for bias (Ransohoff & Gourlay, 2010; Ioannidis, 2005). In this section, we provide an introduction to biostatistics and cover the essentials of descriptive and inferential statistics including estimation and hypothesis testing. In addition, we discuss major types of study designs and the importance of sensitivity and specificity, measures of absolute and relative risk, common errors and sources of bias in scientific studies.

10.2. 102

Descriptive Statistics

Biostatistics Before we can discuss the steps in developing a good clinical study and the appropriate statistical testing methods, we must go over the basics of descriptive statistics. The basic statistical problem is that we are trying to infer the properties of the underlying population from a limited number of measurements from the population. In order to successfully do this, we must understand how to describe the sample data and define the relationships between the sample and population.

10.3.

Measures

Central Tendency: Mean, Median,

and

Mode

The mean, median, and mode are statistics used to describe a distribution. The mean is the average of all measurements. It is important to distinguish the difference between the mean of a measurement in a population vs. the mean of a measurement in a sample; the population mean is often denoted by µ and the sample mean is denoted by . The sample mean is simply a point estimate for the population mean. This will be further discussed in the following section. The median is the middle measurement when all of the measurements are sorted in an ascending or descending order, which can be a better measure of central tendency in skewed distributions. In normal (bell-shaped) distributions the average and median values are the same. The mode is the measurement with the highest frequency. Based on these three measures of central tendency one can understand the shape of the distribution. Furthermore, depending on the type of measurements and shape of the distribution one may choose one or more of these measures of central tendency to describe their data set.

10.4.

Measures of Spread: Range, variance and Standard Deviation

Sample range is the difference between the highest and the lowest measurements. Therefore, it is a very sensitive measure of variability because of the extreme observations. For situations in which there are extreme observations, some researchers use the inter-quartile range (IQR) which represents the difference between the 25th percentile and 75% percentile. Sample variance (s2) is another important measure of variability, which is calculated by the following formula, where xi are the individual measurements and n is the sample size:

∑ ( xi − x ) n

s =

i =1

n −1

Since the unit of variance is squared of the original unit of measure, the sample standard deviation (s) is often used as another measure of spread, which is simply the square root of the sample variance.

∑ ( xi − x ) n

s= s =

i =1

n −1

It is important to distinguish the difference between population and sample measures of spread. For example, population standard deviation (s) is a measure of spread over the entire population of size N with a mean of µ; similarly, population variance is denoted by s2. The reason for using “n-1” in calculating sample variance (s2) and standard deviation (s) is to ensure that the estimates for variability remain 103

Clinical Review for the USMLE Step 1 unbiased. This concept is discussed in standard statistical textbooks and we refer the reader to “Fundamentals of Biostatistics” by Bernard Rosner for additional information.

∑ (xi − µ ) N

σ=

10.5.

i =1

Normal Distributions

In practice, many measurements including weight and height, have a bell-shaped distribution. Mathematically these distributions can be characterized by a normal (guassian) distribution with mean µ and standard deviation s. The normal distribution is symmetrical and has the property that about 68% of the observations lie within one standard deviation from the mean, 95% within 2 standard deviations and 99.7% within 3 standard deviations.

Figure 1. A normal distribution of the population with mean µ and standard deviation s.

10.6.

Skewed Distributions

Not all distributions are normal in nature. In fact, skewed distributions are common in clinical data. In a negatively skewed distribution (i.e. skewed towards the left), the mean is less than the median. In a positively skewed distribution (i.e. skewed towards the right), the median is less than the mean. In a bimodal distribution, there are two modes, one mean, and one median. For irregular distributions, one may be interested in describing the data in terms of the median and interquartile range.

104

Biostatistics

Figure 2. A negatively skewed curve has a mode that is greater than the median, which is greater than the mean (left-skewed). A positively skewed curve has the opposite finding (right-skewed).

10.7. Estimation

and

Bias

As stated earlier, one of the objectives of statistics is to infer the properties of the underlying population from a sample (i.e. subset of the population). Statistical inference can be subdivided into two main areas: estimation and hypothesis testing. Estimation is concerned with estimating the values of specific population parameters. It is therefore, very important to understand the relationships between the sample characteristics and population parameters.

10.7.1

Point and Interval Estimators for the Population Mean

A natural estimator for µ is the sample mean , which is referred to as a point estimate. Suppose we want to determine the appropriate sample size for estimating the mean of a population (µ) which is unknown. We can start by taking a random sample to determine the sample mean and sample variance. However, the sample mean values can change from sample to sample. Therefore, it is necessary for us to determine the variation in the point estimate (e.g., sample mean). Assuming that the sample size is large (n>30), we can determine an interval estimate (e.g. 95% confidence interval) for the population parameters. For example if the population parameter is µ, a 95% confidence interval can be calculated by the following formula. The value 1.96 is the exact value determined from the normal distribution, which is based on the fact that 95% of the measurements are within 1.96 (approximately 2) standard deviations of the mean.

x ± 1.96

s2 n

The quantity to the right of the mean is known as the margin of error or the bound on the error of estimation (b). In general, as sample size increases b decreases. However, this inverse relationship is not linear. In order to decrease b by half, one must increase the sample size by a factor of 4. This relationship between margin of error, b, and sample size allow researchers to calculate the appropriate sample size to achieve the desired bound on the error with 95% confidence and will be further elaborated in the sample size determination section.

105

Clinical Review for the USMLE Step 1 10.7.2

Standard Error of the Mean

The standard error of the mean (SEM) or standard error (SE) is the standard deviation of sample mean. There is a mathematical relationship between the standard deviation of the measurements in the population and the SEM. This mathematical relationship helps to calculated SEM based on one random sample of size “n”. SEM is equal to the standard deviation divided by the square root of the sample size “n”. The SEM is affected by the sample size; as the sample size increases, the SEM decreases.

s n

SEM =

10.7.3

Point and Interval Estimators for the Population Proportion

In clinical studies, one is often interested in assessing the prevalence of a certain characteristic of the population. In this case, it is important to determine the point and interval estimators for the population proportion (p). The point estimator for the population proportion is defined as the proportion of the observed characteristic of interest in the sample.

ˆ = p

x n

For large samples, such that npˆ (1− pˆ ) ≥ 5 , a 95% confidence interval for the population proportion p is calculated as follows:

pˆ ± 1.96

pˆ (1 − pˆ ) n

The quantity to the right of the sample proportion ( pˆ ) is known as the margin of error or the bound on the error of estimation (b). As shown before in the case of point estimates for the population mean, this relationship can be used to estimate the appropriate sample size, which will be explained later.

10.7.4

Bias

Generally, bias is defined as ‘a partiality that prevents objective consideration of an issue’. In statistics, bias means ‘a tendency of an estimate to deviate in one direction from a true value’. In terms of the population means and proportion estimates described in the previous sections, bias can be defined as:

Bias = ( x − µ ) Bias = ( pˆ − p ) 106

Biostatistics From a statistical perspective, an estimator is considered unbiased if the average bias based on repeated sampling is zero. For example,  is an unbiased estimator of µ and pˆ is an unbiased estimator for p. However, there are multiple sources of bias inherent in any study that may occur during the course of the study, from allocation of participants, delivery of interventions, to measurement of outcomes. Bias can also occur before the study begins or after the study during analysis. Late look bias occurs with reexamination and re-interpretation of the collected data after the study has been un-blinded. Lead-time bias occurs when earlier examination of patients with a particular disease lead to earlier diagnosis, giving the false impression that the patient will live longer. Measurement bias occurs when an investigator familiar with the study does the measurement and makes a series of errors towards the conclusion they expect. Recall bias occurs when patients informed about their disease are more likely to recall risk factors than uninformed patients. Sampling bias occurs when the sample used in the study is not representative of the population and so conclusions may not be generalizable to the whole population. Finally, selection bias occurs when the lack of randomization leads to patient’s choosing their experimental group which could introduce confounding.

10.8.

Hypothesis Testing

10.8.1

Developing a Hypothesis

A research question can be formulated into null and alternative hypotheses for statistical testing. The null hypothesis states that there is no difference between the parameter of interest and the hypothesized value of the parameter. Whereas the alternative hypothesis is that there is some kind of difference. The alternative hypothesis cannot be tested directly; it is accepted by default if the test of statistical significance rejects the null hypothesis. In the case of comparing two population parameters, the null hypothesis is that there is no difference between groups (A or B) on the measured outcome. Whereas the alternative hypothesis is that there is a difference between the measured outcome and the group (A or B). Alternatively, the null hypothesis can be written as no association between group (A or B) and measured outcome vs. alternative hypothesis that there is an association between group (A or B) and the measured outcome. In later sections, you will see that some researchers prefer to write the hypotheses in terms of ratio of the two population parameters [e.g., Relative Risk (RR) or Odds Ratio (OR)]. In this case the null hypothesis can be written as RR=1 (OR=1) vs RR≠1 (OR≠1).

10.8.2

Other Elements of Testing Hypothesis

In addition to the null and alternative hypotheses, we must have a test statistic, a rejection region, and p-value to conduct a formal testing hypothesis. A test statistic calculates the difference between the observed data and the hypothesized values of the parameters assuming the null hypothesis is true. For example, for comparing means of two normal distributions we can use a test statistic, which has a tdistribution under the null hypothesis. Rejection region is the range of values of the distribution of the test statistic for which the null hypothesis is rejected, in favor of the alternative hypothesis. Traditionally, for each testing hypothesis one must determine a cut off value for the rejection region, based on a probability of type I error (α = 0.05).

10.8.3

Types of Error

Type I error occurs when the null hypothesis is rejected despite being true. The probability of type I error (α) is usually considered acceptable at 5%. P-value is the probability of observing more extreme values than what has been already observed in the sample assuming the null hypothesis is true. If pvalue < α, then the null hypothesis can be rejected. On the other hand, type II error occurs when the null hypothesis is not rejected when it should be. The probability of type II error (β) is more difficult 107

Clinical Review for the USMLE Step 1 to calculate because we usually do not know the true value of the parameter of interest under the alternative hypothesis. Additionally, it is important to note that as alpha increases, beta decreases and the power of the study increases.

10.8.4

Power

The power of a test is the probability of rejecting the null hypothesis when it is false. Mathematically, power is defined as 1-β. The power of a test is directly related to its sample size; increasing sample size results in a higher power. However, the power is also directly dependent upon the variance of the measurement. Using more sensitive and specific instruments that can measure a finer gradient (such as reliably estimating HDL to 3 decimal places) can also improve the power of a study. An insufficiently powered study can lead to false acceptance of the null hypothesis and thereby lead to a type II error. In other words, a study may incorrectly conclude that there is no difference between two groups (e.g., two treatments) when one really existed. To avoid these errors, the power of a study must be determined by the need to estimate expected differences between two groups.

10.8.5

Sample Size Determination

The sample size (n) is the total number of patients enrolled in a particular study. This number plays a critical role in the statistical power and relevance of the findings from the study. The sample size can be determined through two inferential techniques. First, for determining the minimum sample size required to estimate a certain parameter of interest within a certain margin of error we need the variance of the measurement, level of confidence and the margin of error. Referring back to the definition of margin of error, we can calculate the sample size for estimating the difference between two means (µ1-µ 2) based on two independent samples equal size with the following formula:

 1.96  2 2 n1 = n2 ≥   ⋅ (σ 1 + σ 2 )  B  For estimating the mean of one population, the sample size formula is slightly different and we refer the reader to Rosner’s textbook “Fundamentals of Biostatistics”. Secondly, for the testing hypothesis, sample size is determined from variance of the measurement, level of confidence and effect size. For comparing two population means, the effect size is defined as the absolute difference between the mean of the two populations divided by the standard deviation of the measurement of the control group. Together, the formula for sample size for a two population study with an α=0.05 and β=0.2 (i.e. 80% power) is as follows:

n1 = n2 ≥

(1.96

(

+ 0.84 ) σ 12 + σ 22 ∆2 2

)

where s12 and s22 are the variances of each population and D = |m1 – m2|. This method is only appropriate when the sample size between the two groups is the equal. For unequal groups we refer you to Rosner’s textbook. 108

Biostatistics To determine the sample size for estimating a population proportion (p) within a certain margin of error (B) with 95% confidence, we need to have an initial estimate for the population proportion of interest. If no such estimate is available the most conservative sample size can be determined by replacing p=0.5 in the following formula:

 1.96  n≥  ( p)(1 − p )  B  Furthermore, to determine the required sample size for comparing two population proportions assuming an absolute difference of delta (p1-p2) and equal sample sizes in both groups, we will use the following formula. This formula is specifically for having at least 80% power (β=0.2) with α=0.05, where D = |p1 – p2|.

n1 = n2

(1.96 ≥

+ 0.84

)2 [ p1 (1 − p1 ) + p2 (1 − p2 )] ∆2

Similar to before, if p1 and p2 are unknown the most conservative estimate of n1 and n2 can be obtained by assuming a value of 0.5 for p1 and p2 in the above formula. This method is only appropriate when the sample size between the two groups is the equal. For unequal groups we refer you to Rosner’s textbook “Fundamentals of Biostatistics”.

10.9. Tests

Significance

10.9.1

T-Test

The Student’s t-test was developed in 1908 by William S Gosset using the penname Student. He created this statistical test as a method of monitoring the quality of Guinness stout, comparing one batch to another and ensuring that production was of consistent quality. The t-test assumes that the groups being compared come from a normally distributed population. There are three different types of t-tests: one sample t-test, two sample t-test and paired-sample t-tests. The one sample t-test compares the mean of a population to a specified (hypothesized) value. In the two-sample t-test, two independent samples are compared for differences between the population means. However, if the two samples being compared are dependent or matched, a paired t-test must be used. The limitation of the t-test is that it can only compare two groups at any given time. For comparing more than two group means we will introduce one-way analysis of variance (ANOVA) in the next section.

10.9.2

ANOVA

The analysis of variance (ANOVA) is a statistical procedure based on the F-test that can be used to simultaneously compare means from more than two groups. Similar to the t-test, ANOVA assumes that the populations being compared have normal distributions. It is particularly useful when comparing dose response curves of a medication given at differing doses to a group of patients. ANOVA helps to avoid inflation of type I error potentially caused by conducting multiple t-tests between groups when 109

Clinical Review for the USMLE Step 1 there are more than 2 groups.

10.9.3

Chi-Square Test of Indepdendence

The Chi-square test of independence allows testing for association or lack of it between two categorical variables. For example, in testing associations between disease status (D+/D-) and ethnicity (Caucasian, African American, Hispanic, Other) we can form a contingency table that provides the count for the frequency of observations in each combination of the rows and columns. The Chi-square test of independence has (r-1)(c-1) degrees of freedom where r is the number of rows and c is the number of columns in the contingency table. The rejection region for the chi-square test will be on the right tail of the Chi-square distribution. For computation of test statistics and p-values one can use standard statistical software.

10.9.4

Regressions and Correlations

Up to this point we have discussed hypothesis and statistical testing methods; the next step is to evaluate if there are any correlations between the outcome variable and group (class) variables. Linear-regression methods allow one to study how an outcome variable (y) is related to one or more predictor variables (x1,x 2,….xk).

10.9.5

Simple Linear Regression

Simple linear regressions are often fitted to the data using the Least Squares method where the best-fit line is determined by minimizing the sum of squared distances of the data points from the regression line. The simple linear regression equation often takes the form, where a is the y-intercept and b is the slope of the regression line in the population (Equation 13). y = a + bx The slope of the regression line (b coefficient) represents the estimated average increase in y per one unit increases in x. It is used to make predictions between the two variables, x and y. However, predictions are not always easy to make with clinical data and often we are interested in describing the relationship between x and y. In this case, the sample correlation coefficient (r) is a useful tool for quantifying the relationship between variables and is better suited than the estimated regression coefficient. The population correlation coefficient is denoted by ρ. In other words, r is a natural point estimator for ρ.

10.9.6

Correlation

Correlation coefficients help to describe linear relationships between two variables. It is of vital importance to understand that correlation does not imply causation. In correlation analysis, it is important to look at the scatter plot which is a graphical presentation of pairs of (X, Y) coordinates plotted on the X-Y axis. The X is the independent variable and the Y is the dependent variable. The correlation coefficient must lie between -1 and 1. A correlation coefficient of 0 means that there is no linear relationship between the two variables (or X and Y are uncorrelated). However, the two variables might still be otherwise related (e.g., U shaped-relationship). A correlation coefficient between 0 and 1 means a positive correlation exists, as X goes up, the Y variable generally goes up. A negative correlation implies an inverse relationship, as X increases the Y variable generally decreases. Thus, the correlation coefficient provides a quantitative measure of dependence between the two variables. Please note that dependence of Y on X does not imply that there us a causal relationship between X and Y. 110

Biostatistics

10.10.

Study Designs

and

Measures

Association

As mentioned in the previous section, it is important to determine correlations and associations between the dependent and independent variables. In this section we discuss the concepts of associations in relation to the study designs implemented.

10.10.1 Study Design It is important to design a study that will answer the proposed research question in a non-biased and efficient manner. As stated earlier, it is important to clearly define the “disease” and “treatment” variables so that one can effectively assess a disease-treatment relationship. Randomization, blinding, minimizing bias, using placebos, internal controls, and a sufficient sample size should be used whenever possible. However, not all scientific questions are practically answered by high quality, multi-institutional, randomized controlled trials. As a result, a variety of study designs are available for various types of epidemiologic, clinical and translational research.

10.10.2 Case Study Case studies examine the outcome of a single patient with a disease who received a particular treatment. Case studies are useful to note interesting or odd effects of treatment, or to note an off-label use of a medication, and they may spur more rigorous clinical investigations.

10.10.3 Case-Control Study Case-control studies are retrospective studies that identify two groups of patients; one group with the known disease (cases) and another group without the disease (controls). The goal is to compare the proportion of a certain exposure between case and control groups. These studies are often susceptible to recall bias as patients with knowledge of their disease are likely to recall being subjected to a particular exposure (e.g., high tension power lines). However, case-control studies are very useful for identifying risk factors of a rare disease. Additionally, confounding factors (i.e. factors that are associated with both the disease and exposure) may also introduce bias. In this case, matched case-control studies are used to minimize confounding. For example, when attempting to identify risk factors for type II diabetes through a case-control study it is important to control for age because age is associated with both type II diabetes and various exposures.

10.10.4 Cohort Study Cohort studies are prospective studies that follow a predetermined disease-free group of patients over a period of time. As the study progresses, some individuals develop the disease and others do not. The development of the disease is then related to the exposure variables observed over the time period of the study. These studies sometimes require a long span of time, during which loss of patients is likely to occur. Cohort studies are useful when examining the effect of various risk factors on the development of disease.

10.10.5 Cross-Sectional Study In cross-sectional studies, the patient population is asked about their current disease status and current and/or past exposure status to various risk factors. Cross-sectional studies compare the prevalence of disease at one point in time between exposed and unexposed individuals. This is different than the prospective (cohort study) where the incidence of disease rather than prevalence of disease is investigated. 111

Clinical Review for the USMLE Step 1 10.10.6 Clinical Trial Clinical trials are distinguished by several traits that help make their findings more valid and reliable. Good clinical trials are randomized, which helps to minimize selection bias. They are double-blinded, which minimizes measurement bias by reducing confounding by investigators and patients who may be aware of the therapy they are giving or receiving. Multi-centered trials eliminate confounding due to local or regional differences and limited sample sizes. Placebo controls help to ensure that the trial is double-blind and helps to reduce measurement bias. A crossover design ensures that a patient receives a therapy for at least half of the trial and a placebo for the remainder â&#x20AC;&#x201C; it helps to serve as an internal control and reduces measurement bias. The best clinical trials incorporate as many of these traits as possible. They are designed in such a way that their outcomes can typically be trusted if all tenets of the study design are faithfully followed. The major determent to clinical trials is their high cost. One note regarding clinical trials: in order for a randomized study to be properly evaluated, the sample size must be carefully predetermined.

10.11.

Measures

Associations Between Two Binary Variables

Depending on the study design, different measures of association can be used to display relationships between variables. As mentioned earlier, the Chi-square test of independence can be used to test the null hypothesis that the exposure and disease are not associated with each other against the alternative that there is an association. However, there are several methods to measure associations between two binary variables including odds ratio and relative risk. In a case control study, where a group of patients who have the disease are compared to a group of patients who do not have the disease with respect to their exposure, the data can be organized in the form of a 2 x 2 contingency table. Disease

Exposure

Figure 3. Illustration of the 4 possible scenarios from a â&#x20AC;&#x153;disease-exposureâ&#x20AC;? relationship.

10.11.1

Odds Ratio

The odds ratio is a descriptive statistic that can be thought of as determining the strength of an association between two binary variables. The odds ratio is defined as the ratio of odds of exposure among patients who have the disease relative to the odds of exposure among patients who do not have the disease. The odds of an event refers to the probability of the event occurring over the probability of the event not occurring. Simply, the odds ratio is calculated by the formula below. It is often used in retrospective, case-control and cross-sectional studies to evaluate the particular effect of a risk factor on disease.

Odds Ratio =

ad bc

Standard statistical packages provide 95% confidence intervals for odds ratios. If the 95% confidence intervals for odds ratios do not include 1, then one can conclude that there is an association between 112

Biostatistics the disease and exposure. Also there is a formula for calculating the 95% confidence intervals for odds ratios based on the information in the contingency table. For additional information we refer the reader to Rosner’s textbook “Fundamentals of Biostatistics”.

10.11.2 Relative Risk Relative risk is used to compare the chance of a particular disease between the exposed and non-exposed groups. For example, in a cohort study, the risk of a smoker developing lung cancer would be compared to the group of non-smokers and the result given in terms of the relative risk of lung cancer. Relative risk is calculated as follows:

Relative Risk =

a (a + b ) c (c + d )

Standard statistical packages also provide 95% confidence intervals for relative risk. If the 95% confidence intervals for relative risks do not include 1, then one can conclude that there is an association between the disease and exposure. The formula for calculating the 95% confidence intervals for relative risks can be found in Rosner’s textbook “Fundamentals of Biostatistics”. The relative risk must be used with care as minor differences in risks between the two groups can result in a large ratio. In these cases, you must also report the absolute risk for the disease, which is simply the probability of the disease.

10.11.3 Attributable Risk To compare risks of disease between exposed and non-exposed groups in a cohort study, one can calculate the attributable risk. It is calculated as the difference between the incidence of disease in exposed group and incidence of disease in non-exposed group. Therefore, it represents the additional incidence of disease related to exposures and often called the risk difference.

Attributable Risk =

a c − a+b c+d

10.11.4 Associations Versus Causal Relationships It is important to note that associations do not imply causal relationships. In fact, in clinical research it is very difficult to establish causal relationships. Depending on the study design, one can build evidence for or against a causal relationship. For example, in randomized control trials it is easier to establish causal relationships than in retrospective studies. Randomized controlled trials with adequate sample size and blinding are usually the best evidence for a cause and effect relationship. When investigating whether an exposure has a causal relationship with a disease, it is important to evaluate if the association is an artifact of measurement bias or random variation (chance). If the association is not due to bias and seems unlikely, then one must consider if the association is occurring indirectly, potentially through confounding factors. If one does not find confounding and the study is well designed a causal relationship is likely. For more detailed discussion on causality, we refer the reader to Fletcher’s book “Clinical Epidemiology” and Rothman’s book “Modern Epidemiology”. 113

Clinical Review for the USMLE Step 1

10.12.

Diagnostic Tests

So far the focus of this chapter has been on the use of statistics in the development of various clinical studies to investigate the associations between exposures and disease. However, clinicians are also interested in assessing the predictive power of diagnostic tests. In order to assess the accuracy of a diagnostic test result, one must know the personâ&#x20AC;&#x2122;s true status of the disease. Results from a diagnostic test can be classified as true positives, true negatives, false positives, and false negatives. A true positive occurs when a test designed to determine the presence of a disease reports a correct answer. A true negative occurs when a test correctly reports that a disease is not present. False positives can be psychologically detrimental to a patient, such as when a test reports positive HIV status when the patient actually does not have this disease. They can also result in increased cost of care for unnecessary treatments since the patient has been falsely identified as diseased. False negatives can prevent a patient from receiving therapy when a test incorrectly reports that a patient does not have a disease.

Test

Total

â&#x2C6;&#x2019;

Disease

TP + FN

â&#x2C6;&#x2019;

FP + TN

Total TP + FP

FN + TN

Table 41. The four results that can be obtained from a test for a particular disease, along with the calculations for sensitivity, specificity, positive predictive value, and negative predictive value.

10.12.1 Sensitivity Sensitivity is a measure of the proportion of true positives, calculated as the number of people tested positive among all who have the disease. A highly sensitive test will have a low rate of false negatives. Further, if the sensitivity is high enough, and the test results negative, one can trust that the patient does not have a disease. Sensitive tests are often valuable as screening tests for a population.

10.12.2 Specificity Specificity is a measure of the proportion of true negatives, calculated as the number of people tested negative among all who do not have the disease. Specific tests have very low rates of false positives, so 114

Biostatistics a true positive result is considered to be trustworthy. If a patient obtains a positive result on a specific test, they are effectively ruled in for a particular disease.

10.12.3 Positive Predictive Value Positive predictive values are used to determine the chance of having a disease given a positive test result. It is calculated as the number of true positives divided by the total of positive test results. The positive predictive value is used in conjunction with the pretest probability to determine the chance the patient truly has a disease. For example, doing a test for the Ebola virus is unlikely to be meaningful, even with a positive result, on a healthy American in Nebraska who has never traveled to Africa.

10.12.4 Negative Predictive Value The negative predictive value determines the chance of not having a particular disease given a negative test result. It is calculated as the number of true negatives divided by the total number of negative test results. The negative predictive value is also used in conjunction with pretest probability and clinical suspicion to determine whether a patient is likely to have a particular disease.

115

Section Editors Sapan S. Desai, MD, PhD

Danny O. Jacobs, MD, MPH

Assistant Professor Department of Surgery Duke University Medical Center

Professor and Chair Department of Surgery Duke University Medical Center

HEMATOLOGY

Contributors Gowthami Arepally, MD, PhD

Alice D. Ma, MD

Associate Professor of Hematology Department of Medicine Duke University Medical Center

Hematology (adapted from the Clinical Review of Vascular Surgery)

Sapan S. Desai, MD, PhD

Eric Mowatt-Larssen, MD

Assistant Professor Department of Surgery Duke University Medical Center

Ali Azizzadeh, MD Associate Professor Department of Surgery University of Texas at Houston Pathophysiology of Thrombosis and Obstruction (adapted from the Clinical Review of Phlebology and Venous Ultrasound)

Scott K. Pruitt, MD, PhD

Tara Brennan, MD

Associate Professor Resident Department of Surgery Department of Ophthalmology Duke University Medical Center University of Illinois

Leontine Narcisse, MD, PhD

Jerimiah Mason, MD

Fellow Resident Department of Surgery Department of Surgery Westchester Medical Center Baptist Medical Center

Niketa Desai, PharmD Pharmacist Department of Pharmacology Long Island University Surgical Principles (adapted from the Clinical Review of Surgery)

Basic Science

1. Basic Science 1.1. Embryology There are three main lineages for all blood cells: erythrocytes, lymphocytes, and myelocytes. This chapter will discuss red blood cells and all of their associated disorders. The last section of this textbook will discuss white blood cells, immunology, and their related disorders.

1.2. Developmental Structure

and

Function

During development, hematopoiesis begins in the yolk sac, where it remains until about 3 months. Starting at about 1 month and continuing until birth, the liver begins to serve as the primary site for hematopoiesis. The spleen and lymph nodes augment the function of the liver; after birth, both of these locations serve a secondary function to permit the maturation of lymphocytes. Hematopoiesis in the bone marrow begins at about 4 months and continues throughout life. Hematopoiesis occurs in different locations during development, eventually occurring primarily in bone marrow in the adult. In children, this is primarily in the femur and tibia; in adults, hematopoiesis generally occurs in the pelvis, vertebrae, and sternum.

Figure 1. Hematopoiesis from the fetus to adult. Copyright M. Komorniczak. Used with permission.

1.3. Erythrocytes 1.3.1

Anatomy

Multipotential hematopoietic stem cells differentiate into common myeloid and common lymphoid progenitor cells. The common lymphoid progenitor cell is discussed further in the immunology section. The common myeloid progenitor cell differentiates into the megakaryoblast, proerythroblast, myeloblast, and mast cells. Proerythroblasts differentiate into basophilic erythroblasts, then polychromatic erythroblasts, followed by normoblasts. At this point, these cells lose their nuclei and become reticulocytes. Reticulocytes mature into erythrocytes, also known as red blood cells (RBCs). 117

Clinical Review for the USMLE Step 1

Figure 2. Hematopoiesis. Copyright A. Rad. Used with permission.

RBCs have a highly deformable membrane skeleton, which permits travel through tiny capillaries that are half of the RBCs normal diameter. The most important of these structural proteins are the ankyrin complex that links the skeleton to the plasma membrane, and the protein 4.1R complex that helps to anchor various transporters and also plays a role in expressing glycoproteins. The ankyrin complex also contains a protein known as band 3, which helps to transport carbon dioxide and helps to regulate RBC physiology. A variety of transporters play a role in RBCs. In addition to the standard Na+/K+ ATPase found on most cells, there are also water transporters and a number of ion symports and antiports. Interaction of the RBC with other cells is mediated by the ICAM-4 complex and BCAM glycoprotein complex.

1.3.2

Physiology

RBCs carry hemoglobin, which binds to oxygen ironcontaining heme groups. This Figure 3. RBC plasma membrane and cytoskeleton components. oxygen is carried to tissues, Copyright Tim Vickers. Used with permission. 118

Basic Science

Figure 4. Cytokines and growth factors that play a role in hematopoiesis. Copyright Mikael Haggstrom. Used with permission. which is then exchanged for carbon dioxide. The carbon dioxide is carried by RBCs back to the lungs, where it is exchanged with oxygen. Approximately 20 trillion RBCs travel throughout the body at any given time, corresponding to about 5 million erythrocytes per microliter. Hemoglobin binds to oxygen in a sigmoid-shaped fashion. This is the result of cooperative binding, in which additional molecules of oxygen bind easily after at least two are bound, for a maximum of four molecules of oxygen per heme molecule. This binding can be modified by several factors: increase in altitude leads to higher levels of 2,3 bisphosphoglycerate (2,3-BPG), leading to a right-shift of the dissociation curve seen in the figure below. Fetal hemoglobin has a higher affinity for oxygen than adult hemoglobin, thereby ensuring that the fetus will receive an ample supply of oxygen; this leads to a leftshift of the curve. Decreasing pH and increasing temperature both lead to a right-shift.

119

Clinical Review for the USMLE Step 1

1.4. Platelets The megakaryoblast, discussed above, differentiates into promegakaryocytes, which becomes megakaryocytes and buds off platelets. Platelets have a variety of cytokines and growth factors that help lead to hemostasis. This is discussed in more detail in the following section.

1.5. Coagulation An exploration of the coagulation cascade and its attendant contributors is important to understand the various pathologies that contribute to DVT. A breakdown in one of several critical steps is all that is necessary to initiate a hypercoagulable state. Normal coagulation relies on three main contributors, including the exposed endothe- Figure 5. Oxygen-hemoglobin dissociation lium, platelets, and circulating proteins in the plasma. curve. Copyright Aaron Sharpe. Used with Just as important as these three main contributors, fi- permission. brinolytic enzymes are also required to help reform the clot and restore vascular patency. This last component is critical for normal wound healing. Normal coagulation typically begins with trauma to the vessel wall, exposing thrombogenic proteins under the endothelium such as von Willebrand Factor (vWF). vWF binds to a variety of circulating clotting factors, including collagen and factor VIII. This creates a matrix upon which platelets bind using glycoprotein Ia/IIa and Ib/IX/V receptors. Platelet activation then leads to release of alpha and dense granules. Release of thrombogenic proteins and growth factors occurs, leading to platelet clumping and the formation of fibrinogen cross-links using glycoprotein IIb/IIIa receptors. This process is known as primary hemostasis. Disruption of primary hemostasis, such as in disseminated intravascular coagulopathy (DIC), druginduced reactions with quinidine, quinine, vancomycin, or gold salts, bone marrow suppressed states, cardiopulmonary bypass, and alcohol toxicity, leads to the inability to form an enduring clot and presents as mucocutaneous bleeding. Defects in primary hemostasis can be diagnosed with platelet aggregation assays, von Willebrand Factor functional assays, and a platelet function analyzer (PFA). After formation of the platelet plug, secondary hemostasis is initiated with the coagulation cascade to form a stable fibrin plug. Both an intrinsic and extrinsic pathway are available to initiate secondary hemostasis; this dual pathway ensures that even patients with defects in primary hemostasis eventually develop some form of enduring clot over time. The most important pathway in secondary hemostasis is the extrinsic pathway, which relies upon the transmembrane receptor tissue factor (TF). Tissue factor is found within vascular endothelium, adventitia, brain, lung, heart, and placenta. While deficiencies in factors VIII and IX (hemophilia A and B, respectively) have been identified, the absence of tissue factor is typically incompatible with life.63 Constitutively low production of tissue factor is associated with spontaneous hemorrhage in the heart, lung, and placenta. Tissue factor is normally unmasked from the vascular wall following trauma. However, this factor is expressed by monocytes and possibly neutrophils, and may initiate thrombosis in patients with disseminated intravascular coagulation. Tissue factor expression upon neutrophils has been implicated 120

Basic Science as one of the causes of autoimmunity-based hypercoagulable disorders such as antiphospholipid antibody syndrome.

1.5.1 Pathway

Extrinsic

Trauma initiates a process whereby tissue factor interacts with factor VII, forming an activated complex and beginning the cycle of thrombosis. This activated complex leads to the activation of factor X and the beginning of the final common pathway that both the extrinsic and intrinsic pathways share, discussed below. The extrinsic pathway has a number of strict controls to prevent runaway thrombosis. This is necessary as factor VII is one of the most common factors in circulation and the lack of strict regulation would lead to rapid propagation of clot. The tissue factor â&#x20AC;&#x201C; factor VIIa complex is inhibited by tissue factor pathway inhibitor (TFPI), a single chain polypeptide that also inhibits factors Xa and IIa (thrombin).

1.5.2 Pathway

I n t r in s i c

Figure 6. Platelets and the two types of granules they contain. Alpha granules contain insulin-like growth factor 1 (IGF-1), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-B), platelet factor 4 (PF4), von Willebrand Factor (vWF), thrombospondin, and fibronectin. Dense granules contain ADP, ATP, calcium, and serotonin. Both types of granules are necessary for the coagulation cascade to function correctly. Copyright Surgisphere Corporation. Used with permission.

While the extrinsic pathway seems critical for thrombosis, defects in the intrinsic pathway are associated with delayed clot formation with arterial injury. The primary importance of the intrinsic pathway therefore appears to be with arterial thrombosis; clot formation throughout the veins and much of the rest of the body appears to be controlled by the extrinsic pathway.54,60-62 Indeed, elevated levels of factor XI has been found to be associated with increased risk of myocardial infarction and an independent risk factor for stroke. Contact activation initiates the intrinsic pathway when factor XII binds to an appropriately charged sur121

Clinical Review for the USMLE Step 1

Figure 7. The intrinsic and extrinsic pathway of coagulation with the interplay between the various types of factors demonstrated. Illustration by Joe Dunckley. Used in accordance with the GNU Free Documentation License Version 1.2. face, typically the site of some sort of injury. This initiates a cascade reaction where a series of trypsinlike enzymes amplify the reaction and promote thrombosis. Factor XII is activated, leading in turn to the activation of factor XI. These factors work together to activate factor IX; a deficiency of this factor leads to hemophilia B (discussed below). Factor IXa binds to activated factor VIII to initiate the activation of factor X and the beginning of the final common pathway; defects in factor VIII lead to hemophilia A. Of note, independent activation of factor XI can also occur, as seen in patients with defects in factor XII (Hageman factor deficiency).

1.5.3

Final Common Pathway

The final common pathway begins with factor Xa and is regulated by factor V. The activation of factor V is inhibited by protein C; the activation of protein C is modulated by protein S. Therefore, protein C and S serve as inhibitory mediators for coagulation and their deficiency leads to a hypercoagulable state; this is seen in warfarin administration without prior anticoagulation with heparin. Protein C and S are vitamin K dependent factors with short half-lives, and are down-regulated within the first 24-48 hours of warfarin administration. This leads to a transient hypercoagulable state while the other factors are still being down-regulated to sufficient levels. 122

Basic Science Activated factors X and V lead to the conversion of prothrombin (factor II) to thrombin (factor IIa). Thrombin leads to feedback regulation by stimulating the production of protein C and thrombomodulin. Thrombin serves to convert fibrinogen to fibrin, leading to the deposition of the hemostatic plug. Cross-linking of the fibrin clot occurs with the action of factor XIII, the production of which is also upregulated by thrombin. Organization of this blood clot occurs via plasmin-mediated fibrinolysis. Proper functioning of the coagulation cascade requires the factors discussed above, along with adequate concentrations of calcium and vitamin K. Calcium is a cofactor that is required for the activation of various factors; its deficiency is associated with coagulopathy. Vitamin K is required for the synthesis of factors II, VII, IX, X, and proteins C and S. A third protein, protein Z, is also regulated by vitamin K; this protein appears to play a role in degradation of factor Xa and XI. Defects in protein Z have been associated with hypercoagulable disorders.

1.5.4

Regulation

Regulation of the coagulation cascade relies on a variety of mediators. Protein C and S inhibit the production of factor Va, leading to cessation of further thrombin production. Protein C and S production are up-regulated by thrombin, leading to a feedback inhibition reaction at the level of the final common pathway. Tissue factor pathway inhibitor inhibits tissue factor, temporizing clot formation at the extrinsic pathway level. Prostacyclin (PGI2) leads to the production of adenylyl cyclase and cAMP production by platelets, leading to sequestration of calcium and general inhibition of coagulation.

1.5.5

Thrombolytics

Two other complex systems help to control coagulation: the first is the thrombolytic system, which involves plasmin and tissue plasminogen activator (tPA), and the second involves a group of inhibitors of the coagulation factors, including antithrombin III, protein C, and protein S. The thrombolytic system dissolves fibrin clots using the serine protease plasmin. Plasmin is formed from its inactive precursor plasminogen. Interestingly, plasmin is also activated by thrombin, which thereby limits its own clot-forming ability. The second anticoagulant system is made up of antithrombin III and proteins C and S. Antithrombin breaks down factors IXa, Xa, Xia, XIIa, and thrombin, leading to inhibition of coagulation at both the intrinsic and final common pathways, and its activity is enhanced up to 2000-fold by heparin.

1.5.6

Monitoring

There are several general tests of clotting factors commonly used to measure overall function of the coagulation cascade. The activated partial thromboplastin time test (PTT) measures the intrinsic pathway, and will be increased in deficiencies of factors VII, IX, XI, XII, von Willebrand fibrinogen. PTT testing is used to monitor heparin efficacy in patients on heparin drips. The prothrombin time test (PT) measures the extrinsic pathway and will be abnormal in deficiencies of factors II, V, VII, X and fibrinogen. Because of variations in PT level reporting, the international normalized ratio (INR) was developed to allow comparison of levels across laboratories. PT/INR testing is used to monitor vitamin K and warfarin efficacy. The coagulation cascade is a complex interplay between dozens of proteins and cells. Its seamless function is required to avoid coagulopathies and hypercoagulable states. The division into an intrinsic and extrinsic pathway play unique roles in coagulation, and offer scientists numerous targets to deal with 123

Clinical Review for the USMLE Step 1 disorders in coagulation.

1.6. Overview

Hemostasis

Hemostasis is the process whereby cells and circulating proteins interact to form an intravascular blood clot in response to vessel injury. This is a critical protective mechanism to occlude blood vessels and prevent life-threatening hemorrhage. This physiological process is generally referred to as â&#x20AC;&#x2DC;hemostasis.â&#x20AC;&#x2122; Thrombosis, by contrast, occurs when the coagulation system is activated by pathologic conditions such as atherosclerosis, infection or inflammation, leading to the formation of intravascular thromboses that obstruct blood flow and/or embolize to a distant site. Effective clotting requires the integrated action of three distinct components: 1) plate- Figure 8. Fibrinolysis. Copyright J.F. Wolff. Used with lets, which mediate primary hemostasis, 2) permission. circulating clotting factors, which mediate secondary hemostasis, and, 3) fibrinolytic enzymes, which dissolve clots to restore vascular patency and promote wound healing. Defects or activation in one of these components can lead to bleeding or clotting complications.

1.6.1

Primary Hemostasis

Primary hemostasis refers to the initial and rapid interaction of platelets with the injured vessel wall. Primary hemostasis is initiated by exposure of subendothelial proteins, such as collagen and von Willebrand Factor (vWF) and subsequent adhesion of platelets. Platelet adhesion is rapidly accompanied by platelet activation and aggregation to form a platelet plug at the injured site. Defects in primary hemostasis manifest as mucocutaneous bleeding within minutes to hours of injury and are primarily caused by quantitative or qualitative disorders of platelet function. Vessel wall dysfunction (inherited or acquired) can also lead to mucocutaneous bleeding, but is less commonly encountered in clinical practice. Testing for primary hemostasis involves measuring platelet counts and assessing platelet function using the platelet function analyzer (PFA), platelet aggregation studies and measurement of von Willebrand factor levels and activity.

124

Basic Science Table 1. Common conditions associated with derangements in bleeding or clotting. Associated with bleeding •

Sepsis/DIC

•

Non-heparin drugs (GP IIb/IIIa inhibitors, quinidine, quinine, vancomycin, gold salts and others)

•

Post-transfusion purpura

•

Marrow suppression (chemotherapy, radiation)

•

Sequestration due to cirrhosis and/or shock liver

•

Dilutional thrombocytopenia

•

Cardiopulmonary bypass

•

Alcohol toxicity and/or withdrawal

Associated with clotting •

Heparin-Induced Thrombocytopenia (HIT)

•

Thrombotic-thrombocytopenic purpura (TTP; drug induced)

•

No bleeding or clotting complications

•

Pseudothrombocytopenia

1.6.2

Secondary Hemostasis

Secondary hemostasis is the process leading to the formation of a stable fibrin plug through a sequential activation of clotting enzymes. The coagulation system is activated through exposure of plasma proteins to subendothelial tissue factor (TF). TF binds to Factor VIIa and activate Factors X to Xa (FXa) and Factor IX or IXa (FIXa). Once activated, FXa localizes to a phospholipid membrane (typically platelet derived) and with its cofactor, FVa, cleaves prothrombin (FII) to thrombin (FIIa). Thrombin, one of the most potent activators of primary (platelet mediated) and secondary (clotting factor mediated) hemostasis, potentiates further clotting through: 1) cleavage of fibrinogen, thus enabling polymerization of fibrin, 2) activation of platelet receptors, 3) activation of endothelium, 4) conversion of Factors V, VIII and XI to their activated forms (thus promoting further thrombin generation), 5) activation of FXIII leading to cross-linking of fibrinogen, and 6) activation of the enzyme, thrombin-activated fibrinolytic inhibitor (TAFI) which prevents premature fibrinolytic degradation of fibrin. Naturally occurring anticoagulants, such as protein C, S and antithrombin serve to regulate thrombin generation at sites distant from vascular injury. Defects in secondary hemostasis typically manifest as delayed bleeding within hours to days of initial injury. Disorders of secondary hemostasis are caused by acquired or congenital causes. Tests for secondary hemostasis include global tests of coagulation, the prothrombin time (PT), activated partial thromboplastin time (aPTT) and assessing the functional activity of individual clotting factors.

1.6.3

Fibrinolysis

Fibrinolysis is the physiologic process by which clots are dissolved to restore vascular patency. The 125

Clinical Review for the USMLE Step 1 enzyme, plasmin, is the principal mediator of fibrinolysis. Plasmin is converted from its precursor, plasminogen, by endogenous plasminogen activators present in the intravascular (tissue plasminogen activator, tPA) or extravascular compartments (urokinase plasminogen activator, uPA). The principal regulators of fibrinolysis are 2-anti-plasmin, which inhibits plasmin, and plasminogen activator inhibitors (PAIs), which bind and inhibit circulating tPA. Defects in fibrinolysis result in significant bleeding with injury and/or delayed bleeding due to clot instability. Assessment of fibrinolytic pathways is performed through measurement of fibrinolytic proteins (fibrinogen, plasminogen, 2-anti-plasmin, Factor XIII), and fibrin degradation products (fibrin split products, D-dimer).

2. Hematologic Disorders 2.1. Preoperative Assessment A medical history is the most vital tool for assessing surgical risk of bleeding. Relevant medical history includes information regarding spontaneous or traumatic bleeding, menstrual bleeding history (in females), severity of bleeding with minor and/or major procedures, comorbidities, especially hepatic disease, and family history of bleeding disorders. Medications should be reviewed for drugs that interfere with clotting function (aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), clopidogrel, warfarin, and/or low-molecular weight heparins). If the bleeding history is negative, current guidelines do not advise further coagulation testing. If the clinical history is positive for bleeding, then further clinical evaluation by a hematology consultant is advised.1

2.2. Approach

The Bleeding Patient

Clinical evaluation of any symptomatic bleeding requires immediate bedside assessment. Initial evaluation should include assessment of hemodynamic stability, rate of blood loss, and source of blood loss. Hemodynamic instability should be rapidly addressed with appropriate interventions to restore blood pressure and/or cardiopulmonary function. Major blood loss is usually defined as 50% loss of blood volume (~3.8-5.3 L) over a three hour period or 150 mL/min. In cases of major blood loss, it is paramount to determine type of bleeding (surgical vs. coagulopathic bleeding) and direct interventions to arrest bleeding (including volume support, blood products and/or surgery). Distinguishing surgical from coagulopathic bleeding may be challenging, particularly in patients who have had intraoperative or immediate postoperative complications, such as hypotension and/or prolonged periods of tissue ischemia. As well, previously undiagnosed acquired or inherited coagulopathies may manifest for the first time after surgical trauma. In general, surgical bleeding tends to be localized to the site of surgery, with excessive bleeding occurring at the surgical site or surrounding tissue planes. Coagulopathic bleeding can manifest either locally at site of surgical trauma, with a disproportionate amount of blood loss for a given procedure, or can be generalized and diffuse with bleeding from other sites of minor trauma (including venipuncture and catheter sites) and/or spontaneous bleeding. Laboratory abnormalities (PT/aPTT or fibrinogen) may be seen with coagulopathic bleeding, whereas surgical bleeding, if not severe or life-threatening, is generally associated with normal laboratories. Coagulopathic bleeding can be caused by a variety of congenital or acquired bleeding disorders. For patients without known history of bleeding and/or congenital bleeding disorders, the temporal relationship of bleeding to surgery may offer clues to type of hemostatic defect. Bleeding from mucocutaneous sites within minutes to hours of surgery, including bleeding at the surgical incision, implies defects 126

Hematologic Disorders in primary hemostasis. Assessment should be directed at platelet and/or vessel wall function, recent anti-platelet therapies, and/or acquired qualitative or quantitative platelet defects (see below). Delayed bleeding (hours to days after surgery) occurs from defects in secondary hemostasis, most often due to complications arising from anticoagulant therapies, medical comorbidities, and/or surgery (sepsis, dilutional coagulopathy). Severe derangements of fibrinolysis can manifest as intraoperative or immediate post-operative bleeding, depending on the etiology of fibrinolytic defect.

2.3. Acquired Bleeding Disorders The following sections review the diagnostic and therapeutic considerations for patients with commonly acquired bleeding disorders in the surgical setting. Bleeding complications arising from congenital disorders are beyond the scope of this discussion and are reviewed elsewhere.2

2.3.1

Bleeding From Platelet Defects

Bleeding from platelet dysfunction manifests as mucocutaneous bleeding and occurs within minutes of injury. Bleeding can be caused by quantitative or qualitative platelet defects.

Thrombocytopenias Acquired thrombocytopenias in surgical patients can be caused by consumption, immune destruction and/or marrow suppression (from drugs or infection). Assessment of acquired thrombocytopenia should include review of patients preoperative baseline platelet counts (if available), thorough evaluation of medication history, in particular, heparin use, and examination of the peripheral blood film to rule out platelet clumping or pseudo-thrombocytopenia. Thrombocytopenia is a common manifestation of bacteremia and/or sepsis and often occurs in the absence of disseminated intravascular coagulation. Depending on the etiology, acquired thrombocytopenias may be associated with bleeding or clotting complications. For non-surgical patients with non-immune mediated platelet destruction, bleeding risk is increased with platelet counts <10,000/ÂľL. Prospective data are lacking on threshold platelet counts necessary for maintaining hemostasis during surgical procedures. For post-operative patients, prophylactic platelet transfusions to keep platelet counts above 50,000/ÂľL are advised within 24 hours of major surgery and/ or with active bleeding. Table 2. Minimum platelet levels prior to completing surgery. Type of Surgery

Threshold Platelet Count /Âľ L

Ocular surgery or neurosurgery

100,000

Major Surgery with risk factors for bleeding

50,000-100,000

Major Surgery, non-critical sites

50,000

Minor procedures (lumbar puncture, epidural anesthesia, endoscopy, central line, liver biopsy, etc.)

50,000

Heparin-Induced Thrombocytopenia Heparin-Induced Thrombocytopenia (HIT) is a recognized immune complication of heparin therapy. HIT is caused by antibodies directed to complexes containing heparin, and a platelet protein, Platelet 127

Clinical Review for the USMLE Step 1 Factor 4 (PF4). The spectrum of illness associated with PF4/heparin antibodies ranges from asymptomatic antibodies (in most individuals) to isolated thrombocytopenia in 1-5% of patients and/or lifethreatening thrombosis in a smaller subset of patients (0.5-1%). Clinical HIT is diagnosed by the presence of absolute (platelet count <150,000/µL) or relative thrombocytopenia (decrease from baseline platelet counts of 30-50%) within 5-7 days of heparin therapy, and/or development of new thrombosis, which develops in 20-50% of patients with thrombocytopenia. Mortality from thrombotic complications remains high (6-27%). Diagnosis of HIT is made using clinical criteria: 1) drop in platelet count or thrombosis within 4-14 days of heparin therapy (in previously unexposed patients or within 24 hours in previously exposed patients) 2) exclusion of other causes and demonstration of PF4/heparin antibodies by serologic or platelet activation assays. Treatment is directed at avoiding heparin therapy and using alternative anticoagulants, such as the direct thrombin inhibitors (argatroban, lepirudin or bivalirudin).

Bleeding From Qualitative Platelet Defects Bleeding from acquired platelet dysfunction in hospitalized patients is most frequently caused by drugs and/or medical comorbidities. Platelet function can be inhibited by drugs targeting platelet function (aspirin, aspirin derivatives, clopidogrel and GPIIb/IIIa inhibitors) or drugs with off-target effects (selective serotonin reuptake inhibitors, antibiotics, etc). Medical conditions associated with acquired platelet dysfunction include renal or liver disease, paraproteinemia or marrow disorders (leukemia, myelodysplasia and/or myeloproliferative diseases).

Bleeding from ASA/Clopidogrel The effects of aspirin and clopidogrel on platelet function are permanent for the 7-10 day life-span of the platelet. Recovery of platelet function is dependent on synthesis and release of new platelets by megakaryocytes. Generalized bleeding is not increased with aspirin or clopidogrel therapy (bruising or epistaxis <2-4%), unless the patient has a coexisting defect in hemostasis. Surgical bleeding is increased with clopidogrel and drug should be discontinued 7-10 days prior to surgery. It is never appropriate to transfuse platelets for elective procedures in patients who have consumed aspirin or clopidogrel. These patients should discontinue drug and have their procedures rescheduled.

Bleeding From GPIIb/IIIa Inhibitors GPIIb/IIIa inhibitors [abciximab, eptifibatide (a cyclic heptapeptide), and tirofiban (a nonpeptide)] lead to nearly complete inhibition of platelet aggregation due to occupancy of platelet GPIIb/IIIa, the platelet fibrinogen receptor. Antiplatelet effects wane rapidly, depending on drug half-life (4‑36 hours). Bleeding rates with GPIIb/IIIa inhibitors is comparable to heparin therapy. For severe or life-threatening bleeding secondary to GPIIb/IIIa inhibitors, reversal of therapy can achieved with discontinuation of drug, followed by platelet transfusion. Timing of platelet transfusion must take into account the clearance of drug from plasma (10-30 minutes for abciximab, and approximately 2 hours for eptifibatide and tirofiban), to keep fresh platelets from being inactivated by circulating drug.

Bleeding From Platelet Dysfunction Platelet dysfunction caused by medical disorders or other drugs is most effectively addressed by treating the underlying medical condition and/or drug discontinuation. In the event of severe or life-threatening bleeding, platelet transfusions are recommended to maintain platelet counts >50,000 / µL. Other therapeutic options include use of desmopressin (1-deamino-8 D-arginine vasopressin or DDAVP).

128

Hematologic Disorders 2.3.2

Bleeding From Hemostatic Defects

As stated previously, it is often difficult to discern bleeding from surgical and non-surgical causes. This section covers bleeding from hemostatic derangements caused by drugs, medical comorbidities or coagulopathy arising from surgical complications.

2.3.3

Bleeding From Anticoagulants

Anticoagulant agents exert their inhibitory effects on clot formation through direct inhibition of clot formation (thrombin inhibitors) or through augmentation of inhibitory pathways (antithrombin III or proteins C & S). Hemorrhagic episodes occur predictably when full dose anticoagulation (UFH or LMWH) is given within 12-24 hours of surgery. Excessive post-operative bleeding is not seen with thromboprophylactic doses of unfractionated heparin (UFH) or low-molecular weight heparin (LMWH). In general, hemorrhagic complications correlate with the intensity of anticoagulation (therapeutic > prophylactic), concomitant use of GPIIb/IIIa inhibitors or thrombolytic therapy, gender (F > M), patient comorbid conditions (including renal and/or liver disease) and coexisting hemostatic defects (congenital or acquired platelet or clotting factor deficiency).

Bleeding from Warfarin For elective procedures or surgery, it is recommended that warfarin be discontinued 4-5 days prior to the planned procedure. LMWH can be started when the INR falls below 2 and discontinued 12 hours before surgery. Prophylactic infusion of FFP may be required of the INR is greater than 1.6, but is not required when the INR is below this value. In emergency cases or when bleeding is noted due to warfarin, following the guidelines of the American College of Chest Physicians for warfarin reversal is recommended.3 Depending on the degree of the INR elevation and the severity of bleeding, patients may require vitamin K, FFP, or consideration of infusion of a prothrombin complex concentrate such as Bebulin of Profilnine or recombinant activated factor VII (NovoSeven).

Bleeding From UFH For elective procedures or surgery, discontinuing therapeutic doses of UFH 4 hours prior to the procedure and measuring an aPTT is all that is needed, as normal hemostasis is restored in this time frame in most cases. If the aPTT remains elevated, then hourly measurements are advised until the aPTT returns to baseline. In cases where hemorrhage is brisk or life-threatening, the anticoagulant effects of UFH can be reversed with protamine sulfate, a positively charged protein extracted from fish sperm, at a ratio of 1 mg of IV protamine for 100 units of UFH. For patients who are on continuous infusion of heparin, the dose of heparin administered within 2-2.5 hours should be calculated to arrive at an approximate protamine dose. If the dose of heparin is unknown, the maximal tolerated protamine dose of 50 mg can be administered slowly over 10 minutes followed by serial measurements of the aPTT. Side effects of protamine include hypersensitivity reactions, including anaphylaxis, hypotension and pulmonary hypertension. Allergic responses to protamine are more common in patients who have been previously exposed to the drug for heparin neutralization or through protamine containing insulin [Neutral Protamine Hagedorn (NPH) insulin].

129

Clinical Review for the USMLE Step 1 Bleeding From LMWH and Fondaparinux For patients receiving therapeutic doses of LMWH who require elective procedures or regional anesthesia, a delay of 24 hours after the last dose of LMWH is recommended. Therapeutic dose LMWH should not be restarted for 24 hours after a major procedure or neuraxial anesthesia. Prophylactic doses of LMWH, however, can be safely administered within 12-24 hours of most procedures. Protamine is only partially effective in reversing the anti-Xa effects of LMWHs, with maximum neutralization of 6075% to be expected. For suspected overdose, or life threatening hemorrhage, manufacturers of LMWHs recommend IV protamine at a dose of 1Â mg per 100 mg anti-Xa IU of LMWH, followed by a second 0.5 mg per 100 anti-Xa IU if the aPTT is prolonged. Recombinant VIIa has been used for life-threatening bleeding from LMWHs or fondaparinux.

Bleeding from Direct Thrombin Inhibitors The hirudin analogs, lepirudin and bivalirudin, and argatroban are three currently approved agents which directly inactivate circulating and clot bound thrombin. Presently, there are no antidotes for reversing the hemorrhagic effects of these agents. Both lepirudin and bivalirudin can be removed from circulation through hemodialysis. There is no mechanism for removing argatroban from the circulation.

2.3.4

Bleeding From Medical Comorbidities

Coexisting renal and/or liver disease is associated with higher rates of intraoperative and post-operative bleeding. Vitamin K deficiency may arise from decreased oral intake, especially when coupled with the use of parenteral antibiotics. Surgical bleeding may also be the first manifestation of an underlying congenital or acquired bleeding disorder (such as von Willebrand disease or hemophilia). Laboratory abnormalities will often direct identification of the hemostatic defect. Therapy for bleeding secondary to medical conditions should be individualized and proceed in consultation with a hematologist.

2.3.5

Acquired Factor V Inhibitors

Acquired clotting factor inhibitors occur rarely, but are associated with significant morbidity and mortality. In vascular surgery, acquired Factor V is the most commonly encountered due to contamination of topical thrombin with small amounts of bovine Factor V, which cross-reacts with human factor V. This immunologic cross-reactivity in some cases triggers development of an inhibitory antibody to human Factor V. Factor V inhibitors typically manifest 5-10 days after surgery with profound bleeding and are typically associated with a prolonged PT and aPTT Diagnosis of Factor V inhibitors is made through plasma mixing studies, by mixing patient plasma with normal plasma at a 1:1 ratio. The mixing study distinguishes a Factor V deficiency (correction of PT/aPTT with mixing) from acquired Factor V inhibitors (which do not correct the PT/aPTT after mixing) Patients who are bleeding may respond to transfusions of platelets, which carry their own store of Factor V which is less accessible to inhibition. Plasma exchange and IVIG have also been reported to be effective.

2.3.6

Bleeding From Surgical Complications

Excessive bleeding after surgery may result from the surgical procedure itself (from vessel injury) or complications resulting from surgery including dilutional coagulopathy, use of colloid plasma expanders (dextran or starch), and consumption of clotting factors with or without disseminated intravascular coagulation (DIC). Hypothermia and acidosis also inhibit the function of coagulation factors and contribute to the coagulopathy.

130

Hematologic Disorders

2.4. Dilutional Coagulopathy Dilutional coagulopathy results from excessive transfusion of red cell concentrates without replacement of plasma and/or platelets. Replacement of 1.5 blood volumes with packed red cells can lead to prolongation of the PT/aPTT and decreases in platelet counts and fibrinogen. Laboratory tests (CBC, PT/aPTT and fibrinogen) should be monitored in patients receiving >10-15 units PRBCs and appropriate blood products (fresh frozen plasma, FFP; cryoglobulin or platelets) should be transfused to correct the coagulopathy.

2.4.1

Disseminated Intravascular Coagulation

Consumption of clotting factors and/or platelets occurs with major surgery, and can be exacerbated by prolonged hypotension, acidosis, hypothermia or tissue ischemia. In severe cases, consumption of clotting factors may initiate DIC and profound hemostatic derangements. Evaluation for DIC in the postoperative setting is difficult. In non-surgical patients, laboratory abnormalities (decreased fibrinogen and platelet counts (with or without microangiopathic hemolysis), elevated D-dimers and prolonged PT/aPTT) can be used to support a diagnosis of DIC in the appropriate clinical context (sepsis, obstetric catastrophe, massive trauma, cancer). However, in the surgical patient, tissue injury resulting from surgery as well as elevation of acute phase reactants leading to elevations in D-dimer and fibrinogen may mask signs of DIC. A recommended strategy for DIC in the post-surgical patient includes laboratory assessment of CBC, PT/aPTT, fibrinogen and peripheral blood film. Treatment is generally supportive and includes transfusion of blood products and correction of the underlying cause, if one can be identified.

2.4.2

Colloid Plasma Expanders

Colloid plasma expanders used in surgery (hydroxyethylstarch or gelatin solutions) can impair hemostasis beyond dilutional effects on coagulation. The exact mechanisms for starch induced coagulopathy is not known, but changes in activity of Factor VIII, von Willebrand factor (vWF), diminished platelet activation and defects in fibrin polymerization have been described. Changes in coagulation parameters are correlated with molecular weight of the polymer (hetastarch, MW 450kDa > pentastarch MW=200Â kDa) and are dose dependent (>20 mL/kg/d). Starch solutions are primarily excreted by the kidney and can remain in circulation for 2-4 days after administration. Coagulopathy can be corrected with appropriate replacement, if abnormalities in vWF or FVIII can be identified. Cryoprecipitate has been used successfully in some patients but not others.

2.5. Hypercoagulable States Although thrombosis can affect any vascular bed, the pathogenesis of arterial and venous thrombosis is often distinct and only rarely overlaps. Arterial thrombosis is principally caused by acute or chronic endothelial injury resulting from atherosclerosis. Atherosclerotic rupture exposes subendothelial matrix, rich in tissue factor, collagen and other proteins, and enable rapid platelet adhesion and activation. Arterial occlusions are characterized by platelet rich thrombi, as adherent platelets, stabilized by vWF and fibrinogen, are able to withstand the higher shear forces and flow rates found in the arterial bed. Atraumatic acute arterial thrombi in the limbs can occur from plaque rupture from advanced atherosclerosis or from cardiac or noncardiac sources of emboli. Cardiac emboli can arise from complications of atrial fibrillation, intraventricular mural thrombi, or valvular disease. Noncardiac emboli may arise from arterial aneurysms, remote atherosclerotic plaque rupture, paradoxical venous thrombi or recent procedures. 131

Clinical Review for the USMLE Step 1 Venous thrombi occur in vascular beds with lower flow rates and are composed of red cells organized in a fibrin mesh. The elements of Virchowâ&#x20AC;&#x2122;s triad first conceptualized over 150 years ago by the German pathologist, Rudolf Virchow, remain essential to our current view of the pathogenesis of venous thrombosis, which involves changes in: 1) blood flow 2) clotting factors and 3) endothelial injury. Thrombotic risk factors are characterized as inherited or acquired, although acquired risk factors are most often the trigger for thrombosis in patients with and without inherited thrombophilic tendencies. The majority of antithrombotic agents in clinical use (antiplatelet agents and anticoagulants) affects thrombus initiation or extension, and can therefore be considered prophylactic agents. Antithrombotic therapy used for the prevention of thrombus initiation is considered primary prophylaxis, whereas preventive therapy directed at clot extension is considered secondary prophylaxis. Fibrinolytic agents, in contrast, lead to dissolution of clots, and are used in the management of active thrombosis. In general, antiplatelet agents appear to be more effective in arterial thrombo-occlusive disease, and anticoagulants more useful in the treatment of venous thromboembolic disease, although clinical overlap of these agents occur in a variety of disease settings.

2.6. Venous Thromboembolism 2.6.1

Thromboprophylaxis in Surgery

Asymptomatic DVT occurs in 15-25% of patients undergoing surgery not receiving thromboprophylaxis and symptomatic venous thromboembolism (VTE) occurs in ~2% of patients undergoing vascular surgery. Higher rates of VTE have been reported in patients undergoing aortic aneurysm repair and aortofemoral bypass. Thromboprophylaxis should be considered for most surgical procedures.7

2.6.2

Postsurgical Acute Venous Thromboembolism

When patients present with acute VTE in the postsurgical setting, treatment is complicated by a higher bleeding risk. Full-intensity anticoagulation should be avoided for 5-7 days or longer after major (open) intraabdominal surgery or surgery involving a vital organ. Use of an inferior vena cava (IVC) filter may be considered in this setting. For patients undergoing minor procedures or at low risk of bleeding, anticoagulation with UFH is recommended, as this agent can be reversed with protamine in the event of bleeding. A hematology consultation is advised to assist in determining the optimal perioperative management of patient with acute VTE.

2.6.3

Perioperative Anticoagulation

Patients on long-term anticoagulation may require anticoagulation in the perioperative or postoperative setting. Risk stratification for perioperative anticoagulation must be individualized due to the number of variables affecting both thrombotic and bleeding risk. Variables to consider include: 1)Â indication for anticoagulation therapy, 2) remoteness of thrombotic event, 3) type of surgery and attendant hypercoagulable and bleeding risk, and 4) age and comorbid illness. If patients have had recent arterial or venous thrombosis (<3 months), elective surgery should be deferred due to the high hypercoagulable risk posed by surgery. For those patients with recent thrombosis and an urgent surgical indication, consultation with a hematologist or internist is advised to determine need for pre/post-operative anticoagulation and/or adjunctive therapies (inferior vena caval filters or IVCs). For those with more remote clotting histories, indications for post-operative anticoagulation must be individualized due to the heterogeneity of disease conditions and types of procedures. 132

Hematologic Disorders

2.7. Anemias 2.7.1

Microcytic Anemia

Iron-Deficiency Anemia Iron-deficiency anemia is due to decreased iron stores following poor intake, excess loss, or poor absorption. Iron-deficiency anemia is the most commonly encountered anemia in general practice. It is most common in the reproductive years of women and in pregnant women. The most common cause in men is the result of an occult GI bleed. Other causes include alveolar hemorrhage, nosocomial loss, CRF treated with hemodialysis, following surgery, and various types of hemolysis. Iron-deficiency anemia presents with constitutional symptoms, exertional dyspnea, anorexia, melena, hematochezia, and / or hemoptysis, depending on the particular cause of blood loss. Objective signs include glossitis, angular stomatitis, koilonychias, pallor; iron-deficiency anemia can also be entirely subclinical. Anisocytosis and increased RDW are early signs of this disorder, and MCV indicates a hypochromic microcytic anemia. These results, combined with low ferritin, are diagnostic for irondeficiency anemia. Treatment involves replacing iron stores and correcting any underlying etiology. Ferrous sulfate is the agent of choice to replenish iron stores in the body.

Sickle Cell Anemia (SCA) Sickle cell anemia (SCA) is a commonly inherited disease that is associated with significant morbidity and decreased lifespan. An autosomal recessive defect in the beta chain of the adult hemoglobin (HbA) leads to the sickle cell hemoglobin (HbS). Due to defects in RBC deformability, obstruction of blood vessels leads to sickle cell pain crises and organ damage, in addition to anemia. SCA presents with constitutional symptoms and anemia. Painful crises occur intermittently due to vessel blockade (and possibly hand-foot syndrome) cause swelling and pain in the distal upper and lower extremities. Stroke is common, along with TIAs and RIND. Priapism may also occur with SCA. Acute presentations can include acute chest syndrome (ACS), which may present with severe chest pain due to blockade within the pulmonary vasculature. Chronic SCA can present with growth retardation, hepatomegaly, splenomegaly, pallor, jaundice, cardiomegaly with an SEM, skin ulceration, and cholelithiasis. A proliferative retinopathy is often present as well. Serious complications may also occur similar to an infection. Diagnosis of SCA is made by hemoglobin studies. SCA is definitively cured only by bone marrow transplantation. In most individuals, treatment centers on avoiding pain crises, giving prophylaxis for infection, and reducing the symptoms and damage from SCA. Fluid repletion is commonly the first step in any acute presentation. NSAIDs are the first line of treatment for pain management followed by hydroxyurea (by some clinicians). Penicillin is often given to avoid pneumonia, which is common in SCA, and folic acid supplements.

Alpha-Thalassemia Alpha-thalassemia is the result of a hereditary defect in hemoglobin synthesis leading to an excess of beta-globins and the formation of hemoglobin H tetramers. Alpha-thalassemia affects Africans, Asians, Mediterraneanâ&#x20AC;&#x2122;s, and Europeans. A cis deletion is one in which two alpha genes are lost on the same chromosome; cis loss has a greater potential to lead to more serious disease in offspring. Deletion of 133

Clinical Review for the USMLE Step 1 just one gene is asymptomatic and clinically insignificant. A cis deletion or trans deletion leads to alphathalassemia. Loss of three alpha hemoglobin genes leads to chronic hemolytic anemia. Loss of all four alpha hemoglobin genes leads to death in utero due to hydrops fetalis. Alpha-thalassemia has variable penetrance and can lead to a hemolytic anemia. Multiple blood transfusions are necessary in some individuals, leading to hemochromatosis and widespread organ damage. Pallor is evident with significant anemia. Jaundice and hepatosplenomegaly are also typically present, along with folic acid deficiency. Ulceration and a predisposition to infection are common. A hypochromic, microcytic hemolytic anemia is typically present. Pigment gallstones from the hemolytic anemia may also develop. Hemoglobin electrophoresis demonstrates HbH. Treatment for alpha-thalassemia involves supportive therapy, rapid resolution of infections, transfusion, if symptomatic severe anemia hemoglobin titers occur below 7 g / dL, treatment of hemochromatosis, and in severe cases, a bone marrow transplantation â&#x20AC;&#x201C; the only definitive cure. Hemoglobin H disease, also known as Bartâ&#x20AC;&#x2122;s hemoglobin, requires blood transfusions for survival. Alpha-thalassemia minor leads to subclinical disease.

Beta-Thalassemia Beta-thalassemia presents with an excess of alpha-globins leading to alpha-globin tetramers. Deletions and substitutions within the genetic framework account for most cases of beta-thalassemia and spontaneous disease is possible. Beta-thalassemia deals with a maternal and paternal allele; as a result, damage to one allele leads to reduced formation of the beta-globin. Damage to both alleles leads to formation of only alpha chains. Beta-thalassemia is especially common in Italians, Greeks, and Southeast Asians. Beta-thalassemia presents as a congenital condition that leads to severe jaundice and anemia early in life. Constitutional symptoms, symptoms of anemia, and hypersplenism are common. Gallstones may also be present. Diagnostic workup proceeds in the same fashion as alpha-thalassemia. Beta-thalassemia major leads to early splenomegaly and symptoms of anemia, and typically requires transfusions to maintain hemoglobin above 3-5 g / dL. Thalassemia intermedia leads to a hemoglobin titer between 6 and 9 g / dL. Thalassemia minor leads to clinically insignificant disease. Treatment for beta-thalassemia includes transfusion for symptomatic, severe anemia and supportive therapy is a must. Like alpha-thalassemia, splenectomy may be necessary to decrease the number of required transfusions. Early treatment for infections is required. Bone marrow transplantation is curative.

2.7.2

Macrocytic Anemia

Megaloblastic Anemia Megaloblastic anemia is the presence of immature erythroblasts with an increase in MCV. Megaloblastic anemia is commonly found in vitamin B12 deficiency or folate deficiency. The former may be due to an autoimmune defect leading to pernicious anemia, poor intake, or malabsorption due to ileal disease. The latter may be due to alcoholism, poor intake, chronic hemolytic anemia, or various malabsorption syndromes. Various chemotherapy drugs may also lead to megaloblastic anemia. Megaloblastic anemia is more common with increasing age. African American women and the elderly are most at risk.

Folate Deficiency Folate deficiency may be the result of poor dietary intake, increased demand, as in pregnancy, or increased demand, as in chronic hemolytic anemias. Any number of hemolytic anemias may lead to an in134

Hematologic Disorders creased requirement in folate levels. Malabsorption syndromes such as Crohn disease or other enteropathies can lead to failure to properly absorb folate. Antagonists to folate such as methotrexate, or those agents that affect metabolism such as alcohol, sulfasalazine, triamterene, TMP-SMX, barbiturates, and nitric oxide can impede the use of folate by RBCs. Exposure to heavy metals or toxins such as arsenic or chlordane can also lead to retardation of folate utilization. Folate-deficiency megaloblastic anemia presents with pallor and glossitis. There are no neurologic deficits.

Vitamin B12 Deficiency Vitamin B12 deficiency may be a result of many of the causes that lead to folate deficiency. In addition, pernicious anemia due to antibodies against parietal cells may lead to diminished amounts of intrinsic factor required for binding and absorption of vitamin B12. Lack of animal protein in strict vegetarian diets can also lead to deficiencies in vitamin B12. Diverticulosis and bacterial overgrowth, or infection by D. latum also lead to decreased vitamin B12 available for absorption. Vitamin B12-deficiency megaloblastic anemia presents with pallor, glossitis, and a peripheral sensory neuropathy that advances to a loss of deep tendon reflexes (DTR). Confusion and memory loss may be present. Delirium and dementia may occur in later stages. Diagnosis of megaloblastic anemia is made by increases in MCV, identified decrease in folate and / or vitamin B12, and the presence of an anemia. Hypersegmented neutrophils may be present in pernicious anemia. A Schilling test may be done to test the ability to absorb vitamin B12. Methylmalonic acid is normal in folate-deficiency megaloblastic anemia but positive in vitamin B12-deficiency megaloblastic anemia. Antibodies to intrinsic factor can be demonstrated for pernicious anemia. Treatment for megaloblastic anemia is to replace the vitamin deficiency. Care should be taken in reversing a vitamin B12 deficiency by folate. Folate, however, will not prevent further progression of the neurologic symptoms from a vitamin B12 deficiency. Transfusion is occasionally undertaken in severe anemia, but pulmonary edema may develop. Vitamin replacement is the standard of care.

2.7.3

Normocytic Anemia

Anemia of Chronic Disease The most common cause of a normocytic anemia is anemia of chronic disease (ACD); ACD is also the second most common type of anemia. While ACD tends to be a normocytic normochromic anemia, some presentations may have a microcytic anemia. ACD is due to decreased bone marrow production of erythrocytes after longstanding chronic disease, itself the result of a combination of erythropoietin resistance, decreased production, and decreased RBC half-life. ACD may also be due to chronic inflammation, cancer, and systemic diseases. ACD tends to develop with a moderate- or low-grade anemia and is typically subclinical in presentation. More severe cases may present with symptoms of anemia. Treatment of the primary disease is the only way to resolve ACD. Blood transfusions are rarely required.

Sideroblastic Anemia Sideroblastic anemia presents with ring sideroblasts in the bone marrow, decreased heme synthesis, and a normocytic anemia. The general cause is a disruption in the normal metabolism of mitochondria leading to decreased ATP available for consumption by the RBC. This injury may be the result of numerous etiologies, including hereditary mechanisms such as a congenital X-linked disorder, an autosomal 135

Clinical Review for the USMLE Step 1 dominant disorder, an autosomal recessive disorder, and inherited mitochondrial cytopathy; acquired etiologies include myelodysplastic syndrome (MDS), certain drugs such as alcohol, INH, chloramphenicol, and cycloserine, toxins such as lead and zinc, and nutritional deficiencies such as lack of copper or pyridoxine. MDS is a dysfunction in hematopoietic stem cell function that affects all three cell lines (myeloid precursors, erythroid precursors, and megakaryocytes) leading to ineffective erythropoiesis, marrow dysfunction, and eventually, the development of acute leukemia. Various drugs lead to sideroblastic anemia through blockade of the heme biosynthetic pathway; INH in particular has been implicated in numerous cases of sideroblastic anemia. Sideroblastic anemia presents with moderate or severe anemia with the typical symptoms of anemia â&#x20AC;&#x201C; including constitutional symptoms such as fatigue, dizziness, and decreased exercise tolerance. A history identifying a particular etiology may also be present, such as alcoholism or toxin exposure. Basophilic stippling is evident on examination of a peripheral blood smear; hypochromia and microcytosis may be present in some cases instead of the typical normocytic anemia. Treatment of sideroblastic anemia involves reversing those etiologies that are amenable to treatment. Blood transfusions are often required in other cases. Pyridoxine is sometimes effective. Monitoring iron load and using deferoxamine to avoid hemochromatosis is the standard of care in any situation involving chronic transfusions.

Aplastic Anemia Aplastic anemia is the development of pancytopenia as a result of an acquired or familial syndrome that leads to bone marrow failure. Acquired disease may be the result of exposure to viral infections such as EBV, HIV, HBV, or dengue fever, mycobacterial infection, autoimmune disease, toxic chemical exposure including benzene, chemotherapeutic agents, arsenic, and estrogens, and exposure to ionizing radiation. Many other medications can also lead to aplastic anemia, but they are a rare complication. Insecticides and gold compounds in particular can lead to serious illness. Aplastic anemia affects fewer than 1 patient in 100,000, and generally peaks in the elderly. Transient causes include vitamin B12 or folate deficiency and infection by agents such as parvovirus B19. Aplastic anemia presents with abnormalities in bleeding, epistaxis, fever, pharyngitis, easy bruising, and various constitutional symptoms. Signs of anemia are present, along with oral ulcerations and retinal hemorrhage. Severe aplastic anemia has anemia with reticulocytopenia, thrombocytopenia, neutropenia, and a hypocellular bone marrow. Pancytopenia is found on CBC, and bone marrow biopsy confirms the diagnosis. A dry bone marrow tap is more typical of an infiltrative marrow disease, not aplastic anemia. Therapy for aplastic anemia revolves around correcting any reversible causes of the anemia and consideration of a bone marrow transplantation. Immunosuppressive therapy may be needed in patients who cannot receive a transplantation; cyclosporine and antithymocyte globulin are used in this case. Infection prophylaxis is important for good care.

2.7.4

Specific Anemias

Fanconi Anemia Fanconi anemia is an inherited failure of the bone marrow leading to pancytopenia and aplastic anemia. This autosomal recessive disease occurs due to mutations in several different genes that code for proteins responsible for DNA repair; the outcome is a series of birth defects, bone marrow dysfunction, and carcinogenesis. About 1 in 300 persons are carriers, but only about 1 in over 300,000 persons is 136

Hematologic Disorders affected. Ashkenazi Jews are more affected by Fanconi anemia. Morbidity in this disorder is due to bone marrow failure, the development of leukemia, and carcinogenesis. Fanconi anemia presents with growth retardation, anatomic defects in the genitourinary system, and radial ray anomalies. CafĂŠ au lait spots are present, along with petechiae and numerous constitutional symptoms. Symptoms of thrombocytopenia and pancytopenia are predominant over time. Short stature is nearly universal, along with profound defects of the head, face, and remaining skeleton. Conductive deafness and congenital cardiac defects are typically present. Diagnosis is made by chromosomal analysis and the presence of marrow failure. Imaging studies confirm the skeletal defects. Symptomatic and supportive therapies are the standard of care for patients with Fanconi anemia. Stem cell transplantation may prevent aplastic anemia, MDS, and leukemia. Surgical intervention is often necessary to repair limb defects.

Hemolytic Anemia Hemolytic anemia leads to early destruction of RBCs and presents with anemia when the bone marrow cannot compensate for the loss of RBCs. Numerous causes exist, but major ones include G6PD deficiency, hereditary spherocytosis, sickle cell anemia, DIC, HUS, TTP, prosthetic valves, and PNH. It is present in about 1 in 20 anemias and leads to symptoms only with severe anemia. Hemolytic anemia presents with symptoms of anemia. Tachycardia, dyspnea, and weakness are typically present in severe cases. Bilirubin pigmented stones may lead to cholelithiasis. Repeated transfusions may lead to hemochromatosis. A history of use of certain medications, such as penicillin, quinine, or L-dopa may be responsible for an immune reaction leading to hemolytic anemia. Favism is especially common in the Mediterranean type of G6PD. Pallor, jaundice, splenomegaly, leg ulcers, and other symptoms of anemia may be present on physical exam. Diagnosis is made by peripheral blood smear and standard tests for anemia. Treatment for hemolytic anemia is similar to that for any other type of anemia â&#x20AC;&#x201C; transfusions with symptomatic, severe anemia, avoiding triggers that worsen the anemia, and treating reversible causes.

Cold Hemolytic Anemia Cold agglutinin hemolytic anemia occurs due to IgM antibodies that induce a complement-mediated lysis of RBCs. The IgM antibodies may be due to a clonal expansion of B cells, or following infection by Mycoplasma pneumoniae, EBV, influenza, and HIV. Agglutination of the IgM antibodies and subsequent hemolysis occurs especially in colder temperatures, hence the name of this disease. Low titers of IgM are found in otherwise healthy persons; elevations may occur with infection, autoimmune disease, or periods of significant stress. Only 1 in 300,000 persons are affected. Cold agglutinin hemolytic anemia presents with Raynaudâ&#x20AC;&#x2122;s phenomenon with significant symptoms during cold weather. Constitutional symptoms are typically present, along with symptoms from any concurrent infection. Dark urine may also be present with cold weather due to significant peripheral hemolysis. Pallor is typically present, but splenomegaly and jaundice are absent in this disease. It is differentiated from warm hemolytic anemia (discussed above) because this disorder is present only with cold temperatures. Diagnosis is made in a manner similar to that of other hemolytic anemias and with cold agglutination studies. Treatment is to avoid the cold and to properly protect the patient against cold weather. Otherwise, standard therapy for anemia is undertaken but rarely necessary as this anemia is typically mild in nature. 137

Clinical Review for the USMLE Step 1 Plasmapheresis may be intermittently necessary to remove excess IgM.

Paroxysmal Hemolytic Anemia (PHA) Paroxysmal hemolytic anemia (PHA) is also known as autoimmune hemolytic anemia (AIHA), a type of hemoglobinuria that occurs due to an autoimmune disorder leading to significant intravascular hemolysis and anemia. It is typically present during periods of significant stress such as infection. PHA is distinct from other hemolytic anemias in that it is highly symptomatic and also has a proteinuria with a Bence Jones-type of polypeptide. PHA is due to low temperatures leading to binding of a polyclonal IgG to RBCs inducing intravascular hemolysis. Postviral infections may induce the formation of this antibody and subsequent disease. PHA presents with significant symptoms of anemia that develop insidiously after cold exposure. Significant lower extremity pain and severe constitutional symptoms are acutely present. Renal failure can occur due to the significant level of hemolysis taking place. A concurrent viral infection may be present. Diagnosis is made by clinical history and confirmation through an anemia workup. LDH and unconjugated bilirubin are high, and free hemoglobin may be found in the plasma â&#x20AC;&#x201C; a testament to the rapid intravascular hemolysis taking place. A positive D-L antibody test also indicates cold temperaturemediated lysis of RBCs after the temperature rises. Treatment is similar to that of cold agglutinin hemolytic anemia. Rapid treatment of infections is necessary. Hydration is necessary to avoid renal failure and damage. Folic acid supplements are recommended, as they are in virtually all anemias.

Paroxysmal Nocturnal Hemoglobinuria Paroxysmal nocturnal hemoglobinuria (PNH) is the formation of dark urine due to hemolysis that occurs over time. Hemolytic anemia is present due to lack of deformability in the RBC membrane. Thrombosis of large vessels may occur in this disorder. Hemopoietic deficiencies may also be present and lead to pancytopenia or aplastic anemia. This triad distinguishes PNH from other hemolytic anemias. The underlying defect is due to inability to manufacture glycosyl-phosphatidylinositol (GPI), an anchor that latches proteins onto the cell membrane. The defect is in the phosphatidylinositol glycan class A (PIGA) gene, among defects found on other genes. PNH presents with dark urine early in the morning, but hemolysis continues throughout the day. Venous thrombosis may present with abdominal pain, hepatomegaly, ascites (as in Budd-Chiari syndrome), and symptoms of aplastic anemia. Painful skin nodules may be present, and severe headaches may occur as a result of the venous thrombosis. A predisposition to infection may also occur. Diagnosis is made by identifying the genetic defects and demonstrating the pathophysiology of PNH. Acidified serum lysis and the Ham test are diagnostic, along with a complement lysis sensitivity test. Stem cell transplantation is curative, but rarely an option. Glucocorticoids are sometimes used to alleviate the symptoms of PNH. Other standard principles of anemia therapy are used with PNH. As in other cases of bone marrow failure and aplastic anemia, antithymocyte globulin (ATG) has been used with success.

Hereditary Spherocytosis (HS) Hereditary spherocytosis (HS) is a familial disorder that can lead to severe hemolytic anemia. Loss of the RBC membrane leads to decreased integrity and an increased risk of hemolysis. These spherical RBCs are sequestered by the spleen, leading to marked splenomegaly in severe cases. HS may be due to 138

Hematologic Disorders defects in spectrin, ankyrin, band 3, and protein 4.2. Northern Europeans are affected the most by this usually autosomal trait. Morbidity and mortality are determined by the severity of the anemia. HS presents with anemia, jaundice, and splenomegaly. The nature of the anemia varies by individual, but it can be very severe and lead to significant mortality. Reticulocytosis and increased mean corpuscular hemoglobin concentration (MCHC) are common. Peripheral blood smears identify spherocytes, and hyperbilirubinemia may be detected. The osmotic fragility test may also be used to identify RBCs susceptible to hemolysis â&#x20AC;&#x201C; a sensitive but not specific test of acquired deficiencies in the RBC skeleton. Treatment of HS involves antibiotic and vaccination prophylaxis to avoid infections prior to splenectomy. Cholecystectomy may be required with severe cholelithiasis. Splenectomy is curative, but care should be taken to avoid infection by encapsulated organisms such as S. pneumoniae, H. influenzae, and Neisseria spp.

Glucose-6-Phosphatase Dehydrogenase Deficiency (G6PD) Glucose-6-phosphatase dehydrogenase (G6PD) deficiency is an X-linked disorder that affects nearly half a billion people around the world. Its protection against malaria is the likely reason G6PD deficiency is so prevalent. Defects in the ability to oxidize certain reactions lead to excess glutathione, which in turn leads to free radical formation and premature damage to RBCs. G6PD presents with neonatal jaundice and acute hemolytic anemia. Drug-induced hemolysis or consumption of fava beans leading to hemolytic anemia is common. Jaundice and splenomegaly is found on physical exam. Most patients are entirely asymptomatic. Diagnosis is confirmed by measuring the activity of G6PD enzyme. Alleviating symptoms by discontinuing the offending agent is the only treatment necessary, in addition to avoiding fava beans and giving supportive therapy in acute exacerbations.

2.8. Transfusion Reactions Transfusion reactions occur due to immune reactions against donated blood that does not match that of the recipient. Serious reactions can lead to death, and rapid identification and reversal are necessary. Acute reactions may be due to immunemediated reactions with various antibodies; those antibodies against the major blood groups (AB) can lead to death through notable intravascular hemolysis. Non-ABO antibodies result in extravascular reactions and are milder. Nonimmune Figure 9. Pentose phosphate pathway. Copyright reactions occur with damage to the donated RBCs G.D. Besten. Used with permission. leading to hemoglobinuria and hemoglobinemia. 139

Clinical Review for the USMLE Step 1 The presence of various cytokines in the donated blood can precipitate additional APRs and lead to constitutional symptoms. Immune reactions can present as severe anaphylaxis and lead to shock and death. Fatal reactions affect 4 persons in a million; nonfatal immune reactions affect 1 in 10,000 persons. Allergic reactions occur in 1 in 300 persons, and anaphylaxis may occur in 1 in 50,000 persons. Multiparous women are more likely to have symptoms than other groups. Transfusion reactions present with the aforementioned symptoms. Early signs include fever, dropping BP, flushing, anxiety, and wheezing. Later signs include DIC. In nonhemolytic reactions, only fever is present along with mild constitutional symptoms and hypotension. Allergic reactions may present with a maculopapular rash and pruritus. Anaphylactic reactions may present with dyspnea, wheezing, anxiety, bronchospasm, and hypotension. In transfusion-related acute lung injury (TRALI), SOB, hypoxia, and orthopnea with cardiac decompensation may be present. Diagnosis is made by workups for anemia and a direct Coombs test. Transfusion reactions are treated by stopping the transfusion and careful observation. Prophylaxis against renal failure and DIC are necessary. Diuresis may be necessary. Acetaminophen is used for fever, diphenhydramine for mild allergic reactions, and epinephrine for anaphylactic reactions. Severe symptoms may require admission to ICU and supportive therapy. A workup for sepsis may be necessary.

2.9. Other Red Blood Cell Conditions 2.9.1

Polycythemia Vera (PV)

Polycythemia vera (PV) is the development of a neoplastic marrow that leads to uncontrolled erythrocytosis, myelocytosis, and megakaryocytosis. The end result is thrombosis and bleeding diatheses. PV is rare. PV begins with symptoms of hyperviscosity in the vessels leading to thrombosis, headache, tinnitus, visual defects, angina, and claudication. Bleeding diatheses occur, and marked splenomegaly is present. Excess degranulation of mast cells and basophils can lead to pruritus. A red complexion is common, along with HTN. All hematopoietic cells are increased in number. Over half a million platelets are typically found in a CBC, along with elevated WBCs. PV is treated by therapeutic phlebotomy to reduce hematocrit (Hct) to 40%. Hydroxyurea may be necessary for myelosuppression. Platelet aggregation can be inhibited with anagrelide. Splenectomy is helpful.

2.9.2

Porphyria

Porphyria refers to six distinct disorders that are defects in metabolic enzymes leading to neuropsychiatric manifestations, abdominal pain, and accumulation of porphyrins in tissues. Porphyria is categorized as porphyria cutanea tarda, acute intermittent porphyria, erythropoietic protoporphyria, variegate porphyria, hereditary coproporphyria, and congenital erythropoietic porphyria. Specific enzyme defects lead to each of these specific porphyrias. Porphyria cutanea tarda may be acquired through HCV, exposure to hydrocarbons, alcohol abuse, and use of estrogens. Risk of developing porphyria is tied to liver disease and factors that affect the function of the liver. Porphyria cutanea tarda is the most common porphyria, and affects 1 in 10,000 persons. The others are significantly rarer. Congenital porphyrias present early in life, while porphyria cutanea tarda and acute intermittent porphyria present in young adults. Caucasians are affected more than other groups. Acute intermittent porphyria may present with constitutional symptoms, dysuria, incontinence, fever, 140

Hematologic Disorders extremity pain or pain in the torso, loss of the sensorium, seizures, disorientation, depression, hallucinations, and paranoia. Delta-aminolevulinic acid dehydratase deficiency porphyria presents similar to acute intermittent porphyria. Porphyria cutanea tarda presents with photosensitivity, bullous vesicles followed by crusting, blistering of the skin, red urine on standing, hypertrichosis, pigmentation changes on the skin, acanthosis, and onycholysis. Erythropoietic protoporphyria presents with early onset of photosensitivity even with room lights, gallstones, hepatic disease, and acanthosis. Variegate porphyria presents similar to acute intermittent porphyria but with photosensitivity and lesions like porphyria cutanea tarda. Hereditary coproporphyria presents like variegate porphyria. Congenital erythropoietic porphyria is similar to erythropoietic porphyria except with a much earlier presentation. Alopecia and ocular abnormalities may be seen in this version. Acute intermittent porphyria is associated with HTN, CRF, hepatocellular carcinoma, and depression. Porphyria cutanea tarda is associated with a more infectious etiology, including HIV, HCV, hemochromatosis, and hepatocellular carcinoma. Diagnosis is made by examining metabolites in the urine, examining the venous blood by a total porphyrin test, and quantitative tests for porphyrins. Treating the porphyrias requires avoiding precipitating factors such as alcohol, estrogen, various medications such as NSAIDs and sulfonylureas, and iron supplements. Phlebotomy may be required to avoid hemochromatosis. Chloroquine may be necessary. Protection against the sun is necessary, and antioxidant therapy may be useful. Glucose is administered with neuropsychiatric manifestations, gabapentin for seizures, and hematin with severe symptoms. SSRIs are administered for depression. Avoiding the precipitating factors is the key for long term control.

2.10. Platelets 2.10.1

and

Coagulation

Immune Thrombocytopenic Purpura (ITP)

Also known as idiopathic thrombocytopenic purpura (ITP), this bleeding diathesis presents with thrombocytopenia, purpura, and petechiae along with a predisposition towards hemorrhage. The presence of autoantibodies against platelets leads to decreased platelet longevity due to macrophage phagocytosis in the spleen. The antibody appears to be against a GPI anchor. ITP is a relatively rare disorder due to its subclinical nature in most patients. Concurrent SLE, AML, CML, or MDS may be present; the disorder may also follow infection by EBV, VZV, CMV, rubella virus, HAV, HBV, HCV, HIV, or a generic URI. Medications that can lead to sensitization include quinine, cephalothins, rifampicin, gold salts, NSAIDs, HTN medications, diuretics, and abciximab. Heparin-induced thrombocytopenia (HIT) may also lead to ITP. ITP may lead to morbidity through intracranial hemorrhage or bleeding in other parts of the body. Petechiae and ecchymoses are typically present. Neurologic exam may be positive for findings, and a hemopericardium may be identified in some individuals. Diagnosis is confirmed by CBC and large platelets found in peripheral blood smears. Antiplatelet antibodies may also be present. A positive Coombs test is common. Marrow biopsy is normal. ITP is treated with corticosteroids, IVIG or Rho immune globulin (RhIG), and platelet transfusions, if severe bleeding is present. Splenectomy results in remission.

2.10.2

Von Willebrand Disease

Von Willebrand disease (vWD) is a bleeding diathesis that prevents hemostasis in response to vascular damage. Adhesion to platelets is impaired and stabilization of various coagulation factors never occurs. vWD is rather rare and morbidity varies. vWD is an inherited autosomal condition with onset at a young age; females especially present at onset of menarche.

141

Clinical Review for the USMLE Step 1 vWD presents with bleeding diatheses leading to epistaxis, easy bruising, and hematoma formation. Significant menstrual bleeding is possible. GI bleeds do not occur as frequently. A deficiency in von Willebrand factor (vWF) is diagnostic. This activity of vWF can be measured using a ristocetin activity test, while the presence of vWF can be determined with an antigen test. A PTT is increased in vWD, while PT is normal. The most severe vWF disease occurs in type III disease. Treatment of type I vWD involves DDAVP which leads to a rise in vWF due to release from storage vesicles. Type II vWD is treated with DDAVP as well, but concentrates with factor VIII and vWF may be necessary prior to surgery. Treatment of type III vWD involves vWF-containing factor VIII concentrates. Platelet transfusions are also therapeutic.

2.10.3

Hemophilia A

Hemophilia A is an X-linked recessive disorder with factor VIII leading to a bleeding diathesis through disruption of the normal coagulation cascade. Spontaneous bleeding can occur, and significant bleeding with trauma is possible. Incidence is 1 in 5,000 persons but the lifespan is normal if no blood-borne illnesses are transmitted through transfusion. Males are significantly more affected; females tend to be carriers. Hemorrhage occurs frequently with hemarthrosis, CNS complaints, GI bleeds, genitourinary bleeds such as hematuria, epistaxis, hemoptysis, compartment syndromes from hematomas, and contusions. Physical exam elicits signs of hemorrhage including tachycardia, tachypnea, hypotension, and orthostatic hypotension. Lab studies indicate a normal PT, elevated aPTT, normal platelet count, and deficits in factor VIII levels. Hemophilia A is treated with factor VIII infusions (recombinant factor VIII is preferred). Oral hemorrhage may be treated with a combination of factor VIII and epsilon aminocaproic acid to reduce fibrinolysis. DDAVP may increase levels of factor VIII.

2.10.4

Hemophilia B

Hemophilia B is an X-linked recessive disorder that leads to defects in factor IX and subsequent hemorrhage. 1 in 5,000 persons are affected and lifespan is normal in the absence of blood-borne illness from transfusion. Hemophilia B presents like hemophilia A. Hemoglobin, PT, and platelets are normal. aPTT is increased. Factor IX is decreased significantly. Hemophilia B is treated with recombinant factor IX infusion; epsilon aminocaproic acid is used with oral bleeds to prevent fibrinolysis.

2.10.5

Vitamin K Deficiency

Vitamin K is a lipid soluble vitamin that is essential for the formation of clotting factors. It is produced by colonic bacteria. Terminal ileum disease prevents normal vitamin K production and absorption. It presents as hemorrhagic disease of newborns (HDN) in infants; in adults, it presents as a bleeding diathesis. Other causes include parenchymal liver disease such as cirrhosis, in which case vitamin K supplements have little effect (fresh frozen plasma [FFP] is required), malabsorption syndromes, biliary disease, cholestyramine, coumadin, and various other medications (INH, rifampin, barbiturates, and others), lupus anticoagulant, DIC, polycythemia vera, cystic fibrosis, and leukemia. Vitamin K deficiency, if severe enough, presents as complaints of significant hemorrhage following mild trauma. Ecchymoses, petechiae, hematomas, and oozing of blood are common. GI bleeds, hematuria, menorrhagia, epistaxis, and mucosal bleeds occur frequently. PT and aPTT are elevated. Des-gamma142

Pharmacology and Treatment carboxy prothrombin (DCP) is present in the absence of vitamin K. Treatment for vitamin K deficiency involves correcting the cause of the underlying deficit and providing vitamin K supplements. FFP is necessary in severe disease. Subcutaneous injections of phylloquinone (vitamin K 1) can be given; menadione (vitamin K 3) can be given orally in malabsorption syndromes. Phytonadione can also be directly injected in severe disease. Green leafy vegetables and oils provide a good source of vitamin K.

2.10.6

Malaria

Malaria is the result of infection by Plasmodium protozoa carried by the Anopheles mosquito leading to potentially serious illness. Plasmodium species that can cause infection include P. falciparum, P. vivax, P. ovale, and P. malariae. P. falciparum can be fatal. P. falciparum and P. vivax are commonly responsible for new infections. Infection begins after a mosquito transmits the infection to a human host. The liver phase begins first with transmission to hepatocytes. Blood borne illness occurs a few weeks later with merozoites developing into trophozoites then schizonts inside RBCs. The erythrocyte phase begins, and merozoites are released a short time later when the RBC undergoes lysis. Fever occurs, and additional RBCs are infected. The immune system now steps in to control the infection, but death can occur with P. falciparum before a sufficient host reaction develops. Gametocytes can form during this process and lead to repeated infections. Nearly 3 million deaths occur annually throughout the world due to malaria; malaria is not endemic to the United States. Constitutional symptoms can be quite severe with malaria and a flu-like illness may develop. P. falciparum in particular can induce coma due to cerebral infection leading to seizure. Severe anemia is also possible, along with renal failure due to blockade of vessels supplying the renal cortex. Pulmonary edema is also present in some cases. P. falciparum and, more rarely, the other causes of malaria can also cause death due to splenic rupture. Diagnosis is made by blood smears and identification of the parasites. A rapid dipstick test for P. falciparum exists. Treatment for malaria includes adequate prophylaxis to avoid infection. Atovaquone / proguanil are commonly prescribed for prophylaxis, but it is not for use by pregnant women or children. Doxycycline is also often used, but the same contraindications apply. Mefloquine is safe for use by pregnant women; contraindications include patients with depression or other psychiatric illnesses, a history of seizures, and those with cardiac conduction abnormalities. Primaquine is used in certain situations, but G6PD deficiency is an absolute contraindication, along with pregnant women. Chloroquine, hydroxychloroquine, insect repellants (such as N,N-diethyl-m-toluamide [DEET]) are also used.

3. Pharmacology 3.1. Anticoagulants

and

Treatment

Hemostatic Agents

Common anticoagulants and hemostatic agents are discussed in the two tables on the prior page.

3.2. Blood Products Whole blood can be divided into packed red blood cells (PRBCs), fresh frozen plasma (FFP), platelets, and cryoprecipitate. Whole blood is rarely used as a resuscitative product due to its immunogenicity and the greater effectiveness of partial blood products. In patients with acute hemorrhage, resuscitation with PRBCs is the initial blood product of choice. However, due to the lack of coagulation factors and 143

Clinical Review for the USMLE Step 1

Mechanism

Dosing

Monitoring

Half-Life

Duration

Side Effects

Reversal Agent

Trade Name

4-6 hours

Clearance

Anticoagulant 60-90 min (dose-dependent)

Protamine sulfate

aPTT

Reticuloendothelial

Indicationdependent

Protamine sulfate 60-75% effective

Antithrombinmediated antiIIa, Xa, XIa

Renal

None

HIT (<1%), cross-reactive with HIT antibodies

Unfractionated heparin (UFH)

Formulationdependent

None

HIT (1-5%), osteoporosis, hypersensitivity, hypoaldosteronism (rare)

Anti-Xa level

Formulationdependent

Renal

Formulationdependent

None known

Antithrombinmediated antiXa > anti-IIa

24 hours

Multiple agents

21 hours

Low molecular weight heparin (LMWH)

Anti-Xa level

None; can be hemodialyzed

Antithrombinmediated antiXa only

Renal

Fondaparinux

Non-neutralizing antibodies (50%)

Pentasaccharide

4-6 hours

2.5 mg SC (prophylactic); 5-10 mg SC for therapeutic dosing

1.3 hours

None; can be hemodialyzed

aPTT

Renal and proteolytic cleavage

0.15 mg/ kg/hr IV

Non-neutralizing antibodies (<1%)

Direct thrombin inhibitor

1.5-3 hours

Refludan

25 minutes

Lepirudin

aPTT

Direct thrombin inhibitor

None

Angiomax

Hepatic

Bivalirudin

aPTT

2-4 hours

2 mg/ kg/min IV continuous infusion

40-50 minutes

Argatroban

Direct thrombin inhibitor

20-60 hours

Vitamin K, fresh frozen plasma PT/INR

Hepatic cytochrome p450 Coumadin

2-5 days

1 mg/kg IV bolus up to 2.5 mg/kg/ hour IV over 4 hours

Argatroban

Warfarin

Indicationdependent

Skin necrosis, hypersensitivity, purple toe syndrome Vitamin K antagonist

Table 28. Common anticoagulants and their Mechanism of Action.

144

IV or SC: 0.3 mg/kg

Dosing

Aminocaproic acid (Amicar)

Peak drug levels seen at 2 hours, but clinical effects may take days

Minutes

None

None (shortened PT and high factor VIIa levels seen due to in vitro effects on assay)

None

Platelet function analyzer (PFA), factor VIII activity, or vWF levels

30-60 minutes after IV infusion; 6090 minutes after SC or nasal administration

60 seconds

Drug Monitoring

Peak Effects

Table 29. Common hemostatic agents and their Mechanism of Action.

IV dosing: 4-5 g IV over 1 hour followed by 1 g/ hour (maximum dose is 30 mg/ day) 2 hours

Interferes with fibrinogen binding sites on plasminogen

Recombinant factor VIIa (Novo7)

Variable PO dosing

IV dosing (bolus or continuous in2.3 hours fusion) depending on indication

Enhancement of thrombin generation on the surface of activated platelets

N/A

Topical administration

75 minutes

Half-Life

Fibrin sealants

Transiently increases Nasal: 1.5 mg/ factor VIII and mL solution with vWF one spray per nare

Mechanism

Consists of human fibrinogen and thrombin; may include additives such as human factor XIII or aprotinin

Desmopressin

Hemostatic Agent

Surgical bleeding, hyperfibrinolysis, and sealing of suture lines and anastomoses

Prophylaxis or treatment for patients with congenital hemophilia with inhibitors, congenital bleeding disorders, or acquired hemophilia

Skin grafts and sealing of suture lines / anastomoses

Low surgical risk (mild hemophilia A, vWD type I), patients with congenital or acquired platelet dysfunction

Approved Indications

Thrombosis in patients without congenital bleeding problems

Hypersensitivity to human blood products or aprotinin

Thrombogenic potential with risk of myocardial infarction

Complications

Pharmacology and Treatment

145

Clinical Review for the USMLE Step 1 platelets, administration of more than 2 units of PRBCs should be accompanied with FFP and platelets. In patient with hemophilia or severe bleeding, administration of cryoprecipitate is also of benefit as it contains factor VIII, factor XIII, vWF, and fibrinogen - all of which are in either low concentration or missing from FFP.

3.3. Jehovah’s Witnesses Jehovah’s Witnesses typically refuse blood transfusion as it constitutes a transplant of a foreign substance into their body. Some members will accept blood plasma fractions, and others will accept autologous transfusions. When a Jehovah’s Witness patient may require blood as a result of major surgery, it is best to ask about their religious beliefs and restrictions ahead of time.

4. References

146

Chee, Y.L., et al., Guidelines on the assessment of bleeding risk prior to surgery or invasive procedures. British Committee for Standards in Haematology. British Journal of Haematology, 2008. 140(5): p. 496-504.

Ragni, M.V., C.M. Kessler, and J.N. Lozier, Clinical aspects and therapy for hemophilia. In Hematology: Basic Principles and Practice, R. Hoffman, et al., Editors. 2009, Churchill Livingstone Elsevier, Philadelphia, PA.

Ansell, J., et al., Pharmacology and Management of the Vitamin K Antagonists. Chest, 2008. 133(6 suppl): p. 160S-198S.

Douketis, J.D., et al., The Perioperative Management of Antithrombotic Therapy. Chest, 2008. 133(6 suppl): p. 299S-339S.

Kearon, C., et al., Antithrombotic Therapy for Venous Thromboembolic Disease. Chest, 2008. 133(6 suppl): p. 454S-545S.

Sobel, M. and R. Verhaeghe, Antithrombotic Therapy for Peripheral Artery Occlusive Disease. Chest, 2008. 133(6 suppl): p. 815S-843S.

Geerts, W.H., et al., Prevention of Venous Thromboembolism. Chest, 2008. 133(6 suppl): p. 381S-453S.

References

147

Section Editors Sapan S. Desai, MD, PhD

Danny O. Jacobs, MD, MPH

Assistant Professor Department of Surgery Duke University Medical Center

Professor and Chair Department of Surgery Duke University Medical Center

Contributors

CNS & PNS

Niketa Desai, PharmD

Daniel Murariu, MD

Pharmacist Resident Department of Pharmacology Department of Surgery Long Island University University of Hawaii Head and Neck Surgery (adapted from the Clinical Review of Surgery)

Stephanie Mayer, MD

William Eward, DVM, MD

Resident Resident Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center

Jocelyn Wittstein, MD Resident Department of Surgery Duke University Medical Center Orthopedic Surgery (adapted from the Clinical Review of Surgery)

Judson Williams, MD

Mark Shapiro, MD

Resident Associate Professor Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center Vascular Trauma (adapted from the Clinical Review of Vascular Surgery)

Sapan Desai, MD, PhD

Michael Lidsky, MD

Assistant Professor Resident Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center

Luigi Pascarella, MD

Cynthia Shortell, MD

Resident Professor Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center Surgical Principles (adapted from the Clinical Review of Vascular Surgery)

Introduction

1. Introduction The USMLE outline combines a discussion of central nervous system and peripheral nervous system topics with psychopathology in this section. What follows is a discussion of the basic embryology, anatomy, and physiology of the CNS and PNS, followed by a series of topics on pathology and therapy. Psychopathology is handled separately.

2. Embryology 2.1. Embryogenesis

Figure 1. Embryology. Copyright Wikimedia. Used with permission. The zygote is formed on day 0 with the fertilization of the ovum with a single sperm in the fallopian tube. This prompts the ovum to complete metaphase II and embryogenesis begins. Over the first week, the blastocyst forms, having undergone cleavage, compaction, differentiation, and cavitation. Implantation then occurs in the uterus on about day 7. Over the following week, the bilaminar disk is formed within the blastocyst. The mesoderm begins to form and spread; during this time, the syncytiotrophoblast and cytotrophoblast form. The syncytiotrophoblast secretes B-hCG. 149

Clinical Review for the USMLE Step 1

Figure 2. The three layers created during embryogenesis. Copyright Wikimedia. Used with permission. During the third week of embryogenesis, gastrulation occurs. Three germ layers are formed, incluing the ectoderm, mesoderm, and endoderm. The cranial-caudal axis is formed, along wiht the optic and otic placodes. The upper limb buds appear and the rostral neuropore closes. In the fourth week, the caudal neuropore is closed (this is folate-dependent). The lower limb buds develop at this time. During week five, retinal pigment develops; this is followed by digital rays in week six, midgut herniation in week seven, and growth in body length weeks eight through eleven. The fetus continues to mature over the next two months, and lanugo hairs develop starting at about 20 weeks. The pupillary light reflex is intact starting around week 31. The fetus grows to term over the next two months.

2.2. Embryologic Tissue Derivatives The embryologic tissue derivatives include the ectoderm, mesoderm, and endoderm. The ectoderm is divided into the surface ectoderm and neuroectoderm. The surface ectoderm consists of the epidermis, dermis, anterior pituitary, and lens of the eye. The neuroectoderm includes the central nervous system (including the posterior pituitary, pineal), neural crest, and peripheral nervous system (including the adrenal medulla, APUD cells, melanocytes, and thyroid C cells). The ondontoblasts and pia also come from the PNS. The mesoderm gives rise to the cardiovascular system, Figure 3. Gastrulation. Copyright Pidalka. hematopoietic system, spleen, kidney, adrenal cortex, Used with permission. muscle, bone, and dura. The endoderm gives rise to the lungs, liver, thyroid, parathyroid, thymus, and pancreas. The notochord and nucleus pulposus of intervertebral disk also come from this layer.

2.3. Branchial Apparatus 2.3.1

Branchial Apparatus 1

The branchial apparatus can be divided into six major sections, but not all of them are present at the time of birth. The first apparatus gives rise to a branchial cleft, branchial arch, and branchial pouch. The first branchial cleft is derived from the ectoderm and becomes external auditory meatus. The first branchial arch is derived from the mesoderm and becomes the malleus and incus (dorsal portion), and a mandibular portion (Meckelâ&#x20AC;&#x2122;s cartilage) that gives rise to the facial bones. All of the facial bones form through endochondral bone formation except the mandible. The mandibular portion also forms muscles of mastication (temporalis, masseter, medial pterygoid, lateral pterygoid) along with two accessory muscles (anterior belly of digastric and mylohyoid), gives rise to the tensor veli palatini and tensor 150

Embryology tympani, the maxillary artery, and is innervated by the mandibular division of the trigeminal nerve (V3). Treacher Collins syndrome can develop due to a defect in this arch and presents with an abnormal external ear, mandibular hypoplasia, and a lower eyelid defect. The Pierre Robin sequence can present with mandibular hypoplasia, cleft palate, eye and ear defects. Two other more common defects also occur: cleft palate which is due to failure of the palatine processes to fuse with the nasal septum, and cleft lip from failure of the maxillary and nasal processes to fuse. First branchial pouch is derived from the endoderm and becomes the middle ear cavity.

2.3.2 Branchial Apparatus 2 Figure 4. Neural crest and neural The second branchial apparatus also includes a cleft, arch, and plate. Copyright Vojtech Dostal. pouch. The second branchial cleft degenerates but may remain as a cervical sinus cyst of the neck if second arch does not completely Used with permission. fuse with epicardial ridge; this leads to fistula formation and is typically treated with excision. Branchial cleft cysts are treated with the Sistrunk procedure and require excision of a portion of the branchial arch derivative, the middle portion of the hyoid bone. The second branchial arch forms the stapes, styloid process, and part of hyoid bone. It also is responsible for the muscles of facial expression, stapedius, stylohyoid, and posterior belly of digastric. It is supplied by the facial nerve (VII). This arch also gives rise to the stapedial artery and hyoid artery. The second branchial pouch gives rise to the palatine tonsil.

2.3.3

Branchial Apparatus 3

The third branchial apparatus forms the third branchial cleft, which may remain as a cervical sinus cyst of the neck, the third branchial arch which forms the greater horn of the hyoid, stylopharyngeus muscle, common carotid artery, and is innervated by the glossopharyngeal nerve (IX), and the third branchial pouch, which forms the inferior parathyroid glands, thymus, and may lead to thymic cysts embedded within the thyroid.

2.3.4

Branchial Apparatus 4

The fourth branchial cleft may remain as cervical sinus cyst of the neck. The fourth branchial arch forms the thyroid, cricoid, and arytenoid cartilage of larynx, cricothyroid, levator veli palatini, and pharyngeal constrictor muscles, the aortic arch and right subclavian artery, and is innervated by the superior laryngeal nerve, a branch of the vagus (X). The fourth branchial pouch forms the superior parathyroid glands and ultimobranchial body (and eventually forms the parafollicular C cells of thyroid). DiGeorge syndrome may arise due to defects in the third and fourth branchial arches. This is due to a defect in chromosome 22, and is also referred to as velocardiofacial syndrome or CATCH 22 syndrome. It leads to Tetralogy of Fallot, cleft palate, learning disorders, hypocalcemia, T-cell immune deficiency, feeding problems, renal defects, hearing loss, seizures, and skeletal defects. It affects approximately 1:1500 babies.

151

Clinical Review for the USMLE Step 1 2.3.5

Branchial Apparatus 5

The fifth branchial apparatus is completely resorbed during development.

2.3.6

Branchial Apparatus 6

The sixth branchial arch forms the intrinsic muscles of the larynx except the cricothyroid, gives rise to the pulmonary trunk and ductus arteriosus, and is innervated by the recurrent laFigure 5. Monozygotic and dizygotic ryngeal nerve, a branch of the vagus nerve (X). twins. Copyright Wikimedia. Used with permission. 2.4. Twins Monozygotic twins are derived from one zygote that separates. They may be monoamniotic or diamniotic, and monochorionic or dichorionic. One amnion or one chorion means monozygotic. Dizygotic twins are derived from two separate zygotes with independent fertilization and requires two separate amnions, chorions, and placentae. Conjoined twins are monozygotic twins with incomplete separation.

2.5. Neural Plate Tube 2.5.1

and

Neural

Figure 6. Neural plate and growth signals. Copyright Wikimedia. Used with permission.

Development

The neural plate and neural tube are induced by the notochord. It induces the neural groove to involute and form a closed neural tube and is composed of ectoderm. The neural tube eventually gives rise to the CNS. The neural crest cells remain in the dorsal portion and extend to become the PNS.

2.5.2

Neural Tube Defects

Anencephaly occurs from failure of the rostral neuropore to close. It leads to failure to develop the cerebrum with exposed CNS structures at birth and is generally incompat- Figure 7. Embryologic derivatives of the brain. Copyible with life. Encephalocele is due to pro- right Wikimedia. Used with permission. trusion of encephalic membranes through a 152

Embryology skull fissure. This condition is often fatal or presents with severe mental retardation. Spina bifida presents in several forms. Spina bifida occulta is due to failure of the outer portion of vertebral column to close and presents with only a tuft of hair at the site. There is no protrusion of the spinal cord. This is the mildest version of spina bifida and presents with incontinence, slight ataxia, and minor loss of sensation to lower extremities. Meningocele presents with damaged meninges protruding through a vertebral column defect. There is little loss of function. Meningomyelocele has protrusion of meninges and CNS matter through a vertebral column defect with visible cyst formation. It contains nerves and membranes and leads to paralysis and loss of sensation distal to site of damage. There is often hy- Figure 8. Components of the vestibular sysdrocephalus. There is increased risk of spina bifida in tem. Copyright Sapan Desai. Used with perpregnant women taking medications for epilepsy and mission. poor folic acid intake.

2.5.3

Parts of the CNS

The hindbrain, or rhombencephalon, gives rise to the myelencephalon and metencephalon. The myelencephalon gives rise to the medulla, 4th ventricle, and CN VIII, IX, X, XI, XII. The metencephalon gives rise to the pons, cerebellum, 4th ventricle, and CN V, VI, VII, VIII. The mesencephalon is composed of the midbrain, which is the least differentiated part of the mature brain. The mesencephalon includes the tectum, superior colliculus, inferior colliculus, cerebral peduncle, midbrain tegmentum, crus cerebri, substantia nigra, and pretectum. It is also involved with the substantia nigra, basal ganglia. The prosencephalon includes the diencephalon and telencephalon. The diencephalon includes the epithalamus, thalamus, hypothalamus, and subthalamus. It primarily plays a role in sensory and motor information relay between various parts of the Figure 9. Development of the inner ear. Copyright Sapan brain. The telencephalon gives rise to the Desai. Used with permission. cerebrum and also contains limbic system, part of the basal ganglia, corpus striatum, and olfactory bulb. 153

Clinical Review for the USMLE Step 1

Figure 10. Stem cells and hair cells of the inner ear. Copyright Sapan Desai. Used with permission.

2.6. Development 2.6.1

of the Inner

Ear

Embryology

There are three distinct germ lines that lead to the development of the inner ear. The ectoderm forms the external auditory meatus (cleft 1); the mesoderm forms the malleus and incus from arch 1, stapes from arch 2, tensor tympani from arch 1, and stapedius muscle from arch 2. The endoderm creates the middle ear cavity, Eustachian tube, and mastoid air cells from pouch 1.

2.6.2

Stem Cells of the Inner Ear

The supporting cells of the inner ear may regress to become precursor stem cells, which in turn can undergo mitosis and differentiation to form hair cells and more supporting cells

2.6.3

Anatomy

The inner ear is composed of six sensory organs on each side: the utricular macula, saccular macula, cristae ampullares (3X), and cochlea. The first five are involved with the vestibular system and are responsible for horizontal, vertical, and angular acceleration. The cochlea is involved with the auditory system and is responsible for hearing. A variety of mechanosensory hair cells convert ion currents into 154

Anatomy nerve impulses; their location on these sensory organs is interpreted by the brain into positional and auditory information.

2.7. Development 2.7.1

of the

Eye

Embryology

The optic placode forms from the neural ectoderm that later gives rise to the diencephalon. The optic stalk and optic sulcus forms from the optic placode, the optic vesicles form from the sulcus, and the optic neural crest cells begin to form which will give rise to CN II. The optic cup forms which will later become the retina; the rim will become the iris. The lens placode develops from surface ectoderm. Maturity occurs over the next few weeks with completion of innervation and terminal differFigure 11. Anatomy of the eye. Copyright R.H. Castilentiation of structures. hos. Used with permission.

2.7.2

Anatomy

The major structures of the eye include the lens, cornea, iris, retina, and macula. Light converges onto retina, through the cornea. The iris is the colored ring that controls size of pupil. The retina is the sensory neuroepithelium with rods and cones; the highest concentration of cones is the macula.

3. Anatomy 3.1. Vascular Supply 3.1.1

to the

Head

and

Neck

Aortic Arch

The aorta arises from the left ventricle, gives off the right and left coronary arteries, and travels 5 cm to the sternum, where it becomes the arch of the aorta. At the apex, it gives rise to the brachiocephalic, left common carotid, and left subclavian arteries before continuing as the descending aorta. The brachiocephalic artery, occasionally referred to as the innominate artery, gives rise to the right subclavian and right common carotid arteries. At the distal portion of the arch is the ligamentum arteriosum, which shunts blood from the pulmonary artery to the aorta during ontogeny. Crossing anterior to the arch is the left vagus nerve, which sends the left recurrent laryngeal nerve around the arch and back up to the neck. The right recurrent laryngeal nerve hooks around the right subclavian artery as it comes off the brachiocephalic trunk.

3.1.2

Common Carotid Artery

The left common carotid artery arises as a direct branch of the aortic arch, while the right common carotid artery is a branch of the brachiocephalic artery as it gives rise to the right subclavian. The left 155

Clinical Review for the USMLE Step 1 common carotid artery is closely associated with the recurrent laryngeal nerve and thoracic duct, and eventually travels with the vagus and phrenic nerves as it goes more superior. The right common carotid artery has a similar relationship with these two nerves in the neck. Within the neck, the common carotid artery is enclosed by the carotid sheath, an extension of the deep cervical fascia. The sheath also includes the internal jugular vein and vagus nerve, and may occasionally include the descending branch of the hypoglossal nerve. The common carotid artery divides into the external and internal carotid arteries at the upper border of the thyroid cartilage, Figure 12. Aorta and other major vessels from the heart. Copy- at the level of the fourth cervical verright Mikael Haggstrom. Used with permission. tebra. The common carotid artery rarely has other branches, but they may occasionally include the thyroid arteries (superior and inferior), pharyngeal artery, and vertebral artery.

3.1.3

External Carotid Artery

The external carotid artery bifurcates to form the maxillary artery and superficial temporal artery within the parotid gland. It is anterior and medial to the internal carotid artery. Careful dissection is required as it is crossed by the hypoglossal nerve near its superior extent. The glossopharyngeal nerve is located posterior to this artery. The external carotid artery gives off the superior thyroid artery, facial artery, occipital artery, posterior auricular artery, and the two terminal branches discussed above.

3.1.4

Internal Carotid Artery

The Bouthillier classification is used primarily by neurosurgeons to divide the internal carotid artery into seven distinct segments. The internal carotid artery at its take off contains the carotid bulb. The carotid nerve plexus is intimately associated with the internal carotid and emanates from the superior cervical ganglion. The internal carotid artery is the chief supply to the circle of Willis anastomosis Figure 13. Carotid artery. Adapted from Grayâ&#x20AC;&#x2122;s that supplies blood to the brain. Anatomy. Used with permission. 156

Anatomy 3.1.5

Carotid Bifurcation

The carotid bifurcation is an important neurovascular structure. Within the bifurcation near the internal carotid artery, the carotid bulb contains mechanoreceptors and baroreceptors. Stimulation leads to bradycardia and vasodilatation via a parasympathetic reaction. The carotid sinus contains chemoreceptors which serve as detectors for CO2 and acidosis. Stimulation here leads to a sympathetic response.

3.1.6

Vertebral Arteries

The vertebral artery is the first branch of the subclavian artery and provides extensive collateral blood flow to the brain via the circle of Willis. The vertebral artery travels posterior to the transverse process of C6, then enters the transverse foramina until it reaches C1. It then travels posterior to the arch of the atlas and penetrates the skull through the foramen magnum. Anterior to the vertebral arteries at their takeoff are the internal jugular veins and inferior thyroid artery. The inferior cervical sympathetic ganglion is in close proximity to the artery when it is located proximal to the transverse processes. A portion of the vertebral artery may be uncovered within the suboccipital triangle, bound by the superior oblique, inferior oblique, and rectus capitis posterior major muscle. The suboccipital nerve is in close proximity to the vertebral artery at this point. The left vertebral artery tends to be somewhat larger and have higher flows compared to the right.

3.1.7

Circle of Willis

The circle of Willis provides a redundant blood supply to the entire brain via two paired arteries derived from branches of the aorta. The major blood supply comes from the paired internal carotid arteries and is supported by the paired vertebral arteries. Despite this rich anastomosis, the branches emanating from the circle of Willis tend to be end arteries. Hence, even brief disruptions in blood supply to these targets, such as via emboli or severe Figure 14. Circle of Willis. Copyright R.H. Castilhypotension, can lead to ischemia and stroke. hos. Used with permission.

3.1.8 the Brain

Blood Supply Targets in

The anterior choroidal artery supplies the optic tract, amygdala, LGN, hippocampus, internal capsule, and thalamus. The anterior cerebral artery supplies the frontal lobes, medial aspect of parietal and temporal lobes. The middle cerebral artery is among the most common pathways for stroke, and supplies the frontoparietal somatosensory cortex. The posterior cerebral artery distributes blood to the occipital 157

Clinical Review for the USMLE Step 1

Figure 15. Divisions of the brain. Copyright Sapan Desai. Used with permission. and inferior temporal lobes, and the hippocampus. The posterior communicating artery is one of the few anastomotic branches in the brain. The anterior spinal artery supplies the ventral portion of spinal cord, while the posterior spinal artery supplies the dorsal portion of spinal cord. The vertebral artery goes to the medulla. The anterior inferior cerebellar artery goes to the anterior inferior cerebellum and caudal pons. The posterior inferior cerebellar artery goes to the inferior cerebellum. The superior portion of the cerebellum is supplied by the superior cerebellar artery. The inner ear is supplied by the internal auditory artery.

3.1.9

Venous Drainage

The venous drainage of the brain begins with the cerebral veins, which empty into the dural venous sinuses, which ultimately empty into internal jugular veins. Another means of emptying is via the emissary veins. The basilar venous plexus communicates with the vertebral venous plexus. The cerebral venous system is composed of a valveless system with numerous anastomoses.

3.2. Vascular Supply 3.2.1

to the

Upper Extremity

Subclavian Artery

The blood supply to the upper extremity begins as the subclavian artery, a direct branch off the aorta to the left extremity and a branch of the brachiocephalic trunk for the right extremity. The first part of the 158

Anatomy subclavian artery travels to the medial border of the anterior scalene muscle, and is located anterior to the vagus and phrenic nerves. The artery is posterior to the sternohyoid and sternocleidomastoid muscles, and gives rise to the vertebral artery, internal thoracic artery, and thyrocervical artery. The second part of the subclavian artery travels posterior to the anterior scalene muscle and gives rise to the costocervical trunk. At this location proximal to the clavicle, the subclavian vein is located inferior and anterior to the subclavian artery. The third part of the subclavian artery commences at the lateral border of the anterior scalene muscle and becomes the axillary artery at the lateral Figure 16. Subclavian and axillary artery. Adapted from border of the first rib; this part gives Grayâ&#x20AC;&#x2122;s Anatomy. Used with permission. rise to the dorsal scapular artery.

3.2.2

Axillary Artery

The axillary artery is divided into three parts based on its relationship to the pectoralis minor muscle. The first part of the axillary artery is proximal, the second part posterior, and the third part lateral to the pectoralis minor. The second part of the axillary artery is intimately associated with the brachial plexus cords. The superior thoracic artery arises from the first part, thoracoacromial and lateral thoracic arteries from the second part, and the subscapular and two circumflex arteries to the head of the humerus from the third part. Due to an anastomosis between the suprascapular artery and dorsal scapular artery, the axillary artery may be clamped proximal to the subscapular artery. The axillary artery supplies the upper arm and becomes the brachial artery at the border of the teres major.

3.2.3

Brachial Artery

The brachial artery divides into the radial and ulnar arteries at the cubital fossa. The brachial artery travels with the median nerve for much of its course. Several important collateral vessels are given off from the brachial artery, including the deep brachial, and superior and inferior ulnar collateral arteries. The deep brachial artery has branches that anastomose with recurrent branches emanating from the radial artery along with the inferior ulnar collateral artery. Due to its close proximity to the humerus, a fracture of this bone can compromise the brachial artery.

3.2.4

Radial Artery

The radial artery is located in the anterior and lateral compartment of the forearm. It ends as the deep palmar arch after passing between the dorsal interosseus muscle and through the anatomic snuff box. The Allen test is done prior to using the radial artery for access as part of an arteriovenous fistula or insertion of an arterial line. This test is done by elevating the hand and making a fist, occluding the radial and ulnar arteries, opening the hand and confirming that it has pallor, then releasing the ulnar artery pressure to verify satisfactory collateral flow to the hand. The ulnar artery is typically the dominant artery to the hand; if the Allen test is abnormal, it implies that the radial artery is the dominant supply 159

Clinical Review for the USMLE Step 1 and should not be used to avoid vascular compromise to the hand.

3.2.5

Ulnar Artery

The ulnar artery travels along the medial forearm and terminates as the superficial and deep palmar arch near the pisiform bone. The artery is proximal to the median nerve at its take off.

3.2.6

Venous Drainage

The veins of the upper extremity are divided into a superficial and deep distribution. The superficial distribution starts as the dorsal plexus of the hand and eventually gives rise to two major veins, the cephalic and basilic. The cephalic vein is lateral, while the basilic is medial. The major vein in the deep distribution is the brachial vein, which travels with the brachial artery. The brachial vein eventually joins the basilic at the lateral border of the teres minor; together they join the cephalic vein to form the axillary vein.

3.3. Vascular Supply to the Abdomen and Pelvis 3.3.1

Abdominal Aorta

The abdominal aorta gives rise to the major visceral arteries and eventually supplies blood to the lower extremity via the terminal common iliac artery branches. It begins at the diaphragm at T12 to give off the celiac trunk at T12, superior mesenteric and suprarenal arteries at L1, renal and Figure 17. Major arteries of the arm. gonadal arteries at L2, inferior mesenteric artery at L3, and Adapted from Grayâ&#x20AC;&#x2122;s Anatomy. Used the common iliac bifurcation at L4. Various lumbar arteries with permission. also arise between L1 and L4. Collaterals around the aorta include the internal thoracic artery, which becomes the superior epigastric artery after it gives off the musculophrenic artery at the diaphragm; the superior epigastric anastomosis with the inferior epigastric artery, a branch of the external iliac artery. There are also collaterals between the inferior mesenteric artery and internal pudendal artery, and occasionally collaterals between the lumbar arteries and the internal iliac artery.

3.3.2

Celiac Artery

The celiac artery supplies the stomach, liver, duodenum, pancreas, and spleen. Its branches include the left gastric artery, splenic artery, and common hepatic artery. The splenic artery gives rise to six short gastric arteries, left gastroepiploic artery, and continues on to supply the spleen. The common hepatic artery gives rise to the gastroduodenal artery, then becomes the proper hepatic artery. The gastroduodenal artery becomes the anterior superior and posterior superior pancreaticoduodenal arteries and the right gastroepiploic artery. The proper hepatic artery gives off the cystic artery before dividing into the 160

Anatomy right and left hepatic arteries. In a quarter of all individuals, the left hepatic artery arises as a branch off the left gastric artery. In one in ten people, either a branch of or the entire common hepatic artery arises directly from the SMA. A small percentage of patients may have the hepatic artery arise directly from the aorta. The right hepatic artery may be replaced and arise entirely from the SMA; alternatively, an accessory right hepatic artery may arise from the SMA or aorta and complement flow from the natural right hepatic artery arising from the proper hepatic trunk.

3.3.3 Superior Mesenteric Artery The superior mesenteric artery gives rise to the anterior inferior and posterior inferior pancreaticoduodenal arteries, the jejunal and ileal branches, Figure 18. Abdominal aorta. Adapted from Grayâ&#x20AC;&#x2122;s Anatomy. the ileocolic artery, and the right and Used with permission. middle colic arteries. The ileocolic artery also supplies the cecum.

3.3.4

Inferior Mesenteric Artery

The inferior mesenteric artery gives rise to the left colic artery, sigmoid arteries, and superior rectal artery. Loss of this artery may occur as part of a graft placement to treat an abdominal aortic aneurysm; sufficient collateral flow must be confirmed to avoid a potential compromise of the sigmoid colon.

3.4. Vascular Supply 3.4.1

to the Lower

Extremity

Iliac Artery

The common iliac artery arises at L4 at the bifurcation of the aorta, and travels about 4 cm to the pelvic brim, where it divides into the internal and external iliac arteries. The internal iliac artery, frequently referred to as the hypogastric artery, gives rise to a plethora of branches that supply the pelvis, gonads, rectum, and anus. During open and endovascular repair of abdominal aortic aneurysms, preservation of one hypogastric artery is sufficient to preserve pelvic perfusion due to extensive collateralization. This includes anastomosis between the superior and middle rectal arteries, lumbar and iliolumbar arteries, and the medial and lateral sacral arteries. The external iliac artery gives rise to the inferior epigastric artery (discussed above), deep circumflex artery, and continues as the femoral artery at the inguinal ligament. 161

Clinical Review for the USMLE Step 1 3.4.2

Femoral Artery

The common femoral artery gives rise to the deep femoral artery superiorly within the thigh and continues as the femoral artery. The deep femoral artery forms a cruciate anastomosis around the femoral bone and provides collateral flow via anastomosis with recurrent branches below the popliteal fossa.

Figure 19. Major arteries of the leg. Copyright M.C. Strother. Used with permission.

3.4.3

Popliteal Artery

The popliteal artery is the continuation of the femoral artery after it passes through the adductor canal and hiatus (also known as Hunterâ&#x20AC;&#x2122;s canal). After forming a collateral supply around the knee, the popliteal artery bifurcates into the anterior tibial artery and the tibial-peroneal trunk. This trunk then quickly divides into the peroneal artery and posterior tibial artery. Congenital deformity of the muscle or tendon insertions into the popliteal fossa can lead to compression of this artery, causing popliteal artery entrapment syndrome (discussed below). 162

Anatomy 3.4.4

Tibial Artery and Lower Branches

The anterior tibial artery supplies the anterior compartment of the leg and dorsum of the foot as the dorsalis pedis. A number of recurrent branches are given off, which help provide a small collateral flow with branches of the deep femoral artery. The dorsalis pedis artery is anterior to the ankle and lateral to the extensor hallucis longus tendon. It may be naturally absent in up to 2% of patients. The posterior tibial artery supplies the posterior compartment of the leg and travels posterior and inferior to the medial malleolus. The peroneal artery supplies the lateral compartment and anastomosis with the anterior tibial artery.

3.4.5

Venous Drainage

The venous drainage of the lower extremity is much more extensive than that of the upper extremity, and also more susceptible to venous disorders due to its dependent position. Like the upper extremity, the venous system of the leg is divided into a superficial and deep system. The superficial veins of the leg start with the dorsal venous arches on the feet, which form the great and small saphenous veins. Various perforator branches and a posterior arch vein join the saphenous veins in the distal lower extremity. As they travel superiorly, the veins of Giaccomini and the anterolateral veins of the thigh join the great saphenous vein. A significant junction is present in the groin, where the circumflex iliac vein, inferior epigastric vein, external pudendal vein, and great saphenous vein come together at the saphenofemoral junction. This eventually forms the femoral vein. The great saphenous vein is more anterior and medial, while the small saphenous is posterior and somewhat lateral. The deep veins of the leg include the soleal sinusoids, which join the peroneal, and anterior and posterior tibial veins to form the popliteal vein. The popliteal vein joins the deep femoral vein to form the common femoral vein. After receiving inflow from the superficial system, the common femoral vein continues as the external iliac vein, then common iliac vein (after joining the internal iliac vein), and inferior vena cava.

3.5. Cranial Nerves 3.5.1

CN I - Olfactory Nerve

The olfactory nerve is cranial nerve one. It is a sensory nerve that originates from the telencephalon with its nucleus located in the anterior olfactory nucleus. Its function is to transmit smell from the olfactory foramina found in the cribriform plate, which is located in the ethmoid.

3.5.2

CN II - Optic Nerve

The optic nerve is cranial nerve two and is also a pure sensory nerve. Its nuclei are located in the ganglion cells of the retina, but it originates from the diencephalon. Its function is to transmit visual information via the optic canal. There are a variety of disorders that affect the optic nerve. Patients with trauma or mass effect upon the optic nerve have a presentation that depends upon the site of injury. Damage to the fibers proximal to the optic chiasm causes total loss of vision on the ipsilateral side to the damage, as the fibers have not yet crossed. 163

Clinical Review for the USMLE Step 1 Damage to the optic nerve at the optic chiasm leads to bitemporal hemianopsia - that is, loss of vision on the lateral side of both eyes. The optic chiasm is located near the pituitary gland and pituitary hyperplasia or tumors can have a mass effect here. Damage to the optic nerve fibers distal to the chiasm (that is, after they have crossed at the chiasm) leads to contralateral vision loss in one visual field only. The specific loss depends on exactly which fibers are damaged.

3.5.3

CN III - Oculomotor Nerve

The oculomotor nerve is a motor nerve that originates in the anterior midbrain. Its nuclei are located in the oculomotor nucleus and Edinger-Westphal nucleus. It supplies all major muscles of the eye except the superior oblique and lateral rectus. It also innervates the pupillary sphincter muscle and ciliary body muscles. The nerve travels to the Figure 20. Cranial nerves and their origination brain via the superior orbital fissure. points. Copyright D.W. Stultz. Used with permisThe Edinger-Westphal nucleus supplies the iris sion. constriction muscles and is a parasympathetic nucleus. Inability to constrict a pupil occurs with certain diseases such as syphilis and may be traced back to destruction of this nucleus. Multiple sclerosis and trauma can also lead to paralysis of the oculomotor nerve. The swinging flashlight test can be used to sequentially shine a bright light in both eyes. Both eyes should accomodate to the light no matter which eye has the light in it. However, damage to one part of the tract (such as demyelination secondary to multiple sclerosis) will lead to only one eye to react to the bright light.

3.5.4

CN IV - Trochlear Nerve

The trochlear nerve is the fourth cranial nerve and is a motor nerve. It supplies the superior oblique muscle of the eye and is responsible for its lateral rotation. It originates from the midbrain Figure 21. Optic nerve and chiand its nucleus is the trochlear nucleus. asm. Adapted from Grayâ&#x20AC;&#x2122;s Anatomy. Used with permission.

3.5.5

CN V - Trigeminal Nerve

The trigeminal nerve is a three part cranial nerve that has both motor and sensory components. It originates from the pons and has several nuclei, including a sensory trigeminal nucleus, spinal trigeminal nucleus, mesencephalic trigeminal nucleus, and trigeminal motor nucleus. Its motor component inner164

Anatomy

Figure 22. Major cranial nerves and their ganglia. Sympathetic and parasympathetic fibers labeled. Copyright NetterImages. Used with permission. vates the muscles of mastication. Its sensory components supply the face via three branches: V1 is the ophthalmic branch and goes to the upper face via the superior orbital fissure; V2 is the maxillary branch and innervates the middle of the face via the foramen rotundum; finally, V3 is the mandibular branch and innervates the lower face via the foramen ovale. 165

Clinical Review for the USMLE Step 1 A stroke to the medulla can lead to a condition known as Wallenberg syndrome. In this case, pain and temperature sensory loss can occur on one side of the face, but affect the contralateral side of the body. This is because the sensory fibers that come from the face via the trigeminal nerve and go to the ascending spinothalamic tract do not cross, while those from the body have already decussated. The touch and positional information from the face is sent to the ventral posteromedial nucleus (VPM) of the thalamus, while similar information from the rest of the body is sent to the ventral posterolateral nucleus (VPL). This information is then further processed by the sensory cortex located in the postcentral gyrus in the parietal lobe. This sensory map can be portrayed in the form of a homunculus, which has an exaggerated face and hands. Pain and temperature is also sent to the same nu- Figure 23. Homunculus. Copyright Wikimedia. clei as touch and positional information. However, Used with permission. as this information may lead to automatic responses, it is also distributed to the various other nuclei for automatic processing.

3.5.6

CN VI - Abducens Nerve

The abducens nerve is cranial nerve six and controls the lateral rectus muscle to abduct the eye. This nerve originates from the pons and is controlled by the abducens nucleus; it travels to the lateral rectus muscle via the superior orbital fissure. The abducens nerve is the most commonly affected cranial nerve in patients with tuberculosis; this can lead to difficulty with conjugate gaze, internuclear ophthalmoplegia (INO) and generation of saccades. Normally, conjugate gaze is mediated by the medial longitudinal fasciculus (MLF), which coordinates the actions of CN III, IV, and VI.

3.5.7

CN VII - Facial Nerve

The facial nerve is the seventh cranial nerve and is a combination of a motor and sensory nerve. It is derived from the pons at the cerebellopontine angle, with nuclei located in the facial nucleus, solitary nucleus, and superior salivary nucleus. The facial nerve innervates the facial muscles and also the posterior belly of the digastric and stapedius muscles. The sensory portion includes taste from the anterior 2/3s of the tongue via the chorda tympani; the ganglia for these nerves are found in the geniculate ganglion. Parasympathetic fibers via the greater petrosal nerve innervate all of the salivary glands except the parotid gland; the parotid gland is supplied by the glossopharyngeal nerve. The facial nerve travels through the stylomastoid foramen after traveling through the internal acoustic canal. Viral infection can lead to Bellâ&#x20AC;&#x2122;s palsy, which presents as partial paralysis of the facial nerve. Bellâ&#x20AC;&#x2122;s palsy can also be secondary to Lyme disease. Viral infections can be treated with a prednisone taper, while Lyme disease should be treated with doxycycline. 166

Anatomy 3.5.8

CN VIII - Vestibulocochlear Nerve

The vestibulocochlear nerve is the eighth cranial nerve. It is divided into the vestibular portion and the auditory portion. The vestibular nerve innervates five sensory organs responsible for balance, including the utricular macula, saccular macula, and three cristae ampullares. The two maculae are responsible for linear acceleration, while the three cristae ampullares sense angular acceleration. The auditory division of the nerve innervates the cochlea and is responsible for sensing sound. As discussed previously, these end organs conduct mechanosensory information into electrical signals through the action of potassium currents. The precise location of the sensory hair cells that convert this information is coded into positional or frequency information that tells the brain where the body is moving in three dimensions (for the vestibular Figure 24. Facial nerve. Adapted from Grayâ&#x20AC;&#x2122;s Anatosystem) or what frequency of sound is being my. Used with permission. heard (for the auditory system). The vestibulocochlear nerve emanates lateral to the facial nerve at the cerebellopontine angle. Its nuclei are located in the vestibular nuclei and cochlear nuclei. It travels in the internal acoustic canal with the facial nerve.

3.5.9 CN IX Glossophar yngeal Nerve The glossopharyngeal nerve is the ninth cranial nerve and has both sensory and motor components. It comes from the medulla with nuclei located in the nucleus ambiguus, inferior salivary nucleus, and solitary nucleus. It is responsible for taste from the posterior 1/3 of the Figure 25. Vestibulocochlear nerve. Copyright Sapan Desai. Used with tongue, salivary innervation permission. 167

Clinical Review for the USMLE Step 1 to the parotid gland, and motor innervation to the stylopharyngeus. It travels via the jugular foramen.

3.5.10

CN X - Vagus Nerve

The vagus nerve is the tenth cranial nerve and has both motor and sensory functions. It emanates from the medulla and has nuclei in the nucleus ambiguus, dorsal motor nucleus of the vagus, and solitary nucleus. The vagus nerve is motor to the laryngeal and pharyngeal muscles. It also supplies all major organs via parasympathetic fibers. All of the muscles of the larynx are supplied by the recurrent laryngeal nerve except the cricothyroid muscle; this is supplied by the external laryngeal branch of the vagus nerve. Damage to the recurrent laryngeal nerve can occur during thyroid surgery and lead to changes in voice; in more serious cases, it can lead to paralysis of the vocal folds and difficulty swallowing. Bilateral damage can lead to inability to protect the airway. The parasympathetic function of the vagus nerve upon the heart leads to lowerFigure 26. Depolarization of hair cells and ion curing of the heart rate. This occurs via the release of acetylcholine. A feedback loop rents. Copyright Sapan Desai. Used with permission. located near the carotid bifurcation works via the carotid sinus to regulate the heart rate. A baroreceptor here reacts to increased blood pressure by activating the vagus nerve to lower the heart rate; as a result, massage of the carotid sinus can lead to syncope in susceptible individuals.

3.5.11 Nerve

CN XI - Spinal Accessory

The spinal accessory nerve is a motor nerve that innervates the trapezius and sternocleidomastoid muscles. Its nuclei are located in the nucleus ambiguus and spinal accessory nucleus. It travels via the jugular foramen.

3.5.12

CN XII - Hypoglossal Nerve

Figure 27. Major distal cranial nerves and their The hypoglossal nerve is a motor nerve that inner- ganglia. Adapted from Grayâ&#x20AC;&#x2122;s Anatomy. Used vates all of the muscles of the tongue except the pala- with permission. 168

Anatomy toglossus (which is innervated by the vagus nerve). It emanates from the medulla and has its nucleus in the hypoglossal nucleus. It travels via the hypoglossal canal. Damage to this nerve can occur with carotid artery surgery and can lead to difficulty with swallowing and speech.

3.6. Brain Nuclei 3.6.1

Medulla

The medulla is responsible for the autonomic outflow to the heart and lungs, autonomic outflow to the spinal cord, sound localization, sneezing, coughing, swallowing, and suckling. Through this autonomic outflow, it controls involuntary functions including the heart rate, blood pressure, and respiration. Motor fibers cross at the pyramidal decussation of the medulla. Sensory information including proprioception, pain, deep touch, and vibration from the middle and lower portion of the body travel to the fasciculus gracilis. Similar information from the upper body travels to the cuneate fasciculus. The inferior olivary nucleus helps to coordinate Figure 28. Cross section of the brain through the medulla. Adapted from Grayâ&#x20AC;&#x2122;s Anatomy. Used with permission. movement.

3.6.2

Pons

The pons regulates autonomic outflow throughout body. It also serves as a sensory relay between the cerebellum and cerebrum. It generates the impulses that convert inspiration to expiration; at night, it is responsible for dreaming. It contains nuclei for the trigeminal sensory nucleus, and nuclei for cranial nerves VI through VIII. Central pontine myelinolysis can occur when correcting hyponatremia too quickly. Administration of hypertonic saline in this condition can lead to rapid swelling of the brain, necrosis of neurons, and cerebral hemorrhage. With the colocation of nuclei that help control eye movements, motor function, and the vestibular nuclei, the pons works to coordinate movement with motion of the eyes and remainder of the body. It also serves as a nexus for hearing, taste, and sensorimotor for the face. Destruction of the pons can lead to locked-in syndrome where higher order consciousness remains fully intact, but the ability to communicate with the outside world is destroyed with the exception of some eye movements controlled by the oculomotor nerve.

3.6.3

Cerebellum

The cerebellum plays a major role in coordinating motor functions by contributing to precise and ac169

Clinical Review for the USMLE Step 1 curate movements. Defects in the cerebellum can lead to dysfunction in fine motor control and motor learning. The cerebellum is linked with multiple brain nuclei via a series of tracts, including the motor cortex and spinocerebellar tract. The cerebellum contains two major types of neurons, known as granule cells and Purkinje cells; the cerebellum has more cells than the rest of the brain combined. These cells are distributed among several major regions of the cerebellum. The flocculonodular lobe connects with the vestibular nuclei to coordinate balance and proprioception. The spinocerebellum helps to coordinate fine motor function via the spinocerebellar tract. The cerebrocerebellum helps to plan future movements and ensure that transitions from one movement to another are smooth. Two additional zones help to synchronize movement: the intermediate zone compares intended motor activity with actual motor activity, while the lateral zone plays a role in body posture information integration. The cerebellum contributes to the cerebral peduncles along with the cortex and spinal cord. The cerebral peduncle contains the corticospinal tract and corticobulbar tract and helps to relay motor fibers to various thalamic nuclei. It includes the midbrain, crus cerebri, substantia nigra, and pretectum.

3.6.4

Epithalamus

The epithalamus is a portion of the diencephalon and connects the limbic system to the thalamus and other parts of the brain. It includes the pineal gland, which is responsible for the secretion of melatonin and helps to create a sense of day and night through diurnal variation. Melatonin also functions as an antioxidant, activates the immune system, and regulates hunger and thirst.

3.6.5

Thalamus

The thalamus is also a part of the diencephalon and serves as a relay system to transmit sensory information to the cortex. It modulates signals going to and from the cortex. The functions of the thalamus

Figure 29. The origination of the vestibulocochlear nerve and major nuclei of the brain related to the eighth cranial nerve. Copyright Sapan Desai. Used with permission. 170

Anatomy can be divided into a series of nuclei that control various functions: •

Anterior – memory formation

•

Dorsomedial – emotional behavior

•

Centromedian – basal ganglia modulation

•

Ventral anterior – motor relay facilitates movement

•

Ventral lateral – motor relay facilitates movement

•

Ventral posterolateral – somatosensory relay from body from ALS and DC/ ML system

•

Ventral posteromedial – somatosensory relay from face via trigeminothalamic tract; also includes taste

•

Lateral dorsal – sensory and emotional integration

•

Lateral geniculate nucleus – visual relay

•

Medial geniculate nucleus Figure 30. Nuclei of the thalamus. Copyright Madhero88. Used – auditory relay with permission.

•

Pulvinar – sensory integration

•

Reticular – arousal, sleep, reticular activation

3.6.6

Hypothalamus

The hypothalamus is a neuroendocrine organ that helps to convert neuronal signals into endocrine modulators that control the pituitary gland. It is also a part of the diencephalon and controls body homeostasis, maintains temperature, hormone levels, osmolarity, coordinates autonomic nervous system activity, and maintains proper sympathetic and parasympathetic outflow. Like the thalamus, the hypothalamus can also be divided into a series of nuclei that serve discrete functions. The medial preoptic nucleus controls the parasympathetic nervous system and releases GnRH. The supraoptic nucleus releases oxytocin and vasopressin. Damage to this nucleus can lead to diabetes insipidus. The suprachiasmatic nucleus also helps to release vasopressin, and projects to the pineal gland to help control circadian rhythms. The paraventricular nucleus releases oxytocin, vasopressin, and cortcotropin-releasing hormone (CRH). The anterior nucleus is larger in male heterosexuals and is thought to control sexual preference. It also controls temperature regulation. 171

Clinical Review for the USMLE Step 1 The dorsomedial nucleus inhibits eating and drinking and also regulates the blood pressure and heart rate. Damage leads to hyperphagia. The ventromedial nucleus plays a role in satiety. The arcuate nucleus is responsible for dopamine release to control prolactin secretion; it is also involved in appetite. The lateral nucleus plays a role in thirst and hunger. The posterior nucleus regulates the response to cold and controls sympathetic outflow. The mammillary bodies are part of the limbic system and are involved in memory formation and retrieving memory.

3.6.7

Subthalamus

The subthalamus is a portion of the diencephalon responsible for efferent outflow to the striatum. It receives flow from the substantia nigra and striatum.

3.6.8

Basal Ganglia

Overview The basal ganglia are a group of nuclei that connect the thalamus to the forebrain. The primary function of this group of nuclei is to coordinate complex executive tasks while inhibiting other impulses. Diseases that affect the basal ganglia therefore lead to disinhibition and problems with motor coordination; examples include Parkinson’s disease, Huntington’s disease, and Tourette’s syndrome. The basal ganglia use a variety of neurotransmitters.

Striatum The largest part of the basal ganglia is the striatum, composed of the caudate and putamen, and separated by the internal capsule. The majority of the neurons within the striatum are inhibitory (and therefore use GABA as their primary neurotransmitter). The striatum links to the cortex and helps to coordinate the sensorimotor aspects of decision-making. Destruction of the dopaminergic innervation to here and the substantia nigra occurs in Parkinson’s disease. Atrophy occurs in the striatum in Huntington’s disease.

Globus Pallidus The globus pallidus is divided into an internal segment and external segment. Like the striatum, these neurons are also typically inhibitory and use GABA as their primary neurotransmitter. The external segment receives motor information from the striatum, then forwards impulses to the subthalamic nucleus where excitatory impulses are produced. The internal segment also receives information from the striatum, but functions via both a direct and an indirect pathway.

Subthalamic Nucleus In contrast to the remainder of the basal ganglia, the subthalamic nucleus has primarily excitatory neurons that work via glutamate. The subtahalmic nucleus works with the indirect pathway to generate stimulatory impulses to the substantia nigra.

Direct and Indirect Pathway Figure 31. Facing page. The basal ganglia and their interconnections with other parts of the brain. Neurotransmitters are also noted. Copyright Mikael Haggstrom. Used with permission. 172

Anatomy

173

Clinical Review for the USMLE Step 1

Figure 32. Illustration of the interconnections of the basal ganglia. Copyright Wikimedia. Used with permission. The direct pathway has connections to the internal segment of the globus pallidus directly from the striatum. The indirect pathway functions via the external segment of the globus pallidus, which sends impulses to the internal segment via the substantia nigra. The direct pathway sends stimulatory impulses from the cortex to the striatum. The striatum sends inhibitory impulses to inhibitory neurons in the substantia nigra; this leads to disinhibition of the thalamus, which feeds back to the cortex and sends stimulatory information. The result is a hyperkinetic state in the motor system. With the direct pathway, there is net disinhibition of the thalamus. The indirect pathway starts with stimulatory information from the Figure 33. Copyright Wikimecortex, which activates inhibitory neurons in the striatum. This leads dia. Used with permission. to disinhibition of the external segment of the globus pallidus, which leads to stimulation of the subthalamic nucleus and inhibition of the substantia nigra. The thalamus is inhibited, which feeds back to the cortex and leads to inhibition of the motor system. With the indirect pathway, there is net inhibition of the thalamus due to more GABAergic pathways in the system. 174

Anatomy 3.6.9

Substantia Nigra

The substantia nigra is a portion of the midbrain that is involved in attention and movement, and in reward pathways. It is abnormal in Parkinsonâ&#x20AC;&#x2122;s disease. The pars reticulata contains inhibitory neurons similar in function to the internal segment of the globus pallidus. The pars compacta plays an important role in motor control and is the primary area of dysfunction in Parkinsonâ&#x20AC;&#x2122;s disease.

3.6.10

Amygdala

The amygdala is a sexually-dimorphic nucleus that shrinks upon castration. It plays a key role in emotion-based memory, anxiety, phobias, fear conditioning, drug addiction, autism, and depression.

3.6.11

Hippocampus

The hippocampus is a series of neurons that are a part of the limbic system. It is found in the temporal lobe and is involved in memory and navigation. It is commonly damaged in Alzheimer disease. The hippocampus plays an important role in new memory formation, especially episodic memory and declarative memory. Damage leads to anterograde and retrograde amnesia. Anterograde amnesia is the inability to form new memories following an insult or trauma. It occurs in Wernicke-Korsakoff syndrome and direct damage to brain nuclei. Retrograde amnesia is the inability to recall old memories prior to insult or trauma, and temporarily occurs following ECT for depression. It occurs in direct damage to brain nuclei.

Figure 34. Cross section of the midbrain showing key nuclei and pathways. Copyright Wikimedia. Used with permission. 175

Clinical Review for the USMLE Step 1 3.6.12

Ventral Tegmental Area

The ventral tegmental area plays a major role in connecting mesolimbic pathway to the nucleus accumbens. It uses a series of dopaminergic pathways and creates a pleasure pathway with incentive-based motivation. It modulates the mesocortical pathway, which connects the ventral tegmental area to the frontal lobe. Defects in the ventral tegmental area are tied to schizophrenia. The ventral tegmental area is directly targeted by cocaine and plays a role in addiction.

3.6.13

Frontal Lobe

The frontal lobe plays a major role in impulse control, judgement, language, memory, motor function, problem-solving, sexual behavior, socialization, spontaneity, planning and coordination of behavior, cognitive maturity, and speech. Our personality is controlled by the frontal lobe. Speech production is controlled by Broca’s area. The precentral gyrus, located on the posterior portion of the frontal lobe, serves as the primary motor cortex.

3.6.14

Parietal Lobe

The parietal lobe integrates sensory information and helps manipulate objects in three dimensions. It is responsible for visuospatial processing. The somatosensory gyrus is located on the anterior portion of the parietal lobe.

3.6.15

Temporal Lobe

The temporal lobe serves as an auditory relay from the cochlea and has an auditory association area. It helps with the comprehension of speech through Wernicke’s area. The arcuate fasciculus connects Wernicke’s with Broca’s. The temporal lobe also has a facial and visual recognition system, is responsible for episodic and declarative memory, and is also the location for the hippocampus and amygdala.

3.6.16

Occipital Lobe

The occipital lobe is the visual association cortex and has the reading and writing centers located within.

3.6.17

Spinal Cord Organization

Dorsal Column-Medial Lemniscus The dorsal column-medial lemniscus pathway is a sensory pathway responsible for fine touch. It goes from the skin to thalamus, then to the cortex. It uses Meissner’s corpuscles in the dermis for sensation. This tract crosses in the brainstem.

Spinothalamic Tract The spinothalamic tract is responsible for pain, temperature, itch, and crude touch. It is a part of the anterolateral system and crosses in the spinal cord.

Corticospinal Tract The corticospinal tract is the motor outflow from the brain. The lateral corticospinal tract crosses in the pyramids, while the medial corticospinal tract crosses at the spinal cord root level. 176

Anatomy

Figure 35. Major tracts of the spinal cord. Copyright Mikael Haggstrom. Used with permission.

Vestibulospinal Tract The medial vestibulospinal tract has a bilateral projection to the cervical cord and is responsible for head adjustments in response to vestibular stimuli. The lateral vestibulospinal tract is an uncrossed projection through the ipsilateral spinal cord and helps to maintain balance and posture.

Spinal Reflex The primary spinal reflex is the deep tendon reflex. The most common example of this is the â&#x20AC;&#x153;kneejerkâ&#x20AC;? reflex that tests the stretch receptors. A spinal cord arc occurs with motor neurons leading to a closed loop reaction that does not involve the brain at all.

3.7. Triangles 3.7.1

of the

Neck

Anterior Cervical Triangle

Overview The anterior cervical triangle is bound by the sternocleidomastoid muscle laterally, the inferior border of the mandible superiorly, and the anterior midline of the neck medially. The anterior cervical triangle may be subdivided into four smaller triangles: the submandibular, submental, carotid, and muscular.

Submandibular Triangle The submandibular triangle is delimited by the inferior border of the mandible, and the anterior and posterior belly of the digastric muscle. The submandibular gland is the largest structure within this triangle. Other structures within this triangle are the anterior and posterior facial veins, facial artery, submental branch of the facial artery, the superficial and deep layer of the submaxillary fascia, and hypoglossal nerve. The facial artery is a branch of the external carotid artery and enters the submandibular triangle under the posterior belly of the digastric, the stylohyoid muscle, and the submandibular gland. It then becomes superficial and lies under the platysma when it encounters the mandible.

177

Clinical Review for the USMLE Step 1

Figure 36. The anterior cervical triangle. Copyright Olek Remesz. Used with permission.

Submental Triangle The submental triangle is bound by the anterior belly of the digastric muscle laterally, the hyoid bone medially, the mylohyoid muscle posteriorly, the midline medially, and the skin and superficial fascia anteriorly. Lymph nodes draining from the chin, lower lip, floor of the mouth, and tip of the tongue are found in this triangle.

Carotid Triangle The carotid triangle is bound by the sternocleidomastoid muscle posteriorly, the anterior belly of the omohyoid anteriorly, and the posterior belly of the digastric superiorly. The hyoglossus muscle, inferior and middle constrictors of the pharynx, and thyrohyoid are noted medially. The common carotid artery, its bifurcation as the external and internal branches, vagus nerve, spinal accessory muscle, hypoglossal nerve, ansa hypoglossi, and cervical sympathetic nerves are within the carotid triangle. The jugular lymph nodes drain in the supraclavicular lymph nodes.

Muscular Triangle The muscular triangle is bound by the anterior belly of the omohyoid superiorly, sternocleidomastoid muscle inferiorly, midline of the neck medially, prevertebral fascia and muscle posteriorly, and the deep layer of the deep cervical fascia, sternohyoid muscle, and cricothyroid muscle anteriorly. The thyroid and parathyroid glands, trachea, esophagus, and sympathetic trunk are found within the muscular triangle.

178

Anatomy

Figure 37. The posterior cervical triangle. Copyright Olek Remesz. Used with permission.

3.7.2

Posterior Cervical Triangle

Occipital Triangle The occipital triangle is bound by the sternocleidomastoid, trapezius, and omohyoid muscles. The spinal accessory nerve crosses the occipital triangle as it travels to the trapezius. A variety of lymph nodes and the external jugular vein also cross this space.

Subclavian Triangle The subclavian triangle is bound by the clavicle, omohyoid, and sternocleidomastoid. The third portion of the subclavian artery runs through this space. The brachial plexus can also be accessed through this triangle.

3.8. Innervation 3.8.1

Nerves of the Upper Extremity

Overview The brachial plexus forms the backbone of the network of nerves that supplies the entire upper extremity and emanates from spinal nerves C5, C6, C7, C8, and T1. Although these roots, trunks, divisions, cords, and branches anastomose to various degrees, a simplified model of the function of each of these roots is illustrated in the following table:

179

Clinical Review for the USMLE Step 1 Table 3. Major function of various nerve roots. C5

Shoulder abduction, extension, and external rotation; some elbow flexion

Elbow flexion, forearm pronation and supination, some wrist extension

Diffuse loss of function in the extremity without complete paralysis of a specific muscle group, consistently supplies the latissimus dorsi Finger extensors, finger flexors, wrist flexors, hand intrinsics

The ulnar nerve is responsible for innervations to the intrinsic muscles of the hand. Transection of this nerve is not repaired primarily.

Hand intrinsics

Long Thoracic Nerve The long thoracic nerve (C5, C6, C7) supplies the serratus anterior muscle, and is commonly tested in the context of a modified radical mastectomy with axillary dissection. Damage to this nerve during that operation can lead to â&#x20AC;&#x153;winged scapula,â&#x20AC;? which is evident when the patient pushes against a wall with an outstretched arm. The long thoracic nerve descends along the lateral border of the pectoralis minor and medial border of the teres major.

Thoracodorsal Nerve The thoracodorsal nerve (C6, C7, C8) travels with the subscapular artery, crosses the axilla, and innervates the latissimus dorsi. Variations in its course may take the crossing somewhat more inferiorly. Care must be taken to avoid transaction of this nerve during an axillary dissection as part of a mastectomy.

Pectoral Nerves The lateral pectoral nerve (C5, C6, C7) passes through the coracoclavicular fascia to supply the pectoralis major. The medial pectoral nerve (C8, T1) supplies the pectoralis minor and major muscles.

Musculocutaneous Nerve The musculocutaneous nerve (C5, C6, C7) is the chief nerve supply to the coracobrachialis, biceps brachii, and brachialis. This nerve travels along the lateral aspect of the arm between the biceps and brachialis. Direct damage to this nerve is therefore rare given the extensive muscular protection.

Median Nerve The median nerve (C5, C6, C7, C8, T1) is a major nerve from the brachial plexus and travels along the medial aspect of the arm just lateral to the brachial artery. It crosses the brachial artery at its bifurcation within the cubital fossa and travels medially. The median nerve primarily supplies the flexors and pronators of the distal upper extremity. Branches also supply the hand. The median nerve travels deep to the flexor retinaculum and may be affected in carpal tunnel syndrome.

Axillary Nerve The axillary nerve (C5, C6) supplies the teres minor and deltoid muscles. Damage to this nerve may occur with anterior dislocation of the shoulder or fracture of the head of the humerus. Erb-Duchenne palsy occurs following damage to the superior roots of the brachial plexus (C5, C6), 180

Anatomy

Figure 38. The brachial plexus. Adapted from Grayâ&#x20AC;&#x2122;s Anatomy. Used with permission. leading to paralysis of the deltoid, biceps, brachialis, coracobrachialis, brachioradialis, supraspinatus, infraspinatus, teres minor, and subscapularis. The upper limb is adducted at shoulder, medially rotated, and extended at the elbow. Erb-Duchenne palsy is the result of excess traction on the neck as can occur during delivery or from falls.

Radial Nerve The radial nerve (C5, C6, C7, C8, T1) supplies the triceps brachii and the extensor compartment of the arm. This nerve initially travels in the posterior compartment of the upper arm, and then crosses through the lateral intermuscular septum to travel in the anterior compartment. In the upper arm, it is located along the radial groove of the humerus and is therefore susceptible to damage in a midshaft fracture. The nerve is also located in close proximity to the lateral epicondyle. The superficial branch of the radial nerve travels deep to the brachioradialis. The radial nerve also supplies muscles of the hand. Saturday night palsy is due to injury to the radial nerve as a result of a mid-shaft humerus fracture. It leads to wrist drop. The deep branch of the radial nerve can be injured by deep puncture wounds to the forearm, leading to extension of the thumb and the metacarpophalangeal joints. Superficial damage leaves a coin-shaped area distal to the bases of the 1st and 2nd metacarpals without sensation.

181

Clinical Review for the USMLE Step 1

Figure 39. The brachial plexus. Copyright Marshall Strother. Used with permission.

Ulnar Nerve The ulnar nerve (C8, T1) is a mostly unprotected nerve that supplies several flexors and muscles of the hand. It is most likely to be injured at the medial epicondyle of the humerus. The ulnar nerve travels along the posterior and medial aspect of the humerus, then travels with the ulnar artery in the forearm. This nerve passes superior to the flexor retinaculum. Klumpke palsy is due to lower brachial plexus injury. It occurs when a person grabs something to break a fall. The dorsal and ventral roots of the spinal nerves that form the inferior trunk of the brachial plexus (C8 and T1) may be avulsed. As a result, the short muscles of the hand are affected. It presents as claw hand.

3.8.2

Nerves of the Lower Extremity

Overview There are three major plexuses that provide innervation to the pelvis and lower extremities. The lumbar plexus includes a variety of cutaneous and motor nerves to the inguinal region and proximal lower extremity. The sacral plexus predominantly supplies the distal lower extremity, while the coccygeal plexus supplies structures of the perineum and anus.

Lumbar Plexus The chief nerves of the lumbar plexus are the iliohypogastric, ilioinguinal, genitofemoral, lateral femoral cutaneous, obturator, and femoral nerves. The lateral femoral cutaneous nerve provides sensory innervation to the lateral thigh. The obturator nerve (L2, L3, L4) passes through the psoas major, deep to the common iliac artery, and through the obturator canal. It provides sensory innervation to the medial thigh and motor to the adductor muscles. The femoral nerve (L2, L3, L4) travels with the femoral vessels deep the inguinal ligament and provides sensory innervation to the majority of the lower leg and motor to the quadriceps (i.e. the rectus femoris, vastus lateralis, vastus medialis, and vastus intermedius). The major sensory branch is the saphenous nerve, which travels with the great saphenous vein deep to the sartorius.

182

Anatomy Sacral Plexus The common fibular, tibial, and sural nerves are major branches of the sciatic nerve, itself a major derivative of the sacral plexus. The superior and inferior gluteal nerves and cutaneous nerves to the thigh also emanate from the sacral plexus. In conjunction with the cutaneous nerves from the lumbar plexus, branches of the sural nerve provide sensory innervation to the entire leg. The sacral plexus includes nerve roots from L4, L5, S1, S2, S3, and S4.

Coccygeal Plexus

Figure 40. Lumbar plexus. Adapted from Gray’s Anatomy. Used with permisThe coccygeal sion. plexus is formed by roots S4 and the coccygeal nerve. It gives rise to the pudendal nerve, a somatic nerve that regulates the function of the bulbospongiosus and ischiocavernosus muscles, external anal sphincter (via the inferior rectal branch), scrotum (via the superficial perineal nerve), and genitalia (via the dorsal nerve of the penis or clitoris).

3.8.3

Major Reflexes

These nerves also play a role in several important reflexes. Testing these reflexes is especially important as part of a trauma workup, as a specific dysfunction may be an indicator of spinal cord injury. Table 4. Major reflexes of the upper and lower extremities. Biceps Reflex

C5, C6 – Musculocutaneous nerve

Triceps Reflex

C6, C7 – Radial nerve

Patellar Reflex

L3, L4 – Femoral and common peroneal nerves

Ankle Reflex

L5, S1 – Tibial nerve

183

Clinical Review for the USMLE Step 1 3.8.4

Autonomic Nervous System

Parasympathetic Nervous System The autonomic nervous system is divided into the parasympathetic and sympathetic nervous systems. The parasympathetic nervous system has its cell bodies in the brainstem (CN III, VII, IX, X) or sacral spinal cord (S2-S4). These preganglionic neurons synapse with their postganglionic neurons in either the parasympathetic ganglia of the head or near their target organ. The primary targets of the parasympathetic nervous system are visceral organs. They function to dilate blood vessels in the gastrointestinal tract prior to digestion, induce bradycardia, cause pupillary constriction, and induce erection and sexual arousal.

Sympathetic Nervous System The sympathetic nervous system has its cell bodies in the lateral horn of the spinal cord, within the intermediolateral cell column. These preganglionic, general visceral efferent neurons are located between T1 and L2, and synapse with their postganglionic neurons on the sympathetic chain, prevertebral ganglia such as the celiac or mesenteric ganglia, and chromaffin cells of the adrenal medulla. The sympathetic nervous system leads to tachycardia, diverts blood away from the gastrointestinal system, dilates the pupils, and stimulates orgasm. The primary neurotransmitter of the autonomic nervous system is acetylcholine. The effector organs such as the adrenal Figure 41. The autonomic nervous sysgland use epinephrine. tem. Adapted from Grayâ&#x20AC;&#x2122;s Anatomy. Used with permission.

4. Physiology 4.1. Neurons 4.1.1

Cell Biology

Neurons are specialized cells that respond to chemical signals, generate an electrical impulse, and release neurotransmitters. Synthesis of neurotransmitters and other proteins occurs in the soma. Input is received via dendrites, which make contact with axons from other neurons. Axons transmit electrical signals, up to 1.5 meters along the dorsal column. Axons transport neurotransmitters using microtubules. Kinesins and dyneins are ATP-linked proteins that can transport proteins along the microtubule chains. Neurons generate electrical impulses that travel along the axon through sodium, potassium, chloride, and calcium ions. The action potential transmits this charge rapidly down the axon. Myelinated fibers permit faster transmission as the charge will jump from one node of Ranvier to another down the 184

Physiology sheath. Once the action potential is started, it becomes an all-or-nothing phenomenon. The impulse is generated once the sum of the excitatory inputs and inhibitory inputs is calculated from the various dendrites. Peripheral nerve fibers can be divided into one of three groups. A fibers are typically motor or sensory. They are large diameter, myelinated, and carry impulses rapidly. B fibers are preganglionic fibers, myelinated, and small diameter. C fibers are unmyelinated, thin diameter fibers that typically carry pain, temperature, and pressure. Their lack of myelin is why touching a hot stove leads to a rapid reflex first, followed by the sensation of pain and heat.

4.1.2

Neurotransmitters

Neurons use a variety of neurotransmitters to effect changes on target neurons (and other cells throughout the body). Acetylcholine is the predominant neurotransmitter and can activate ligand-gated ion channels, muscarinic receptors, and nicotinic receptors. GABA is the predominant inhibitory neurotransmitter of the nervous system and binds to anion channels that release chloride and hyperpolarize the target neuron, making it more difficult to activate them. Glutamate is an excitatory neurotransmitter that can bind to ligand-gated ion channels such as AMPA, NMDA, or metabotropic receptors. Excess stimulation can lead to damage via release of toxic amounts of calcium and sodium.

Figure 42. Components of a neuron and its axon terminals. Copyright Mariana Ruiz. Used with permission. 185

Clinical Review for the USMLE Step 1 Dopamine functions via a variety of G-protein linked receptors. D1 and D5 are excitatory, while D2-D4 are inhibitory G proteins. Serotonin functions via 5-HT receptors and is generated by tryptophan.

4.2. Supporting Cells Supporting cells of the nervous system include a variety of cells. Astrocytes modulate the internal environment of the brain and help control the flow of blood in the brain. As such, astrocytes are the primary constituent of the blood-brain barrier, a highly selective membrane that permits travel of vital minerals, electrolytes, fluids, and certain drugs while excluding larger proteins and cells (such as RBCs). Oligodendrocytes produce myelin. Ependymal cells produce cerebrospinal fluid (CSF), which circulates within the ventricles, brain, and spinal cord. The CSF is produced in the choroid plexus and travels from the lateral ventricle, through the foramen of Monro, into the third ventricle, through the Sylvian aqueduct, and into the fourth ventricle. From there, it travels into the subarachoid space and spinal cord via the foramen of Luschka and foramen of Magendie. The CSF helps to maintain the buoyancy of the brain and contains isotonic concentrations of sodium, potassium, and chloride. It is relatively poor in RBCs, WBCs, glucose, and protein. Ependymal cells are also thought to serve a stem cell-like function in that they can repopulate neurons and supporting cells of the CNS. Schwann cells function like oligodendrocytes in the peripheral nervous system. They produce myelin and also produce a template that peripheral nervous system neurons can use to help regrow their axons. This requires the Schwann cells to remain largely intact, and peripheral nerve regrowth is effective only over short distances and with minimal injury to surrounding structures. Microglia are macrophages located in the nervous system. Their primary role is immunologic.

4.3. Brain Death Brain death is distinct from a persistent vegetative state and coma. Brain death implies the total and permanent cessation of all brain activity and occurs due to neuronal cell death following anoxia. The specific legal definition varies between death of the brain stem and death of the entire brain, but the effect is generally the same. The only reflexes that may be present are the corneal reflex and the vestibuloocular reflex. There are no spontaneous respirations, no response to pain, and no cranial nerve reflexes. Brain death can be diagnosed only after excluding drug overdose (especially barbiturates and alcohol) and a vegetative state. There is no signal on EEG. A persistent vegetative state occurs following severe brain damage that leads to disruption of consciousness. Basic brain functions, including spontaneous respiration and cranial nerve reflexes, are maintained. However, there is no voluntary communication with the outside world. A persistent vegetative state is distinguished from locked-in syndrome, which occurs following trauma to the pons where consciousness is not disrupted but the ability to communicate with the outside world is severely restricted.

4.4. Peripheral Vascular Resistance Peripheral vascular resistance relies on the tone of the vasculature. Both intrinsic and extrinsic mediators regulate the overall tone within a vascular bed. Peripheral vessels are predominantly found in the skin as well as muscle beds. Sympathetic tone is primarily responsible for the peripheral vascular resistance in the skin and superficial tissue, and responds to body temperature. Activation of the sympathetic nervous system results in vasoconstriction peripherally, an attempt to conserve heat. On the other hand, when body temperature rises, a vasodilation reflex occurs as sympathetic tone is withdrawn. 186

Physiology The vasculature found within a muscle bed is innervated by not only a system that vasoconstricts, but also one that vasodilates. Postural changes elicit vasoconstriction of the arterial system in an attempt to maintain blood pressure. However, in times of stress (i.e. exercise), metabolites build up, and combined with ischemia of exercise, the vascular bed vasodilates in an attempt to increase peripheral blood flow. The balance of vasodilator and vasoconstrictive mediators is responsible for the overall peripheral vascular resistance.Â

4.5. Autoregulation Autoregulation is responsible for maintaining constant and consistent blood flow to a target region or organ as perfusion pressure increases and decreases. Conceptually, as blood pressure rises and falls, resistance vessels constrict or dilate, respectively, to ensure a constant level of flow through that vessel. This is particularly important in the cerebral vasculature, in that a rising blood pressure elicits a constrictive response to protect the brain from hypertension. Autoregulation, mediated by local and sympathetic mediators, preserves blood flow over a range of blood pressures.

4.6. Venous Hemodynamics Veins are thin, compressible, valve-containing structures that contain a significant percentage of the bodyâ&#x20AC;&#x2122;s blood supply. Both the deep and superficial veins in the periphery are responsible for returning blood to the heart, and do so in a fluctuant manner. This rapidly changing flow through the venous system can be explained by the forces that act on blood within the system: dynamic pressure transmitted through the vasculature from the contractile force of the heart, hydrostatic pressure that is affected by gravity, and filling pressure that varies with venous elasticity. Given that the contractile forces of the heart are transmitted through the arteries and capillaries, it may be negligible at the venous level. Hydrostatic pressure, on the other hand, varies depending on where it is measured with regards to the heart, with the greatest hydrostatic pressure being found at the point most inferior to the heart in an upright individual. Lastly, in applying what we know about orthostatics, the venous system alone does not constrict in response to the increased blood volume (i.e.,Â when a patient is moved from supine to upright), which corresponds to a relatively innate filling pressure. The characteristic filling pressure is what is responsible for the great capacitance of the venous system that separates it from the arterial system. Understanding each entity is important, but it is the combination of these factors within the venous system that generates the overall venous pressure.

4.7. Respiratory Flow Variation Respiration has significant impact on flow through the venous system. Not only does venous return rely on the dynamic pressure transmitted through the arterial system from the heart as well as the pumping effect of the muscles, there is significant pull generated by changes in pressure within the thoracic and abdominal cavities. Inspiration involves descent of the diaphragm into the abdomen, which in turn increases the intraabdominal pressure. This increase in pressure impedes venous flow from the legs into the central venous system because the pressure gradient between the two systems is diminished. On the other hand, during expiration, the diaphragm ascends back into the chest, decreasing intraabdominal pressure, thereby allowing increased flow into the vena cava. This concept also applies to venous flow from the upper extremities and head, in that inspiration and the resultant descent of the diaphragm decreases the intrathoracic pressure, and venous blood is then drawn into the chest.

187

Clinical Review for the USMLE Step 1

4.8. Vasoactive Mediators 4.8.1

MMPs

Proteases are enzymes involved in many bodily processes, including hemostasis, the inflammatory response, and the migration of inflammatory and remodeling cells. Proteases are involved in intimal hyperplasia as well. Plasmin, formed from plasminogen, is a potent activator of such proteases, including matrix metalloproteinases (MMPs). These MMPs, together with plasmin and other proteases, work to break down, rebuild, and remodel the extracellular matrix. There are three subclasses of MMPs. First are the interstitial collagenases, which act on type I and type III collagen. Next, gelatinases, alter gelatin, type IV and type V collagen, as well as elastin. Lastly, the stromelysins, function to degrade laminin, fibronectin, and proteoglycans. It is the lack of balance between activation and inhibition of these proteases that is thought to lead to atherosclerotic plaque formation as well as their instability that ultimately leads to plaque rupture. MMPs are also involved in the pathogenesis of aneurysmal disease, the intimal hyperplastic response of vein grafts, as well as vein wall remodeling that eventually leads to varicosities.

4.8.2

Nitric Oxide

Nitric oxide, previously called endothelium-derived relaxing factor, acts as a potent vasodilator within the microcirculation. Nitric oxide is produced from arginine in a process catalyzed by nitric oxide synthase, an enzyme present within endothelial cells. As shear stress increases, the force acting on the endothelium also increases which activates nitric oxide synthase, and vasodilation is achieved. Nitric oxide is a lipophilic gas that acts on a receptor that functions as a guanylyl cyclase. Once activated, the guanylyl cyclase converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP-dependent protein kinases go on to phosphorylate myosin light chain kinase (MLCK) and SERCA. MLCK is inactivated by phosphorylation which leads to a decreased activation of myosin light chain (MLC), yielding less interaction between actin and myosin. In addition, phosphorylation activates SERCA, which removes calcium from the intracellular space, thus reducing calcium ions available for contraction. Therefore, nitric oxide leads to vasodilation be relaxing vascular smooth muscle cells within the vessel wall.

4.8.3

VEGF, EGF, and Angiogenesis

Vascular endothelial growth factor (VEGF) is an important growth factor that leads to the production of new endothelial cells. It has great impact not only in embryogenesis, but also in the formation of collateral circulation in the setting of ischemia. Epidermal growth factor (EGF) is another stimulant of endothelial cell proliferation and migration important in angiogenesis that works via tyrosine kinase pathways. Angiogenesis requires the formation of new capillary-like structures that bud from existing vessels. This process is promoted by antigenic factors such as VEGF. Hypoxia is thought to be a dominating stimulus that leads to the production of VEGF, ultimately leading to the production and sprouting of new vessels.

4.9. Cerebral Perfusion Pressure The cerebral perfusion pressure (CPP) is the pressure generated by blood flow to the brain. There are three constituents that modify the CPP, including the mean arterial pressure (MAP), intracranial pressure (ICP), and jugular venous pressure (JVP). Cerebral perfusion pressure is defined as the difference between the MAP and ICP. CPP divided by the cerebral vascular resistance (CVR) yields cerebral blood 188

CNS and PNS Pathology flow, a quantity that is difficult to measure directly. CPP = MAP â&#x20AC;&#x201C; ICP The major constituents that affect ICP include brain volume, cerebral spinal fluid (CSF), and blood. Changes in one or more of these variables can lead to a rise in intracranial pressure, which in turn can reduce cerebral perfusion pressure, decrease, blood flow to the brain, and cause cerebral ischemia with stroke. Normal MAP ranges between 60 and 150 mmHg and ICP is typically about 10 mmHg. Autoregulation within the brain modulates CPP to between 70 and 90 mmHg. Once the limits of autoregulation are exceeded, a drop in CPP below 70 mmHg leads to cerebral ischemia. In selected, stable patients, the tolerated range for CPP can vary between 50 and 150 mmHg, and a lower limit for children of 60 mmHg may be tolerated. Urgent correction of potential causes of CPP derangement is required. Rising ICP should be treated with a ventriculostomy drain. Rapid sequence intubation, sedation, mannitol, hypothermia, paralysis, and raising the head of the bed are all means of mitigating a rise in ICP. Pressors may be used to increase MAP to overcome a continuing rise in ICP. Hyperventilation to cause a PaCO2 of 35 mmHg may reduce cerebral vasospasm and improve circulation. Hypotonic saline can also be used to control ICP to some extent. Severe derangements in intracranial pressure may lead to uncal herniation and death. Early signs include papillary dilation with a sluggish reaction, suggesting compromise of the ipsilateral oculomotor nerve from overstretching. Table 5. Intracranial pressure Drug

Mannitol

Indications

Mechanism of Action

Reduce intracranial pressure

Hypertonic solution to increase water and salt excretion in distal tubule

Oliguric renal failure

Also opens BBB through shrinking the endothelial cells

Sweetener for diabetes

5. CNS

and

Complications

Rare

Notes Sometimes used as an adulterant for opioid abuse Also given for tropical fish poisoning

PNS Pathology

5.1. Spinal Cord Pathology 5.1.1

Spinal Cord Compression

Compression of the spinal cord is a neurologic emergency that requires prompt medical attention to avoid lifelong sequelae. Common causes include tumor spread to the back, disk herniation, abscess, and hematoma formation. The most common site of compression is the thoracic spinal cord. Cord compression presents as sudden onset of neurologic symptoms distal to the site of spinal cord compression, with symptoms including sudden weakness in lower extremities, incontinence, sexual dysfunction, and sensory changes. Pain is common in nearly all patients. Diagnosis is made by careful history and physical exam, including a full neurologic exam that identifies focal deficits. Plain films are typically diagnostic, but MRI and CT myelogram are all used for additional information.

189

Clinical Review for the USMLE Step 1 Cord compression is treated with immediate steroid therapy, including high doses of dexamethasone. The key to this treatment is to reduce any inflammation and prevent further injury. Cancer-induced compression should be treated with chemotherapy or radiation therapy, while surgical options are available for disk herniation, hematoma, and abscesses. Outcome depends on the promptness of medical therapy, but the majority of patients are able to regain their baseline function, if they had good function previously.

5.1.2

Syringomyelia

Syringomyelia is divided into a communicating cavitation or noncommunicating cavitation of the spinal cord. Communicating syringomyelia is associated with Arnold-Chiari malformation, and noncommunicating syringomyelia is typically secondary to spinal cord trauma. Neurologic symptoms include sensory deficits and some lower motor neuron defects. The cervical spinal cord is most commonly affected. Treatment involves surgery.

5.1.3

Subacute Combined Degeneration (SACD)

Subacute combined degeneration is due to vitamin B12 deficiency, itself commonly the result of intrinsic factor deficiency, decreased intake, terminal ileum disorders, Diphyllobothrium latum infection, or atrophic gastritis. In addition to the megaloblastic anemia that develops, vitamin B12 deficiency leads to weakness of the extremities with paresthesia. Ataxia is common. Plantar extension and hyperreflexia are found on physical exam, along with deficits in vibration sensation and proprioception. Treatment is to administer vitamin B12.

5.1.4

Anterior Spinal Artery Infarction

Anterior spinal artery infarction is rare and leads to flaccid paralysis followed by spastic paresis through ischemic damage to the spinal cord. Vibration and proprioception remain intact, but pain and temperature are lost.

5.1.5

Spinal Cord Trauma

Patients with trauma to the head and neck are also at risk for specific trauma to the spinal cord. Direct trauma to the vertebral column can also lead to herniation of discs, bony fragments, and direct injury to the spinal cord. Hematoma formation can lead to occlusion, while vascular disruption can lead to ischemia. All patients who are suspected of head, neck, or back trauma should be stabilized in a hard cervical collar (i.e. a Miami J) and backboard. Expeditious clearing of the cervical spine and removal of the backboard should be completed. Injuries to the spinal cord are most likely to occur at the cervical level (55%), followed by the thoracic (30%) and lumbar (15%) regions. Spinal shock may occur with injuries above T5, leading to loss of background excitability from loss of lower pathways, decreased reflex function for at least 1 week and perhaps permanently, and loss of vestibulospinal and reticulospinal pathways. This leads to bradycardia, vasodilation, and hypotension. Treat spinal shock with fluids and pressors. Nonpenetrating injuries of the spinal cord that occurred within 3 hours should be treated with 24 hours of methylprednisolone. Injuries that occurred within 8 hours should be treated with 48 hours of methylprednisolone. Injuries that occurred greater than 8 hour ago should not be treated with steroids. These findings are based off the somewhat controversial NASCIS trials.

190

CNS and PNS Pathology Clearance of the C-spine in an intubated and sedated patient without neurologic findings can be done with a CT scan through T1, but ligamentous injury cannot be excluded. If suspected, extension/flexion films and physical exam are key. An MRI is also a sensitive test for detecting ligamentous injury. Cord compression is commonly the result of tumor, disk herniation, abscess, or hematoma formation â&#x20AC;&#x201C; especially in the thoracic levels. Disturbances to the upper central cord lead to loss of sensory and motor function in the distal upper extremities with sparing of the lower extremities. Brown-Sequard syndrome occurs in the setting of severe trauma in which anatomic or functional hemisection of the spinal cord has occurred. It presents with hemiparesis with limb drift, hyperreflexia, spasticity, Babinski sign, and loss of contralateral pain and temperature. Damage above T1 leads to Horner syndrome, which presents with miosis, ptosis, and anhidrosis. This particular manifestation can occur with metastatic lung cancer. Complete spinal cord transection above T6 will lead to autonomic dysreflexia in about half of all patients and leads to cardiovascular instability, hypertension leading to hemorrhage and seizures, and vasoconstriction below the level of injury. Unopposed parasympathetic activation leads to diaphoresis, vasodilation, and headache. Autonomic dysreflexia often occurs in response to an uncomfortable stimulus below the level of injury.

5.2. Brain Pathology 5.2.1

CNS Malformations

There are two major CNS malformations that commonly appear on the exam. Arnold-Chiari malformation is a congenital disorder that presents with a small posterior fossa, cerebellum malformation, vermis herniation, and hydrocephalus. It can present with stridor, no gag reflex, dysphagia, spastic quadriparesis, nystagmus, syncope, progressive loss of function, pneumonia, and GERD. Dandy-Walker malformation is another congenital defect that presents with a large posterior fossa, no vermis, and CSF foramen atresia. It presents with ataxia, syringomyelia, microcephaly, spina bifida, and cardiac anomalies. Empty sella syndrome presents with a missing pituitary incidentally seen on CT; however, hormonal Figure 43. Spinal cord trauma. Copyright F.P. function remains normal. Jacquot. Used with permission. 191

Clinical Review for the USMLE Step 1 5.2.2

Cerebrovascular Disease

Epidemiology Cerebrovascular accidents (CVA) affect more than 400,000 patients a year with a rapid increase projected over the next 50 years. Stroke is the third leading cause of death; overall, it is the second leading cause of death worldwide. Men are at more risk than women, and up to Âź of all strokes affect individuals under the age of 65.

Etiology Cerebrovascular disease (CVD) and cerebrovascular accidents present with acute focal neurologic deficits commonly due to loss of circulation to a portion of the brain. Also known as a stroke, there are numerous types of CVAs. Broadly, CVA is categorized as either hemorrhagic or ischemic. Ischemic strokes are commonly secondary to embolism from elsewhere in the body or intracranial thrombosis. Disruption of the blood flow leads to neuronal death and infarction of the brain. Common sources of the embolism include valvular or mural thrombi, carotid circulation, and occasionally, the right heart in the presence of a right to left shunt. About 1/5 of all strokes lead to lacunar infarcts (which involve the subcortical cerebrum and brainstem). Lacunar infarcts are most common in patients with DM and HTN. Lacunar infarcts lead to either a pure sensory deficit, a pure motor deficit, or a hemiparetic stroke with ataxia. Sources of thrombus formation include the branch points within the circle of Willis and near the internal carotid artery (ICA). Stenosis, atherosclerosis, and platelet defects are common causes of arterial blockade; other causes are hypercoagulable states, polycythemia, and sickle cell anemia. Overall, other causes of stroke include vascular dissection, hypotension, and excessive hemorrhage. Risk factors that increase CVA include increasing age, HTN, smoking, CHD, LVH, atrial fibrillation, hypertriglyceridemia, oral contraceptive use, pregnancy, and hypercoagulable states. Thrombotic strokes are typically slower in onset, while embolic strokes are sudden in onset.

Pathophysiology of Ischemic Stroke The brain is highly sensitive to disruption in blood supply. An ischemic cascade begins almost immediately following loss of perfusion and eventually leads to irreversible infarction. The area of the brain that still receives some transient blood flow is a region of reversible ischemia; this region forms a sort of penumbra (think of the sun during a full eclipse) around the area of the stroke. The result of ischemia is a failure of membrane transport, large calcium influx, large quantities of neurotransmitter release with additional calcium influx, and local oxidative and ischemic injury. Large amounts of inflammatory mediators are created and free radical injury occurs. Degradation of the cell membrane occurs, and necrosis and apoptosis take place. The region that has infarcted has little chance of restoration. Current medical efforts attempt to save the region of the ischemic penumbra through limitation of toxic free radical formation, reducing the duration of ischemia, and protecting the neurons from additional insults. Reperfusion must take place within 3 hours to avoid permanent damage to the penumbra. Short of removing the arterial blockade, little can be done to reverse the changes in the region of apoptosis and necrosis.

Pathophysiology of Hemorrhagic Stroke Hemorrhagic stroke is categorized as either subarachnoid bleeds or intracerebral bleeds. Subarachnoid bleeds most commonly occur as the result of head trauma, AV malformations, and aneurysms. Intracerebral bleeds may occur in HTN, bleeding diatheses, and amyloidosis. Hypoperfusion may also lead to stroke and affect especially the parasagittal strips of the cortex (a region known as the watershed area 192

CNS and PNS Pathology where the end points of the circulation to the brain are located). Hemorrhagic stroke leads to direct injury to neurons by the toxic effects of blood. Compressive injury and electrolyte imbalances worsen the injury. Hemorrhagic strokes worsen with rising in the morning and evolve over a period of minutes. There are several types of CVA that may occur. The term “stroke” refers to the presence of infarcted tissue in the brain. A “stroke in evolution” is progressive, ongoing injury. A “completed stroke” has caused irreparable harm to a certain portion of the brain and has been stable in its course for a few days. There is a type of stroke that spontaneously resolves with no damage; this type is known as a “transient ischemic attack” (TIA) and typically resolves within 30 minutes to 24 hours. Repeated TIAs are referred to as “crescendo TIAs.”. A TIA that lasts more than 24 hours but less than 3 weeks and has progressive improvement is known as a reversible ischemic neurologic deficit (RIND). TIAs and RINDs are highly indicative of a future stroke potential.

Presentation CVAs present as an acute neurologic deficit or an altered state of consciousness. Numerous constitutional symptoms are typically present in addition to one or more of the following: abrupt onset of paresis, visual deficits, vestibular or hearing deficits, aphasia, dysarthria, and ataxia. Physical exam may uncover cardiac or vasculature abnormalities or evidence of trauma that can be used to pinpoint the cause of the stroke. A full neurologic exam is required and together with diagnostic testing, can be used to identify the precise site of neurologic injury. There are four major stroke syndromes that can occur depending on the anatomic location of the ischemic injury and the particular artery that is affected. Strokes from occlusion of the anterior cerebral artery (ACA) present with changes in mental status, impaired judgment, apraxia, and weakness of the contralateral lower extremities. Other symptoms commonly include incontinence and personality or behavioral changes. The region that is affected is mostly the frontal lobe. Middle cerebral artery (MCA) strokes lead to contralateral hemiparesis and hemiplegia with sensory loss. Ipsilateral hemianopsia presents with a gaze preference ipsilateral to the side of injury. Agnosia and aphasia may occur especially if the dominant hemisphere is affected. Upper extremity deficits are typically prominent. The posterior cerebral artery (PCA) may occlude and present as changes in vision via a homonymous hemianopsia or blindness, agnosia, defects in memory, and altered mental status. The PCA can also lead to Weber syndrome through cranial nerve (CN) III palsy (leading to contralateral hemiplegia, or contralateral ataxia [known as Benedikt syndrome]). Strokes of the vertebrobasilar artery present with a number of diverse deficits and are difficult to diagnose. Symptoms include vestibular effects (such as vertigo or nystagmus), visual effects (including diplopia or field deficits), motor defects (such as dysarthria or dysphagia), ataxia, syncope, and loss of pain and temperature sensations on the ipsilateral face and contralateral body. Other stroke syndromes typically present with ipsilateral symptoms. Occlusion of the paramedian branches can lead to lockedin-syndrome with only intact eye movements but complete quadriparesis. Blockage of the posterior inferior cerebellar artery (PICA) can lead to Wallenberg syndrome, presenting as ipsilateral loss of sensation to the face and contralateral paresthesias of the body. Horner syndrome occasionally accompanies PCA and PICA stroke. Horner syndrome includes hemianhidrosis, unilateral effects, ptosis, miosis, and enophthalmos. Occlusion of the cerebellar arteries presents with vertigo, nystagmus, nausea, and vomiting. Ataxia of 193

Clinical Review for the USMLE Step 1 an extremity is also common. Occlusion of the anterior inferior cerebellar artery (AICA) presents with gaze palsy, deafness, tinnitus, and weakness of the ipsilateral face. Infarctions affecting the lenticulostriate arteries branching from the MCA are most commonly affected in patients with HTN. A pure sensory stroke may occur with loss of sensory information in one half of the body. A pure motor stroke may occur with loss of motor ability in the face or one of the extremities. Ataxic hemiparesis may also result as a combined motor and sensory loss leading to ataxia. Dysarthria with retardation of normal motor and sensory transmission may occur leading to weakness and impediments in normal motion of one of the extremities or face. Table 6. Clinical Diagnosis of Stroke Anterior cerebral artery

Changes in mental status, impaired judgment, apraxia, and weakness of the contralateral lower extremities, incontinence & personality or behavioral changes.

Middle cerebral artery

Contralateral hemiparesis and hemiplegia with sensory loss. Ipsilateral hemianopsia. Agnosia and aphasia may occur, especially if the dominant hemisphere is affected. Upper extremity deficits are typically prominent.

Posterior cerebral artery

Changes in vision, agnosia, defects in memory, and altered mental status. Weber & Benedikt syndromes.

Vertebrobasilar artery

Vestibular effects, visual effects, motor defects, and loss of pain and temperature on the ipsilateral face and contralateral body.

PICA

Wallenberg syndrome, Horner syndrome.

AICA

Vertigo, nystagmus, nausea, and vomiting. Ataxia of an extremity, gaze palsy, deafness, tinnitus, and weakness of the ipsilateral face.

Lacunar infarcts

Sensory stroke may occur with loss of sensory information in half of the body. A pure motor stroke may occur with loss of motor ability in the face or one of the extremities. Ataxic hemiparesis may also result as a combined motor and sensory loss leading to ataxia. Dysarthria with retardation of normal motor and sensory transmission may occur leading to weakness and impediments in normal motion of one of the extremities or face.

Diagnosis Noncontrast CT is the initial preferred test and is mandatory for distinguishing the various types of stroke and identifying the particular location of injury. Patients with acute ischemic stroke may entirely bypass this diagnostic study and be taken for immediate therapy. CT has normal findings in the first 6 hours; however, edema over this time leads to changes in the form of a hypodense region. Lumbar puncture should be done in all patients suspected of having a subarachnoid hemorrhage, as CT changes are sometimes nonspecific in this particular etiology. Carotid duplex scanning is done in patients who may have stenosis of the carotid artery, leading to possible endarterectomy in some patients. Echocardiography and other diagnostic studies are also used if particular causes of stroke are suspected. MRI is useful in patients that have a cerebellar or lacunar defect. Angiography is the definitive study that precisely identifies even subtle occlusion.

Glasgow Coma Scale (GCS) The Glasgow coma scale is used for rapid neurologic assessment following acute head injury or stroke. It is closely tied to outcome and is often used to dictate therapy in certain instances. The GCS ranges between 3 and 15, with 3 being the worst. Three responses are gauged, including eye response, verbal response, and motor response. The eye responses range from 1-4, and include no eye opening (1 point), eye response to pain (2), eye response to verbal command (3), and spontaneous eye response (4). No verbal response gets 1 point, incomprehensive sounds (2), inappropriate words (3), confused (4), and 194

CNS and PNS Pathology oriented gets 5 points. Motor responses range from no response (1), extension to pain (2), flexion to pain (3), withdrawal from pain (4), localizing pain (5), and obeying commands (6). A range of 13 or more correlates with mild or nonexistent brain injury. Between 9 and 12 is considered a moderate injury, and less than 9 is a severe injury. Table 7. Glasgow Coma Scale (GCS) Eye response

No eye opening (1 point), eye response to pain (2), eye response to verbal command (3), and spontaneous eye response (4).

Verbal response

No verbal response gets 1 point, incomprehensive sounds (2), inappropriate words (3), confused (4), and oriented gets 5 points.

Motor response

No response (1), extension to pain (2), flexion to pain (3), withdrawal from pain (4), localizing pain (5), and obeying commands (6).

Interpretation

>13 mild or nonexistent brain injury; 12-9 moderate injury; <9 is severe.

Treatment Treatment of stroke depends on the particular type and severity of stroke. Basic emergency management includes establishing airway, breathing, and circulation (ABCs), especially with a GCS of less than 9 or dropping GCS scores. Lidocaine, pancuronium, succinylcholine, and oral endotracheal intubation may be necessary with increased intracranial pressure (ICP). Hyperventilation is the key to decreasing ICP and cerebral blood flow. Hydration status should be assessed and overhydration prevented. Lowering BP is necessary with HTN, and commonly used agents include nitroprusside and labetalol. Antipyretics should be used with fever, and cerebral edema prevented. Use of calcium-channel blockers such as lubeluzole may be beneficial very early in the evolution of stroke to avoid calcium influx. Free-radical scavengers such as tirilazad and citicoline and stabilizers of neuronal membranes such as citicoline are useful later in the ischemic cascade. Antibodies against leukocyte adhesion molecules, such as enlimomab, may serve a neuroprotective role. Anticoagulation with heparin may have some protection in progressive stroke and especially with occlusion affecting the vertebrobasilar artery. However, anticoagulation for stroke has up to a 4% risk of hemorrhage. Contraindications for anticoagulation include concomitant HTN, bleeding diatheses, and intracranial hemorrhage. Tissue-plasminogen activators (t-PA) can be used to restore cerebral blood flow and help resolve an evolving neurologic defect. However, the use of tPAs such as streptokinase, urokinase, or alteplase can increase mortality in some groups through increased intracranial bleed (which can lead to death in up to half of all patients). Overall, 1 in 8 patients had full recovery with t-PA treatment, 1 in 17 had intracranial bleeds, and 1 in 40 died from complications of therapy. Of all the medications available for t-PA, only alteplase is recommended and approved for therapy; streptokinase is not recommended. t-PA therapy should be given within 3 hours in order to be effective. TIAs should be treated with antiplatelet agents including aspirin and clopidogrel. Anticoagulation may be necessary with heparin and warfarin. Carotid endarterectomy should be considered if the carotid artery is implicated as a causative agent.

Complications There are several complications to stroke. Several syndromes may develop. Anosognosia may occur with the inability to identify parts of the body as belonging to the individual. Aphasia may occur with defects in spoken or written language comprehension or expression. Broca aphasia may occur with inability to express speech or write. Wernicke aphasia may occur through impaired comprehension but copious 195

Clinical Review for the USMLE Step 1 amounts of nonsensical speech. Apraxia can occur with the inability to repeat learned motor motions. Dysarthria is the inability to speak, and dysphagia is difficulty with swallowing. As discussed above, numerous stroke syndromes can occur including Horner syndrome, Wallenberg syndrome, Weber syndrome, and Benedikt syndrome.

5.2.3

Head Trauma

Trauma to the head consists of lacerations to the scalp, fractures of the skull, and intracranial damage. The closed space of the calvarium makes it especially susceptible to intracranial injury, as the resulting hematoma and cerebral edema can lead to a significant alteration in cerebral blood flow and potential herniation of the brain. The initial approach to a trauma patient with suspected intracranial injury is to complete the ATLS protocol. The airway, breathing, and circulation should all be secured. Attention should be paid to the patients neurologic examination. A concise but complete head to toe examination should be completed, and the entire examination carefully documented. Should the patient require urgent intubation, the neurologic examination prior to sedation and/or paralysis should be documented. Once the patient is stabilized and is a suitable candidate for imaging, a diagnostic CT of the head and neck should be completed. Plain films of the thoracic, lumbar, and sacral spine should be completed unless there is a specific focus of concern, in which case CT reformats of the entire spine should be completed. Due to the thin soft tissue overlying the bone, there is little potential for soft tissue to occlude bleeding and promote hemostasis. As a result, scalp lacerations tend to bleed profusely. Hemostasis is the first line of management and consists of applying stitches or staples to close the laceration once it has been thoroughly irrigated and debrided. More extensive injuries that disrupt all of the layers of the scalp may require a split thickness skin graft for closure. Severe injuries to the head may lead to skull fractures; these injuries are divided into displaced and nondisplaced. Non-displaced fractures can typically be managed conservatively, but a thorough workup for intracranial injury and potential hematoma formation should be completed. Displaced injuries require retrieval of the bony fragments and intraoperative irrigation, debridement, and repair. All open skull fractures should also be managed surgically. Basilar skull fractures can lead to drainage of CSF. Most cases will resolve spontaneously, but continuing drainage 7 days after the injury may require operative repair. Severe basilar skull fractures may lead to disruption of the vestibulocochlear complex and require urgent repair to minimize the risk of damage to this nerve. Intracranial injury is commonly secondary to severe acceleration or deceleration causing diffuse axonal injury from the excessive shearing forces. Intracranial injury can also lead to shearing forces on the bridging veins and intracranial arteries, causing hemorrhage and additional damage. Mild intracranial injury leads to a temporary loss of consciousness, referred to as a concussion. Supportive management and observation are typically all that is required for concussions. More severe injuries may lead to cerebral edema and hemorrhage with an increase in ICP and reduction in CBF. Aggressive surgical management may be necessary in severe cases to avoid neural compromise from hernation and ischemic injury.

Figure 44. Epidural hemorrhage. Copyright J.F. Wolff. Used with Following severe head trauma, spinal cord function may remain inpermission. tact with brisk deep tendon reflexes in patients who are brain dead. 196

CNS and PNS Pathology A patient with a closed head injury who has hypernatremia and a urine osmolarity greater than 300 should receive DDAVP for the treatment of diabetes insipidus. The Cushing response involves bradycardia, hypertension, and irregular respirations, and is a sign of a head injury. Hypotension in the setting of head trauma requires urgent fluid resuscitation. Most patients with head injury will receive 24 hours of seizure prophylaxis.

5.2.4

Epidural Hemorrhage

An epidural hemorrhage may occur secondary to trauma to the head that causes a temporal bone fracture. Hemorrhage occurs from rupture of the middle meningeal artery, a branch of the maxillary artery. Epidural hemorrhages typically have a lucid interval following the initial trauma. As the bleeding continues and causes a mass effect on the brain, rapid deterioration occurs. The diagnosis is typically made by head CT, which reveals a hemorrhagic mass that does not cross suture lines. Treatment typically involves surgery to control the bleeding and evacuate the clot.

5.2.5

Subdural Hemorrhage

Subdural hemorrhages can also occur following trauma, but they are far more likely to occur in susceptible individuals including the elderly and alcoholics. In these individuals, atrophy of the brain leads to increased distance of the brain from the surrounding dura and greater mobility. Following trauma, rupture of the bridging veins can occur leading to venous bleeding. Symptoms progress over time. Diagnosis is made by head CT and shows blood crossing suture lines. Treatment is supportive and may involve surgery if the patient continues to hemorrhage. decompensate. A subdural hematoma is associated with a high Figure 45. Subdural Copyright J.F. Wolff. Used with permortality rate due to the underlying brain contusion that likely mission. accompanies this presentation.

5.2.6

Subarachnoid Hemorrhage

Subarachnoid hemorrhage may be the result of a ruptured berry aneurysm. It is more common in susceptible populations, such as those with adult polycystic kidney disease, EhlersDanlos syndrome, and Marfan syndrome. The most common location is at the anterior communicating artery. Patients commonly present with a severe headache, and diagnosis is made by head CT. Treatment is typically supportive, but surgery may be needed in some patients.

5.2.7

Headache

Introduction Headaches are a common complaint among many patients, Figure 46. Subarachnoid hemorbut the causes of headache are vast and of varying importance. rhage. Copyright J.F. Wolff. Used with Primary causes of headache include migraines, tension head- permission. 197

Clinical Review for the USMLE Step 1 aches, and cluster headaches. Secondary causes include intracranial hemorrhage, tumor, meningitis, temporal arteritis, and glaucoma. The top ten causes of headache include various headache syndromes such as migraine, cluster headaches, and tension headaches, subarachnoid hemorrhage, meningitis, HTN, masses, temporal arteritis, trigeminal neuralgia, brain abscess, pseudotumor cerebri, and subdural hematoma. Worrisome headaches occur when they are of new onset in a patient who has no prior history of headaches. Extremely severe headache may herald an intracranial hemorrhage and requires rapid diagnosis and treatment.

Migraine Headache Migraine headaches are thought to occur as a result of vasodilation following cerebral vasoconstriction. More than 1 in 10 persons are affected, women more than men. The majority of patients have a positive family history. Migraines may present with or without an aura that precedes the actual onset of the headache. Auras are focal neurologic findings that include photophobia, sonophobia, tinnitus, bright lights, ataxia, weakness, or any other focal, stereotyped, repeated occurrence that precedes the migraine. This type of migraine is known as a classic migraine. Migraines without auras, known as common migraines, present with photophobia and sonophobia along with symptoms of the headache. The headache itself leads to nausea and vomiting, and general constitutional symptoms. A prodrome that occurs before the onset of the migraine may occur several days prior to migraine and may include lethargy, depression, edema, or food cravings. Migraines are ongoing for several hours, are unilateral, and present as a severe, throbbing pain. Migraine headaches are treated by avoiding triggers, reducing stress, and resting in a dark, quiet environment. NSAIDs are commonly used, along with ergotamines. Sumatriptan, a 5-HT receptor agonist, is popular among patients with migraines; however, in sufficient doses, this class of drugs may cause vasospasm. Metoclopramide may be given as an antiemetic. Migraine prophylaxis includes calcium channel blockers, beta blockers, and SSRIs.

Tension Headache Tension headaches occur following significant stress, and typically present as head and neck stiffness. Tension headaches have no prodrome, no aura, and are bilateral. They worsen over the course of the day. Tension headaches are described as a band-like or vise-like pain that surrounds the head or neck region. Tension headaches are alleviated by NSAIDs. If severe, narcotics can be used. Amitriptyline, a tricyclic antidepressant, has been used as tension headache prophylaxis.

Cluster Headache Cluster headaches are severe, periorbital pains that significantly worsen immediately after onset. They tend to occur in clusters, and the unrelenting, severe facial pain that occurs is highly debilitating. Cluster headaches may last up to an hour and a half, occur several times a day, and last for up to a month or two. Associated symptoms include rhinorrhea, injected conjunctiva, lacrimation, ptosis, miosis, facial sweating, and nausea. There are no obvious triggers. Treatment for cluster headaches is to use high-flow oxygen, lidocaine, ergotamine, sumatriptan, and antiemetics for symptomatic control. Verapamil, methysergide, prednisone, and indomethacin are all effective in some patients for prophylaxis.

198

CNS and PNS Pathology 5.2.8

Giant Cell Arteritis (GCA)

Giant cell arteritis, also known as temporal arteritis, is an immune-mediated, idiopathic inflammation of the temporal artery. Giant multinucleated cells are found in the region, and the majority of patients suffer from polymyalgia rheumatica. GCA affects mostly women and patients over 60 years of age. GCA presents with a unilateral headache pain along the course of the temporal artery. Palpation of the arteries yields thickened, tender arteries. Claudication can occur leading to ischemic changes in the masseter, temporalis, and tongue. Ipsilateral loss of vision may also occur. A pulsatile flow may be apparent in the temporal artery. Diagnosis is made by an elevated ESR and CRP, and confirmed by biopsy of the temporal artery. Corticosteroids are used to control the inflammation and reduce symptoms of temporal arteritis. Corticosteroids also protect the vision. NSAIDs are used for pain control.

5.2.9

Normal Pressure Hydrocephalus (NPH)

Normal pressure hydrocephalus (NPH) is increased CSF but no increase in ICP. NPH is commonly the result of subarachnoid hemorrhage, meningitis, tumor, or trauma. NPH presents with a triad of gait disturbance, incontinence, and dementia. Treating the gait disturbance is often successful, but the dementia usually is refractory to medical management. Diagnosis of NPH is made by ruling out other etiologies by a normal LP, detecting ventricular hypertrophy on CT or MRI, and finding improvement in symptoms after a therapeutic LP. Treatment for NPH involves therapeutic CSF removal, placing a ventriculoperitoneal shunt to remove excess CSF, and possibly removing a portion of the choroid plexus.

5.3. Sensory Disturbances 5.3.1

Acute Blindness

There are a number of causes for sudden loss of vision. Although many of these are discussed in more detail in the Clinical Review of Ophthalmology, a brief discussion of some of these etiologies is pertinent here. Central retinal artery occlusion (CRAO) is a sudden, painless loss of vision due to ischemia to the retina. A red spot is present on the fovea. Treatment of CRAO is to remove the embolism to avoid permanent blindness. Retinal detachment is another potentially treatable cause of blindness, and commonly presents with flashes of light and floaters. Optic neuritis is a painful loss of vision on one side due to inflammation of the optic nerve leading to demyelination. Many of these patients experience this as their first manifestation of MS. Optic neuritis typically resolves with steroid therapy. Finally, vitreous hemorrhage is due to bleeding into the vitreous humor and leads to progressive blindness. Therapy is to coagulate the bleeding or perform a vitrectomy.

5.3.2

Hearing Loss

Conductive Hearing Loss Hearing loss may be due to either a problem with conduction or with the vestibulocochlear nerve (CN VIII). Loss of hearing due to conductive abnormalities are often attributed to impaction of excessive amounts of cerumen, external auditory canal swelling and blockade, perforation of the tympanic membrane (30 dB), fluid within the middle ear (40 dB), cholesteatoma, otosclerosis, and abnormalities within the malleus, incus, and stapes. Otosclerosis is proliferation of the temporal bone leading to impingement of the footplate of the stapes and thus the inability of the ossicular chain to transmit mechanical waves in the fluid of the inner ear. 199

Clinical Review for the USMLE Step 1 Stapedectomy is the preferred treatment for otosclerosis; a prosthesis is then placed to permit transmission of sound.

Sensorineural Hearing Loss Sudden loss of hearing can occur for a variety of poorly understood reasons. This condition presents an otolaryngology emergency that requires prompt treatment to help these patients regain their hearing. Sudden loss of hearing can be treated with high dose steroids that are tapered over a period of weeks. Antivirals have also been shown to have some positive effect. The combination of prednisone 60 mg over a three week taper in addition to famcyclovir 500 mg TID for 10 days has been shown to lead to recovery in 67% of all patients that experience this condition. Other types of sensorineural hearing loss may be due to damage to the hair cells of the cochlea responsible for transducing the mechanical sound vibrations into the electrical signal of the nervous system. Common causes include exposure to loud noises on a regular basis, unfavorable congenital or genetic traits, age-related changes (known as presbycusis), infection, inflammation, and tumor growth. Age-related changes tend to be symmetrical. Presbycusis may also lead to difficulties with speech discrimination. Asymmetric hearing losses may be due to acoustic neuromas of the vestibulocochlear nerve. In such patients, there is typically poor speech discrimination, tinnitus, disequilibrium, and other symptoms. Diagnosis of acoustic neuroma is preferably made through gadolinium MRI.

5.3.3

Vertigo

Vestibular disorders affect people of all ages. The incidence of vestibular dysfunction increases with age, and as many as one-third of those between 65-75 years of age report significant problems with dizziness and imbalance. Some of the more serious vestibular diseases, such as Ménière’s disease, affect 16 out of 100,000 people every year. More serious disorders can lead to imbalance, nausea, confusion and disorientation, headaches, and vertigo (which is not to be confused with dizziness). Vestibular disorders center on the sensations of vertigo, dizziness, lightheadedness, syncope, and ataxia. When dealing with patients with a chief complaint of dizziness, it is important to elucidate the precise nature of the complaint in more descriptive and precise terms. The more serious disorders can lead to imbalance, nausea, disorientation, headaches, acute and chronic vertigo, and even death. A more thorough account of vestibular disorders is presented in the Clinical Review of Otolaryngology. While spinning in a circle and attempting to walk around is relatively benign, dizziness becomes significantly more disruptive with age causing falls and, therefore, one of the leading causes of death in the elderly. This situation is likely exacerbated by various medications consumed by this population that have side effects that further disrupt normal vestibular function. Differentiating central vertigo from peripheral vertigo is important. Central vertigo is gradual in onset and occurs with defects in other sensory functions. A vertical nystagmus is often present. Causes of central vertigo can be from acoustic neuroma, hemorrhage, or ischemia. Multiple sclerosis may also present with central vertigo. Peripheral vertigo presents suddenly with hearing loss and tinnitus. There is typically a horizontal nystagmus. Causes of peripheral vertigo include benign paroxysmal positional vertigo (BPPV), Ménière’s disease, labyrinthitis, and antibiotic ototoxicity. Treatment of vestibular disorders should be tailored to the particular etiology. Ménière disease is typically treated with low-salt diet and diuretics, followed by labyrinthectomy, if the disorder is refractory to medical management. BPPV is treated with the Dix-Hallpike maneuver. Labyrinthitis is treated with meclizine and diazepam. 200

CNS and PNS Pathology

5.4. Infectious Diseases 5.4.1

Rabies

Rabies is the progressive and lethal infection that ravages the nervous system. Rabies is exceedingly rare, but common causes include bites from raccoons, skunks, feral dogs, foxes, and exposure to bats. Corneal transplants may also lead to rabies in rare instances. Replication of the rabies virus occurs in the region of the bite, followed by transmission to the CNS, peripheral nerves, and salivary glands. The prodromal phase in rabies infection leads to irritability, hydrophobia, GI symptoms, pain, and aerophobia. The excitation phase leads to hyperactivity with disorientation and seizures. Lethargy appears later with cardiac and respiratory decompensation, shortly followed by death. Diagnosis is confirmed by the presence of Negri bodies and positive antibody tests with polymerase chain reaction (PCR). Rabies is treated with rabies immunoglobulin and a human diploid cell rabies vaccine. Isolation is required and prophylactic vaccination is used with high-risk populations.

5.4.2

Bacterial Meningitis

Bacterial meningitis is commonly the result of infection of the pia and arachnoid membranes by Streptococcus pneumoniae (over half of all cases), Neisseria meningitidis, Listeria monocytogenes, gram-negative rods, Haemophilus influenzae, and group B streptococcus (GBS). Young adults are likely to have meningitis from N. meningitidis; IC patients are more likely to suffer from L. monocytogenes; neonates are likely to acquire GBS perinatally. Infection may occur through the bloodstream, direct invasion, or from otitis or sinusitis. Meningitis presents with headache, neck stiffness, fever, and photophobia. Mental status changes leading to increasing Glasgow coma scale scores is common. Kernigâ&#x20AC;&#x2122;s sign is typically positive with extension of the knee and thigh leading to pain in the back. Brudzinskiâ&#x20AC;&#x2122;s sign is positive demonstrating neck flexion and leads to knee and hip flexion. CBC indicates a leukocytosis with PMNs. Blood cultures are positive in about half of all individuals. Lumbar puncture indicates increased neutrophils, increased protein, low glucose, and high opening pressure. CSF culture is more sensitive than blood culture. The presence of numerous monocytes indicates infection by L. monocytogenes. Treatment of bacterial meningitis is empirical and typically includes vancomycin plus cefotaxime or ceftriaxone. This is also the standard treatment for Streptococcus pneumoniae. If N. meningitidis is the identified cause, treatment can proceed with penicillin G or ceftriaxone. L. monocytogenes infection is treated with ampicillin and gentamicin.

5.4.3

Viral Meningitis

Viral meningitis, also referred to as aseptic meningitis, is more common than bacterial meningitis. Viral meningitis is typically benign with signs and symptoms similar to that of bacterial meningitis. Lumbar puncture (LP) typically indicates high WBCs with mostly lymphocytes, normal protein and glucose, and a normal or high opening pressure. Treatment is primarily supportive.

5.4.4

Fungal Meningitis

Fungal meningitis presents with a high WBC count of mostly lymphocytes on LP. Protein is high, glucose is low, and opening pressure is high. Treatment of fungal meningitis is with appropriate antifungals. 201

Clinical Review for the USMLE Step 1 5.4.5

Viral Encephalitis

Viral encephalitis is typically more of an aseptic meningoencephalitis that generally occurs in teenagers and young adults. Viruses interact with various cell surface molecules to propagate their infection; for example, the rabies virus takes advantage of acetylcholine receptors. Infection may occur through retrograde neuronal infection or spread through the vasculature. Unlike viral meningitis, viral encephalitis may lead to significant destruction and neuronal cell death and even be fatal. Nearly 1 in 10,000 persons are affected annually. Causes include HSV, VZV, influenza virus, enterovirus, rabies virus, lymphocytic choriomeningitis virus (LCV), lassa fever, mumps, measles, nipah virus, eastern equine virus (EEV), western equine virus (WEV), St. Louis Encephalitis, West Nile virus, Dengue fever, Colorado tick fever, and a whole host of more rare causes. Viral encephalitis presents with acute fever, headache, neck stiffness, focal neurologic findings, seizures, stupor and coma. CNS changes are common. HSV is the most common infectious cause. Lymphocytes dominate the CBC. Viral cultures and antibody tests can be attempted by collecting the CSF or even a brain biopsy in some cases. Low density lesions may be found on CT scan with HSV infection, especially around the temporal lobe. More details about these infections can be found in the Clinical Review of Neurology. Treatment for viral encephalitis includes supportive management after protecting the airway. Reducing ICP and seizure prophylaxis is important. Ribavirin, ACV, and other antivirals are sometimes effective.

5.4.6

Brain Abscess

A brain abscess may develop insidiously or following trauma, surgery, or with spread from a nearby infection such as sinusitis or otitis media. The incidence has increased with AIDS, and mortality is very high if the abscess ruptures. Common causes are S. aureus, S. intermedius, Bacteroides, Prevotella, Fusobacterium, Enterobacteriaceae, Pseudomonas, and other infectious agents. Brain abscess is typically present for only a few weeks prior to diagnosis. Symptoms of neurologic impingement occur, including headache, neurologic changes and deficits, fever, seizures, nuchal rigidity, and papilledema. Rupture may lead to rapid decompensation. Abscess in the cerebellum may lead to defects in motor balance and subsequent ataxia and nystagmus. Abscess in the brainstem may lead to auditory and facial nerve defects. Frontal abscess may lead to mental status changes. Temporal lobe abscess may lead to visual defects. CT is the preferred test to determine the extent of disease. Surgical excision with long-term antibiotic use is the standard of care following precise planning of the surgical approach with the aid of CT. Penicillin is a good choice against streptococci and staphylococci. Metronidazole is used against gram-negative bacilli. Ceftazidime is used against Pseudomonas. A third generation cephalosporin with metronidazole is commonly used with otitis, mastoiditis, and sinusitis. Dental infections get penicillin and metronidazole. Vancomycin plus a cephalosporin is used following trauma or surgery.

5.4.7

Botulism

Botulism occurs due to ingestion of toxins formed by Clostridium botulinum leading to flaccid paralysis. It commonly occurs from poor preparation and canning of foods, and contamination of open wounds. It presents after about one day and its effects are due to blockade of acetylcholine release in peripheral nerves. Symptoms include dry mouth, diplopia, dysphagia, dysarthria, weakness of the extremities, and weakness of respiratory muscles. Constitutional symptoms are typically present, including nausea and vomiting, diarrhea, and abdominal cramping. Diagnosis is by serology to detect the toxin. Honey carries botulinum spores and can lead to botulism in infants through replication in their relatively imma202

CNS and PNS Pathology ture GI tract (doubtful see recent literature). The toxin may be inactivated after ten minutes of boiling, but destroying the spores requires several hours of boiling. Botulism is treated by administering the antitoxin and decreasing absorption by inducing vomiting or diarrhea. Penicillin and antitoxin are given if the focus is a contaminated wound. Ventilator support may be necessary to avoid respiratory failure.

5.5. Neurodegenerative Disorders 5.5.1

Alzheimer Disease (AD)

Alzheimer disease results in dementia, cognitive deficits, and behavioral changes in more than 5 million people in the US. The elderly are the fastest growing population in the US, and the prevalence of AD is expected to increase significantly. The lifetime risk is on the order of 1 in 3 individuals, with increasing risk with age. AD is the leading cause of death after cancer and cerebrovascular disease, and the primary cause of death is intercurrent illness. AD increases with age and af- Figure 47. Alzheimerâ&#x20AC;&#x2122;s disease. Copyright NIH. Used with permission. fects both men and women equally. AD is tied to the development of neurofibrillary tangles (NFTs), senile plaques (SPs), and cerebrocortical atrophy in the temporal lobe. NFTs and SPs occur in other neurodegenerative conditions and in normal aging, but AD is distinct in that the temporal lobe has a preponderance of these two anatomic defects with neuronal loss and synaptic degeneration. While NFTs and SPs are not pathognomonic for AD, their coexistence in sufficient numbers in the temporal lobe is diagnostic. Later stages of AD have NFTs and SPs in other regions of the brain. Causes include genetic risk factors such as APP on chromosome 21, presenilin I on chromosome 14, presenilin II on chromosome 1, Figure 48. Neurofibrillary tangles in Alzheimerâ&#x20AC;&#x2122;s disand various other markers on chromosomes ease. Copyright KGH. Used with permission. 12 and 19; advancing age-related changes, 203

Clinical Review for the USMLE Step 1 and head injury. AD presents with progressive memory deficits, cognitive impairment, and personality changes leading to dementia and loss of higher order brain functions over time. Delirium is not present, which would signify an entirely separate etiology. A mini mental status examination (MMSE) and a language examination make up the repertoire of physical exam tools available to the clinician. CT and MRI are used to diagnose the cerebral atrophy and rule out other causes of brain damage. EEG has specific findings in AD. Treatment for AD is limited and there is no cure or therapy that slows its progression. Alleviating psychiatric and psychologic factors (such as anxiety) help somewhat, along with behavioral therapy and cognitive therapy. Managing any concurrent psychiatric ailments is important (see the Clinical Review of Psychiatry for a more thorough discussion of these agents). Anticonvulsants such as gabapentin in particular may be useful. Acetylcholinesterase (AChE) inhibitors such as donepezil, tacrine, and rivastigmine may assist in the treatment of AD by avoiding ACh depletion in the cerebral cortex and hippocampus. N-methyl-D-aspartate (NMDA) antagonists such as memantine may assist in various neurodegenerative conditions by preventing overstimulation of glutamate receptors. Depression is commonly found in AD, and the use of antidepressants is the key to alleviating some of the symptoms of AD. Free-radical scavengers are also occasionally used.

5.5.2

Parkinson Disease (PD)

Parkinson disease affects 1 out of 500 individuals. It is more common in men and PD increases with age, especially after the age of 60. PD is the result of loss of pigmented dopaminergic neurons from the substantia nigra (SN) especially in the ventral lateral SN. Lewy bodies (which are dense core bodies found within neurons throughout the cortex, nucleus basalis, locus ceruleus (LC), intermediolateral (IML) column, and the SN) are also found. Lewy bodies are non-specific findings in PD. Defects in the output of the basal ganglia-thalamocortical motor circuit as the transmissions pass through the SN lead to abnormalities in motor suppression. Failure to activate the direct pathway and inhibit the indirect pathway in the striatum leads to the pathognomonic features of PD, discussed below. Causes include genetic predisposition, exposure to certain pesticides or industrial toxins, and use of 1-methyl4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Oxidative damage leading to lipid peroxidation has also been implicated. PD is predominantly a clinical diagnosis made by the presence of an asymmetric resting tremor, bradykinesia, rigidity, gait abnormalities, and constitutional symptoms. Tremor and motor derangements progress with axial flexor, dysphagia, and autonomic dysfunction. The three most important signs in diagnosing PD include a resting tremor, rigidity, and bradykinesia. Postural instability arises later in the disease. The rigidity takes the form of either a lead-pipe rigidity or cogwheel rigidity. Loss of spontaneous movements and slowness of motion characterizes bradykinesia. Loss of righting reflexes leads to postural instability. Dementia occurs late in the disease and Figure 49. Lewy bodies in Parkinsonâ&#x20AC;&#x2122;s disease. affects about 1/3 of patients. Imaging studies are Copyright Andreas Becker. Used with permission. used only to exclude other etiologies. Positron emission tomography (PET) and single photon 204

CNS and PNS Pathology emission CT (SPECT) are useful for diagnosis. Treatment of PD centers on supportive therapy to reduce symptoms and retain baseline functioning for as long as possible. Selegiline is used as a neuroprotective agent against MPTP toxicity. Tocopherol, or vitamin E, has also been used with some benefit and increases the time before levodopa is necessary. The use of levodopa becomes necessary in reducing the symptoms of Parkinsonism, but some studies suggest that long-acting dopamine agonists such as bromocriptine, pergolide, pramipexole, ropinirole, and cabergoline are preferred in certain situations. Stereotaxic surgery to stimulate portions of the thalamus has been found to be beneficial in some groups of patients. Pallidotomy can be done to reduce dyskinesia. Newer therapeutic options may offer transplantation of dopaminergic cells to the affected region.

5.5.3

Huntington Disease (HD)

Huntington disease (HD) is a progressive, autosomal dominant disorder that leads to neuron loss within the cortex and basal ganglia. Atrophy of the caudate and putamen nuclei occurs with atrophy of other related structures over time. The basic cause is a triplet CAG expansion in a protein product that leads to derangements in synaptic vesicles, microtubules, and mitochondria with concomitant mutant protein accumulation and the development of cellular inclusions. Disease occurs with neuronal cell death from excessive inclusion. Other causes of HD include increased excitotoxicity, oxidative stress, impaired neuronal energy metabolism, and apoptosis. HD affects 5 out of 100,000 people and is more common in certain European populations. It manifests itself in the 50s with death several decades later, primarily from pneumonia or cardiovascular disease. HD in younger patients reflects genetic inheritance with anticipation. HD presents with chorea, a movement disorder that begins with increased fidgeting followed by flailing of the extremities in a phenomenon known as hemiballism. Chorea progresses to dystonia, bradykinesia, rigidity, postural instability, and finally, an akinetic-rigid state. Clonus and spasticity are present later in disease. Ocular abnormalities and tic disorders are common Figure 50. Inclusion bodies seen in early on. Early onset of HD (known as the Westphal variant) Huntingtonâ&#x20AC;&#x2122;s disease. Copyright Steleads to early dementia and the development of a seizure disor- ven Finkbeiner. Used with permission. der. Impairments in cognition proceed at variable rates, and depression is common. Changes in personality can occur. Imaging tests are used to rule out other disorders. Genetic testing is used to confirm the diagnosis by identifying multiple CAG repeats. Treatment involves reducing the chorea with agents such as tetrabenazine, various benzodiazepines, or anticonvulsants. Levodopa can be used to modify the bradykinesia and rigidity. Depression should be treated early with selective serotonin reuptake inhibitors (SSRIs). Antipsychotics may be used to modify psychotic symptoms and irritability. Personality changes should be addressed with medications as appropriate. Surgical ablation and cell transplant options are currently being studied.

205

Clinical Review for the USMLE Step 1 5.5.4

Multiple Sclerosis

Multiple sclerosis (MS) is a progressive, inflammatory, demyelinating disorder of the CNS that leads to physical disability. Infiltration of lymphocytes and macrophages into nervous tissue cause inflammation and disruption of the nerve. Surgery and other external stressors may be a trigger for onset. The initial presenting sign may be acute blindness, followed by rapid resolution. After a waxing and waning course, neurodegeneration progresses rapidly. Weakness and fatigue are universal. Cognitive changes occur in some, ataxia in others, along with hemiparesis, depression, and psychomotor changes. Bilateral facial weakness and trigeminal neuralgia are strongly indicative of MS. CSF studies reveal oligoclonal banding, normal glucose, normal or high protein, and high WBC count with excess IgG. MRI is used to localize the regions of sclerosis. MS is treated with supportive care while miniFigure 51. MRI changes seen in MS. Copyright mizing the effects of intercurrent illness and psyBrookhaven National Labs. Used with permission. chomotor stressors. Amantadine or modafinil are beneficial for fatigue mitigation. Disease progression can be slowed with interferon beta-1a, interferon beta-1b, and glatiramer acetate. Acute exacerbations can be minimized with methylprednisone, and high-dose IV steroids may be beneficial in certain situations.

5.5.5

Myasthenia Gravis

Myasthenia gravis is a rare autoimmune disorder that leads to weakness and fatigue as a result of antibody-mediated loss of the acetylcholine receptor (AChR) and neuromuscular junction (NMJ). MG is exacerbated by a number of drugs, including penicillamine. MG presents as variable weakness worsened on exertion and improved with rest. Extraocular muscles (EOM) are weak and ptosis may be present in many patients. CXR is used to rule out thymoma, which affects 25% of patients, and thymectomy may forestall symptoms for many years. Electromyography (EMG) is diagnostic, and the edrophonium test can be used when other studies are deemed inconclusive. MG has no clear treatment. Inhibitors of AChE have been used with some effect; medications include pyridostigmine and neostigmine. Immunomodulation with prednisone, azathioprine, and cyclosporine A (CsA) has some benefit. Plasmapheresis can remove antibodies emergently and prevent relapse.

5.5.6

Pseudobulbar Palsy

Pseudobulbar palsy is bilateral dysfunction of cranial nerves IX through XII, leading to a dysfunction in speech, deglutination, and mastication. Failure of deglutination may lead to aspiration. The cause is an upper motor neuron lesion within the pyramidal tract. There are a variety of causes, including head trauma, MS, and bilateral hemisphere infarction. 206

CNS and PNS Pathology

5.6. Sleep Disorders 5.6.1

Normal Sleep Stages

Sleep is separated into four distinct stages and REM sleep. Stage 1 is typically only 5% of the sleep cycle, and is a period of light sleep. Stage 2 of sleep is about 45% of the time, and is a deeper sleep. The deepest sleep occurs in stages 3 and 4, during which one-quarter of the sleep cycle is spent. Stages 3 and 4 of sleep are the period during which night terrors, sleepwalking (somnambulism), and bed-wetting occurs. REM sleep consumes one-quarter of the sleep cycle, and is the period during which dreaming occurs. There is a loss of muscle tone during REM sleep, increased processing by the brain of the daily events, memory retention, erections, and elevated use of oxygen by the brain. REM sleep occurs every 90 minutes, increases in duration during the night, and decreases with age. The extraocular movements that occur in REM sleep are due to action potentials emanating from the paramedian pontine reticular formation, also known as the conjugate gaze center. Waveforms vary by the period of sleep or wakefulness. When a person is awake with their eyes open, beta waves, or high frequency, low amplitude waves, predominate. A person who is awake with their eyes closed has mostly alpha waves. Stage 1 of sleep is characterized by theta waves. Stage 2 of sleep has sleep spindles and K-complexes. Stages 3 and 4 of sleep have delta waves, which are the lowest frequency but highest amplitude waves found on an EEG. REM sleep has beta waves. The mnemonic BATS Drink Blood can be used to remember the waveforms seen in wakefulness and sleep. Table 8. Stages of sleep and their associated wave forms Stage 1, Light sleep

Theta waves

Stage 2, Deeper sleep

Sleep spindles and K complexes

Stage 3, Deepest sleep

Delta waves

Stage 4, Deepest sleep

Delta waves

REM, Rapid eye movement and dreaming

Beta waves

5.6.2

Sleep Disorders

Sleep is initiated by the serotonergic raphe nuclei. Acetylcholine aids in initiating the onset of REM sleep. Elevated levels of norepinephrine reduce REM sleep. Night terrors and sleepwalking seen in stages 3 and 4 can be reduced through the use of benzodiazepines. Bed-wetting, known as enuresis, can be reduced with imipramine. Sleep disorders are separated into dyssomnias and parasomnias. Dyssomnias are primary sleep disorders that are characterized by a difficulty in initiating or maintaining sleep. This leads to difficulty in feeling rested after sleep, and can lead to excessive sleepiness. The five types of dyssomnias are insomnia, hypersomnia, narcolepsy, breathing-related sleep disorder, and circadian rhythm sleep disorder. Parasomnias are disorders that occur during sleep that can lead to arousal from sleep. Parasomnias include excessive nightmares, sleep terrors, and sleep walking. Secondary sleep disorders can also occur, and are attributable to other psychiatric illnesses, a general medical condition, or a substance-induced sleep disorder. Narcolepsy occurs when an individual suddenly falls asleep. Hallucinations may accompany narcolepsy 207

Clinical Review for the USMLE Step 1 â&#x20AC;&#x201C; if the hallucinations occur just as the person is falling asleep, they are known as hypnagogic hallucinations; those that occur just as the person is waking up are known as hypnapompic hallucinations. A person who experiences an episode of narcolepsy while standing, and then falls to the floor, experiences cataplexy. Narcolepsy is best treated with stimulants.

5.7. Epilepsy 5.7.1

Introduction

Epilepsy is the presence of recurrent seizures, or abnormal bursts of CNS activity leading to abnormalities in motor behavior, autonomic activity, and changes in consciousness. There are two types of seizures, generalized and partial seizures. Generalized seizures are broken down into tonic-clonic, or grand mal seizures, absence or petit mal seizures, atonic seizures, and myoclonic seizures. Common causes of seizure include vascular defects, cerebral infection, penetrating trauma to the head, autoimmune disorders, metabolic derangements, neoplasm, psychiatric causes, and idiopathic causes.

5.7.2

Tonic-Clonic Seizures

Tonic-clonic seizures begin with a loss of consciousness (LOC) and loss of postural control, followed by the tonic phase. The tonic phase is characterized by muscle rigidity throughout the body. The clonic phase follows, with rhythmic contractions of the extremities. Incontinence is often a feature of tonicclonic seizures. EEG changes reflect the abnormal activity taking place.

5.7.3

Absence Seizures

Absence seizures are brief disruptions of consciousness leading to the individual appearing as if they are not paying attention or concentrating on the task at hand. There are occasionally some motor cues, including lip-smacking, chewing, or partial loss of motor tone. Bilaterally synchronous slow wave activity is seen on EEG.

5.7.4

Atonic Seizures

Atonic seizures are brief losses of consciousness and postural tone, leading to a sudden fall to the floor in standing individuals. This type of seizure is similar to the cataplexy of narcolepsy.

5.7.5

Myoclonic Seizures

Myoclonic seizures are muscle contractions without a superimposed loss of consciousness. Myoclonic seizures are more common in neurodegenerative disorders.

5.7.6

Partial Seizures

Partial seizures are broken down into simple and complex partial seizures. Simple partial seizures have a straightforward sensory, motor, or autonomic abnormality during the seizure. The nature of the defect is dependent on the particular part of the brain that has the epileptiform focus. Complex partial seizures meet the criteria for simple partial seizures, except there is a superimposed disturbance in cognition. This type of seizure activity is the most common type of seizure disorder found in adults. Dream-like sensations may be present during the seizure.

208

CNS and PNS Pathology 5.7.7

Status Epilepticus and Preictal Symptoms

Seizures can present with preictal symptoms such as auras or sensations. Postictal symptoms typically include delirium, amnesia, or focal paralysis (known as Todd paralysis). Status epilepticus presents with continuous seizures.

5.7.8

Diagnosis and Treatment

Diagnosis of seizure activity is made by electroencephalogram. Derangements in electrolytes and other causes of seizures must be identified and appropriately treated. CT scan or MRI is used to identify any anatomic defects. Seizure treatment includes securing the ABCs. Reversible causes should be treated immediately. The initial drugs of choice are benzodiazepines, including lorazepam or diazepam. If potentiating GABA function does not inhibit the epileptic focus, treatment with phenytoin or fosphenytoin is initiated to inhibit sodium-dependent action potentials. Phenobarbital, a barbiturate, is added. Finally, if seizures continue with this complex regimen, midazolam or propofol can be added to induce anesthesia. Firsttime seizures are treated only with a clear family history, abnormal EEG, or abnormal neurologic exam. Tonic-clonic seizures are primarily treated with valproic acid, followed by lamotrigine to increase GABA availability or decreasing glutamate release, respectively. Absence seizures are treated with ethosuximide or valproic acid. Myoclonic and atonic seizures are primarily treated with valproic acid. Partial seizures are all treated with carbamazepine, phenytoin, valproic acid, or lamotrigine. Side effects of seizure treatment are numerous. Phenytoin may lead to ataxia, dizziness, diplopia, hirsutism, and rash. Phenobarbital can lead to ataxia and rash. Valproic acid may cause ataxia, hepatotoxicity, thrombocytopenia, GI irritation, or hyponatremia. Lamotrigine is implicated in causing Stevens-Johnson syndrome, in addition to rash and ataxia.

5.8. Cancer Brain tumors kill over 13,000 patients a year, but metastatic tumors to the brain occur in more than 80,000 additional cases. Metastasis occurs most commonly from the breast, lung, and melanomas. Brain tumors are the most common solid tumor in children. The most common tumors include gliomas, meningiomas, and schwannomas. Brain tumors in adults are commonly the result of exposure to radiation or HIV infection. Genetic transmission also occurs, but most tumors tend to occur earlier in age. Brain tumors present with headache in most patients. The headache is present on awakening and disappears within an hour or so. Headaches with brain tumors can rouse a patient from sleep, and typically worsen when lying supine. A common cause of a new headache in older patients is a brain tumor. Nausea and vomiting are typically present, along with focal neurologic changes including vision loss, weakness, and seizures. Diagnosis is made by CT, MRI, and confirmed by biopsy. Treatment for brain tumors consists of decreased ICP with steroids, followed by surgical resection, chemotherapy, and radiation.

209

Clinical Review for the USMLE Step 1 Table 9. Brain and spinal cord cancers. Types

Presentation

Notes

Glioblastoma multiforme

Palisading tumor cells with necrosis, hemorrhage, rapid growth, bilateral.

Elderly most affected; most common primary tumor; malignant, often fatal; found in cerebral hemispheres.

Meningioma

Psammoma bodies. May present as a cranial nerve palsy.

Women most affected especially at cerebral hemispheres; benign tumor outside of brain; treat with resection.

Schwannoma

Palisading tumor cells; typically vestibulocochlear schwannoma; if bilateral, consider NF-2 (Chr 22).

Later in life or hereditary. May be spontaneous or secondary to neurofibromatosis 2.

Oligodendroglioma

Fried egg appearance, calcifications.

Slow growing, indolent.

Pituitary adenoma

Bitemporal hemianopsia, typically secretes prolactin (amenorrhea in women with gynecomastia).

Rathkeâ&#x20AC;&#x2122;s pouch.

Astrocytoma

Diffuse with Rosenthal fibers. High grade tumor.

Narrow and diffuse subtypes. Typically benign in children, but may herald a poor prognosis in adults.

Medulloblastoma

Hydrocephalus, mass effects, rosettes.

Children most affected, especially at cerebellum; very malignant but radiosensitive.

Ependymoma

Rosettes with rod-shaped inclusions.

Most common spinal cord tumor with metastasis to vertebral body; 4th ventricle. Excellent prognosis if found early.

Hemangioblastoma

Foam cells, vascularity, polycythemia from EPO production.

Cerebellar, VHL syndrome (WT-1 w/ aniridia).

Craniopharyngioma

Calcification in remnant of Rathkeâ&#x20AC;&#x2122;s pouch â&#x20AC;&#x201C; no hormone production.

Benign, childhood.

Neuroblastoma

Unilateral or bilateral retinal tumor development.

Occurs in children, commonly in cerebral hemispheres. Related to defects in the N-myc oncogene. Very young children most affected; most common eye tumor of children. Related to Rb gene deletions.

Retinoblastoma Lymphoma

May lead to headaches, visual defects, and personality changes.

Chordoma

Embryonal tumor found near the sacrum

Due to derangements in B cell function.

5.9. Salivary Gland Tumors Tumors of the salivary glands may affect the parotid, submandibular, sublingual, or minor salivary glands. The larger glands are more likely to have benign tumors, while the smaller glands are more likely to present with malignant masses. The most common site for a salivary tumor is the parotid gland. Malignant tumors typically present with an enlarging mass, paresthesia of cranial nerves (i.e. CN VII, IX), and discomfort. All masses should have a fine needle aspiration for pathologic evaluation, along with a CT or MRI for staging and surgical planning. Pleomorphic adenomas are the most common benign parotid gland tumors. This tumor may be superficial or deep. Superficial tumors are best treated with a facial nerve-sparing superficial parotidectomy. Deep tumors should be treated with careful resection of the parotid gland with sparing of the facial nerve. Papillary cystadenomas (Warthin tumor) may also occur in the tail of the parotid gland and are treated similar to pleomorphic adenomas. While 80% of parotid gland tumors are benign, 20% may be malignant and typically present as a mucoepidermoid or adenoid cystic tumor. Low grade malignant tumors of the parotid gland can be treated a nerve-sparing parotidectomy. However, high-grade, ag210

Psychopathology gressive tumors should elicit a total parotidectomy with modified radical neck dissection and adjuvant radiotherapy. Resection of the facial nerve with nerve interposition can be completed if there is any evidence of perineural invasion, which is especially common with the high-grade cancers.

6. Psychopathology 6.1. Psychotic Disorders 6.1.1

Psychosis

Psychosis is impairment in the ability to distinguish what is real from what is not. Examples of psychosis include hallucinations, delusions, illusions, ideas of reference, ideas or influence, and disorganization of thought. A primary psychosis is differentiated from a mood disorder that has psychotic features in that a mood disorder is fundamentally characterized by the affective disarrangement. Some components of psychosis can include ideas of influence, in which an individual believes that some outside force or entity is controlling them; ideas of reference, in which an individual believes that people on television or on the radio are speaking directly to the person; noesis, in which a person feels a revelation has been made to them and that they are a leader; and clang associations in which words are associated based on similar sounds (homonyms).

6.1.2

Schizophrenia

Schizophrenia is one of the most common psychoses, affecting nearly 1% of the population. Schizophrenia is defined as a psychotic disorder with psychosocial dysfunction lasting greater than six months. Schizophrenia tends to occur in young adults, earlier in men than in women with nearly one third of women having their first psychotic episode in their 30s. Schizophrenia is more likely to be diagnosed in the indigent, and although a number of theories have been postulated, they have yet to be scientifically proven. Several studies have also indicated that schizophrenia is more prevalent in individuals with lower socioeconomic status. One hypothesis is that patients with schizophrenia are less likely to maintain steady jobs and thus fall into a lower economic standing due to chronic joblessness. Schizophrenia has a strong genetic component, but does occur spontaneously. A neurobiological basis has been postulated, known as the dopamine hypothesis. According to this theory, schizophrenia is due to an increase in activity of the dopaminergic pathways. This is substantiated by the Mechanism of Action of antipsychotics, which serve to reduce dopamine levels in the brain. Further, postmortem studies have demonstrated elevated levels of dopamine receptors in certain subcortical nuclei of the brain. The dopamine hypothesis also explains why cocaine and other amphetamines lead to psychosis, as these drugs are known to work through a dopamine-mediated mechanism. Schizophrenia has both positive and negative symptoms. Positive symptoms include having: disorganized, unusual type of thinking; auditory or visual hallucinations; eccentric behavior. Negative symptoms are the absence of normal mentation and psychosocial functions. For example, amotivation, isolation, and poor hygiene are all negative symptoms. It appears that certain medications are better suited for treating positive symptoms of schizophrenia, while others are better for dealing with the negative symptoms. The formal diagnosis of schizophrenia requires the presence of two or more of the following criteria, including delusions, hallucinations, dysarthria (disorganized speech), disorganized or catatonic motor behavior, and the presence of negative symptoms. The negative symptoms can be characterized as flat211

Clinical Review for the USMLE Step 1 tened affect, alogia (lack of words), and asociality (isolation from others). Schizophrenia, as a clinical diagnosis, also requires significant alterations in oneâ&#x20AC;&#x2122;s psychosocial or occupational function. Finally, these symptoms must be present for more than six months. Straightforward presentations of schizophrenia are primarily managed through medical intervention. For example, neuroleptics, also known as antipsychotic agents, are used to treat both acute presentations and for maintenance. In patients with schizophrenia that is refractory to simple medical management, a combination of agents is necessary to achieve satisfactory resolution of symptoms. These agents include psychosocial interventions, such as stable reality-oriented psychotherapy, family interventions, structured environments, and possibly electroconvulsive therapy (ECT).

6.1.3

Schizophreniform Disorder

Schizophreniform disorder meets the criteria for schizophrenia with the exception of time-constraint. Schizophreniform disorder is the name given for the psychosis with schizophrenia-type features, but with a time course less than six months but more than one month. Patients who develop schizophreniform disorder tend to go on to develop schizophrenia, although some develop a mood disorder with psychotic features instead. Schizophreniform disorder is additionally differentiated from schizophrenia in that social withdrawal is not required for this diagnosis.

6.1.4

Brief Psychotic Disorder

A brief psychotic disorder is characterized as a short-lived, acute derangement with features similar to schizophrenia without a triggering event. Psychotic symptoms last for at least one day, but must resolve within one month with a return to normal baseline functioning. If symptoms last for more than one month a diagnosis of schizophreniform disorder and eventually schizophrenia must be considered.

6.1.5

Schizoaffective Disorder

Schizoaffective disorder is the presence of schizophrenia-like features but with an overlying mood disturbance. In order for this diagnosis to be tenable, psychotic features must persist in the absence of any mood disturbance. For example, a patient must have schizophrenia-type symptoms only for a certain period of time, and then have symptoms of both a mood disorder and schizophrenia simultaneously during a different period of time. Treatment of schizoaffective disorder is centered on treating the psychosis and the mood disturbance. These patients require treatment with both an antipsychotic medication and a mood stabilizing medication. Antidepressants and electroconvulsive therapy are also used as needed in the management of schizoaffective disorder.

6.1.6

Delusional Disorder

Delusional disorder is characterized by the presence of delusions without other psychotic features. These fixed, false beliefs are nonbizarre, and are characterized by things that could happen in real life such as being followed, being poisoned, etc. Paranoid personality disorder is often an overlying condition in delusional disorder. Delusions in this disorder must be present for at least one month. The patient cannot meet criteria for any other mood disorder, and no social maladjustment is necessary for diagnosis.

212

Psychopathology Management of delusional disorder involves psychotherapy. No attempt to support or refute the delusion should be made; rather, the therapy should focus on creating a strong alliance with the patient. With time, the alliance may aid the patient in coming to terms with his or her fixed, false beliefs. Antipsychotics have also been used in treatment, but with few positive results.

6.2. Mood Disorders 6.2.1

Mood and Affect

Mood is defined as oneâ&#x20AC;&#x2122;s emotional state, and differs from affect in that the latter is the external manifestation of feelings. Affect is what others see, while mood is what the individual feels inside.

6.2.2

Overview

Mood disorders are separated into three separate categories: unipolar mood disorders including major depressive disorder (MDD) and dysthymic disorder; bipolar mood disorders including bipolar I, bipolar II, and cyclothymic disorder; and substance-induced mood disorders or mood disorders due to a general medical condition.

6.2.3

Major Depression

Major depressive disorder is characterized by patients who have had one or more major depressive episodes. There are profound emotional changes with a concomitant changes in sleep patterns, interest in other activities, energy, and appetite. The lifetime prevalence of depression ranges from 5 to 20%, and it is twice as common in females as compared to males. Major depression is a psychiatric disorder that is not tied to a particular socioeconomic class, which is in contrast to schizophrenia. Major depression disorder primarily affects adults between twenty and forty years of age. The rate of recurrence is 60% after one episode. Risk factors for depression vary, but the highest correlation is with the actual or perceived loss of a person close to the patient. Recent theories postulate that this loss leads to a sudden shift in oneâ&#x20AC;&#x2122;s regular egosyntonic controls and positive feedback mechanisms for self-regard, leading to a cognitive distortion and subsequent negative misperception of the external environment. Depression has a strong genetic component, and has a strong concordance in monozygotic twins. A genetic defect appears to lead to a dysfunction in normal amine neurotransmitter levels, especially in the hypothalamic-pituitary-adrenal axis. Clinical manifestations of major depression vary, but disturbances in sleeping patterns are nearly universal complaints. Sleep studies in depressed individuals have noted a decrease in stage 3 and 4 of sleep (delta waves). There is an increased time spent in REM sleep (beta waves), with decreased latency of the rapid eye movement (hence, faster onset of REM sleep). Other changes in major depression include having a depressed mood for the majority of the day on a regular and consistent basis, difficulty sleeping or excessive sleeping, anhedonia (lack of pleasure), feelings of worthlessness and guilt, low energy with chronic fatigue, decreased ability to concentrate on tasks, change in appetite with a resultant change in weight, psychomotor retardation or agitation, change in libido, and suicidal tendencies. Depression is best treated with psychotherapy and medical intervention. Antidepressant medications are the mainstay of medical treatment, and the best prognosis is found in patients treated with these medications coupled with psychotherapy, especially if the depression is severe. A number of classes of 213

Clinical Review for the USMLE Step 1 antidepressants are available, and it appears that tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAOIs) work well. Atypical antidepressants include thyroid hormone, psychostimulants, and lithium carbonate. All of these have all been used with positive effect. In depression refractory to medical treatment, electroconvulsive therapy has been used with positive effect. Anxiolytics may also be used as indicated, while phototherapy presents itself as an option in patients with seasonal mood disorders. The symptoms of depression can be remembered with the mnemonic SIG E CAPS, or sleep changes (hypersomnia or insomnia), interest (loss thereof), guilty feelings and worthlessness, energy changes (decreased), concentration deficits, appetite changes (increased or decreased), psychomotor agitation or retardation, and suicidal ideations. Depression may present with psychotic features, such as nihilistic delusions in which there are strong feelings that one’s self or others have been destroyed. Severe such delusions are termed Cotard syndrome. Such patients may complain of many bizarre losses, including various organs within their body, status, strength, respect, possessions, and so forth. Nihilistic delusions may also involve the world becoming nothingness. Cenesthetic delusions are also possible, in which there are false beliefs that things are occurring within the body.

6.2.4

Bipolar I Disorder

Bipolar I disorder is the most serious variant of the three bipolar disorders (bipolar I, bipolar II, and cyclothymic disorder). Bipolar I disorder is diagnosed in patients following a single episode of mania. These patients have major depressive episodes during their lifetime. The prevalence of bipolar I is approximately 1%, with an equal preponderance in males and females. Bipolar I disorder has a strong relationship to genetic heritage. Triggers for bipolar I include the typical psychosocial stressors, and disturbances in the sleep / wake cycle. The formal diagnosis of this disorder also requires several of the following criteria to be met: pressured speech, flight of ideas and / or racing thoughts, distractibility, increase in goal-directed activity and / or impulsivity, excess of pleasurable activities including hypersexuality, spending excess amounts of money, decreased need for sleep with only a few hours of sleep every night, and delusions of grandeur / inflated ego. One of the key indicators for bipolar disorder is the attempt to treat a major depressive episode with antidepressants, leading to a rapid manic episode. In these patients, since a substance is responsible for causing the manic episode, the formal diagnosis is really substance-induced mood disorder. Other psychiatric illnesses presenting with some features of bipolar disorder include schizoaffective disorder, cluster B borderline personality disorder, and depression with agitation. Bipolar I disorder is best clinically managed by antipsychotics and with benzodiazepines when patients present acutely (discussed below). Other drugs commonly used with positive effect include lithium carbonate (the most commonly used mood stabilizer when renal impairment is not present), and valproic acid (also known as depakote; the intramuscular version is known as depakene). Should these first-line agents fail, carbamazepine, gabapentin, lamotrigine, and long-acting benzodiazepines can be added to the treatment regimen. Finally, bipolar I disorder refractory to medical intervention can be treated with electroconvulsive therapy. The successful treatment of bipolar I disorder requires the use of a mood stabilizer to prevent cycling from “highs” and “lows.” Since patients with this diagnosis are often resistant to treatment, the use of psychotherapy is key in increasing compliance with medications. The first line treatment is lithium, followed by valproate, carbamazepine, and lamotrigine.

6.2.5

Bipolar II Disorder

Bipolar II disorder is similar to bipolar I disorder except for the absence of significant mania. Patients 214

Psychopathology with bipolar II have a milder form of mania, known as hypomania. These patients may still experience profound major depressive episodes. The lifetime prevalence of bipolar II disorder is half that of bipolar I disorder, ranging at approximately 0.5%. Like bipolar I, bipolar II is a cyclic disorder that varies between “highs” and “lows.” A similar proportion of these patients commit suicide as in bipolar I disorder. The treatment of bipolar II disorder is similar to that of bipolar I.

6.3. Anxiety Disorders 6.3.1

Anxiety

Anxiety is the over-reactive response to an impending challenge or event that is not congruent with the actual stress level of challenge or event. Anxiety disorders are the most common type of psychiatric illness, affecting nearly 8 percent of all people.

6.3.2

Overview

There are various types of anxiety disorders, including panic disorder with or without agoraphobia, agoraphobia, social phobia, a specific phobia, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute stress disorder, posttraumatic stress disorder (PTSD), substance-induced anxiety disorder (SIAD), anxiety disorder due to a general medical condition, and anxiety disorder not otherwise specified (NOS).

6.3.3

Panic Disorder

Panic disorder has a lifetime prevalence of two to three percent, and is most common in women. It typically has an onset in young adults. Agoraphobia has a similar prevalence, demographic breakdown, and onset. Patients with only agoraphobia are less likely to seek treatment; hence, most patients with agoraphobia seen in a clinical setting are likely to also have a panic disorder. Panic disorder has many possible pathologic bases, including excessive sensitivity to carbon dioxide (CO2), dysfunction in the locus ceruleus (LC) (controls arousal), elevated catecholamine levels in the central nervous system (CNS), and dysfunction in the gamma-amino butyric acid (GABA) receptor. The latter has been thought to be a potential mechanism mediating panic attacks due to the ability of benzodiazepines, which act through a GABA pathway, to prevent future recurrence of panic disorders. The converse has also been demonstrated: some patients can be induced to have anxiety disorder with GABA antagonists. Panic disorder is characterized by recurrent, random, unexpected attacks of disabling anxiety. These patients may occasionally experience severe dread of open places, where escape from a potentially difficult situation may be difficult. Panic disorder may occur with or without agoraphobia, and agoraphobia may occur by itself. Panic disorder often has a trigger, and can include the presence of being in any stressful or fearful situation. Four or more of the following symptoms are required for the formal diagnosis of panic disorder and these symptoms must reach a peak within ten minutes of the stressor: palpitations or accelerated heart rate (with or without chest pain); accelerated respiratory rate, shortness of breath, or a feeling of being choked; trembling or shaking; diaphoresis; chills or hot flashes; nausea, vomiting or acute gastrointestinal distress; dizziness or lightheadedness; depersonalization (detachment from self) or derealization (feeling of artificiality); fear of losing control or going crazy; a sense of impending doom or fear of dying; and paresthesia. 215

Clinical Review for the USMLE Step 1 Episodes of panic disorder occur suddenly and without warning, peak within ten minutes, and last between five and thirty minutes. These patients must experience these episodes for at least one month with significant worry about impending attacks, brooding about the sequelae of these attacks, and manifest a change in behavior in an attempt to minimize the implications of having these episodes. When panic disorder significantly affects a personâ&#x20AC;&#x2122;s lifestyle, it becomes a clinical disorder. Panic disorder is primarily treated with a combination of medical interventions and cognitive-behavioral therapy (CBT). Certain selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, and benzodiazepines have been shown to have positive effect. Benzodiazepines are good for immediate relief, while SSRIs or TCAs are the drug of choice for maintenance. Cognitive-behavioral therapy uses a combination of relaxation techniques and desensitization to mitigate the onset and complications of panic disorder. Teaching a patient that the episodes of panic disorder are innocuous can often reduce the severity of this psychiatric condition. Finally, exposure therapy can be used to teach a patient fearful of open spaces (agoraphobia) that such situations do not pose a danger.

6.3.4

Specific Phobia

The irrational fear seen in specific phobia is out of proportion with the actual danger. Diagnosis is made when the anticipation of being in a particular situation or the presence of a particular object leads to an extreme anxiety reaction and distress and with an impairment of oneâ&#x20AC;&#x2122;s lifestyle and interpersonal relationships. Symptoms must be present for at least six months, if the onset of this disorder is in individuals younger than eighteen. Specific phobias often remits spontaneously, if the onset is in childhood. Chronic specific phobias can be treated with exposure therapy, with systematic desensitization, or flooding. No medical intervention is necessary.

6.3.5

Social Phobia

As in specific phobia, a social phobia may be diagnosed in patients younger than eighteen only when it has been present for greater than six months. A generalized social phobia may be diagnosed if the patient responds with an anxiety reaction to any situation, or a limited social phobia may exist if only particular triggers exist for the anxiety reaction. Social phobia is managed with cognitive-behavioral therapy, but medication may be required for proper social functioning. SSRIs, low-dose benzodiazepines, and beta-blockers are available. Flooding and systemic desensitization are two approaches used in cognitive-behavioral therapy with good outcomes. Individual and group psychotherapeutic approaches have also been used and a combination of all of these therapies has been shown to have the best outcome.

6.3.6

Generalized Anxiety Disorder

Generalized anxiety disorder is characterized by an irrational fear of virtually every aspect of common, everyday events. Generalized anxiety disorder is diagnosed only when patients are found to worry to an excessive level with high feelings of anxiety. These patients experience excessive anxiety about every facet of their life, including excessive worry about interpersonal relationships, occupational situations, personal health, and the environment around them. This level of incongruent anxiety must be present for at least six months, and the worrying must be difficult to control. The formal diagnosis of generalized anxiety disorder also requires the presence of restlessness from the anxiety, fatigue, irritability, 216

Psychopathology sleep disturbances, difficulty concentrating, and tension in the musculoskeletal system. The key to this diagnosis is that the worry has to do with everyday, normal events, not the worrying associated with experiencing another psychiatric disorder or its manifestations. Generalized anxiety disorder is best managed with a combination of cognitive-behavioral therapy with relaxation techniques, and medical intervention through the use of benzodiazepines, non-benzodiazepine anxiolytics such as buspirone, beta-blockers, and gabapentin. Benzodiazepines are effective medications, but are limited in their use due to their habit-forming nature. Benzodiazepines are recommended for the immediate relief, while SSRIs, venlafaxine, and buspirone are better for maintenance.

6.3.7

Posttraumatic Stress Disorder

Posttraumatic stress disorder is characterized as an anxiety disorder with the patient repeatedly experiencing the original traumatic event. The patient attempts to block the recollection of this traumatic event. S/he is also in a hyperaroused state. Posttraumatic stress disorder affects nearly one percent of the population, especially women, and can occur in any age group at any time after the traumatic event. Posttraumatic stress disorder has been neurologically characterized by an increase in volume of the hippocampus. Patients with posttraumatic stress disorder report experiencing or witnessing a horrific and /or potentially deadly event. These patients repeatedly experience this event through thought insertions and intrusive dreams, hallucinations, illusions, or flashbacks. Treatment of posttraumatic stress disorder centers on the use of psychotherapy and symptom-based psychoactive medications, including antidepressants as necessary. SSRIs, buspirone, and mood stabilizers have positive effect in the treatment of PTSD. Anxiolytics such as beta-blockers, benzodiazepines, and clonidine are recommended as necessary.

6.3.8

Obsessive-Compulsive Disorder

The obsessions of this disorder include intrusive, repeated ideas or thoughts that lead to episodes of anxiety. Compulsions of this disorder are stereotyped, purposeful mental or physical rituals that the patient does in order to neutralize the obsessive ideas he or she is experiencing. Hence, a long-standing obsession can lead to compulsions in an effort to decrease anxiety and mitigate the perceived threat of not doing the action. The management of obsessive-compulsive disorder is best done with clomipramine and selective serotonin reuptake inhibitors. Cognitive-behavioral therapy in the form of flooding, systematic desensitization, or response prevention has also been used in some patients with positive effect.

6.4. Cognitive Disorders 6.4.1

Illusions

A clear definition of illusions, delusions, and hallucinations is important to have a good understanding of various psychiatric illnesses. An illusion is an inaccurate interpretation of an actual outside stimulus. For example, believing that a boat is sounding a foghorn to warn of an impending crash when one hears a semi truck horn is an example of an illusion.

217

Clinical Review for the USMLE Step 1 6.4.2

Delusions

Delusions are fixed, false beliefs that exist despite evidence to the contrary. Delusions are not an appropriate term if those beliefs are consistent with the beliefs of a particular culture or society. For example, a religious person believing in God is not a delusion; however, the belief that aliens are invading Earth is a delusion. Delusions are a malformed thought where the content of the thought itself is incorrect. Delusions are different than loose associations because the thoughts are connected to each other in a disorganized way.

6.4.3

Hallucinations

Hallucinations are sensory perceptions in the absence of any outside stimuli. Believing that werewolves are attacking one is an example of a hallucination. There are a number of types of hallucinations. Tactile hallucinations involve feeling something in the absence of touch stimuli; they are especially common in substance abuse disorders such as delirium tremens in alcohol withdrawal, in cocaine abusers, and in amphetamine psychosis (these hallucinations are known as formication). Visual and auditory hallucinations such as hearing voices are especially common in schizophrenia. Olfactory hallucinations may occur as part of the aura of migraines or epilepsy.

6.4.4

Delirium

Delirium is characterized by changes in attention and cognition due to a particular medical condition or substance. The most common substance-induced causes of delirium include alcohol or benzodiazepine withdrawal and toxicity from anticholinergic drugs. Delirium predominantly affects hospitalized, postsurgical patients, especially those over 65 and in intensive care units (ICUs). Delirium is hallmarked by a disturbance of consciousness leading to deficits in attention and arousal, an alteration in cognition and memory, relatively rapid development over a period of hours, and a distinct medical condition or substance-related trigger. In delirium, the sleep-wake cycle is disturbed, and profound psychomotor agitation may be present. There may be difficulty separating delirium from dementia, especially since dementia is a positive predictor for the onset of delirium. The key differences are that delirium is reversible, develops relatively quickly, and the presence of an obvious, immediate precipitating factor. Delirium carries with it a 50% chance of mortality in one year. Treatment of delirium includes mostly supportive therapy while addressing the cause of the delirium. Haloperidol has been used as an antipsychotic to reduce agitation. Benzodiazepines can also be used as needed. Brightly lit rooms, plenty of cues to help orient the patient, and the presence of health care personnel and family can help reassure a delirious patient.

6.4.5

Dementia

Overview Dementia is distinguished from delirium in that dementia presents over a period of weeks to years, and so is much more gradual in onset. Dementia is stable over the short term, versus the fluctuating nature of delirium. Dementia also tends to be progressive over time, while delirium tends to improve with supportive therapy. Dementia may or may not impair attention, while delirium causes severe impairments to attention. Both delirium and dementia cause cognitive impairments, but the deficits in dementia also affect executive function of the brain. Both delirium and dementia affect the sleep / wake cycle and cause a labile affect with mood disturbances. While a specific, temporally near precipitant is typically present with delirium; the precipitant for dementia tends to be more chronic and distant, if it can be 218

Psychopathology identified at all. Dementia is the presence of memory impairment with superimposed cognitive deficits. Dementia is due to progressive neural loss secondary to an organic brain disorder, trauma, infection, infarction, hypoxia, or other biological precursor. Dementia has a prevalence of 3% after age 65, and over 20% in patients over 85. There are multiple causes of dementia, but some of the more prominent include Alzheimer disease, cerebrovascular disease, HIV, trauma to the head, Parkinson disease, Huntington disease, Pick disease, and Creutzfeldt-Jakob disease.

HIV-Dementia HIV-dementia is due to viral encephalitis and myelitis. Nearly â&#x2026;&#x201D; of cases are insidious in onset, and â&#x2026;&#x201C; are florid. HIV-dementia presents with decreased memory, loss of concentration, confusion, withdrawal and apathy, dysphoria, ataxia, and muscle weakness. HIV-dementia is often diagnosed as depression, but an accurate diagnosis is critical as death often occurs within four months of onset of symptoms. Recall that death related to HIV infection is common in young adults up to middle age, and so onset of HIV-dementia is typically much earlier than Alzheimer disease.

Vascular Dementia Vascular dementia is due to patchy loss of neurons leading to cognitive deficits. Vascular dementia may be due to intermittent vascular occlusion due to strokes or vasospasm. Onset is usually in the 60s and so occurs earlier than Alzheimer disease but later than HIV dementia. Hypertension is a common overlying pathology and is likely responsible for the widespread, diffuse vascular disease.

6.5. Amnestic Disorders 6.5.1

Overview

Amnestic disorders are deficits of only memory, and are likely the result of a general medical condition or substance use disorder. Damage is common to the mamillary bodies, fornix, and hippocampus â&#x20AC;&#x201C; allimportant components of memory formation. This can lead to the inability to recall old memories and / or to form new memories (retrograde and anterograde amnesia).

6.5.2

Dissociative Disorders

Dissociative disorders are the failure to integrate mental functions, leading to a loss of memory of personal identifying information, fragmentation of personality, and altered reality perception. In dissociative amnesia, a patient is unable to recall his or her identity and other personal information.

6.5.3

Amnesia

Various forms exist. Localized amnesia is characterized by the inability to recall personal information over a certain period of time, typically following head trauma. Selective amnesia is where particular types of information are lost. Generalized amnesia is where the information is lost for the remainder of the lifespan. In continuous amnesia, information from a particular point of time to the present cannot be recalled. Particular categories of information are lost in systematized amnesia.

219

Clinical Review for the USMLE Step 1 6.5.4

Ganser Syndrome

One particular type of dissociative disorder is known as Ganser syndrome, a psychiatric illness that primarily occurs in inmates. These patients are characterized by giving approximate answers to questions, having chronic disorientation, amnesia, and perceptual abnormalities.

6.5.5

Dissociative Fugue

Dissociative fugue occurs in people who suddenly travel to a new place, create an entirely new identity and life, and continue to live as if nothing has transpired. These patients have an amnesia about their past, and have their cognitive and intellectual abilities completely intact. Dissociative fugues often remit over time without treatment or intervention.

6.5.6

Dissociative Identity Disorder

Dissociative identity disorder, formerly known as multiple personality disorder, is the presence of several separate and distinct personalities that have autonomous control over a personâ&#x20AC;&#x2122;s behavior. Patients with dissociative identity disorder often complain of losing time, as each personality is unaware of others. Surveys of patients with this disorder indicate seven distinct personalities on average. Many of these patients are highly suggestible. Many report severe physical or sexual abuse during childhood, while others report abuse in a cult. To complicate this issue, these memories may not necessarily be true, but the individual with the disorder perceives them as real.

6.5.7

Depersonalization Disorder

Depersonalization disorder is a feeling of being detached from the world around the person, as if the person were an onlooker. It leads to a persistent feeling of being detached, but reality testing remains intact. There can be clinically significant stress.

6.6. Somatoform Disorders 6.6.1

Overview

Somatoform disorders are those where individuals present with physical symptoms of a particular ailment without an identifiable medical cause. Somatoform disorders are distinct in that the symptoms produced by the patient are not intentional.

6.6.2

Somatization Disorder

Somatization disorder is one diagnosable somatoform disorder in which an individual has multiple medical complaints with no particular identifiable medical illness. Somatization disorder can only be diagnosed when the patient presents with symptoms in four different parts of the body or parts of the body with different functions. For example, the patient has two distinct gastrointestinal complaints, one sexual complaint, and one neurologic complaint. The last three criteria cannot include pain. Further, a portion of these symptoms must have started prior to age 30 and have been present for several years. Many of these symptoms are refractory to treatment, and occasionally, medical and surgical interventions may actually be iatrogenic causes of some of these complaints. Somatization disorder is more common in females, and there appears to be a genetic cause for it, especially in families with antisocial personality disorder and substance abuse disorder. 220

Psychopathology 6.6.3

Other Somatoform Disorders

Other somatoform disorders include undifferentiated somatoform disorder, which is a less severe form of somatization disorder with fewer complaints and a shorter duration. Conversion disorder is hallmarked by complaints with sensory and motor function not due to a medical cause. Pain disorder involves an exaggerated pain response not congruent with any present medical illness. Hypochondriasis is the fixed, false belief that the individual has a medical illness, but this is most likely a misinterpretation of a normal bodily function. Body dysmorphic disorder is an exaggerated perceived belief that a particular body part has a defect. Pseudocyesis is the development of physical signs of pregnancy and the false belief that one is pregnant in the face of negative laboratory tests and studies.

6.7. Malingering 6.7.1

and

Factitious Disorders

Malingering

Malingering is a psychiatric illness in which a person invents a disorder in order to receive a specific benefit. Symptoms are intentionally produced with the motivation to receive a specific gain. For example, a person may create the symptoms of the flu in order to avoid going to school. This is known as secondary gain because having the symptom (the flu) leads to a specific reward for the patient (avoiding school). Primary gain is the benefit to the patientâ&#x20AC;&#x2122;s ego by having the symptom. Tertiary gain is the benefit to the caretaker due to the patient having the symptom. An example of primary gain is the increase in selfesteem by having the flu; an example of tertiary gain is the satisfaction the physician gains by diagnosing a rare disorder. Primary gain is not seen in malingering by definition as the gain is sought out intentionally. Tertiary gain may or may not be present depending on the caretaker.

6.7.2

Factitious Disorders

Factitious disorder differs from somatization disorder in that the individual with a factitious disorder consciously creates a sign or symptom of a medical illness to have a primary or secondary gain. Factitious disorders are also different from malingering, in which an individual creates an illness to obtain gains that are different from those obtained by being in a sick role (secondary gains). Repeated admission to the hospital and willingness to undergo invasive procedures is termed Munchausenâ&#x20AC;&#x2122;s syndrome. Parents who create symptoms of an illness in a child is termed Munchausenâ&#x20AC;&#x2122;s syndrome by proxy.

6.8. Personality Disorders 6.8.1

Classification of Personality Disorders

Personality disorders are axis II disorders in the five axis evaluation of psychiatric disorders. Personality disorders can be characterized by one of three major types. Cluster A personality disorders include paranoid, schizoid, and schizotypal personality disorders, and can best be characterized as odd or eccentric in nature. Cluster B personality disorders include antisocial, borderline, histrionic, and narcissistic personality disorders, and can be characterized as overly dramatic or emotional in nature. Finally, cluster C personality disorders include avoidant, dependent, and obsessive-compulsive personality disorders, and tend to be anxious or fearful in nature. The dysfunction of personality disorders can be recalled with the mnemonic MEDIC, or maladaptive, enduring, deviation from cultural norms, inflexible, and causing psychosocial impairment.

221

Clinical Review for the USMLE Step 1 6.8.2

Cluster A Personality Disorders

Paranoid Personality Disorder Table 10. Diagnosis of Paranoid Personality Disorder Diagnosis of Paranoid Personality Disorder —DSM 301.0 Inherently distrustful High level of suspicion Requires separation from paranoia associated with psychotic disorders

Schizoid Personality Disorder Table 11. Diagnosis of Schizoid Personality Disorder Diagnosis of Schizoid Personality Disorder –DSM 301.20 Tend to avoid other people, emotionally distant and withdrawn Tend to be related to others in the family with schizophrenia or schizotypal personality disorder Detachment from the world Must be differentiated from avoidant personality disorder, social phobia, and schizophrenia

Schizotypal Personality Disorder Table 12. Diagnosis of Schizotypal Personality Disorder Diagnosis of Schizotypal Personality Disorder –DSM 301.22 Especially tied to patients who have families with a history of schizophrenia Avoid others Characterized by eccentric thoughts, bizarre affects, odd perceptions, incongruent beliefs Distrustful to the point of paranoia

6.8.3

Cluster B Personality Disorders

Antisocial Personality Disorder Table 13. Diagnosis of Antisocial Personality Disorder Diagnosis of Antisocial Personality Disorder – DSM 301.7 Disregard rules, aggressive Lie, cheat and exploit others Impulsive No remorse for illegal or moral actions Must be differentiated from bipolar and substance abuse disorders

222

Psychopathology Borderline Personality Disorder Table 14. Diagnosis of Borderline Personality Disorder Diagnosis of Borderline Personality Disorder –DSM 301.83 High levels of fear, anger, and worry about being abandoned their spouse Shifting idealization and devaluation of others Unpredictable changes in interpersonal relationships Respond with anger and panic or depression to unexpected stressors Tend to be suicidal or feign suicide; risk-taking behavior

Histrionic Personality Disorder Table 15. Diagnosis of Histrionic Personality Disorder Diagnosis of Histrionic Personality Disorder – DSM 301.50 Sexually seductive and socially inappropriate with regard to their hypersexuality Exaggerated emotional outbursts; theatrical attention-seeking behavior Unpredictable changes in interpersonal relationships Must be differentiated from somatization disorder

Narcissistic Personality Disorder Table 16. Diagnosis of Narcissistic Personality Disorder Diagnosis of Narcissistic Personality Disorder – DSM 301.81 Highly egocentric and arrogant (reaction formation to protect them from a fragile ego and low self-esteem) Demand attention and special treatment Little concern for others Differentiate from bipolar disorder with grandiose features

6.8.4

Cluster C Personality Disorders

Avoidant Personality Disorder Table 17. Diagnosis of Avoidant Personality Disorder Diagnosis of Avoidant Personality Disorder – DSM 301.82 Hypersensitive to criticism Feelings of extreme inadequacy to the point where there is no interaction with others due to fear of being singled out Extreme fear of humiliation and rejection by others Differentiate between avoidant personality and generalized social phobia

223

Clinical Review for the USMLE Step 1 Dependent Personality Disorder Table 18. Diagnosis of Dependent Personality Disorder Diagnosis of Dependent Personality Disorder â&#x20AC;&#x201C; DSM 301.6 Unable to function without the assistance from another Strong desire to be taken care of by others Cling to people due to fear of separation Tend to be highly submissive Differentiate from borderline personality disorder

Obsessive-Compulsive Personality Disorder Table 19. Diagnosis of Obsessive-Compulsive Personality Disorder Diagnosis of Obsessive-Compulsive Personality Disorder -DSM 301.4 Adhere to rigid schedules Rigid in interpersonal relationships Quick to judge Devoted to their work Avoid intimate relationships

6.8.5

Treatment

Personality disorders are difficult to treat and are listed as axis II as a result of their ingrained nature. They are often an essential part of a personâ&#x20AC;&#x2122;s makeup and are resistant to simple medical intervention. Therapy therefore consists of a variety of modalities to help the person understand the destructive behavior and make changes. Successful management invovles one or more of the following: long term psychotherapy, cognitive behavioral therapy, changes in interpersonal relationships, and medications such as mood stabilizers, benzodiazepines, SSRIs, and antipsychotics.

6.9. Substance Abuse Disorders 6.9.1

Substance Abuse

Substance abuse is less severe than substance dependence (abuse before dependence). Substance abuse is defined as a malformed pattern of ingestion of a particular substance that leads to impairment in oneâ&#x20AC;&#x2122;s psychosocial obligations. At least one of the following conditions must be fulfilled in order to meet the requirements of diagnosis, including a failure to meet obligations or expectations at school, work, or home; repeated use of a substance in dangerous situations; repeated infractions with the law; or repeated use despite worsening social or interpersonal problems due to the negative effects of the substance.

6.9.2

Substance Dependence

Substance dependence is defined with regard to its clinical impairment, and requires at least three of the following criteria within a one year period for diagnosis: tolerance, withdrawal, repeated use, failed 224

Psychopathology efforts to cut down on use, large amount of time spent trying to obtain the substance, decrease in important social or occupational activities, use despite awareness of psychosocial impairments, use despite physical impairments, and excessive or unintended use of the compound.

6.9.3

Alcohol-Induced Disorders

Overview Alcohol intoxication is characterized by uncoordinated motor activity, slurred speech, imbalance, nystagmus, defect in concentration or memory, stupor or coma, and maladaptive or inappropriate behavior or functioning. Alcohol intoxication is quantified by serum tests such as a blood alcohol level (BAL). Other lab tests in severe, chronic alcohol abuse include elevated high-density lipoprotein (HDL), decreased low-density lipoprotein (LDL), elevated mean red blood cell volume (MCV), and elevated liver enzymes. Alcohol intoxication presents with loss of inhibition over oneâ&#x20AC;&#x2122;s better judgment. Abusers are more prone to emotional lability, lose the ability to enunciate during speech, have difficulty walking and maintaining balance, can lose consciousness with heavy abuse, and in severe cases, fall into a coma. Alcohol dependence is a clinical disorder characterized by tolerance and withdrawal symptoms. The lifetime prevalence of alcoholism (alcohol dependence) is nearly 14%, with males disproportionately affected compared to females. There appears to be a genetic basis for alcoholism, especially in males. Alcoholics also tend to have a family history of antisocial personality disorder and depression. Table 20. Diagnosis of Alcohol Dependence-DSM 303.90 Tolerance

Excessive or unintended use of substance

Withdrawal symptoms

Use despite physical impairment

Repeated use

Failed efforts to cut down on use

Repeated infractions with the law

Large amount of time spent trying to obtain substance

Decrease in social or occupational activities

Use despite awareness of psychosocial impairment

Palmar erythema

Painless hepatomegaly

Acne rosacea

Cirrhosis

Jaundice

Ascites

Atrophy of testicles

Gynecomastia

Dupuytrenâ&#x20AC;&#x2122;s contracture

Wernicke-Korsakoff syndrome

Alcoholics tend to strongly deny their illness, and the importance of obtaining collateral information cannot be overstated. Physical symptoms sometimes indicate the presence of this disorder, including palmar erythema, painless hepatomegaly, and acne rosacea. Advanced alcoholism includes signs of cirrhosis of the liver, jaundice, ascites, atrophy of the testicles, gynecomastia, and Dupuytrenâ&#x20AC;&#x2122;s contracture. Sequelae of each of these clinical symptoms are also present depending on the stage of the alcoholism. There is also an increased incidence of cancer, pneumonia, heart disease, and hypertension. Alcoholism can also be gauged by the CAGE questions, or asking whether the individual has felt a need to cut down on their drinking, whether they have ever been annoyed by the criticism of others regarding their drinking, whether they feel guilty about their drinking, and whether they require an eye-opener or early morning drink. More than one positive answer makes alcoholism likely. 225

Clinical Review for the USMLE Step 1 Wernicke-Korsakoff Syndrome Wernicke-Korsakoff syndrome may also develop in alcoholics due to the destruction of the mamillary bodies. This syndrome develops due to a deficiency in thiamine. The initial stage of this disorder, known as the Wernicke stage, is characterized by nystagmus, ataxia, and mental confusion. Wernicke’s encephalopathy may be reversed with prompt administration of thiamine. However, failure to do so leads to progression to Wernicke-Korsakoff syndrome with Korsakoff’s psychosis, presenting with anterograde amnesia and confabulations. Korsakoff’s psychosis is frequently irreversible, and can be complicated with hallucinations, dementia, neuropathy, depression, and a greater tendency towards suicide. Alcohol-dependent patients also tend to have signs of old rib fractures on X-ray.

Withdrawal The symptoms of alcohol withdrawal include the development of a fine tremor, increased heart rate, increased blood pressure, nausea and vomiting, seizures, anxiety, and in severe cases, hallucinations and delirium tremens. Tremors may peak at approximately one day after cessation of alcohol. Such withdrawal can last nearly a week if untreated, and may be accompanied by nausea and vomiting, headache, tachycardia, and high blood pressure. These withdrawal symptoms, if minor, can be treated with benzodiazepines including oxazepam and chlordiazepoxide. These medications should be titrated to match the withdrawal symptoms and tapered over several days. More severe symptoms of withdrawal include seizures that can begin about half a day after cessation. These seizures can precede delirium tremens, and should be treated with benzodiazepines and prophylactic phenytoin, in high-risk patients. Strong auditory hallucinations may also be present in alcoholic hallucinosis, with an onset within two days after cessation. A neuroleptic such as haloperidol may be administered to treat this etiology.

Delirium Tremens Delirium tremens is serious sequelae of alcohol withdrawal, and can be fatal in 15-20% of patients, if untreated. Delirium tremens is characterized by confusion, disorientation, agitation, perceptual disturbances such as hallucinations, hyperarousal of the autonomic nervous system (ANS), and a mild fever. It typically begins several days after cessation of alcohol, and can occur in one in twenty hospitalized patients with alcohol dependence. Treatment includes benzodiazepines and supportive therapy and may require admission to an intensive care unit (ICU), if there is instability in the blood pressures or other problems of the autonomic nervous system. The duration of delirium tremens is typically three days, but can last up to one month.

Rehabilitation Rehabilitation of alcoholism requires admission to a twelve-step program such as alcoholics’ anonymous, completion of the entire program, and continued avoidance of all alcohol. Side effects of chronic alcohol use include depression and anxiety, both of which should be treated if they continue two to four weeks after cessation of alcohol abuse. Disulfiram can be used in some patients to maintain avoidance of alcohol as this enzyme inhibits aldehyde dehydrogenase; this causes conditioned avoidance. Consumption of alcohol after blocking this enzyme leads to rapid accumulation of acetaldehyde in the bloodstream and subsequent nausea, vomiting, flushing, palpitations, and hypotension. Naltrexone is another medication that can be used to maintain avoidance. This opiate antagonist reduces alcohol intake and frequency of intake. Naltrexone can be taken even if the patient continues alcohol. The Mechanism of Action of Naltrexone may be mediated by reducing the positive reinforcement of alcohol. Overall, alcohol rehabilitation has a fifty percent failure rate. 226

Psychopathology 6.9.4

Anxiolytic, Sedative, and Hypnotic Substance Abuse

Barbiturates and benzodiazepines are examples of drugs that fall into the anxiolytic, sedative, and hypnotic category. These drugs are cross-tolerant with alcohol, and can form a co-dependence. Abuse of these drugs can lead to symptoms similar to alcohol intoxication and withdrawal. It is distinguished from alcohol intoxication by the absence of alcohol in the serum or a urine toxicology screen. Withdrawal symptoms are similar to that of alcohol, and specifically include anxiety, apprehension, restlessness, tremors, nausea and vomiting, weakness and fatigue, hyperreflexia, diaphoresis, seizures, and orthostatic hypotension. Three or more of these symptoms must be present for the diagnosis of substance dependence disorder. Visual and somatic hallucinations, disorientation, and confusion can begin several days after cessation of the drug. Management involves detoxification, administration of benzodiazepines or barbiturates with a controlled taper to minimize withdrawal symptoms, and symptomatic management. Barbiturates tend to be more dangerous than benzodiazepines, and withdrawal can lead to dangerously high fevers (hyperpyrexia) and death. Diazepam or phenobarbital is often used in withdrawal management. In patients who abuse both alcohol and benzodiazepines or barbiturates, a pentobarbital challenge test is required to quantify the tolerance to these compounds and quantify the amount of medication required for a controlled taper. Patients should also be referred to a twelve step program for further rehabilitation.

6.9.5

Opioid Abuse

Morphine, codeine, heroin, meperidine, and hydromorphone are examples of substances that fall under opioid abuse disorders. Heroin is the only one of these substances that is completely illegal in the United States. Lifetime prevalence of abuse is less than 1%, though this number is increasing. Opioids are often taken intravenously, leading to intense pleasure and a diffuse orgasm. After these symptoms occur, general well being follows then subsequent psychomotor retardation, impaired concentration, sleepiness, and fatigue. Upon use, the pupils constrict (miosis), there is respiratory depression, slurred speech, bradycardia, hypotension, and hypothermia. Nausea, vomiting, and constipation can all be present in opiate use. Use of opiates more than three times a day is typically a hallmark of dependent behavior. Similar to the diagnosis of other dependence disorders, opiate dependence also includes one or more of the following: failure to meet school, home, or work obligations, repeated use of substance in dangerous situations, repeated infractions with the law, repeated use despite worsening social or interpersonal problems due to negative effects of the substance. Withdrawal begins within half a day after cessation, and signs and symptoms include dysphoria, rhinorrhea, lacrimation, diaphoresis, mydriasis, piloerection, hypertension, tachycardia, fever, diarrhea, insomnia, and yawning. Severe symptoms include nausea and vomiting, seizure especially in meperidine withdrawal, muscle aches, abdominal cramps, hot and cold flashes, and severe anxiety. Comorbid psychiatric illnesses often exist in opioid abusers, including antisocial or borderline personality disorder, and mood disorders. These patients tend to commit crimes in order to finance their drug habits, and also have a high mortality rate due to the intercurrent intravenously-transmitted illnesses, accidental overdoses, and tendency towards suicide. Opioid abusers should be withdrawn by methadone administration, a mu opiate receptor partial agonist. Methadone causes few positive or negative effects, and so is an ideal substance to take the place of the powerful stimulatory and withdrawal effects of opiates. Clonidine can also be used to treat withdrawal through its alpha-two receptor agonist abilities. Clonidine is effective at treating the acute auto227

Clinical Review for the USMLE Step 1 nomic dysfunction of withdrawal, but has little effect on managing the cravings of the opioid addict. Additional medications include treating abdominal cramps with dicyclomine, nausea with promethazine, and muscle aches with quinine. The combination of medical intervention and rehabilitation programs such as a twelve-step program is necessary, along with long-term administration of methadone. Abuse of narcotic pain medications is particularly prevalent among patients with chronic pain. Management of chronic pain often involves cooperation between clinicians, pain clinics, and the patient. Contracts with the patient to limit the intake of narcotic pain medications and correction of destructive behavior can help make a difference.

6.9.6

Amphetamine Abuse

Cocaine and other amphetamines are commonly abused drugs. These drugs cause stimulation of the central nervous system and tend to drive the sympathetic nervous system. Cocaine can be either snorted in the powder form, or smoked in the crack form. Cocaine has a rapid onset, a short half-life, and a number of side effects. Intoxication with cocaine or other amphetamines includes dysfunctional behavioral changes such as hypervigilance or euphoria, mydriasis, nausea and vomiting, weight loss, confusion, seizures, dyskinesia, coma, muscular weakness, respiratory depression, chest pain, cardiac dysrhythmias, sudden cardiac death, either tachycardia or bradycardia, either hypertension or hypotension, either diaphoresis or chills, and either psychomotor retardation or agitation. Cocaine is one of the few drugs that can cause a tactile hallucination on intoxication, such as a feeling that bugs are crawling all over a person. A transient psychosis with visual hallucinations and paranoia can also occur during intoxication. Withdrawal symptoms can be severe but nonfatal, and include fatigue, nightmares, depression, headache, diaphoresis, muscle cramps, and hunger. Withdrawal typically lasts several days. Amphetamines are available through prescription for the treatment of obesity, attention-deficit hyperactivity disorder, and narcolepsy. Management of amphetamine abuse is typically supportive therapy, as the withdrawal is self-limited and not hazardous. Antipsychotics can be used for extreme anxiety, as indicated. A twelve-step rehabilitation program is required for proper treatment.

6.9.7

Marijuana Abuse

The abuse of marijuana or hashish (cannabis) is common throughout the world. Intoxication causes euphoria, impaired judgment, poor concentration, and decreased memory. Side effects include permanent memory effects, permanent intellectual impairment, testicular degeneration, delirium, and psychosis. Marijuana is a commonly abused drug that leads to a number of side effects. Marijuana leads to a profound feeling of pleasure, but abuse can also lead to anxiety and delusions or hallucinations. One of the effects of abuse is the feeling that time has slowed. Marijuana leads to impaired judgment and withdrawal from society (â&#x20AC;&#x153;stonedâ&#x20AC;?). Appetite is increased and dry mouth with bronchitis are common physical symptoms. The effects of marijuana can best be summarized as follows: respiratory effects, amotivation, and increased risk of mental illnesses. Marijuana increases serotonin through the function of an inhibitory G protein. This is the mechanism by which a dreamlike state is created and gives the sensation that time has slowed. The vomiting that can occur with marijuana is best treated with dronabinol.

228

Psychopathology 6.9.8

Nicotine Abuse

Nicotine abuse leads to symptoms similar to caffeine abuse, including restlessness, difficulty sleeping, anxiety, and in severe cases, cardiac arrhythmias. Withdrawal from nicotine is similar to caffeinewithdrawal, including headaches, anxiety, and weight gain. Nicotine withdrawal also leads to a strong craving and elevated heart rate. Treatment for nicotine abuse is with bupropion, an antidepressant that reduces the craving for nicotine.

6.9.9

Caffeine Abuse

Caffeine abuse is common. Smaller doses of caffeine lead to restlessness and insomnia. Increasing doses can lead to a diuresis and muscle twitching. In susceptible individuals, potentially fatal cardiac arrhythmias can develop. Caffeine leads to an increase in cAMP release in neurons. Caffeine withdrawal is a common cause of headaches seen in a clinical setting. Withdrawal from caffeine also leads to fatigue, depression, and weight gain.

6.9.10

PCP Abuse

PCP (phencyclidine) abuse has been on the decline for sometime due to psychotic effects it induces in many individuals. PCP is one of the few drugs that lead to aggressive and belligerent behavior culminating in homicide or suicide. Individuals intoxicated with PCP tend to be very impulsive and act like they are “drunk”. There is a severe psychomotor anxiety, psychosis, and delirium. The activity of the autonomic nervous system is increased with elevated heart rate. Central nervous system symptoms of PCP abuse include ataxia, vertical and horizontal nystagmus, and fever. PCP withdrawal is unique in that it can lead to a repeat of the symptoms seen in PCP abuse. This occurs because the drug may be reabsorbed by the GI tract. This reabsorption over time can lead to episodes of sudden homicidal violence. Abuse is on the decline as people who abuse these drugs are more interested in the sense of euphoria than going to jail due to homicide.

6.9.11

LSD Abuse

LSD is different than PCP in that LSD breeds a cross tolerance with ecstasy and MDMA, but PCP does not. LSD abuse is like PCP abuse in that it leads to significant anxiety and delusions. LSD also causes profound visual hallucinations and flashbacks. Mydriasis is common. LSD is a partial postsynaptic serotonin agonist, and it is through this mechanism that flashbacks and synesthesias may occur. LSD can also lead to convulsions. There are no significant withdrawal symptoms of LSD. LSD abuse is similar to the effects of ecstasy and MDMA, but the latter two substances can induce a panic psychosis. Abuse is best treated with diazepam. MDMA leads to increased impulsiveness through destroyed serotonin receptors and can lead to memory gaps.

6.9.12

Ecstasy Abuse

Ecstasy is frequently abused in dance clubs, and has a stimulant and euphoric effect. Ecstasy, also known as MDMA, can enhance one’s desire for intimacy. Long-term effects include loss of serotonin axons in the brain. Methamphetamine is a powerful amphetamine that can lead to destruction of dopamine neurons.

229

Clinical Review for the USMLE Step 1 6.9.13

GHB Abuse

Gamma-hydroxybutyrate (GHB) is a steroid drug that promotes an increase in muscle mass; overdoses can cause highs, but can lead to death due to respiratory arrest. The abuse of anabolic steroids can lead to skin atrophy, acne, spontaneous bruising, hypokalemia, cardiomyopathy, osteoporosis, hypertension, diabetes, emotional lability and depression, gynecomastia, testicular atrophy, and alopecia. Abuse is especially common in body builders, and their negative effects occasionally make headlines due to sudden cardiac death in some athletes (not to be confused with idiopathic hypertrophic cardiomyopathy and Brugada syndrome, both of which belong on the differential diagnosis in this case).

6.9.14

Ketamine Abuse

Ketamine is a dissociative anesthetic that can cause hallucinations. Rohypnol is a benzodiazepine that can cause sedation and amnesia, and is frequently used by sexual predators.

7. Pharmacology 7.1. Cholinergic Agents 7.1.1 Cholinergics – Direct Agonists Table 21. Cholinergics – Direct Agonists Drug Bethanechol Pilocarpine

7.1.2

Indications Urinary retention Ileus Closed angle glaucoma

Mechanism of Action

Complications

Stimulates bladder and intestinal smooth muscle

Intestinal hypermotility

Ciliary muscle contraction, opening of meshwork, increased aqueous humor outflow

Miosis

Cholinergics – Indirect Agonists

Table 22. Cholinergics – Indirect Agonists Drug

Indications

Mechanism of Action

Edrophonium

Diagnosis of myasthenia gravis

Increase acetylcholine

Neostigmine

Ileus, urinary retention, myasthenia gravis, reverses NMJ blockade

Increase acetylcholine

7.1.3

Anticholinergics – Muscarinic Antagonists

Anticholinergics have been used for the treatment of iatrogenic Parkinsonism and iatrogenic dystonic reactions. Benztropine and trihexyphenidyl are the most commonly used anticholinergics. Diphenhydramine has also been used, although this particular drug is an antihistamine. Anticholinergics and diphenhydramine are muscarinic receptor antagonists. Side effects are generally excessive anticholinergic activity, such as urinary retention, constipation, blurry vision, sedation, and delirium in elderly.

230

Pharmacology Table 23. Anticholinergics – Muscarinic Antagonists Drug

Indications

Mechanism of Action

Complications

Pupillary dilation Decrease acid secretion in PUD Atropine

Decrease urinary urgency

Inhibits parasympathetic muscarinic receptor

Tachycardia, T, xerostomia, dry skin, mydriasis with cycloplegia, constipation

Inhibits vagally-mediated reflexes

Epistaxis, nasal irritation

Decrease GI motility Reduce airway secretions Ipratropium

Bronchodilator

Table 24. Anticholinergics – Nicotinic Antagonists Drug Succinylcholine

Atracurium

Indications Muscle paralysis Mechanical ventilation Muscle paralysis Mechanical ventilation

Mechanism of Action Rapid onset and short duration with decrease in excitatory potential below threshold. Initial stage with prolonged depolarization leading to fasciculations and muscle pain. Second stage with repolarization but blockade of receptors. Nicotinic receptor blockade. Nondepolarizing blockade can be reversed with neostigmine, edrophonium, and cholinesterase inhibitors.

7.2. Adrenergic Agents 7.2.1

Adrenergic Agonists – Catecholamines

Table 25. Adrenergic Agonists - Catecholamines Drug Dopamine Norepinephrine

Indications

Mechanism of Action

Shock with renal protection

D1, D2

CHF

β1

Shock

α1, α2, β1, β2

Complications Nausea, HTN, arrhythmia.

Open angle glaucoma Epinephrine

Acute asthma

α1, α2, β1, β2

Anaphylactic shock

Increases aqueous humor outflow

Mydriasis

Increase local anesthetic duration Isoproterenol

Bronchodilator Cardiac stimulant

β1, β2, α1

Dobutamine

CHF

β1

Milrinone

Increase cardiac contractility

Phosphodieserase inhibitor

Flushing, angina, arrhythmia

231

Clinical Review for the USMLE Step 1 7.2.2

Adrenergic Agonists – Non-Catecholamines

Table 26. Adrenergic Agonists – Non-Catecholamines Drug

Indications

Alpha-methyldopa

Mechanism of Action

HTN

CNS

Complications Sedation, hemolytic anemia, liver disorders

PTSD Clonidine

Opioid withdrawal

α2, CNS

ADHD, Tourette syndrome, HTN Asthma Ephedrine

Nasal decongestant

α, β

Urinary incontinence Bronchospasm

Albuterol

7.2.3

β2

Premature labor

Alpha Adrenergic Antagonists

Table 27. Alpha Adrenergic Antagonists Drug

Indications

Phenoxybenzamine

Pheochromocytoma Peripheral vascular disease

Mechanism of Action α1, α2

Terazosin

HTN, BPH

α1

Reserpine

Huntington’s disease

Blocks dopamine carrier

7.2.4

Complications Orthostatic hypotension Reflex tachycardia Orthostatic hypotension on first dose, dizziness, syncope, and HA

Beta Adrenergic Antagonists

Beta-blockers are used for the treatment of akathisia, performance anxiety, impulsivity, and lithiuminduced tremors. Beta-blockers alter catecholamine function by diminishing central nervous system arousal, tachycardia, tremor, diaphoresis, and hyperventilation. Side effects are excessive decrease in the sympathetic nervous system, and also masking of diabetes. Depression-like symptoms may also be present in overdose.

232

Pharmacology Table 28. Beta Adrenergic Antagonists Drug

Indications

Propranolol

Akathisia, HTN, angina, migraine, IHSS

HTN Angina pectoris

Metoprolol

Sedation, hyperlipidemia

β1, β2 β1

HTN

Complications

Sedation, hyperlipidemia

Pheochromocytoma and malignant HTN

SVT CHF

Labetalol

Mechanism of Action

Glaucoma

Also used for social phobia, akathisia, impulsivity, and performance anxiety through PNS inhibition.

Sedation

α1, β1, β2

7.3. Serotoninergic Agents Table 29. Serotoninergic Agents Drug Sumatriptan

Ondansetron

Indications Migraines Cluster headaches Treatment of N/V in chemotherapy

Mechanism of Action

Complications

Contraindications

5-HT1D agonist leading to acute vasoconstriction.

Distal paresthesia, ACS

CAD, variant (Prinzemetal) angina

5-HT3 receptor antagonist to reduce vagus nerve activity and reduce serotonin receptor activity in CTZ

Dizziness, generally rare

Hepatic disease (P450)

7.4. Toxicology Table 30. Toxicology. Toxic Agent

Presentation

Treatment

Acetaminophen

Fulminant hepatic failure and renal failure.

NAC

Amphetamine

Increased arousal and significant sympathomimetic effects. Mental status changes, dyskinesia, agitation, formication, chest pain, dry mouth, diarrhea, diaphoresis, HTN, and mydriasis .

Patient restraint and supportive therapy after protecting the airway. Activated charcoal and benzodiazepines can be used. Using neuroleptics to manage psychosis along with dantrolene to relax the skeletal muscles and avoid hyperthermia Phentolamine is used to reduce cardiac activity, and nitroglycerin is given to reduce pain.

Anticholinergics

Skin flushing, dry skin, mydriasis, and changes in mental status. Tachycardia, diminished bowel sounds, ileus, HTN, and myoclonus are also present. Both anticholinergics and certain antihistamines can exert these effects.

ACLS, naloxone, benzodiazepines, activated charcoal, IVF, and the antidote, and physostigmine salicylate are all given.

Antidepressant

TCAs lead to progressive decreases in CNS orientation and eventually coma. Seizures, hypotension, cardiac conduction abnormalities, hypoventilation, and various anticholinergic effects occur.

Treatment is sodium bicarbonate followed by IVF. Vasopressors may be used with severe hypotension. Activated charcoal is also used, along with epinephrine and benzodiazepines for seizure management.

Arsenic

Bloody diarrhea, vomiting, dehydration, QT prolongation, and hepatorenal damage.

Stabilize the patient and use BAL, DMSA, and DMPS.

233

Clinical Review for the USMLE Step 1

234

Barbiturate

Respiratory and cardiac depression and decreased CNS function. Mental status changes and psychiatric changes are common. Decreased bowel sounds are found on exam. Bullous lesions may also be present.

Treat with ABCs, IVF ,ET intubation, administer activated charcoal, and alkalinize the urine with sodium bicarbonate. As in many instances of toxic substance consumption, hemodialysis and exchange transfusions may be required in the most serious cases.

Benzodiazepine

Similar to that of barbiturate poisoning and may be worsened with concomitant ETOH abuse. Confusion, drowsiness, blurred vision, hallucinations, ataxia, hypotonia, amnesia, respiratory depression, and coma.

ABCs, O2, glucose, naloxone, flumazenil to deactivate the benzodiazepine, and activated charcoal.

Beta-Blocker

Arrhythmia, hypotension, bradycardia, renal failure, dilated cardiomyopathy, seizure, bronchospasm, and coma.

ABCs, IVF, gastric lavage, activated charcoal, hemodialysis, close cardiac management including pacing, and atropine, epinephrine, dopamine, and isoproterenol for hypotension are the standard of care. Glucagon, calcium chloride, magnesium sulfate, and insulin are also frequently used to maintain function.

Carbon Monoxide

Constitutional symptoms, lethargy, DOE, depression, incontinence, and changes in memory. Tachycardia, hyperthermia, tachypnea, cherry red skin, flame retinal hemorrhages with red retinal veins, and psychiatric manifestations are common on exam.

Nonrebreather masks with continuous 100% oxygen, intubation, and hyperbaric oxygen.

Caustic Agents

Strong acids or alkali leads to coagulation necrosis especially in the pharynx, esophagus, stomach, and SI. Presentation includes dyspnea, dysphagia, odynophagia, chest pain, abdominal pain, nausea and vomiting, airway obstruction, drooling, peritonitis, and hematemesis.

Diluting alkaline ingestions with water or milk is sometimes done. Emesis is contraindicated. Maintain the ABCs and attempt gastric lavage. Large volume liquid ingestion is often used. Do not use acids with base ingestions or vice versa to avoid heat production and additional damage. Antibiotics are necessary due to extensive tissue injury. Antihistamines are also administered to avoid esophageal damage from stomach acid.

Cocaine

Cardiac arrhythmia, MI, stroke, subarachnoid hemorrhage, malignant hyperthermia, and sudden death. Rhabdomyolysis can also occur. Numerous respiratory, cardiac, neurologic, gastrointestinal, and renal ailments may occur. Mesenteric ischemia is relatively common. CARO and psychiatric manifestations also occur, with significant constitutional symptoms in withdrawal. Systemwide depression is a sign of late stage intoxication.

ABCs, O2, IVF, naloxone, benzodiazepines for seizures, patient restraint, insulin and glucose, epinephrine with caution in cardiac arrest, beta-blockers, and pressor as necessary to avoid cardiovascular collapse. Polyethylene glycol and activated charcoal are also used. Give vitamin B1 before glucose.

Cyanide

A sense of impending doom, numerous constitutional symptoms, neurologic symptoms, SOB, nausea, vomiting, mydriasis, pulmonary edema, cardiac conduction changes, and coma are apparent. Carboxyhemoglobin is present along with methemoglobin.

ABCs, oxygen, sodium bicarbonate, antidotes to cyanide (sodium nitrite, sodium thiosulfate, and hydroxocobalamin), anticonvulsants, and vasopressors are used as indicated. Amyl nitrate is another antidote that is sometimes used.

Digitalis

Palpitations, syncope, dyspnea, CNS changes, yellow-green vision, photophobia, halos, scotomas, GI symptoms, and cardiac conduction changes are present. Toxicity may be the result of drug interactions (see text above).

Provide O2, IVF, and monitor for cardiac functioning. Activated charcoal and antibodies to digitalis are used. Repair any changes in electrolytes and use magnesium sulfate to maintain rhythm.

Ethylene Glycol

Kussmaul respirations due to the severe metabolic acidosis, altered mental status, and formation of oxalate crystals in the kidneys and throughout the body. Serum osmolal gap is present.

IVF, bicarbonate, pyridoxine, thiamine, and ethanol. 4-methylpyrazole (4-MP, also known as fomepizole) has also been used with benefit. Dialysis is also used

GHB

GHB, the date-rape drug, presents with CNS depression, seizure disorder, bradycardia, hypotension, and some hypothermia.

Supportive therapy and maintaining the airway. Gastric lavage is sometimes used. Atropine is used to treat the bradycardia.

Pharmacology Reassure the patient, sedate with benzodiazepines, and restraints are the initial steps. Haloperidol and benzodiazepines for psychosis, ventilatory assistance, and nitroglycerin for elevations in BP.

Hallucinogen

LSD, PCP, ketamine, mescaline, MDMA, and THC, among other psychoactive compounds, presents with hallucinations, psychosis, flashbacks, self-injurious behavior, agitation, abdominal symptoms, and diaphoresis.

Heavy Metals

Lead exposure leads to GI dysfunction, encephalopathy, seizures, and anemia. Arsenic toxicity presents similar to lead toxicity, but a syndrome similar to Guillain-BarrĂŠ syndrome may develop. Mercury toxicity presents with tremor, hematochezia, esophagitis, acrodynia, stomatitis, salivation, and gingivitis.

Lead toxicity is treated PEG, chelation therapy with edetate calcium disodium (EDTA), dimercaprol (BAL), and DMSA, and supportive therapy. Arsenic toxicity is treated with fluid rehydration, PEG, and chelation with BAL, DMSA, or penicillamine. Mercury toxicity is treated with activated charcoal and chelation therapy with BAL, DMSA, and penicillamine. Succimer is another chelating agent similar to BAL.

Iron

GI tract corrosion and subsequent diarrhea and hematemesis. Cell death also occurs and affects the heart, kidney, and lung. Metabolic acidosis and hyperglycemia is common. Coagulopathy can develop with sufficient toxicity along with hepatic dysfunction and hypoglycemia.

Iron toxicity is treated with IVF, O2, and chelation with deferoxamine.

MDMA

Increased activity of the SNS leading to HTN, hyperthermia, and tachycardia. Serotonin syndrome may also develop leading to further breakdown in thermoregulation and rhabdomyolysis. DIC and hepatotoxicity may occur. Hyponatremia also occurs, leading to seizures. Long term psychiatric dysfunction also occurs.

Symptomatic and supportive management to avoid the lethal sequelae of toxicity. Thiamine and glucose are given as necessary. Benzodiazepines are used for seizure control and fluids given to minimize the effects of rhabdomyolysis. Icing the patient helps reduce the very high temperatures that can develop.

Narcotics

Abuse presents as depression of the CNS and respiratory centers, miosis, euphoria, and seizures. Cardiac dysfunction may occur along with orthostatic hypotension.

Naloxone and restraints. Methadone, atropine, and various fentanyl derivatives may be necessary for refractory intoxication. Activated charcoal is also useful.

NSAID

Changes in respiration, S3 gallop, water retention with HTN, mental status changes, tremors, seizures, ulcers, hepatorenal failure, and general malaise.

Salicylate

Significant catabolism leading to metabolic acidosis, respiratory alkalosis, aciduria, delirium, respiratory arrest, aspiration pneumonitis, ototoxicity with tinnitus or deafness, hypotension, U waves and flat T waves with a QT prolongation, CNS depression, GI distress, renal failure, diaphoresis, and dehydration.

ABCs, activated charcoal, hemodialysis, and supportive therapy.

Treated in a manner similar to other types of poisoning. Urine alkalization may be done with sodium bicarbonate. Hemodialysis is the best method of reducing toxic levels of salicylates.

235

Clinical Review for the USMLE Step 1

7.5. Anticonvulsants Table 31. Anticonvulsants Drug

Indications

Carbamazepine Ethosuximide

Mechanism of Action

Partial seizures Tonic-clonic seizures

Blocks post tetanic potentiation

Absence seizures

Sedation, ataxia

Tonic-clonic seizures Partial seizures

Lamotrigine

Diplopia, aplastic anemia, hepatotoxicity, P-450 induction GI Sx, urticaria, SJS

Partial seizures

Gabapentin

Complications

Rash, SJS

Tonic-clonic seizures Partial seizures

Phenobarbital

Tonic-clonic seizures

Sedation, P-450 induction

Status seizures Partial seizures Phenytoin

Tonic-clonic seizures

Blocks sodium channels

Nystagmus, diplopia, ataxia, gingival hyperplasia, hirsutism, anemia, teratogenic, malignant hyperthermia

Status epilepticus Topiramate

Partial seizures

Sedation, nephrolithiasis, weight loss

Partial seizures Valproate

Tonic-clonic

GI Sx, hepatotoxicity, NTDs, alopecia, tremor, pancreatitis

Absence Myoclonic

7.6. Cognitive Agents Donepezil and tacrine have been used for memory loss in Alzheimer disease. These medications reversibly inhibit acetylcholinesterase (AChE) and supplement the loss of cholinergic neurons in Alzheimer disease. Side effects include gastrointestinal upset, bradycardia, and increased gastric acid secretion. Tacrine has been shown to increase liver function enzymes.

7.6.1

Alzheimer Disease

Table 32. Alzheimer Disease Drug

236

Indications

Mechanism of Action

Complications

Contraindications

Donepezil

Alzheimer disease

Inhibits AChe

Used to minimize memory loss

Hypersensitivity.

Tacrine

Alzheimer disease

Inhibits AChe

Used to minimize memory loss

Hypersensitivity, asthma, â&#x2020;&#x2018;LFTs, GI disease, CV disease.

Pharmacology 7.6.2

Parkinson Disease

Table 33. Parkinson Disease Drug Amantidine Levodopa Carbidopa Selegiline

Indications PD

Mechanism of Action

Dyskinesia

PD PD PD

Complications

Enhances dopamine release

Suicide

Replaces dopamine

Arrhythmia

Inhibits dopamine decarboxylase in periphery

Dyskinesia

Decreases conversion of dopamine to norepinephrine

Nausea, dizziness

Enhances levodopa effects

7.7. Anesthetics 7.7.1 Anesthetics – Inhaled Table 34. Anesthetics - Inhaled Drug

Indications

Complications

Notes

Sevoflurane

Anesthesia

Bradycardia, respiratory depression, increased ICP

Rapid onset

Nitrous oxide

Anesthesia

Minimal

Lowest potency, combined with other agents

Desflurane

Anesthesia

Airway irritation, coughing, respiratory depression, increased ICP

Most rapid onset

7.7.2

Anesthetics – Intravenous

Table 35. Anesthetics - Intravenous Drug

Indications

Midazolam

Endoscopy

Ketamine

Short procedures

Propofol

Short procedures

Etomidate

Mechanism of Action

Dissociative anesthetic

Amnesia, sedation.

Complications

Notes

Respiratory depression, amnesia

Benzodiazepine; reverse w/ flumazenil

↑CV, hallucinations, ↑ICP

Arylcyclohexylamine

Hypotension

No cumulative effects, strict aseptic technique must be maintained.

Uncontrolled skeletal muscle activity

237

Clinical Review for the USMLE Step 1 7.7.3

Anesthetics – Local

Table 36. Anesthetics - Local Drug

Indications

Complications

Procaine

Local anesthesia

CNS stimulation, CV stimulation, HTN

Lidocaine

Local anesthesia

CNS stimulation, HTN

Bupivacaine

Local anesthesia

CV toxicity

Notes Greater amounts needed in infected tissue (acidic tissue) Smaller fibers affected first, so pain is lost first, then T, touch, and finally P Give with epinephrine to increase local effects No allergic cross reactivity between esters & amides. Long duration.

7.8. Analgesics 7.8.1

Analgesics – Opioid

Table 37. Analgesics - Opioid Drug

Indications

Mechanism of Action

Morphine

Analgesia

Mu opioid agonists

Fentanyl

Analgesia

Dextromethorphan

Cough suppression

Net effect is change in neural activity along various pathways, especially pain pathways

7.8.2

Complications Substance abuse and dependence, respiratory depression, miosis, CNS depression, constipation

Analgesics – NSAIDS

Table 38. Analgesics - NSAIDs Drug

Indications

Mechanism

Complications

Reversible inhibition of COX-1 and COX-2

Nephrotoxicity, aplastic anemia, PUD

PUD. Renal patients

Reversible inhibition of COX-1 and COX-2

Nephrotoxicity, aplastic anemia, PUD

PUD. Renal patients

Antipyretic

Reversible inhibition of COX in CNS

Hepatic necrosis in OD, glutathione depletion

Hepatitis.

RA, OA

COX-2 inhibition

Avoids PUD. Nephrotoxic. Possible stroke.

PUD. Renal patients.

Irreversible COX1 and COX-2 inhibition inhibits prostaglandin formation

PUD, Reye syndrome, tinnitus, reflex acidosis from reflex hypoventilation due to initial hyperventilation (late stage poisoning)

ETOH, do NOT use in children especially with VZV or influenza infection

Analgesia Naproxen

Anti-inflammatory Antipyretic Analgesia

Indomethacin

Anti-inflammatory Antipyretic

Acetaminophen

Rofecoxib

Analgesic

Analgesic Aspirin

Antipyretic Anti-inflammatory Antiplatelet aggregation

238

Contraindications

Pharmacology 7.8.3

Muscle Relaxants

Drug

Indications

Cyclobenzaprine

Muscle relaxant

Methocarbamol

Muscle relaxant

Metaxalone

Muscle relaxant

Baclofen

Muscle relaxant

Carisoprodol

Muscle relaxant

Mechanism Locus ceruleus

Complications

Contraindications

Myocardial infarction, arrhythmia

Heart disease

Seizures, syncope, bradycardia

Seizures

CNS depression

Leukopenia, hemolytic anemia

Anemia

GABAB agonist

Respiratory depression, ataxia Erythema multiforme, seizures

7.9. Antipsychotics Table 39. Antipsychotic Medications Typical

Atypical

Haloperidol

Risperidone

Fluphenazine

Ziprasidone

Perphenazine

Aripiprazole

Trifluoperazine

Olanzapine

Thioridazine

Clozapine

Chlorpromazine

Quetiapine Clozaril

7.9.1 Indications Antipsychotic medications have a number of uses in treating various types of psychiatric illness. Typical antipsychotics, also known as neuroleptics, and atypical antipsychotics are the two major classes of antipsychotics. Antipsychotics are the drugs of choice for the treatment of psychotic symptoms such as hallucinations, delusions, and bizarre behavior. These psychotic symptoms can belong to any category of psychiatric illness so long as they are positive symptoms. Antipsychotics are generally less effective in treating negative symptoms such as amotivation, akinesia, isolation, and blunting of affect with the exception of clozapine. Antipsychotics have also been used in the treatment of various types of behavioral dysregulation as that seen in Alzheimerâ&#x20AC;&#x2122;s, mental retardation, Tourette syndrome, and in patients with personality disorders.

7.9.2

Mechanism of Action

Antipsychotics are thought to act via a dopaminergic pathway, as that explained previously with regard to the dopamine hypothesis of schizophrenia. According to this hypothesis, antipsychotics block the dopamine 2 (D2) receptor, leading to a decrease in dopamine-mediated positive symptoms of psychosis. This is consistent with the dopamine hypothesis of schizophrenia, which states that the positive symptoms of schizophrenia are due in part to an excessive number of dopamine receptors leading to heightened stimulation of dopamine pathways. This theory is supported by the induction of psychosis with dopamine agonists such as amphetamines. Blockade of the dopamine pathways occurs in the ventral tegmental area and substantia nigra, both of 239

Clinical Review for the USMLE Step 1 which project to the basal ganglia, frontal cortex, and limbic regions of the brain. Reduction of the psychotic symptoms is thought to occur by the blockade in the cortical and limbic regions. However, the notable side effect of extrapyramidal symptoms (EPS) is thought to occur to unintentional blockade of D2 receptors in the basal ganglia.

7.9.3

Side Effects

Antipsychotics have a number of side effects related to their additional, still incompletely characterized functions elsewhere in the brain. Other antipsychotics, especially the atypical antipsychotics, have been found to work through a mechanism in addition to the dopamine blockade. Newer medications have the additional effect of blockading serotonin 5-hydroxytryptamine-2 (5HT2) receptors. Atypical antipsychotics are categorized as such based on their fewer extrapyramidal side effects, and their putative function through 5HT2 blockade. It is thought that blockade of these serotinergic pathways has a protective effect against extrapyramidal symptoms and even contribute to their antipsychotic effects. Of the atypical antipsychotics, risperidone is an example of a medication that preferentially blocks the D2 receptors. Clozapine, on the other hand, is an example of an atypical antipsychotic that primarily blocks the D4 receptor.

7.9.4

Therapy and Drug Reactions

Typical Antipsychotics The typical antipsychotics are thioridazine, chlorpromazine, perphenazine, trifluoperazine, thiothixene, haloperidol, and fluphenazine. Haloperidol and fluphenazine are the most potent of the typical antipsychotics, while thioridazine and chlorpromazine are the least efficacious. Thioridazine and chlorpromazine are highly sedating, while haloperidol and thiothixene are the least sedating. Thioridazine and chlorpromazine cause orthostatic hypotension, while the other drugs have a lower incidence of this. Thioridazine is highly anticholinergic. EPS symptoms are least prevalent with thioridazine and chlorpromazine. Thioridazine also causes a retinopathy and fatal cardiac events, and so is used only for schizophrenia refractory to other medications. A prevalence of anticholinergic effects can be partially reversed with the peripherally acting cholinergic stimulant bethanechol. Table 40. Antipsychotics â&#x20AC;&#x201C; Typical Drug

Indications

Complications

Contraindications

Chlorpromazine

Schizophrenia

TD, NMS, Schizophrenia

Coma, CNS depressants, pregnancy.

Fluphenazine

Schizophrenia

May obscure Reye syndrome, vomiting.

Coma, CNS, BMS, high extrapyramidal toxicity

TD, NMS. Care with lithium.

Coma, CNS depression, Parkinson.

TD, NMS. Heart disease.

Coma, CNS depression.

Schizophrenia Haloperidol

Delirium Tourette disorder

Thioridazine

Schizophrenia

Atypical Antipsychotics The atypical antipsychotics include clozapine, quetiapine, ziprasidone, aripiprazole, olanzapine, and risperidone. Risperidone is the most potent, while quetiapine and clozapine are the least potent. Clozapine and quetiapine are highly sedating, and also cause orthostatic hypotension. Risperidone also causes 240

Pharmacology orthostatic hypotension. Clozapine has anticholinergic effects, while risperidone has few anticholinergic events. All of the atypical antipsychotics rarely cause EPS. Clozapine is noted for causing an agranulocytosis and also myocarditis. Ziprasidone causes prolongation of the QT interval. Risperidone has also been known to cause hyperprolactinemia, which can lead to a decreased sex drive and amenorrhea. Table 41. Antipsychotics - Atypical Drug

Indications

Mechanism

Complications

Clozapine

Schizophrenia

Dopamine antagonist

Agranulocytosis, BMS.

Quetiapine

Schizophrenia

Antagonist at multiple sites

TD, NMS

Risperidone

Schizophrenia

Dopamine and serotonin antagonist

NMS, TD, hyperglycemia

7.9.5

Contraindications MPD, epilepsy, CNS depression, BMS.

Choice of Medication

All antipsychotics are considered to be highly effective in the management of positive symptoms of psychosis. The choice of medication should be based on prior responses, known side effects and the ability of the patient to tolerate them, and whether the form of the medication is suitable for the patient. Of all the antipsychotic medications, clozapine is an effective choice when the other antipsychotics have minimal effect on the psychosis. Clozapine is an ideal candidate for psychiatric illnesses with positive psychotic features that are refractory to other medical treatment as this medication works primarily through blockade of D4 receptors instead of D2 receptors. In patients who require intramuscular (IM) injections of drugs, haloperidol and fluphenazine are suitable candidates. Table 42. Specific Side Effects of Atypical Antipsychotic Medications Drug

Side Effects

Clozapine

Lowering seizure threshold, in addition to its lethal side effect of agranulocytosis, EKG changes, hyperlipidemia

Olanzapine

EKG changes, weight gain, hyperlipidemia

Quetiapine

Cataract formation

Risperidone

Hyperprolactinemia, decreased sex drive, amenorrhea

The administration of antipsychotics requires careful and close monitoring of patients for a number of side effects. The most serious neurologic drug reactions can lead to neuroleptic malignant syndrome (NMS), extrapyramidal symptoms (EPS), and akathisia or restlessness. Patients on clozapine need to be monitored for agranulocytosis by having weekly white blood cell (WBC) counts. Generally, monitoring serum levels of these antipsychotics has little value due to their numerous metabolites. Haloperidol and clozapine are the only exceptions to this rule. The low-potency antipsychotics are noted for having the worst anticholinergic effects, including dry mouth, blurred vision, constipation, and urinary retention. However, these low-potency drugs with the elevated anticholinergic effects counter the extrapyramidal symptoms seen with antipsychotics. The elderly, patients with organic brain disease, and patients on other anticholinergic medications may experience delirium. The low-potency antipsychotics are also notable for lowering the seizure threshold. Clozapine is also noted for lowering this seizure threshold, in addition to its lethal side effect of agranulocytosis. Orthostatic hypotension is common with the low-potency antipsychotics, in addition to risperidone. This orthostatic hypotension is primarily due to blockade of alpha-receptors. 241

Clinical Review for the USMLE Step 1 Cardiac side effects are found with the low-potency antipsychotics, especially thioridazine, ziprasidone, and risperidone. These side effects primarily manifest as long QT syndrome with the risk of torsade de pointes. Clozapine and olanzapine can also lead to EKG changes. Metabolic effects such as weight gain and the onset of diabetes are noted drug reactions of olanzapine and clozapine. Hyperlipidemia is also a noted side effect of olanzapine and clozapine. Pigmentation of the skin and eyes can occur with the typical antipsychotics. Thioridazine is especially noted for causing increased pigmentation of the retina at high doses. Quetiapine may lead to increased cataract formation. Ziprasidone is weight neutral.

7.10. Antidepressants Table 43. Antidepressant Medications SSRIs

TCAs

MAOIs

Fluoxetine

Nortriptyline

Tranylcypromine

Sertraline

Imipramine

Phenelzine

Paroxetine

Desipramine

Fluvoxamine

Clomipramine

Citalopram Escitalopram

7.10.1

Indication

Antidepressants are potent drugs used to treat symptoms of major depression, anxiety disorders, obsessive-compulsive disorder, and other conditions. Antidepressants are divided into SSRIs, TCAs, MAOIs, and miscellaneous compounds with similar effects. All of the antidepressants can be used for the treatment of major depression and dysthymia. In addition, all of these medications, in addition to high doses of benzodiazepines, can be used to treat panic disorder. OCD responds well to clomipramine and to high doses of SSRIs. Obsessions in particular respond well, although as long as three months of therapy may be required in order to evaluate the medication. Further, purging bulimia nervosa is amenable to treatment by any of the antidepressants, especially SSRIs due to their fewer side effects.

7.10.2

Mechanism of Action

Antidepressants work chiefly through effects on monoamine neurotransmitters such as serotonin, norepinephrine, and dopamine. Dopamine is released by the ventral brainstem, norepinephrine by the locus ceruleus, and serotonin by the raphe nuclei. SSRIs function by inhibiting reuptake of serotonin, thereby increasing the length of time serotonin is present in the synaptic cleft. This leads to a potentiation of the serotinergic pathway. TCAs block reuptake of serotonin and norepinephrine. MAOIs block monoamine oxidase, the enzyme that breaks down each of the monoamine neurotransmitters, thereby leading to elevated levels of norepinephrine, dopamine, and serotonin. Each of these classes of medications also has long-term effects that are presently under investigation.

7.10.3

Therapy and Drug Reactions

The SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram. The TCAs include nortriptyline, imipramine, desipramine, and clomipramine. The MAOIs include tranylcypromine and phenelzine. Other antidepressants include bupropion, nefazodone, venlafaxine, mir242

Pharmacology tazapine, and trazodone. Table 44. Antidepressants - SSRIs Drug

Indications

Mechanism

Citalopram

Major depression

Selective serotonin reuptake inhibitor

Fluoxetine

Major depression

Selective serotonin reuptake inhibitor

Sertraline

Major depression

Selective serotonin reuptake inhibitor

Complications

Contraindications Avoid in patients taking MAOIs

CNS stimulation, anorexia, N/V, insomnia, sexual dysfunction, and serotonin syndrome with MAOI

Avoid in patients taking MAOIs Avoid in patients taking MAOIs and disulfiram

Table 45. Antidepressants - TCAs Drug

Indications

Mechanism

Complications

Contraindications

OCD

Clomipramine

Avoid in patients taking MAOIs

Major depression Enuresis

Imipramine

Cataplexy Major depression

Nortriptyline

Block NE and serotonin reuptake

Convulsions, CV toxicity, coma, CNS depression, hallucinations in elderly (anticholinergic effect), hyperthermia

Avoid in patients taking MAOIs, renal or hepatic failure, or after MI Avoid in patients taking MAOIs, or after MI. Avoid in children and pregnant women.

Major depression

Table 46. Antidepressants - MAOIs Drug

Indications

Phenelzine

Major depression

Tranylcypromine

Major depression

Mechanism

MAOA and MAOB inhibition with increase in NE and catecholamines

Complications

Hypertensive crisis with tyramine or meperidine, CNS stimulation, hepatotoxicity, postural hypotension

Contraindications Avoid in CHF, liver disease, with tyramine, with dopamine, with amphetamines, with guanethidine, and in pheochromocytoma Avoid with alcohol, amphetamines, antihypertensives, diuretics, cheese, tyramine

Table 47. Antidepressants - Atypical Drug Bupropion Trazodone Venlafaxine

Indications Nicotine addiction

Mechanism

Complications

Contraindications

Unknown

CNS and CV stimulation, xerostomia, worsening of psychosis.

Seizure disorder, MAOI

Major depression

Inhibits serotonin reuptake.

Priapism, sedation, postural hypotension.

Major depression

Inhibits serotonin and dopamine reuptake.

Anxiety, insomnia.

MAOI, HTN. Monitor BP.

ADHD, depression.

GAD

243

Clinical Review for the USMLE Step 1 First Line Medications The first line of medications that should be used for the treatment of depression should include venlafaxine and TCAs in order to cause remission of the depression. These medications are the drugs of choice due to their effect on the noradrenergic and serotinergic systems. A combination of bupropion and SSRIs may also be used to obtain this effect. The best-tolerated medications include venlafaxine, bupropion, mirtazapine, nefazodone, and SSRIs, which are primarily considered to be the first line medications for the treatment of major depression. These medications have fewer side effects such as orthostatic hypotension, anticholinergic effects, and sedation. Patients with cardiac conduction abnormalities, along with any condition that may be worsened with anticholinergic stimulation (such as glaucoma, prostatic hypertrophy, or constipation) should be initially started on venlafaxine, bupropion, mirtazapine, nefazodone, or SSRIs. SSRIs are typically the best choice in patients with cerebrovascular or cardiovascular defects.

Second Line Medications The next line of medications is the TCAs, of which nortriptyline and desipramine have the least side effects. TCAs can be used as first line agents in younger patients, especially if cost is an issue. MAOIs should be used selectively due to the dietary restrictions and risk of orthostatic hypotension. They are the drugs of choice in patients who have failed other therapies, or in patients who have a seizure disorder â&#x20AC;&#x201C; in such patients, both MAOIs and SSRIs can be used, as they do not affect the seizure threshold. Patients with atypical depression or social phobias respond best to MAOIs or SSRIs. Finally, high dose SSRIs, especially fluvoxamine and the TCA clomipramine are the drugs of choice for the treatment of OCD.

Atypical Antidepressants (Third Line) Approximately half of all patients with major depression will respond after six weeks of use of a single antidepressant medication. Therapy should continue for at least six months, with recurrent or chronic major depression treated on a lifelong basis as needed. Depression refractory to standard treatment can be treated with increasing doses of medications, adding lithium or T3, adding a psychostimulant such as methylphenidate, changing the medication, adding a second medication, or using ECT. Patients on TCAs require serum level monitoring to determine proper dosing regimens. An antidepressant such as bupropion may be appropriate in patients presenting with depression and a history of childhood ADHD.

244

Pharmacology 7.10.4

Side Effects

SSRIs and MAOIs Table 48. Side Effects of SSRI, MAOI, and TCA Therapy SSRI Therapy Nausea

Headache

Akathisia

Insomnia

Sedation

Lack of orgasm or ejaculation

Cannot be combined with MAOIs due to development of fatal serotonin syndrome

MAOI Therapy Hyperadrenergic crisis due to excessive tyramine ingestion Severe hypertension with subsequent myocardial infarction or stroke, Dose-related orthostatic hypotension Certain foods containing tyramine must be avoided Over-the-counter medications must also be avoided, especially pain and cold medicines Tranylcypromine can cause insomnia and agitation Phenelzine can cause daytime sleepiness

TCA Therapy Orthostatic hypotension Anticholinergic effects including constipation, dry mouth, blurred vision, difficulty urinating, hallucinations, seizures, akathisia, agitation, delirium, sexual dysfunction, cardiac toxicity, sinus & ventricular tachycardia, arrhythmias

Side effects of SSRIs include nausea, headache, akathisia, insomnia or sedation, and lack of orgasm and ejaculation. SSRIs cannot be combined with MAOIs due to the development of a fatal serotonin syndrome. Side effects of MAOIs include hyperadrenergic crisis from excessive tyramine ingestion, severe hypertension with subsequent myocardial infarction or stroke, and a dose-related orthostatic hypotension. Certain foods containing tyramine must be avoided when on MAOIs, including cured meats, fish, beer, red wine, and all types of cheese except cream cheese and cottage cheese, and overripe fruits. Over-the-counter medications must also be avoided, especially pain and cold medicines. The development of malignant hypertension can be treated with intravenous phentolamine, an alpha blocker, or nitroprusside infusion. The MAOI tranylcypromine can cause insomnia and agitation, while phenelzine can cause daytime sleepiness.

TCAs TCAs can cause orthostatic hypotension, anticholinergic effects, and sexual dysfunction. Cardiac toxicity can also occur. Elderly patients in particular are susceptible to the orthostatic hypotension that can occur. The anticholinergic effects appear to be centered on constipation, dry mouth, blurred vision, and difficulty with urination. More severe effects include hallucinations, seizures, akathisia, agitation, and delirium. Sinus tachycardia, ventricular tachycardia, ventricular fibrillation, and other arrhythmias are all possible with TCAs, and these medications should be avoided in patients with notable heart disease. Sexual dysfunction centers on impotence in males and decreased arousal in women. The major side effects of TCAs can be remembered with the mnemonic Tri-Câ&#x20AC;&#x2122;s, i.e. convulsions, cardiac arrhythmias, and coma.

245

Clinical Review for the USMLE Step 1 Atypical Antidepressants Venlafaxine is a serotonin and noradrenergic reuptake inhibitor often used for the treatment and induction of remission of major depression. Venlafaxine has fewer side effects than other antidepressants, and is a good first line agent. Trazodone is often given with an SSRI to induce sleep. A side effect of trazodone is priapism. Nefazodone has less sedation and a smaller incidence of priapism.

Other Antidepressants Buproprion is effective in smoking cessation and in ADHD, but can lower the seizure threshold. Mirtazapine is highly sedating. Table 49. Side Effects of Atypical Antidepressants Trazodone

Priapism

Buproprion

Can lower the seizure threshold

Mirtazapine

Highly sedating

7.10.5

Phototherapy

The use of bright lights to treat seasonal major depression is highly effective. Phototherapy is also useful in delayed sleep phase syndromes, with early morning bright light therapy more effective than evening light. Phototherapy has been known to induce mania in certain individuals.

7.10.6

Electroconvulsive Therapy

ECT is a highly effective treatment for major depression refractory to other medications. Anesthetics and paralytics are used to block memory formation and minimize the motor component of seizure activity during ECT sessions. Side effects include temporary short-term memory loss and confusion. Bilateral ECT is more effective than unilateral therapy, but has more side efďťżfects.

7.11. Mood Stabilizers 7.11.1

Indications

Mood stabilizers include lithium, valproate, and carbamazepine. Calcium-channel blockers, benzodiazepines, and antipsychotics have also been used to manage bipolar disorder refractory to other treatment. Mood stabilizers are the drugs of choice for mania. They are used for long-term maintenance of bipolar disorder. Valproate and carbamazepine are also used in patients with a seizure component. Impulsive behaviors can also be controlled with the mood stabilizers. The latter two medications are especially effective in managing rapid cyclers. Lithium can be used to further augment antidepressant medications.

246

Pharmacology Table 50. Mood stabilizers - Typical Drug

Indications

Carbamazepine

Lithium carbonate

Valproate

Bipolar I disorder Major depression Bipolar I disorder Bipolar I disorder

Mechanism of Action

Complications

Blocks Na+ channels to reduce NT release

Agranulocytosis.

Modifies cAMP and G-proteins to affect serotonin, norepinephrine, and GABA metabolism. Increases GABA synthesis, decreases GABA metabolism

Contraindications BMS, hypersensitivity to TCAs or MAOIs, pregnancy, hematologic reactions. Renal disease, CV disease, pregnancy, young children.

Hepatotoxicity, pancreatitis, somnolence, TCP.

Hepatic disease.

Table 51. Mood Stabilizers - Atypical Drug Lamotrigine

7.11.2

Indications Bipolar I disorder, Some childhood disorders Partial seizures

Mechanism of Action Sodium ion channels

Complications Rash, SJS, multiorgan failure.

Mechanisms of Action

The Mechanism of Action of lithium is through modification of cyclic adenosine monophosphate (cAMP) and G-proteins. Lithium works as an ion and travels through certain ion channels. Through these effects, lithium is known to affect serotonin, norepinephrine (both through G-protein mediated effects) and GABA metabolism. Valproate functions by supplementing the role of GABA through increased GABA synthesis, decreased breakdown of GABA, and increased potentiation at the synapse. Carbamazepine functions by blocking sodium channels following depolarization, thereby preventing repolarization of the neuron and aborting future synaptic potentials. Carbamazepine also reduces the release of neurotransmitter into the synaptic cleft, thereby preventing the firing of the postsynaptic neuron.

7.11.3

Lithium

Indications Lithium is the first line treatment as a mood stabilizer for bipolar disorder that does not rapidly cycle. Lithium may be used in any patient who does not have a compromise of their renal function, as it can quickly reach toxic levels if it is not readily cleared. Lithium is also used as an adjunct to antidepressant treatment in major depression. The use of lithium requires frequent monitoring, and also regular blood tests to monitor thyroid stimulating hormone (TSH), creatinine, and other thyroid and renal function tests.

247

Clinical Review for the USMLE Step 1 Table 52. Therapy Using Mood Stabilizer Medications Drug

Indication

Lithium

First line of treatment for bipolar treatment that doesnâ&#x20AC;&#x2122;t rapidly cycle

Valproate

Drug of choice for bipolar rapid cyclers; can control impulsivity with carbamazepine

Carbamazepine

Second line medication for mania

Lamotrigine

Mood stabilizer and antidepressant

Gabapentin

Inhibits seizure disorders, mood stabilizer, and anxiolytic for bipolar disorder. Cannot be used alone

Side Effects The side effects of lithium include tremor, gastrointestinal upset, polyuria, some deficits in memory, worsening of acne, and increase in weight. Thyroid function tests must be regularly conducted as lithium interferes with hormone production, leading to hypothyroidism. As lithium has a narrow therapeutic index, it must be regularly monitored to ensure that it does not rise to toxic levels. It is for this reason that lithium is contraindicated in patients with renal disease. If lithium rises to toxic levels, its side effects can lead to ataxia, confusion, sinus arrest, coma, and death.

7.11.4

Valproate

Indications Valproate is used for bipolar disorder, and as maintenance. Valproate is the drug of choice for rapid cyclers and for mixed bipolar disorder. It has little function against depression or the depressive elements of bipolar disorder. Valproate is used along with carbamazepine to control impulsivity.

Side Effects Side effects of valproate are many, with the most serious being thrombocytopenia, impaired platelet activity, fulminant hepatic or pancreatic failure, and agranulocytosis. Other side effects are similar to lithium, with tremor, gastrointestinal distress, and some sedation.

7.11.5

Carbamazepine

Carbamazepine is a second-line medication for mania. It is often used to treat acute mania and is effective in rapid cyclers and mixed forms of mania. Side effects include those similar to lithium, also nausea, rash, and leucopenia. Toxic doses can lead to depression of the respiratory system, heart block, autonomic dysfunction, and coma. Carbamazepine has also been known to cause agranulocytosis, pancytopenia, and occasionally, aplastic anemia. Carbamazepine levels must be regularly monitored.

7.11.6

Lamotrigine

Lamotrigine is a mood stabilizer originally used as an anticonvulsant. Lamotrigine inhibits sodium channels and thereby stabilizes neuronal membranes. Lamotrigine functions as both a mood stabilizer and antidepressant, and is a good drug to use after a patient fails with the traditional mood stabilizers (lithium, valproate, and carbamazepine). Lamotrigine can cause Stevens-Johnson syndrome, so its dosage should be gradually increased. Physicians should also watch for ataxia, blurred vision, dizziness, nausea and vomiting, and rash. 248

Pharmacology 7.11.7

Gabapentin

Gabapentin has been used to inhibit seizure disorders and functions as a mood stabilizer and anxiolytic for bipolar disorder. Gabapentin cannot be used alone, but is a good adjunct with the traditional mood stabilizers.

7.12. Anxiolytics 7.12.1

Indications

Benzodiazepines are the primary treatment for anxiety disorders and for anxiety features of other psychiatric disorders. Benzodiazepines have also been used for the short-term treatment of insomnia, alcohol withdrawal, mania, catatonia, and dementia. Buspirone is a non-benzodiazepine that has been used for the treatment of generalized anxiety disorder. Alprazolam and clonazepam are high-potency benzodiazepines used for the treatment of panic disorder. Alprazolam, clonazepam, diazepam, and lorazepam are indicated for the treatment of anxiety. Alcohol detoxification can be conducted by chlordiazepoxide and oxazepam. Insomnia is best treated with flurazepam, triazolam, diazepam, and temazepam. Finally, catatonia can be treated by lorazepam. Table 53. Anxiolytics - Typical Drug

Indications

Mechanism of Action

Complications

Anxiety disorder

Alprazolam

Seizure

Panic disorder

Chlordiazepoxide

GABAA receptor agonist that leads to increased frequency of chloride channel opening to decrease synaptic activity

DTs

CNS depressant.

Anxiety disorder

Table 54. Anxiolytics - Atypical Drug Buspirone

Zolpidem

Indications

Mechanism of Action

Complications

Notes

GAD

5HT1A and D2 antagoCNS depressant. Anxiety disorder nist Anxiolytic

NIghtmares, headache, GI Sx, dizziness,

Low addiction potential. No interaction with ETOH. No rebound insomnia. No tolerance with use. No anticonvulsant or muscle-relaxing properties.

Table 55. Barbiturates Drug

Indications Anxiolytic

Phenobarbital

Hypnotic Sedative

Mechanism of Action

Complications

Notes

Induce tolerance Facilitates GABAA and increase length of chloride channel opening to decrease neuronal firing

Low therapeutic index Respiratory depression

Severe withdrawal

Rarely used

249

Clinical Review for the USMLE Step 1 7.12.2

Mechanisms of Action

Benzodiazepines function as an agonist to GABA-A receptors through a chloride ion channel-mediated effect and have immediate action. On the other hand, buspirone functions through positive serotonergic effects at the 5HT1A receptor and through D2 receptor antagonism. Buspirone is slow in onset and is useful only for the treatment of generalized anxiety disorder.

7.12.3

Therapy and Drug Reactions

The benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, diazepam, flurazepam, lorazepam, oxazepam, temazepam, and triazolam. The high-potency benzodiazepines include alprazolam, clonazepam, triazolam, and also lorazepam. The fastest onset is with diazepam, flurazepam, and triazolam. The slowest onset is with oxazepam. Metabolism of all the benzodiazepines is through oxidation except for lorazepam, oxazepam, and temazepam, which are metabolized through conjugation. Alprazolam, chlordiazepoxide, diazepam, flurazepam, and triazolam all have active metabolites. Table 56. Therapy Using Benzodiazepines High potency

Alprazolam, clonazepam, triazolam, temazepam

Fastest onset

Diazepam, flurazepam, triazolam

Slowest onset

Oxazepam

Panic disorder

Alprazolam, clonazepam

Anxiety

Alprazolam, clonazepam, diazepam, lorazepam

Alcohol detoxification

Chlordiazepoxide, oxazepam

Insomnia

Flurazepam, triazolam, diazepam, temazepam

Catatonia

Lorazepam

Benzodiazepines with a rapid rate of onset can lead to â&#x20AC;&#x153;highsâ&#x20AC;? and are more addictive. The benzodiazepines that are metabolized through oxidation require a highly functioning liver and the presence of cirrhosis or other liver dysfunction can lead to toxic accumulation of benzodiazepines and their metabolites. Medications with longer half-lives, such as clonazepam, are favored for the treatment of panic disorder due to a longer duration of therapeutic effect once the medication has reached a therapeutic level. Buspirone is not as effective as benzodiazepines for the treatment of generalized anxiety disorder and its long onset of effect make it a difficult drug to use in patients with severe symptoms. However, buspirone is an attractive option in patients who are addicted to benzodiazepines. No routine monitoring is required of either benzodiazepines or buspirone.

7.12.4

Side Effects

Side effects of benzodiazepines include sleepiness, a paradoxical disinhibition especially in the elderly, carbon dioxide retention to a lethal extent in patients with intercurrent respiratory ailments, and death through overdose when combined with alcohol and barbiturates, as these compounds also work through the same GABA-A receptor. Buspirone can cause nausea, a paradoxical anxiety, dizziness, and a severe withdrawal syndrome if abused.

250

Pharmacology

7.13. Other Medications 7.13.1

Psychostimulants

Psychostimulants have been used for ADHD, narcolepsy, and for depression refractory to other medical intervention. These medications alter neurotransmitter release. Abuse can lead to tolerance and side effects present in other amphetamines. The most commonly used psychostimulants are dextroamphetamine, methylphenidate, and pemoline. Pemoline in particular is tied to an increased rate of hepatic failure. Table 57. Psychostimulants Drug

Indications

Contraindications

Dextroamphetamine

Depression

CV disease, HTN, hyperthyroidism, glaucoma.

Methylphenidate

Depression

Anxiety, glaucoma, tics, Tourette.

7.13.2

Clonidine

Clonidine has been used as a treatment of impulsivity, for Tourette syndrome, and opiate withdrawal. Clonidine is an alpha2 adrenergic agonist that blocks the release of norepinephrine. It also has been used as an antihypertensive agent. Side effects include overdose with consequential hypotension, dizziness, and sedation.

7.13.3

Thyroid Hormones

Thyroid hormones are used to augment therapy for major depression and for the treatment of rapid cycling bipolar disorder. Hyperthyroidism is the only major side effect.

7.14. Major Adverse Drug Effects 7.14.1

Extrapyramidal Symptoms

Neuroleptic-induced Parkinsonism has classic symptoms of Parkinsonism, including lead-pipe rigidity, akinesia, and a fine tremor in the muscles of the head, face, and limbs. Risk factors for extrapyramidal symptoms include high-potency or high dose antipsychotics, being elderly, and having a history of extrapyramidal symptoms (EPS). Onset is typically within a few weeks of starting treatment. Extrapyramidal symptoms can be controlled by anticholinergics as mentioned above, or by lowering or changing the antipsychotic medication. Extrapyramidal symptoms that occur within four hours are classified as acute dystonia; after four days are akinesia; after four weeks are akathisia; and after four months are tardive dyskinesia. Treat acute dystonia with benztropine or diphenhydramine, prevent it with benztropine. Treat akathisia with propranolol and decrease neuroleptics; consider benzodiazepines and anticholinergics instead. Treat dyskinesia with benztropine or amantadine, and decrease the dosage of neuroleptics. Treat tardive dyskinesia by stopping neuroleptics. Administering anticholinergics or decreasing neuroleptics may initially worsen tardive dyskinesia.

251

Clinical Review for the USMLE Step 1 7.14.2

Dystonia

Dystonic reactions are muscle spasms that can affect any muscle in the body, but predominantly center on the muscles of the head and neck. There is a broad range of spasms, including some increased muscle tension to severe tetany with resultant compromise of the airway. Spasms, posturing, dysarthria, and impaired bodily functions are all characteristics of more severe dystonic reactions. Dystonic reactions are most likely to occur after the use of high-potency or high dose antipsychotics, and are more common in younger men. Onset is usually within a few days of starting therapy. Treatment is generally supportive care. Intravenous benztropine (anticholinergic) or diphenhydramine (antihistamine with anticholinergic effects) may be indicated, and discontinuation of the offending agent is usually normal practice, if the symptoms cannot be controlled.

7.14.3

Akinesia

Akinesia typically occurs within 4 days of use of neuroleptic agents. Presentation of akinesia is with difficulty beginning or continuing a motion. There is a marked slowing of voluntary movements, a retardation of initiating movements such as reaching for objects, an inability to repeat stereotyped motions such as clapping hands, difficulty carrying out a sequence of motions, masked facies similar to Parkinsonism, loss of spontaneous gait motions such as swinging of the arms, a shuffling gait, and decreased dexterity. Akinesia is treated by lowering the dose of antipsychotics, changing the medication, or using clozaril as a substitute.

7.14.4

Akathisia

Akathisia is restlessness with anxiety or agitation. Akathisia is a side effect of increasing doses of antipsychotics and SSRIs. Akathisia, when severe, can lead to dysphoria, aggression, and suicide. Cases of akathisia tend to occur within the first few weeks of increasing the dose of a medication. It may be treated by reducing the dose of the offending medication, administering beta blockers such as propranolol, benzodiazepines such as lorazepam, and possibly anticholinergics as mentioned above. Akathisia should not be confused with worsening psychosis.

7.14.5

Tardive Dyskinesia

Tardive dyskinesia (TD) develops over a long period of time of use of antipsychotics. It is more likely to occur in the elderly, females, African Americans, and in patients with mood disorders. Tardive dyskinesia is characterized by choreaform motions, as in Huntington disease, especially of the head and neck muscles. Tardive dyskinesia requires lowering the dose of antipsychotics or changing the medication, and using clozaril instead. Clozaril is an atypical antipsychotic that works through a different mechanism and avoids tardive dyskinesia entirely. Tardive dyskinesia may be permanent.

252

Pharmacology Table 58. Classification of Dystonic Reactions Acute Dystonia

Akathisia

Akinesia

Tardive Dyskinesia

Time Course

4 hours

4 weeks

4 days

Minor Signs

Muscle spasms of the head and neck

Anxiety and agitation

Loss of spontaneous motions

Major Signs

Airway compromise

Dysphoria, aggression, suicide

Masked facies, immobility

Choreaform motions. Permanent.

Treatment

Benztropine, diphenhydramine

Propranolol, benzodiazepines, lorazepam

Clozaril as a substitute

7.14.6

4 months

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a medical emergency that requires prompt intervention. It is a complication of high-dose or high-potency antipsychotics, an effect of rapid dose increases, intramuscular injection of antipsychotics, occurs in patients with agitation or dehydration, and in patients with a history of neuroleptic malignant syndrome. Onset is typically within a few weeks, but it can occur at any point during treatment. Neuroleptic malignant syndrome is characterized by gradual onset of autonomic, motor, behavioral, and laboratory abnormalities. Autonomic dysfunction includes tachycardia and development of cardiac arrhythmias, hypertension or hypotension, diaphoresis, and fever leading to hyperthermia / hyperpyrexia. Motor dysfunction is characterized by rigidity or dystonia, akinesia, mutism, and dysphagia. Behavioral abnormalities include agitation, incontinence, delirium, seizures, and coma. Laboratory tests typically indicate a rise in the creatine kinase (CK), abnormal liver function tests (LFTs), and an increase in white blood cells (WBCs). Treatment of neuroleptic malignant syndrome must be prompt to avoid the more serious sequelae of this disorder. It is typically supportive, but includes discontinuation of the offending agent, use of dantrolene to relax the muscles and minimize myonecrosis, bromocriptine as a dopamine agonist to reverse the dopamine block from the antipsychotics, and symptomatic management. Neuroleptic malignant syndrome develops as a result of antipsychotic medications; patients on both MAOIs and antipsychotics may also develop serotonin syndrome, and distinguishing between the two can be difficult.

7.14.7

Serotonin Syndrome

Serotonin syndrome may occur with the combination of SSRIs and MAOIs, with MAOIs plus antipsychotics, MAOIs plus meperidine or dextromethorphan, and MAOIs plus other opiates. Serotonin syndrome can be life threatening, with autonomic, motor, and behavioral effects similar to neuroleptic malignant syndrome. Specifically, the autonomic effects include tachycardia, hypertension, diaphoresis, fever leading to hyperpyrexia; the motor effects can lead to shivering, myoclonus, tremor, hyperreflexia, and oculomotor abnormalities; and the behavioral abnormalities can include restlessness, agitation, delirium, and coma. Serotonin syndrome can be differentiated from neuroleptic malignant syndrome in that serotonin syndrome does not produce the muscular rigidities seen in neuroleptic malignant syndrome. There is also no dystonic reaction in serotonin syndrome â&#x20AC;&#x201C; the muscular effects tend to lead to increased muscle activity via tremor, shivering, and increased reflexes. Treatment for serotonin syndrome is typically supportive with discontinuation of the offending agents.

253

SKIN & SOFT TISSUE

Section Editors Sapan S. Desai, MD, PhD

Danny O. Jacobs, MD, MPH

Assistant Professor Department of Surgery Duke University Medical Center

Professor and Chair Department of Surgery Duke University Medical Center

Contributors Scott K. Pruitt, MD, PhD

Tara Brennan, MD

Associate Professor Resident Department of Surgery Department of Ophthalmology Duke University Medical Center University of Illinois

Leontine Narcisse, MD, PhD

Jerimiah Mason, MD

Fellow Resident Department of Surgery Department of Surgery Westchester Medical Center Baptist Medical Center

Niketa Desai, PharmD Pharmacist Department of Pharmacology Long Island University Surgical Principles (adapted from the Clinical Review of Surgery)

Issam Koleilat, MD

Prateek K. Gupta, MD

Resident Resident Department of Surgery Department of Surgery Albany Medical College Creighton University Surgical Oncology (adapted from the Clinical Review of Surgery)

Johnny T. Chang, MD

Prateek K. Gupta, MD

Resident Resident Department of Surgery Department of Surgery Brown University Creighton University Plastic Surgery (adapted from the Clinical Review of Surgery)

Introduction

1. Introduction Skin and soft tissue encompasses topics in basic embryology and anatomy, a variety of pathologic disorders that affect this organ system, and a diverse number of medications. As we have done previously, the majority of the pharmacologic and therapeutic options will be discussed in line with the pathology.

2. Basic Science 2.1. Anatomy The skin is divided into the epidermis and dermis. Its purpose is to protect the body from the outside environment by providing a physical, chemical, and immunologic barrier, to provide the sensation of fine touch, pressure, temperature, and vibration via special end organs, regulate temperature through permissive evaporation (i.e. sweating), help to absorb oxygen, nitrogen, carbon dioxide, and produce certain vitamins, and to serve as storage for water and lipids. The epidermis is the outermost layer and is divided into five strata. From outside to in, those layers are

Figure 1. Anatomy of the epidermis, dermis, and subcutaneous layers. Copyright Madhero88. Used with permission. 255

the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum germinativum. The corneum is composed primarily of dead skin cells and provides a barrier to the underlying cells. The lucidum is found in thick skin and is also composed of dead cells; this layer is notable for its oil and melanin content. The granulosum has lamellar bodies, which contain lipids and protein and create a hydrophobic barrier. Keratinization begins in the spinosum, while the bottom-most layer has stem cells for the skin. The dermis contains connective tissue, blood and lymphatic vessels, sweat glands, sebaceous glands, apocrine glands, hair follicles, and sensory receptors. Loose connective tissue is found in the papillary layer. Below this is the thicker reticular layer, which contains the majority of the contents of the dermis. The hypodermis connects to the subcutaneous layer. There are a variety of cell types in the skin. Keratinocytes are the stem cells that form the skin. They also help modulate the immune system via Langerhans cells. Langerhans cells are dendritic cells that primarily reside in the spinosum and function as antigen-presenting cells. Melanocytes produce melanin; accumulated genetic defects in these cells can lead to melanoma. Sensory receptors include Merkel cells, lamellar corpuscles, tactile corpuscles, bulbous corpuscles, and free nerve endings. Merkel cells are derived from the neural crest and respond to light touch. They are associated with Merkel cell cancer. Lamellar corpuscles were previously known as Pacinian corpuscles, and are a mechanoreceptor sensitive to vibration and pressure. Tactile corpuscles were previously known as Meissnerâ&#x20AC;&#x2122;s corpus- Figure 2. Layers of the skin. Copycles and respond to light touch and low frequency vibrations. right Mikael Haggstrom. Used with Bulbous corpuscles respond to stretch and pressure. Free nerve permission. endings respond to pain and include A-delta and C fibers. Collagen in the skin and the underlying muscular layer is arranged in distinct directions. Tension on wounds and scars is varies based on their orientation to these fibers, and is most evident in the face. Langerâ&#x20AC;&#x2122;s lines are cleavage planes between collagen bundles, and incisions oriented parallel to them have improved cosmesis. Relaxed skin tension lines (RSTLs) take into account musculature as well as different body positions, and thus more accurately reflect the directions of minimal and maximal tension in the skin. When not otherwise contraindicated, incisions should be made parallel to the RSTLs.

2.2. Embryology Development of the skin begins at 4 weeks, at which point ectoderm epithelium is formed. By three months, the ectroderm has undergone sufficient division to form the stratified epidermis. Blood vessels and lymphatics populate the dermis via the mesoderm. By five months, hair follicles have matured and melanocytes derived from the neural crest have extended into the skin layers. The primary component of the skin is type I collagen in both the fetus and adult. However, the fetus has a higher type III to type I collagen ratio than the adult. Elastin is not found in the fetus, but is present in the adult.

2.3. Repair

and

Regeneration

Basic Science 2.3.1

Phases of Wound Healing

Wound healing consists of three phases: the inflammatory phase, the proliferative phase, and the maturation or remodeling phase. The inflammatory phase lasts approximately 5 days and is marked by the hemostatic and cellular responses. The proliferative phase begins at day 4 and lasts approximately 3 weeks and sees the creation of a disorganized framework of extracellular matrix and blood vessels. The remodeling phase can last up to a year and consists of the gradual reorganization of matrix and vascular structures into a more functional and stronger form. The inflammatory phase of healing (days 1 through 5) begins immediately after injury with platelets, which participate in coagulation and hemostasis. Platelets release cytokines and growth factors that promote chemotaxis and migration of inflammatory mediators into the injury site. Neutrophils arrive within the first two days and play a minor role in wound healing through phagocytosis of local debris. Macrophages become the dominant cell type by day 3 and release crucial cytokines and growth factors such as IL-1 and TGF-Î˛ that direct the migration and work of other cells. Epithelialization begins during the inflammatory phase with cell migration and mitosis, signaled by the loss of contact inhibition between cells and regulated by various growth factors such as EGF. By the end of the first week, the proliferative phase has begun (days 5 through 21). Fibroblasts become the dominant cell type and rapidly synthesize collagen as well as matrix material such as GAGs (glycosaminoglycans). Although wound tensile strength begins to increase as a result, the collagen is predominantly type III, whereas in normal skin there is a 4:1 ratio between type I and type III collagen. Wound contraction occurs with the appearance of myofibroblasts, specialized fibroblasts with contractile cytoplasmic microfilaments. Angiogenesis begins during the proliferative phase under the influence of factors such as VEGF (vascular endothelial growth factor) secreted by platelets and other cells. The maturation or remodeling phase (week 4 up to 1 year) begins as the rate of collagen breakdown mediated by metalloproteases increases to match the rate of collagen synthesis. Type III collagen is replaced by type I, reestablishing the normal 4:1 ratio. The collagen also becomes more organized and better cross linked, and the tissue becomes less cellular. The wound reaches its peak strength, about 80% of baseline, after about 60 days. Table 1. Wound Strength Two weeks

10%

Three weeks

20%

Four weeks

50%

60 days

80%

Table 2. Collagen Types Type I

Most common type. Found in bone, skin, and tendon. The predominant collagen in mature scars.

Type II

Primary constituent of cartilage.

Type III

Found in embryonic tissue, vasculature, uterus, gastrointestinal tract; the predominant collagen in immature scars.

Type IV

Found in basement membrane.

Risk factors for poor wound healing include increasing age, systemic disease (e.g., diabetes, renal failure, 257

Clinical Review for the USMLE Step 1 liver failure, atherosclerosis), immunosuppression or immunodeficiency, steroids (reversed by vitamin A), malnutrition (protein, caloric, and vitamin), smoking, infection and foreign bodies, and radiation.

2.4. Scar Formation Abnormal scarring may occur in the form of widened, hypertrophic, or keloid scars. Widened scars are marked by normal quantities of collagen spread over a larger area, whereas the histology of hypertrophic and keloid scars are similar and involve excessive collagen deposition. Keloid scars differ from hypertrophic in that keloids grow beyond the normal wound borders. Widened and hypertrophic scars both result largely from excessive tension on the wound, whereas the etiology of keloids is unclear but may be influenced by autoimmune and endocrine factors. Keloids also differ from widened and hypertrophic scars in that the latter generally respond well to treatment (primarily excision and closure), but keloids often worsen and require combination therapy with multiple modalities. In addition, keloids show a much higher correlation with genetic, familial, and racial factors. Table 3. Types of Scars

Description

Widened Scars

Hypertrophic Scars

Keloids

Wide, flat, often depressed

Excessive scar tissue within wound borders

Excessive scar tissue growing beyond wound borders

Low correlation

Significant familial influence, affects blacks more than whites

Race & genetics Gender

Females > Males

Age

Typically < 20 years old

Typically 10-30 years old

Natural history

Develops in 1st 6 months

Develops early, typically subsides

Develops over months, rarely subsides

Location

Arms, legs, abdomen

Flexor surfaces, upper torso

Face, ear lobes, chest

Etiology

Tension, movement

Possibly autoimmune or endocrine factors

Treatment

Excision and closure

Excision and closure, may also benefit from other modalities

Combination therapy (excision and closure alone may worsen scar)

3. Pathology 3.1. Infectious 3.1.1

and Inflammatory

Disorders

Impetigo

Impetigo is the result of S. aureus, GAS, or S. pyogenes infection. These bacteria are commonly found on the skin and anterior nares and may easily migrate to susceptible regions. The nonbullous form of impetigo is the most common, and is generally caused by infection with S. aureus. Infection occurs after even minor trauma leads to openings in the skin and is subsequently followed by bacterial colonization and onset of infection. The bullous form of infection is generally due to S. aureus with particular exfoliative exotoxins that prevent normal cell adhesion. Bullous impetigo may occur even on intact skin. Bullous impetigo presents with rapid onset of blisters with risk factors including hot humid weather, close contact with others, and poor personal hygiene. Clear fluid is contained in the lesion and the lesion has a red base. Lesions tend to be localized and there is no involvement of other systems nor are there 258

Pathology systemic symptoms of infection. Nonbullous impetigo presents as red maculopapular rashes very small in size. These lesions rupture and spread rapidly. Lymphadenopathy is present in the nonbullous form. Spread is through autoinoculation, but the infection resolves on its own. Diagnosis is made clinically, but culture can be done. Anti-DNAase B antibody is typically elevated in cases of streptococcal impetigo. Mupirocin ointment is the best treatment. Oral antibiotics include cephalosporins, penicillins, tetracyclines, TMP-SMX, clindamycin, and linezolid. The latter four are reserved for use against MRSA.

3.1.2

Erysipelas

Erysipelas is a skin infection commonly due to S. pyogenes, GAS, and group G streptococci (GGS). S. aureus, S. pneumoniae, K. pneumoniae, and H. influenzae are other causes. Skin trauma is typically present prior to bacterial inoculation and the onset of infection. Risk factors that decrease the immune response, such as DM, ETOH abuse, HIV, nephrotic syndrome, and other causes of IC may contribute to advanced disease. The infection spreads quickly through the lymphatic system. Erysipelas presents with constitutional symptoms followed by cutaneous symptoms including tenderness, pruritus, burning, and the formation of an indurated, red, shiny plaque. Streak- Figure 3. Erysipelas. Copyright Thoing of overlying skin present due to spread through the lym- ams Sellers. Used with permission. phatics. Petechiae and necrosis may occur in advanced cases. Desquamation occurs with treatment. Diagnosis is confirmed by culture. Methods to reduce inflammation and swelling are used, including rest, ice, and elevation. Wet dresses are applied. Penicillin is given to eradicate the disease (alternatives are cephalosporins and macrolides). Facial infections are treated with dicloxacillin or nafcillin. Other medications include roxithromycin and pristinamycin.

3.1.3

Cellulitis

Cellulitis is the infection of skin and underlying tissues commonly following local trauma. Common causes include S. pyogenes, S. aureus, S. pneumoniae, and more exotic causes in IC patients. Highly virulent organisms in patients with multiple risk factors has a higher rate of mortality. Cellulitis presents with local pain and swelling, numerous constitutional symptoms, and lymphadenopathy. The affected region is red and warm. Hypotension is common. Areas of necrosis may be found in the area. Culture is used for diagnosis. Cellulitis is treated with standard antibiotics against staphylococci and streptococci, which include doxycycline, cephalexin, cefuroxime, erythromycin, clindamycin, nafcillin, and cefazolin. Vancomycin is used with resistant organisms and in paFigure 4. Cellulitis. Copyright Rafael tients with numerous risk factors for more severe disease. Lopez. Used with permission. 259

Clinical Review for the USMLE Step 1 3.1.4

Hidradenitis Suppurativa

Hidradenitis is an infection of the apocrine sweat glands and usually occurs in the axilla and groin. High grade hidradenitis should be treated with excision. However, the mainstay of treatment involves retinoids, steroids, and antibiotics. Surgery should be done only after active infection has resolved.

3.1.5

Staphylococcus Scalded Skin Syndrome

Staphylococcus scaled skin syndrome (SSSS) occurs due to exfoliative toxin release by staphylococcus aureus. The exotoxins (ET-A and ET-B) lead to breakdown in the normal tight junctions that protect the skin. Proliferation occurs underneath the skin. SSSS is most common in children and infants. The infection can be quite severe and culminate in sepsis and death; fatality is relatively high at 5-60% depending on the number of risk factors and severity of disease. SSSS presents with constitutional symptoms of infection, followed by the formation of a macular erythema with local tenderness. The maculopapular rash quickly becomes a series of large blisters, the formation of bullae throughout the body, and loss of the epidermis in sheets. Superficial desquamation occurs throughout the body and healing begins anew. The disease is self-limiting in children with full resolution in a week in the majority of cases; in adults, bacteremia, pneumonia, and more severe disease occurs leading to more fatalities in this population. Diagnosis is made by culture and biopsy. Treatment for SSSS centers around cloxacillin given via IV. Fluid management and correction of any electrolyte disturbances is important.

3.1.6

Toxic Shock Syndrome

Toxic shock syndrome (TSS) is an erythema with systemic manifestations due to S. aureus. The formation of a superantigen known as TSS toxin-1 (TSST-1) leading to cytokine release throughout the body leads to the diffuse injury and systemic symptoms. Shock can occur. TSS presents with symptoms include fever, hypotension, organ involvement, and distal extremity desquamation. Erythema is present with a scarlatiniform eruption. The tongue is cherry red, and hyperemia of mucous membranes is common. Several organs may be involved leading to serious systemwide damage and complications. Diagnosis is made by culture. Supportive therapy is used with TSS, including IVF, pressors, antibiotics, and draining the affected regions. Silver sulfadiazine cream is contraindicated; mupirocin ointment is used instead. Standard antistaphylococcus antibiotics are used as previously discussed.

3.1.7

Candidiasis

Cutaneous candidiasis leads to infections of the skin and mucous membranes, especially in IC patients. It is especially prevalent in the NICU. Cutaneous candidiasis presents with pruritus and a thick white discharge when it affects the vulva and vagina in women. Balanitis leads to pustules, vesicles, and ulcerations with exacerbations after intercourse. Oropharyngeal candidiasis, or oral thrush, tend to occur in IC patients and tends to be self-limiting and self-resolving. This is common in children and infants. Diaper rash is another source. Intertrigo occurs within skin folds due to excessive moisture. Paronychia presents with infection underneath the nail bed. Most infected regions tend to be red and inflamed. Scales may be present. Diagnosis is confirmed with a KOH preparation and microscopic examination of scrapings. 260

Pathology Topical therapy with miconazole, clotrimazole, fluconazole, or itraconazole is typically instituted with rapid resolution. Infants and children are treated with nystatin. Zinc oxide pastes are used for diaper rash, but the aforementioned regimens are also highly effective. Oral candidiasis is treated with nystatin or clotrimazole.

3.1.8

Tinea Corporis

Tinea corporis is caused by the dermatophytoses Trichophyton, Microsporum, and Epidermophyton. These dermatophytoses become a nuisance only after they invade the epidermis; they otherwise coexist with other flora on our skin. Tinea corporis presents as an asymptomatic or pruritic plaque that may scale, crust, or form superficial vesicles. KOH preparation is diagnostic.

Figure 5. Tinea corporis. Copyright Topical azoles are used to treat this infection, including econ- Lucille K. Georg. Used with permisazole, ketoconazole, clotrimazole, miconazole, oxiconazole, and sion. sulconazole. Systemic azoles are rarely used, but include agents such as fluconazole, itraconazole, and ketoconazole. Terbinafine and naftifine are also used.

3.1.9

Tinea Pedis

Tinea pedis is caused by Trichophyton rubrum, which may also lead to tinea corporis. Tinea pedis presents as a pruritic, scaly lesion on the distal lower extremity. It may occur between the digits, lead to keratosis, inflammation, or ulcers. Standard fungal workups confirm the diagnosis. Topical or oral antifungals are used to treat tinea pedis.

3.1.10

Tinea Versicolor

Tinea versicolor is a cutaneous fungal infection due to Malas- Figure 6. Tinea pedis. Copyright sezia furfur infection that occurs in people with risk factors in- James Heilman. Used with permiscluding IC, malnutrition, Cushing disease, and living in a warm, sion. humid environment. Nearly 10% of the population is affected by tinea versicolor. Tinea versicolor presents as abnormal macule with pigmentation of any part of the torso or proximal extremities with scaling. Pruritus is also sometimes found. The macules tend to be circular and coalesce together. Diagnosis is confirmed by direct visualization with an ultraviolet light (Wood lamp), and through KOH examination. Tinea versicolor responds to selenium sulfide, sodium sulfacetamide, ciclopiroxolamine, various azoles, and terbinafine.

3.1.11

Scabies

Scabies is a pruritic and contagious infection by the mite Sarcoptes scabeii hominis. These mites bite through the superficial layer of skin and lays eggs, which later mature on the surface of the skin. After nearly a month of infection, a type IV hypersensitivity reaction occurs. Scabies presents with intense pruritus and with close contacts presenting with a similar complaint. 261

Clinical Review for the USMLE Step 1 Careful examination identifies burrows into the skin, possibly with black dots representing mites. Diagnosis is confirmed by examining of skin scrapings under a microscope. Scabies is treated with decreasing itching with antihistamines, using antibiotics for secondary infections, and removing any crusts or scales to permit proper therapy against scabies with permethrin. Lindane leads to seizures and death in scabies. Crotamiton and ivermectin are other option. Historically, sulfur was used to treat scabies â&#x20AC;&#x201C; it is still a viable option today.

3.1.12

Molluscum Contagiosum

Molluscum contagiosum is due to infection by a DNA poxvirus and transmitted through direct contact. Infected cells become enlarged through numerous inclusion bodies. Molluscum contagiosum can be entirely asymptomatic, or present with pruritus and eczema. Smooth papules are present in groups and tend to be flesh-colored or somewhat lighter. They are generally located on the trunk and proximal extremities. The disease is self-limited. Molluscum contagiosum is treated with cantharidin, tretinoin, podophyllin, trichloroacetic acid, iodine, silver nitrate, phenol, or cryotherapy. Griseofulvin, methisazone, and cimetidine are other options for systemic therapy.

3.1.13

Lyme Disease

Lyme disease is also known as erythema chronicum migrans, and is due to infection by Borrelia burgdorferi introduced into skin by the Ixodes tick. Infection starts with the skin and may proceed to the heart, joints, eyes, and CNS. An excessive immune reaction has also been blamed for some of the symptoms. Nearly 15,000 cases occur annually, although the actual number may be closer to 150,000. Lyme disease presents with a low-grade fever, a flulike prodrome, and numerous constitutional symptoms along with an erythematous maculopapular rash at the site of the bite; a bullâ&#x20AC;&#x2122;seye lesion forms as the rash expands with central clearing. Significant arthritis with swelling and redness develops over time. Bell palsy, aseptic meningitis, peripheral neuropathy, and CNS changes occur in more advanced disease. Lymphocytoma may occur in some patients, and others may develop an acrodermatitis chronica atrophicans with skin inflammation followed by loss of subcutaneous fat and skin atrophy. Diagnosis is confirmed with antibody titers later in disease or via skin biopsy. Lyme disease is treated with amoxicillin, doxycycline, tetracycline, cefu- Figure 7. Lyme disease. Copyright James Gathany. Used with permisroxime, ceftriaxone, erythromycin, and azithromycin. sion.

3.1.14

Herpes Zoster

Herpes zoster, also known as shingles, is a manifestation of VZV reactivation years after initial infection. It is most likely the result of significant stress leading to a partial breakdown in immunity against VZV replication with subsequent dermatomal reactivation. The source is likely a few spinal ganglia containing remnants of an initial VZV infection 262

Pathology Constitutional symptoms are common at the onset of disease, followed by a classic dermatomal distribution of pain or paresthesia that lasts several days. Significant pain may be present along that particular distribution. Erythema is present along with lymphadenopathy in the reactivated region. Vesicles are also present. The distribution tends to stop at the midline of the dermatome, and disease remains unilateral. Zoster may affect the eyes and meninges, and careful followup is required in these cases. Zoster is treated with steroids to reduce pain and inflammation. ACV, VCV, FCV, penciclovir (PCV), and desciclovir (DCV) are used to shorten the disease duration. Vaccinations against VZV may also be useful in preventing shingles. VZIG is also used in some cases and is protective.

3.1.15

Bacillary Angiomatosis

Bacillary angiomatosis is the development of subcutaneous nodules due to vascular proliferation. These nodules occur throughout the body, and infection is due to Bartonella henselae or Bartonella quintana. It is most common in IC patients. Bacillary angiomatosis presents with numerous papulonodular formations throughout the body with large nodules in some locations. Lymphadenopathy and CNS dysfunction are possible. Pulmonary nodules and lesions in other internal locations occur frequently; plain films and CT is sometimes used. Bacillary angiomatosis is treated with erythromycin, tetracycline, TMP-SMX, and rifampin. Treatment is required otherwise the disease is lethal.

3.1.16

Cat Scratch Disease

Cat scratch disease, also known as subacute regional lymphadenitis, is the result of Bartonella henselae inoculation into the skin commonly due to cat scratches. A significant population of stray cats carries B. henselae. It is generally a self-limited infection. Cat-scratch disease presents with lymphadenopathy near the region of injury, constitutional symptoms, and various skin lesions. Some populations may develop systemic disease with encephalopathy, erythema nodosum, pneumonia, breast tumor, and thrombocytopenic purpura. Recurrence may also occur several times at predictable intervals. Treatment involves ciprofloxacin, rifampin, gentamicin, and TMP-SMX.

3.1.17

Malakoplakia

Malakoplakia is the development of yellow nodules and plaques in the genitourinary tract due to E. coli. Malakoplakia commonly affects IC patients. Defective phagocytosis leads to the accumulation of bacteria within phagosomes and subsequent calcification and iron deposition. Malakoplakia presents as ulcerated or papulomatous yellow lesions with drainage, especially in the perineal region. Culture is diagnostic. Malakoplakia is treated with quinolone or TMP-SMX. Bethanechol and ascorbic acid are also beneficial.

3.1.18

Necrotizing Fasciitis

Necrotizing fasciitis is a serious illness that leads to significant necrosis of the fascia, commonly due to GAS, Clostridium, Vibrio, or polymicrobial infection. Rapid spread along fascial planes occurs with the expression of numerous toxins leading to significant damage. Superantigen expression with streptococcus (SSA) can lead to systemic disease. Nearly a quarter of patients die from this ailment. 263

Clinical Review for the USMLE Step 1 Necrotizing fasciitis presents with constitutional symptoms followed by vesicles, erythema, and bullae. Drainage may occur in the area. Painless ulcers may develop into black eschars. Rapid spread and the onset of septicemia and shock occur quickly. Gas is present with GAS and Clostridium infection. Systemic manifestations lead to hypotension, cyanosis, high fever, tachycardia, and CNS changes. Diagnosis is confirmed by biopsy and rapid antigen diagnostic kits. Necrotizing fasciitis is treated with several antibiotics; clindamycin and metronidazole are popular with anaerobes, clindamycin is used with GAS, and Figure 8. Necrotizing fasciitis. Copyright Piotr ampicillin and gentamicin are used with aerobes. Smuszkiewicz. Used with permission. Vancomycin is often added with MRSA or serious infection. IVIG is also administered. Surgical intervention is often necessary and used to reduce the extent of damage and control the disease.

3.1.19

Rocky Mountain Spotted Fever

RMSF is the result of infection by Rickettsia rickettsii leading to widespread endothelial disease and diffuse injury. Multiple organs may be damaged before an adequate host response is made to this potential lethal disease. Severe coagulopathies can result leading to widespread hemostasis and DIC. RMSF presents after an incubation period up to two weeks. Fever, headache, and rash are present with myalgias. Constitutional symptoms develop over time. Fever over 102oF arises and a pink macular rash presents that blanches with pressure. The rashes spread centripetally starting at the distal upper extremity and lower extremity and traveling towards the torso. Papules and petechiae form as the rash spreads and systemic symptoms begin. Jaundice and hepatosplenomegaly occur in later stages. Diagnosis is confirmed with indirect fluorescent antibody (IFA) testing. RMSF requires treatment to avoid its lethal outcome. Antibiotics include doxycycline in all populations except pregnant women, who receive chloramphenicol (regardless of the risk of gray baby syndrome).

3.1.20

Scarlet Fever

Scarlet fever is the sequelae of GAS infection leading to widespread erythema and fever. Toxin production by GAS is implicated as the cause of this rash and disparate inflammation. 1 in 100 persons die from this ailment. Scarlet fever presents following another infection caused by GAS, such as pharyngitis. Severe constitutional symptoms occur quickly and a rash appears soon thereafter. White membranes are found throughout the tongue early in the course, followed by a strawberry red tongue a few days later as the membranes fall off. Erythema becomes generalized and facial flushing is evident. Desquamation occurs after five days. Diagnosis is made clinically and confirmed with culture. Scarlet fever is treated with penicillin G, cephalosporins, or erythromycin.

264

Pathology 3.1.21

Actinomycosis

Actinomycosis leads to soft tissue cellulitis with excretion of sulfur granules through the nose. Significant invasion of the head and neck can occur. The offending organism is typically Actinomyces israelii. Inflammation eventually leads to abscess formation followed by the development of a fistula. Disease is exceedingly rare. Actinomycosis presents with severe constitutional symptoms, signs of systemic infection, and acute infection typically in the region of the head and neck. Spread to nearby structures is common. Trismus is often present, and tenderness with fistula formation can be identified. Edema is significant, an abscesses can be found. Cultures confirm the diagnosis. Actinomycosis is treated with penicillin and surgical debridement. Tetracycline, chloramphenicol, erythromycin, and clindamycin are second line agents.

3.1.22

Aspergillosis

Aspergillosis is the result of Aspergillus fumigatus or other members of this species that lead to disseminated cutaneous fungal infection. Pulmonary infection is the initial disease and the formation of papules, ulcers, and eschars occurs when the infection spreads throughout the body. Mortality in disseminated aspergillosis approaches 100%. Aspergillosis presents with constitutional symptoms followed by dissemination throughout the body. Multiple organ involvement leads to a variety of organ defects. Cutaneous presentation includes multiple papules and plaques that become hemorrhagic and culminate as eschars. Cutaneous nodules tend to be at the site of trauma through which aspergillosis may have initially invaded the system. Diagnosis is confirmed with skin biopsy and staining with methenamine silver or periodic acid-Schiff (PAS). Aspergillosis is treated with amphotericin B, voriconazole, itraconazole, and caspofungin. The latter is effective in strains resistant to amphotericin B.

3.1.23

Coccidioidomycosis

Coccidioidomycosis is due to Coccidioides immitis fungi that lead to significant respiratory infection, followed by global dissemination to cause numerous systemic effects. Coccidioidomycosis tends to be asymptomatic unless it affects an IC patient. After several weeks of incubation, anorexia and headache develop with fever, erythema nodosum, erythema multiforme, and migratory arthralgia. Pneumonia with numerous cavities, nodules, and pneumothorax develop quickly. With dissemination, lymphadenopathy occurs with maculopapular rash, ulcers, and subcutaneous abscess formation. Meningitis occurs in some patients. Biopsy and microscopic analysis confirms the diagnosis. Coccidioidomycosis is treated with antifungals such as amphotericin B and various azoles. Surgical intervention is sometimes necessary to help curtail the infection.

3.1.24

Sporotrichosis

Sporotrichosis is the result of infection by Sporothrix schenckii, commonly lead to cutaneous infection after direct inoculation into the skin from roses and other thorny plants. Sporadic disease is the rule with sporotrichosis, although occasional epidemics have occurred from time to time. Systemic illness in IC patients is typically fatal. Sporotrichosis presents several weeks or months following penetration of the skin barrier by thorny 265

Clinical Review for the USMLE Step 1 plants. Nodules develop that eventually ulcerate, and lymphadenopathy occurs throughout the region of infection. Scaly, localized nodules may also develop. Spread throughout the body can lead to pyelonephritis, orchitis, mastitis, arthritis, synovitis, meningitis, and bone infection. Diagnosis is confirmed by growth on Sabouraud dextrose agar. Sporotrichosis is treated with standard antifungal agents and appropriate supportive therapy in disseminated infection.

3.1.25

Lice

Lice are the result of pediculosis capitus, corporis, or pubis, from the order Anoplura. Lice infection presents as the presence of lice or nits in the head, body, or perineal region. Pruritus is very common, especially at night. Impetigo and lymphadenopathy may accompany infection. Diagnosis is confirmed with a Wood lamp. Treatment of lice is done with controlling fomites, using vinegar with formic acid, permethrin, pyrethrin, dye strips, ivermectin, and malathion.

3.1.26

Varicella Zoster Virus

Chicken pox is the result of VZV infection, commonly occurring in childhood. Reactivation later in life often presents as shingles or zoster. VZV is spread through airborne droplets. After a strong immune reaction with IgG, IgM, and IgA antibodies, VZV may reside as a latent infection in dorsal ganglion cells. This childhood exanthem is typically a selflimiting disease. Chicken pox presents as multiple stages of rashes that begins up to a three weeks after exposure. Constitutional symptoms may be severe in older individuals. Chicken pox presents with a rash, malaise, and low-grade fever followed by the appearance of erythematous macules throughout the body. The macules evolve into papules, vesicles, and pustules that eventually have central umbilication followed by crusting. Vesicles may be located in all regions of the skin. Intense pruritus is common. Adults may also develop pneumonia. Figure 9. Chickenpox. Copyright F. MaDiagnosis is confirmed by Tzanck smear and viral isolation lan. Used with permission. or detection through IFA or EIA. VZV is treated with symptomatic therapy and control of pruritus with calamine lotion, pramoxine gel, oatmeal baths, and antihistamines. ACV decreases the duration of disease if give within one day of onset, but it is used only in children with risk factors for more serious disease. ACV is often given to adults and teenagers; VCV, FCV, and sorivudine may also be used. IC patients should receive ACV in addition to vidarabine and interferon-alpha. VZIG is used in exposed patients, and vaccination is standard for everyone who has not had VZV infection.

3.1.27

Hand-Foot-Mouth Disease

HFMD is due to infection by coxsackievirus A16 or enterovirus 71 that may lead to an epidemic and vertical transmission. This self-limiting infection resolves within a week. Epidemics are common, but disease is rare and mortality from meningoencephalitis or pneumonia even more rare. HFMD presents with constitutional symptoms and cough for several days, followed by distal extremity 266

Pathology lesions that heal within a week. Oral lesions also occur that eventually ulcerate; the tongue may also be affected by these lesions. Cutaneous lesions develop and recede within a week. Infection in pregnant women may lead to IUGR or SAB. Diagnosis is clinical. Most patients do not require therapy. Those that do can be treated with topical anesthetics such as lidocaine, dyclonine, and diphenhydramine for relief from ulceration.

3.1.28

Rubella

Rubella is the rare in children due to significant impact of vaccination programs. Cases of congenital rubella are virtually nonexistent. Young adults are the only reservoir of continuing infection, along with immigrants. Rubella is typically a mild illness that rarely leads to encephalitis, thrombocytopenia, and neuritis. In most cases, rubella presents as constitutional symptoms, a cold-like illness, and a rash that starts as macules first on the face, then on the trunk and extremities. Desquamation follows along with a generalized lymphadenopathy. Arthralgia is a common complaint in adults. Rubella has an incubation period of up to two weeks. Diagnosis is confirmed with antibodies against rubella or viral isolation. Supportive therapy is given for rubella in this self-limited disease.

3.1.29

Measles

Measles leads to more than 1 million deaths annually out of 50 million infections. This highly infectious disease spreads via respiratory droplets and leads to significant immunosuppression. Measles has a 10% fatality rate around the world, but less than 0.5% in developed nations. Measles develops after a two week incubation period with a prodrome of cough, coryza, and conjunctivitis. This prodrome worsens until Koplik spots develop along with fever and photophobia. Koplik spots are blue-white spots commonly found on the buccal mucosa. They expand into a pap- Figure 10. Measles. Copyright Heniz F. ular rash on the face and eventually on the trunk and extrem- Eichenwald. Used with permission. ities. Resolution typically occurs within 10 days. Diagnosis is made clinically and confirmed with laboratory IgM studies. Measles is treated with supportive therapy, vitamin A supplements, and entirely avoided with the MMR vaccine.

3.1.30

Meningococcemia

Meningococcemia is infection from Neisseria meningitidis that commonly leads to meningitis, but may also lead to significant dermatologic manifestations. Meningococcemia presents with constitutional symptoms, myalgia, and arthralgia. Fever is common and is a predictor of worsening disease. Dermatologic manifestations include petechiae, maculopapular lesions, bullae, and hemorrhagic lesions with necrosis. Stellate purpura with a gray color is pathognomonic for meningitis. Diagnosis is confirmed by LP and culture. Penicillin, cefotaxime, and ceftriaxone are commonly used to treat meningococcemia. Management of more serious disease is discussed in the aforementioned textbooks.

267

Clinical Review for the USMLE Step 1 3.1.31

Disseminated Gonococcal Infection

Disseminated gonococcal infection (DGI) due to Neisseria gonorrheae has numerous manifestations, many of which are discussed in our other textbooks. The dermatologic sequelae include a serious dermatitis. DGI presents with constitutional symptoms followed by arthritis, tenosynovitis, and dermatitis. A maculopapular rash is common, but it can evolve into pustules and a hemorrhagic erythema that eventually necroses. Underlying vasculitis can develop with sufficient septicemia. Lesions occur in stages and are commonly found on the distal extremities. Resolution of the dermatologic symptoms typically occurs in a week with sufficient therapy. Treatment involves ceftriaxone and ceftizoxime and more targeted therapy after sensitivities from culture are obtained. Spectinomycin, penicillin, and ampicillin are other options depending on culture results.

3.1.32

Sjรถgren Disease

Sjรถgren syndrome (SS) is the development of a lymphocytic infiltrate in exocrine organs. Sjรถgren syndrome affects about 1 in 100 persons; mortality comes from associated disorders in secondary disease. Females are more affected than males. A polyclonal gammopathy may be present on electrophoretic analysis of serum proteins. ANA, APA, and RF are typically present, along with antibodies to antigen A (SS-A / Ro) and antigen B (SS-B / La). Sjรถgren syndrome is linked to HLA-B8, HLA-Dw3, and HLADR3. Certain HLA-DR components are highly expressed in the exocrine glands, which may account for why the T-helper 1 (TH1) cell-mediated immune reaction targets these regions. Sjรถgren syndrome presents with sicca, leading to xerophthalmia, xerostomia, blepharitis, and dyspareunia from decreased lubrication of the vagina. Dry skin is another common complaint. Parotitis and parotid hypertrophy are commonly present. Xerotrachea leading to dry cough and dyspnea occur occasionally, leading to URI; decreased salivation and lubrication can impede normal swallowing and clearance of food. GERD and esophagitis may occur as a result of xeroesophagea. Artificial tear solutions, frequent sips of water, use of artificial saliva, skin creams, vaginal lubricants, and pain control with NSAIDs are the standard of care. Immunosuppressants such as cyclophosphamide and corticosteroids are used in more severe cases.

3.1.33

SLE

SLE is the result of autoantibody formation that leads to induction of T cells and increased cell death. Apoptosis takes place and increased inflammation and autoimmune antibody production takes place. Deposition of antibody-antigen complexes occurs over time, leading to renal dysfunction, and activation of the complement system. SLE typically is positive for ANA, antibodies to dsDNA, antibodies to histones, anti-Ro and anti-La antibodies, APA, a false positive RPR, anticardiolipin antibodies, and lupus anticoagulant. ESR and CRP are typically elevated, and an anemia of chronic disease (ACD) may be present. SLE presents with numerous constitutional symptoms, especially fatigue, myalgia, and arthralgia. Fever and changes in weight are also present in a majority of patients. Cutaneous manifestations include a malar rash, generalized erythema, skin lesions (such as papules or plaques leading to central scarring and atrophy), discoid lesions, alopecia, panniculitis, nephritis (leading to renal failure or CRF, psychiatric changes, headache, pleuritic chest pain, pleural effusions, dyspnea, pulmonary HTN, nausea, dyspep268

Pathology sia, dysphagia, peritonitis, pericarditis, Libman-Sacks endocarditis, myocarditis, CAD, and vasculitis. Intermittent arthritis, HTN, CHF, splenomegaly. Nearly 1 in 2000 people affected, African American women more than other groups due to a tendency to inherit antibodies to double stranded DNA (dsDNA). Young adult women in particular appear to have a higher rate of contracting SLE. Ten year survival is about 90-95%. SLE tends to lead to death through nephritis, complications and sequelae due to immunosuppressive therapy, and CAD. Drug-induced lupus is the development of an autoimmune syndrome in response to a faulty immune reaction to certain medications. Drug-induced lupus is distinguished from full-blown SLE by complete resolution after cessation of the offending agent. Serum antihistone antibodies are often present in this type of lupus. Offending medications include procainamide, hydralazine, INH, quinidine, methyldopa, chlorpromazine, penicillamine, and alpha-interferon. Antiphospholipid antibody (APA) syndrome is the development of arterial and venous thrombosis, numerous miscarriages in women, and an overall hypercoagulable state due to increased antibody-mediated activation of the platelet cascade.

3.1.34

Scleroderma

Scleroderma is the autoimmune disorder that causes significant fibrosis throughout the body with numerous systemic effects. Induction of collagen production and a general increase in the matrix (ECM) proteins leads to diffuse fibrosis that affects numerous organs. Skin changes are among the initial changes detected, and lead to a wrinkling and aged appearance in otherwise younger persons. Fibrosis of arteries can lead to malignant HTN. Esophageal fibrosis presents with progressive dysphagia. Pulmonary HTN occurs due to fibrosis of pulmonary vessels, which can lead to RHF. Telangiectasias are noted throughout the body. Diagnosis is confirmed by the presence of an SCL-70 antibody to topoisomerase, antibodies to centromeres and various components of the nuclei, a normocytic normochromic anemia, elevations in ESR and CRP, and restrictive lung disease (diminished VC on PFT). Scleroderma may also present as part of the CREST syndrome, which includes calcinosis in the form of malignant calcification leading to nodule formation, esophageal dysmotility, Figure 11. Scleroderma. Copyright AVM. Used with sclerodactyly which decreases the range of permission. motion of the distal upper extremities, and telangiectasias. Therapy for scleroderma includes penicillamine, (to decrease permanent fibrotic changes), captopril (to limit the extent of renal HTN), and calcium-channel blockers (to decrease Raynaudâ&#x20AC;&#x2122;s phenomenon). Corticosteroids have little beneficial effect in treating scleroderma. Treatment SLE proceeds in a simi-

lar fashion to that of RA. Immunosuppression is the key to treatment and NSAIDs are often used for pain control. 269

Clinical Review for the USMLE Step 1 3.1.35

Cutaneous Autoimmune Disorders

Table 4. Cutaneous Autoimmune Disorders Type

Etiology

Pathophysiology

Presentation

Notes

Psoriasis

Increased cell turnover, genetic predisposition, stress, autoimmune dysfunction, superantigens, T cell activity.

Silver scaling occurs with increased cell turnover; part may be due to excess T cell activity and stress occurring in patients with a genetic predisposition.

Many types, typically w/ a silver scale in areas that are most commonly used. May be oral.

Corticosteroids, tar, keratolytics, retinoids, D3 analogs.

Urticaria

Allergic reaction, contact dermatitis, iatrogenic.

Histamine-mediated allergic or nonallergenic mechanism.

Red wheals, purpura, dermographism, angioedema. Intense burning or pruritus.

Diphenhydramine, hydroxyzine, doxepin, cimetidine, corticosteroids, epinephrine.

Bullous pemphigoid

HLA-DQB1, age-related (middle-age), epitope activation, complement activation, chemokine-mediated.

IgG basement autoantibodies leading to blister formation and separating skin at dermalepidermal junction.

Urticarial lesions that become blisters. Many forms but commonly in often used areas.

Corticosteroids, immunosuppressive agents (azathioprine, cyclophosphamide).

Pemphigus vulgaris

HLA-DR4, HLA-DRw6, associated with autoimmune disease including myasthenia gravis and thymoma.

Autoimmune blistering disease due to IgG autoantibodies against keratinocyte surfaces. Complement fixation and T-cell involvement.

Mucosal lesions, cutaneous lesions, flaccid blisters filled with clear fluid. Nail dystrophy.

Corticosteroids, immunosuppressive agents (azathioprine, cyclophosphamide), photochemotherapy.

3.2. Trauma 3.2.1

Heat Exhaustion

Heat exhaustion occurs from dehydration and hyponatremia but with a normal core body temperature; treatment should center on fluid resuscitation and electrolyte replenishment with the patient resting in a cool environment. Heat stroke is more significant with a loss of hypothalamic control over temperature management and CNS dysfunction. Heat stroke should be managed as an emergency to prevent multiorgan failure, rhabdomyolysis, and death. The standard of care with heat stroke is to immediately cool the patient, if their body temperature is over 40 degrees Celsius.

3.2.2

Heatstroke

Heatstroke is the result of uncontrolled heat buildup in the body leading to end-organ damage. Several thousand people die every year from heatstroke, and mortality is high. Heatstroke evolves after symptoms of heat exhaustion occur, which include constitutional symptoms, headache, dizziness, irritability, myalgia, and muscle cramps. Sudden onset of CNS symptoms and psychosis herald heatstroke; diaphoresis is as common as anhidrosis. Orthostatic hypotension is present along with piloerection and tachycardia. With heat exhaustion, the body temperature is less than 41oC. With heatstroke, the temperature is typically more than 41oC (106oF). DIC may be present. Treatment involves cooling the patient with tepid water and large fans after ABCs and IVF.

3.2.3

Cold Weather

Long periods of exposure to the cold can lead to frostbite, especially on commonly uncovered surfaces like the ears, nose, and extremities. Frostbite occurs due to diminished blood flow to a particular region as the body attempts to conserve body heat; treatment of frostbite is to warm the body with warm 270

Pathology water, give the Td vaccine, and consider giving antibiotics to prevent infection. Surgical debridement of affected regions is sometimes necessary. Hypothermia is another complaint that can lead to depressed body temperatures. It presents with shivering, CNS effects, and arrhythmia including an upward J point deflection known as the Osborne wave. Hypothermia is treated with immediately warming the patient and warm IV fluids. Warm-fluid lavage may also be necessary. Death is not declared until the patient has reached room temperature and remains without a pulse.

3.2.4

Hypothermia

Hypothermia is a drop in the core body temperature below 35oC leading to a destabilization in the ability of the body to produce and maintain a normal body temperature. Hypothermia presents with chills, dyspnea, nausea, dizziness, stiffness, weakness, shivering, and ataxia. More severe hypothermia has J waves on EKG, slow reflexes, cold diuresis, delirium, cessation of shivering, and eventually, ventricular fibrillation, hypotension, pulmonary edema, and coma. Treatment of hypothermia is to start ACLS, O2, NG tube, warm hydration, external warming, and core rewarming.

3.2.5

Radiation Toxicity

Ionizing radiation is made up of alpha and beta particles, and gamma rays. Radiation poisoning presents with a prodrome of general malaise, followed by organ failure. Erythema and desquamation of skin can occur. Burns may indicate severe radiation. CNS symptoms include confusion and seizures. Cardiovascular collapse may also occur. Management includes decontamination, washing the skin with soap and water after removing clothing, and giving potassium iodide to minimize thyroid gland damage. EDTA and penicillamine are given to treat poisoning with radioactive lead. Plutonium poisoning and other causes can be chelated with pentetate calcium trisodium (CaDTPA) and pentetate zinc trisodium (ZnDTPA).

3.2.6

Drowning

Death from drowning occurs due to suffocation. Drowning from fresh water causes water to enter the bloodstream and lyse RBCs. Salt water leads to a hypertonic solute in the lungs and passage of intravascular fluids into the lung. Rapid submerging into very cold water can lead to survival for over an hour underwater with no damage, a phenomenon referred to as the mammalian dive reflex. Consciousness is lost within 3 minutes, and brain damage occurs shortly thereafter. First aid involves the Heimlich maneuver, followed by resuscitation and warming the person. Warm IVF, NG tube, bronchodilators to avoid bronchospasm, antibiotics to avoid respiratory ailments, and steroids are used. Shock management is essential.

3.2.7

Anaphylaxis

Anaphylaxis is an allergic reaction with numerous systemic and dermatologic signs. Increased mucous membrane permeability, bronchial smooth muscle tone, and capillary permeability occur as a result of histamine, leukotriene C4, prostaglandin D2, and tryptase. Anaphylaxis is mediated by IgE that leads to a rapid series of effects involving other immune cell mediators. The most commonly implicated agents include antibiotics, IV contrast, bee stings, and various foods. Several hundred deaths occur annually. Anaphylaxis presents with angioedema, urticaria, erythema, and pruritus as skin manifestations. Cough and nasal congestion with rhinorrhea is present, along with dyspnea, chest pain, and hypoten271

Clinical Review for the USMLE Step 1 sion. The eyes may becoming itchy and start tearing. GI distress can occur. Severe cases may lead to circulatory collapse or respiratory arrest. Treatment for anaphylaxis involves maintaining the ABCs, providing O2, IVF, and giving epinephrine for systemic manifestations. Corticosteroids are also used. Beta-agonists are helpful with respiratory symptoms. Antihistamines may also be used to aid with maintaining BP.

3.2.8

Pressure Sores

Decubitus ulcers occur at areas of the body subjected to prolonged focused pressure, particularly posterior bony prominences such as the ischial tuberosities, trochanters, sacrum, and heels in patients with impaired mobility. Other risk factors include sensory loss leading to inability to sense ischemic discomfort, impaired tissue perfusion (e.g., in sepsis), poor nutritional status, advanced age, and diabetes. Pressure sores are classified into 4 stages: •

Stage 1 – erythema without skin disruption

•

Stage 2 – partial skin disruption with blistering, superficial skin loss, or shallow cratering

•

Stage 3 – full-thickness skin loss with subcutaneous tissue involvement, but no fascial disruption

•

Stage 4 – involvement of deep structures (muscle, bone, tendon, etc.)

Stage 1 sores can develop within an hour, and improve quickly by simply relieving pressure on the tissue. Stage 2 sores can develop within hours, and can be managed medically with offloading of pressure, topical dressings, and meticulous wound care. Stage 3 and 4 sores often require serial surgical debridement, and may benefit from surgical flap coverage. However, success of flaps for pressure sores is poor, with recurrence in some studies greater than 80%. In recent years, negative pressure dressing technologies have proven to be an effective tool in pressure sore management. After adequate surgical debridement and clearing of any local infection, a negative pressure dressing can keep the wound clean, reduce buildup of exudate, and enhance wound contraction. Because pressure sores are difficult to treat and frequently recur, prevention is the key to management. High risk patients should be identified early using risk-assessment tools such as the Braden Scale. These patients should be turned frequently and even placed on special beds that passively or actively redistribute weight.

3.2.9

Burns

Classification Burns are classified as first, second, or third degree; some classifications include fourth degree as well. First degree (superficial) burns are epidermal burns that are painful and erythematous but without blistering. Most sunburns are first degree burns. Second degree (partial thickness) burns involve the dermis and form blisters. They are further divided into superficial burns involving the papillary dermis and deep burns involving the reticular dermis. The former is painful and demonstrates blanching erythema with intact hair follicles and other appendages, whereas the latter tends to be pale and associated with loss of hair follicles and appendages. Decreased 272

Pathology sensation may result from deep second degree burns. Third degree (full thickness) burns penetrate both the epidermis and dermis to involve the subcutaneous fat and other tissues. These burns are typically pale and leathery with notable sensory loss. Fourth degree burns involve bone or muscle. In addition to the depth of burns, it is important to convey the size of burns as a percentage of the total body surface area (% TBSA). This can be estimated in adults using the “rule of 9s.” It can also be estimated by noting that in an adult, the palm is approximately 1% TBSA. Note that children age 7 or younger have significantly different proportions.

Inhalational Injury Burns sustained in a closed space, facial burns, singed nose hairs, carbonaceous material in the airway, or respiratory symptoms should raise concern for potential airway compromise. These injuries result from smoke particles and components, not from heat. Arterial blood gas, carboxyhemoglobin, and carbon monoxide levels should be checked. Expedient intubation should be considered in the event of respiratory distress, and bronchoscopy should be pursued in that case. Steroids have not been shown to have any advantage in early management. Pneumonia is the most common infection in burn patients and also the most common cause of death after inhalation injury.

Fluid Resuscitation Significant burns (≥ approximately 20% TBSA) result in massive fluid loss from the burn surface and can lead to shock. Fluid resuscitation is paramount, but excessive fluids may worsen the prognosis. The fluid requirement for the first 24 hours can be estimated using the Parkland formula: Volume = %TBSA x 4 cc/kg Half of this volume in lactated Ringer’s solution is given during the first 8 hours, and the other half over the next 16 hours. The fluid infusion timing should be started from when the burn occurred, but boluses should be avoided. The amount of fluid necessary is dictated by the patient’s urine output; the Parkland formula serves as a guide for initial therapy only. Normal urine output for a young child with burns is 1-2 cc/kg/hr. Adults should make about 0.5-1 cc/kg/hr. Heart rate and systemic vascular resistance initially increase due to release of catecholamines but cardiac output initially decreases.

Acute Treatment Early excision down to well-vascularized tissue with the goal of minimizing necrotic tissue mass to prevent infection is key in the acute management of deep second degree and third degree burns. In the absence of infection, these acute wounds can be covered with autografts, although cadaveric skin, xenografts, and dermal substitutes may be used for temporary coverage. Septic or unstable patients may not be candidates for early coverage. Escharotomy is indicated for circumferential third and deep second degree burns. Around the abdomen, these burns may lead to abdominal compartment syndrome and subsequent intra-abdominal organ failure. Around the chest, they may result in respiratory distress with ventilatory difficulty. In the extremities, they may cause compartment syndrome leading to acute limb ischemia.

273

Clinical Review for the USMLE Step 1 Pseudomonas is the most common cause of burn infections, followed by Staphylococcus, E. coli, and Enterobacter. However, prophylactic systemic antibiotics are not indicated in the acute management of burns. Topical agents with antimicrobial action can decrease the risk of developing burn wound infections. Silver sulfadiazine (Silvadene) is useful, but has limited eschar penetration and may not be effective against Pseudomonas and other gram negative rods. Silvadene can cause a self-limited neutropenia and thrombocytopenia. Mafenide sodium (Sulfamylon) has good eschar and cartilage penetration, and is effective against Pseudomonas and other gram negative rods. However, it tends to be painful and may lead to metabolic acidosis due to carbonic anhydrase inhibition. Bacitracin can be used in areas such as the face. Early enteral feeding is encouraged to decrease gut bacterial translocation and is preferred over TPN. Burn patients have increased metabolic demands and thus need increased caloric and protein requirements. The Curreri formula estimates calorie requirements for burn patients and is 25 kcal/kg/day + 40 kcal/% TBSA/day. Protein requirements vary from 1-2 g/kg/day. The Curreri formula may overestimate calorie needs.

Chemical Burns Acid burns cause coagulation tissue necrosis, whereas alkali burns result in deeper burns from liquefactive necrosis. Both should be managed with generous irrigation. Hydrofluoric acid burns should be treated with topical calcium gel or intradermal calcium gluconate. Tar burns should be cooled, then removed using a lipophilic solvent. Dry powder should be brushed off prior to irrigating with water. Liquid chemical burns should be washed in water.

Electrical Burns Electrical burns and lightning strikes can result in acute cardiopulmonary complications. These injuries can be deeper and more severe than the external wounds may suggest. Deep muscle burns can result in rhabdomyolysis and compartment syndrome. Electrical burns can damage deep structures such as nerves and the spinal cord, bowel, and brain. Electrical current enters at the point of contact and leaves at the grounded area traversing through tissues of least resistance which are usually muscles, nerves and blood vessels. Cardiac arrhythmias are common and need close monitoring. Electrical burns require a higher urine output due to concomitant myoglobinuria. A target urine output of 2 cc/kg/hr should be achieved. Intravenous sodium bicarbonate to alkalinize the urine should be given.

3.2.10

Other Burn-Like Conditions

Toxic Epidermal Necrolysis Toxic epidermal necrolysis (TEN) results in disruption of the epidermal-dermal interface. It can be caused by viruses and bacteria such as S. aureus, as well as various drugs including Dilantin and Bactrim. Patients should be treated with systemic antibiotics if the cause is bacterial; otherwise, they are treated with topical antimicrobials and similar to patients with thermal burns: early excision and grafting of affected surfaces.

274

Pathology Stevens-Johnson Syndrome Stevens-Johnson syndrome, or erythema multiforme, is a severe form of TEN. It is a hypersensitivity reaction that results in the formation of bullae at the epidermal-dermal interface and epidermal necrosis. Treatment is similar to TEN. Steroids are contraindicated in both conditions.

Brown Recluse Spider Bite Brown recluse spider bites may lead to DIC and death. Supportive care is necessary, and dapsone is used in proven bites. Focal but extensive necrosis can occur; resection is completed after the are is permitted to demarcate.

3.3. Cancer 3.3.1

Desmoid Tumor

Desmoid tumors arise from fascia or muscle and are usually benign. They are associated with pregnancy and trauma and Figure 12. Stevens-Johnson Synmay be intra-abdominal or extra-abdominal. Intra-abdominal drome. Copyright Thomas Habif. desmoids are diagnosed by MRI followed by incisional or core Used with permission. biopsy. Abdominal wall desmoids are treated by local excision with negative margins. Recurrence rates are very high but metastasis is rare.

3.3.2

Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common form of skin cancer. It commonly involves the sun-exposed areas of the head and neck in older patients with light skin. Increased incidence has also been noted in immunosuppressed patients. Patients with xeroderma pigmentosum have significantly increased susceptibility to BCC and other types of skin cancer. BCC lesions originate from basal epithelial cells in the epidermis and present as pink, pearly papules with rolled edges and central ulceration. They are classified based on their appearance and growth pattern: nodular, superficial spreading, pigmented, or morpheaform sclerosing. Nodular BCC is the most common type, has the classical appearance, and is historically called a â&#x20AC;&#x153;rodent ulcer.â&#x20AC;? Superficial spreading BCC tends to be red and scaly, and grows horizontally without dermal invasion. Pigmented BCC contains melanin and is often confused with melanoma. Morpheaform sclerosing BCC resemble scars in appearance, have indistinct borders, and therefore tend to have positive margins or recur after excision. BCC is generally locally invasive with low metastatic potential. Less than 0.1% of BCC metastasize to lymph nodes and other distant locations. The primary treatment for BCC is surgical excision with 3 to 5 mm margins. More aggressive lesions, particularly morpheaform sclerosing lesions with indistinct borders, may benefit from margins up to 7 mm. Cure rates for BCC is very high, although there is potential for recurrence; periodic surveillance is necessary. In recurrent cases, cure can usually be achieved with re-excision.

275

Clinical Review for the USMLE Step 1 3.3.3

Squamous Cell Carcinoma

Squamous cell carcinoma (SCC) of the skin is the second most common form of skin cancer. Major risk factors include fair skin, sun exposure, immunosuppression, human papilloma virus, and carcinogens such as nitrates, arsenic, and hydrocarbons. SCC may also develop at the site of chronic wounds. In addition, there are several premalignant lesions that may undergo transformation into SCC. The most common of these lesions is actinic keratosis, which is a scaly, irregularly shaped maculopapular lesion. Actinic keratosis should be treated to prevent transformation into SCC; topical 5-fluorouracil or photodynamic therapy is sufficient in most cases. SCC generally presents as nodular or papular indurated lesion with distinct borders with ulceration and necrosis over time. They are typically red-brown or erythematous, but may also appear similar to BCC. SCC is classified into verrucous type, ulcerative type, and Marjolin’s ulcer. Verrucous SCC is an exophytic, slow-growing lesion with low metastatic potential. Ulcerative SCC is more aggressive and likely to metastasize. Marjolin’s ulcers are metastatic lesions that develop in chronically inflamed tissue, particularly in burn scars after several decades. In general, melanoma has higher metastatic potential than SCC, which has a higher metastatic potential than BCC. Wide local excision with adequate margins is recommended for treatment of most lesions. Margins vary from 4 to 10 mm, and depend on size, depth, location, and grade. Regional lymphadenectomy is indicated if there are palpable nodes or if the lesion is a Marjolin’s ulcer. In cases of high-risk lesions without palpable nodes, sentinel lymph node biopsy may be considered. Radiation and chemotherapy are not indicated for primary treatment, but may play a role in recurrent disease or poor operative candidates. Overall cure rate with wide local excision is 95%. However, prognosis is worse with greater depth of invasion, in certain locations (ears, nostrils, scalp, and extremities), and for Marjolin’s ulcers. SCC in an extremity with a positive node after node dissection carries a 35% 5-year survival rate.

3.3.4

Melanoma

Melanoma accounts for less than 5% of skin cancers, but results in 65% of the deaths from skin cancer. Major risk factors include fair skin and hair, sun exposure, history of sunburns, advanced age, immunosuppression, and positive family history. Males develop melanoma more commonly on the trunk, whereas women develop melanoma more commonly in the lower extremities. While blacks have a 10 to 20 times lower risk of developing melanoma, the prognosis is worse because of delayed diagnosis. Predisposing conditions include atypical mole syndrome or familial B-K mole syndrome, dysplastic and atypical nevi, large congenital nevi, and xeroderma pigmentosum. Melanoma originates from the neural crest cells or melanocytes in the basal layer of the epidermis. Early on, radial expansion occurs with little risk of invasion and metastasis. Metastatic potential increases dramatically as the lesion enters the vertical growth phase. Lesions are classically characterized by the ABCDs: asymmetry, border irregularities, color variation, and diameter > 6 mm. The mnemonic can be extended to E for evolution or change in the lesion’s appearance. Melanoma is classified into superficial spreading, nodular, acral lentiginous, and lentigo maligna types. Superficial spreading melanoma is the most common type and has the typical ABCD appearance. They usually arise from preexisting nevi and are of intermediate malignancy. Nodular melanoma is the most aggressive type, arising without a precursor lesion and starting with the aggressive vertical phase. This type of melanoma forms a dark, raised nodule with sharp margins. There is often invasion into deeper tissue with metastasis at the time of diagnosis. Acral lentiginous melanoma occurs on the palms, soles, subungual areas, and mucosa. It is relatively uncommon in whites, but comprises up to 60% of mela276

Pathology noma in African-Americans. The lesions are flat with irregular borders and colors, but are diagnosed late because of their obscure locations. This delay in diagnosis leads to this type of melanoma having the worst prognosis. Lentigo maligna melanoma is the least aggressive type, with a long radial growth phase as a flat pigmented precursor lesion prior to its vertical growth phase. Melanoma is staged using the TNM (tumor node metastasis) system. Traditionally, primary tumors were described using the Clark levels, which indicate the histologic skin layer to which the tumor has Figure 13. Malignant melanoma. Copyright Nainvaded. Studies have shown, however, that tumor tional Cancer Institute. Used with permission. thickness (Breslow thickness) is a better indicator of prognosis. T0 lesions are confined to the epidermal layer, T1 lesions are up to 1 mm thick, T2 lesions are up to 2 mm thick, T3 lesions are up to 4 mm thick, and T4 lesions are greater than 4 mm thick. Tumors without and with ulceration are denoted by “a” and “b,” respectively (e.g., T1 lesions with ulceration are T1b lesions). Because melanoma treatment and prognosis is based so strongly on Breslow depth, diagnosis should be made based on biopsies that preserve depth information, and not shave biopsies. Wide local excision is the primary treatment modality, with horizontal margins dependent on depth of invasion. T0 lesions may be treated with 5 mm margins, T1 lesions with 1 cm margins, T2 or T3 lesions with 2 cm margins, and T4 lesions with 3 cm margins if possible. The deep margin should be superficial to the underlying fascia. Sentinel lymph node biopsy (SLNB) is indicated for all tumors over 1 mm thick without palpable regional lymph nodes. If there are palpable lymph nodes or positive nodes on SLNB are found, complete regional lymphadenectomy is necessary. Adjuvant therapy is reserved for patients who are not surgical candidates and for palliation. Surveillance for recurrence is critically important. Prognosis for melanoma-in-situ is excellent with 5-year and 10-year survival of nearly 100%, while the presence of positive nodes (stage III) carries a 5-year survival of less than 70%. Metastasis (stage IV) is associated with a 5-year survival of less than 20%. The prognosis is significantly worse for black patients, ulcerated lesions, blue discoloration, and mucosal lesions. Recurrent tumors are likely to be found at the site of excision. Metastasis is most frequently to the lung, brain, and liver. The most common type of tumor metastasis to the small bowel is from melanoma. If the metastasis is isolated to a single site, options for surgical resection should be explored. Chemotherapy and adjuvant therapy are in the form of cisplatin, vinblastine, dacarbazine (CVD) with interferon alpha and interleukin 2. Long term survival benefits are questionable.

3.3.5

Merkel Cell Carcinoma

Merkel cell carcinoma is a rare and aggressive skin cancer originating from neuroendocrine cells. The firm, painless nodules are often found on the head, neck, and extremities. These nodules may be fleshcolored, red, or blue. Surgical excision is the primary treatment modality, but chemoradiation is frequently indicated as adjuvant therapy. 277

Clinical Review for the USMLE Step 1 3.3.6

Paget Skin Disease

Paget disease of the skin is the development of an adenocarcinoma arising from the apocrine sweat glands. Treatment is with excision unless the tumor is invasive into deeper structures. Paget disease of the skin is associated with gastrointestinal cancer. Radiation therapy is beneficial.

3.4. Soft Tissue Tumors 3.4.1

Sarcoma

The initial evaluation of a sarcoma typically reveals a slowly growing soft tissue mass over 5 cm. It is generally painless. A core biopsy or incisional biopsy should be performed to yield a tissue diagnosis. Tumors smaller than 3 cm can be excised en toto. Imaging should be completed with an MRI or CT, but the former is often preferred. Sarcomas tend to spread via a hematogenous route, so lymph node biopsy is typically not necessary. Staging is completed based on histology, size, and presence of metastatic disease. The initial treatment pathway is to complete a margin-negative en bloc resection of the entire tumor; 2 cm margins are preferred. Chemotherapy is effective in Ewing sarcoma and rhabdomyosarcoma. Radiation therapy is also often used.

3.4.2

Stewart-Treves Syndrome

Stewart-Treves syndrome is the development of angiosarcoma from prolonged lymphedema, commonly arising after a modified radical mastectomy with full axillary dissection leading to a disruption of lymphatic channels. Resection and radiation therapy is necessary but five year survival is low.

3.4.3

Kaposi Sarcoma

Kaposi sarcoma is a tumor of the lymphatic endothelium. It arises especially in the setting of HIV/AIDS. HHV8 (human herpesvirus 8) is the responsible virus leading to these characteristic progressive purple plaques. It typically affects the skin but may also spread to the gastrointestinal and respiratory tracts. Antiviral therapy, chemoradiation, and excision are effective.

Figure 14. Kaposi sarcoma. Copyright National Cancer Institute. Used with permission.

278

Pathology

279

MUSCULOSKELETAL

Section Editors Sapan S. Desai, MD, PhD

Danny O. Jacobs, MD, MPH

Assistant Professor Department of Surgery Duke University Medical Center

Professor and Chair Department of Surgery Duke University Medical Center

Contributors Stephanie Mayer, MD

William Eward, DVM, MD

Resident Resident Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center

Jocelyn Wittstein, MD Resident Department of Surgery Duke University Medical Center Orthopedic Surgery (adapted from the Clinical Review of Surgery)

Basic Science

1. Basic Science 1.1. Embryology

and

Histology

Muscle is derived from the myotome, a division of the somites that come from the mesoderm. The myoblasts formed in the myotome form one of three types of muscle: skeletal muscle, smooth muscle, and cardiac muscle. Skeletal muscle is under voluntary control, is generally anchored to bone via tendons, and is involved in locomotion and posture. Smooth muscle is generally involuntary muscle and lines the organs and blood vessels. Cardiac muscle is involuntary muscle but is otherwise similar to skeletal muscle in its makeup. Skeletal and cardiac muscle have sarcomeres and are highly organized, leading to a striated appearance. Skeletal muscle can be distinguished from cardiac muscle in that the former has parallel bundles, while cardiac muscle connects at intercalated disks with significant angulation. Smooth muscle does not have sarcomeres or striations. Skeletal muscle is divided into type I and type II. Type I skeletal muscle is slow to fade and has a high oxygen store. It also has a significantly higher mitochondrial content. Type I muscle is typically found in the postural muscles. Type II skeletal muscle is composed of fast twitch fibers and can rapidly go into anaerobic metabolism to maintain its function. It has lower oxygen stores compared to type I fibers. Figure 1. Actin and myosin filaments. Copyright David Richfield. Myocytes contain myofibrils, Used with permission. which contain sarcomeres composed of actin and myosin chains. Myofibrils are enclosed by endomysium. Groups of muscle fibers are bundled into fascicles by perimysium. Together, groups of fascicles form the muscle, which is enveloped by epimysium. Actin and myosin chains form crosslinks and use calcium ions as an intermediary. They respond to electrical impulses carried by the nervous system and transmitted to the muscle via acetylcholine.

1.2. Physiology 1.2.1

Bone Healing

Fractures disrupt the blood supply to the endosteum and periosteum. A hematoma forms from increased flow to the area induced by vasoactive mediators. This flow also transports inflammatory cells to the fracture site. Fibroblasts are activated and produce collagen at the site.

281

A soft callus forms between days 5-21. Revascularization carries additional progenitor cells to the site, which differentiate based on stress and oxygen conditions at the fracture. A fibrocartilagenous callus stabilizes the fracture, and as the cartilage matrix calcifies and progenitor cells develop into osteoblasts, new bone is formed. This is endochondral bone formation. In response to mechanical loading stresses on the fracture, osteoclasts resorb the immature woven bone while osteoblasts deposit mature lamellar bone in its place. Steroids, nicotine, chemotherapeutic drugs, diabetes, and NSAIDS adversely affect bone healing.

1.2.2

Neurologic Examination Sensory

Motor

Reflex

C5: lateral shoulder, forearm

Deltoid

Biceps

C6: thumb, index finger

Biceps, wrist ext

Brachioradialis

C7: index, middle, ring

Triceps, finger extensors

Triceps

C8: ring, small fingers

Finger flexors

T1: medial forearm

Interossei

L4: distal/posteromedial leg

Quadriceps, tibialis anterior

L5: dorsum and medial foot

Extensor hallucis longus

S1: plantar lateral foot

Gastrocnemius

Knee jerk

Ankle jerk

The L1 through S5 nerves supply the lower extremity. The L1 dermatome is located at the anterior, proximal thigh and innervates the iliopsoas muscle. The L3 dermatome is found at the proximal patella and innervates the quadriceps muscles. The L3 reflex can be tested by the patellar tendon. The L4 dermatome is located at the medial leg and ankle, and innervates the tibialis anterior muscle. The patellar tendon also can be used to test for the L4 innervation. The L5 dermatome is located at the lateral leg and dorsal foot, and innervates the extensor hallucis longus, extensor digitorum brevis, and gluteus muscles. The tibialis posterior and hamstrings can be used to test the L5 reflex. The S1 dermatome is located at the posterior calf and plantar aspect of the foot, and innervates the gastrocnemius and peroneal muscles. The Achilles tendon tests this reflex. The S3-S5 dermatome is located at the perianal area and motor testing is done through rectal exam. Herniation of a lumbar vertebral disc either between L4-L5 or L5-S1 is a common cause of lower back pain. Prolapse of the nucleus pulposus through the annulus fibrosis leads to symptoms of decreased ROM, pain, paresthesia, and decreased reflexes. The specific losses depend on the spinal nerves that are affected. L4 impingement leads to weakened knee reflexes and weakness of the tibialis anterior. L5 effects lead to weakness in the extensor hallucis longus and diminished sensation over the lateral leg. Pinching of S1 leads to a decreased ankle jerk reflex and diminished sensation over the lateral foot. Treatment of lumbar disc herniation is to alleviate pain with NSAIDs. Surgery is used only with significant neurologic symptoms or pain.

1.2.3

Nerve Injury

Nerve injury takes one of three forms, depending on the extent of damage. Neuropraxia occurs secondary to blunt trauma to the nerve leading to infrafascicular edema and disruption of conduction. There is no direct injury to the sheath or axons. Neuropraxia presents with paresthesias with spontaneous recovery within 2 months.

Basic Science

Cervical enlargement

C1 spinal nerve exits above C1 vertebra

C1 C2 C3 C4 C5 C6 C7 C8

C1 C2 C3 C4 C5 C6 C7

Base of skull

C8 spinal nerve exits below C7 vertebra (There are 8 cervical nerves but only 7 cervical vertebrae.)

T1 T1 T2 T2 T3 T3 T4 T4 T5 T5 T6 T6 T7 T7 T8 T8 T9 T9 T10 T10 T11 T11 T12 T12 L1 L1

Lumbar enlargement

C3 C2 C3 C4 C5 T1 T2 T3 T4 T5

C6 T1

T6 T7 T8 T9

C5 C8

T10 Conus medullaris (termination of spinal cord)

T11 C6

L1 T12 C7

C4 C5 C6 C7 C8

T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5 S1 S2

C8 C7

C6 S3 C8 S4 S5

L2 S2â&#x20AC;&#x201C;3

L3 L3 Internal terminal filum (pial part)

Dermatome pattern

Cauda equina

Sacrum External terminal filum (pial part)

S2 S3

Termination of dural sac

S4 S5 Coccygeal nerve

Cervical nerves Coccyx Thoracic nerves Lumbar nerves Sacral and coccygeal nerves

S2 S1

Relationship of nerves to spine L4 S1

S1 L5

Levels of principal dermatomes C5 C5, 6, 7 C8; T1 C6 C6, 7, 8 C8 T4

Clavicles Lateral parts of upper limbs Medial sides of upper limbs Thumb Hand Ring and little fingers Level of nipples

T10 T12 L1, 2, 3, 4 L4, 5; S1 L4 L5; S1, 2 S1 S2, 3, 4

Level of umbilicus Inguinal or groin regions Anterior and inner surfaces of lower limbs Foot Medial side of great toe Outer and posterior sides of lower limbs Lateral margin of foot and little toe Perineum

Figure 2. Dermatomes of the body. Copyright NetterImages. Used with permission. Axontmesis is secondary to blunt trauma to the nerve leading to infrafascicular edema and axonal degeneration. There is no injury to the sheath. Axontmesis presents with disrupted conduction and symptoms of anesthesia and paresthesia. As the axon regenerates, anesthesia disappears. There is typically full recovery within 4 months.

283

Clinical Review for the USMLE Step 1 Neurotmesis is secondary to blunt or shear trauma to the nerve or nerve root causing damage to connective tissue surrounding the axon with disruption of the sheath and axon. Neurotmesis causes immediate anesthesia with the potential for paresthesia and resumption of function. However, the disruption of the sheath may prevent appropriate apposition of nerve fibers and lead to hyperesthesia and allodynia, or even neuroma formation.

1.2.4

Erythrocyte Sedimentation Rate (ESR)

Erythrocyte sedimentation rate is a nonspecific test often used when the clinical suspicion of various rheumatologic disorders is high. ESR is an acute phase reactant (APR) that is increased in the presence of any inflammatory process. The ESR is a test of red blood cell sedimentation due to their attraction to each other from negatively charged proteins and the presence of other APRs. ESR is increased with infection, autoimmune diseases, infarction, cancer, collagen-vascular disease (CVD), and during stress.

1.2.5

Antinuclear Antibodies

Various antibodies to nuclei (ANA) can be found in rheumatologic disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma, and polymyositis. An IgM antibody to IgG is known as rheumatoid factor (RF), and is found nearly universally in RA. RF is nonspecific, as it is also found in various vasculitides.

2. Pathology 2.1. Anatomic Disorders 2.1.1

Developmental Dysplasia of the Hip

Developmental dysplasia of the hip (DDH) is due to the displacement of the femoral head from the acetabulum and occurs during the perinatal period. This displacement leads to a disruption in the normal development of the hip joint. DDH has an incidence of approximately 0.1%, but it may be as high as 3% in populations such as native Indians. Risk factors for DDH include a higher prevalence in females (80% versus 20% in males), breech birth (approximately half of all cases), being the first born, and having Down syndrome. The left hip is typically more affected than the right hip, possibly due to fetal positioning in utero. Plain films of the hip are typically negative until the infant is past six weeks in development due to the high amount of cartilage. Ultrasound is typically the Figure 3. Hip dysplasia. Copyright method of choice to visualize DDH, especially in infants less Heather Hellerhoff. Used with permission. than 3 months of age. Radiographic features of DDH, when evident, include migration of the femoral neck proximal and lateral to the ileum. Signs of delayed ossification occur in the proximal femur in the ossification center. There is also a break in Shentonâ&#x20AC;&#x2122;s line, and the development of a false acetabulum that articulates with the joint. DDH is treated by maintaining a concentric reduction of the femoral head into the hip joint to avoid 284

Pathology the sequelae of uneven growth and development. In neonates with a positive Barlow or Ortolani test, ultrasound should be done at 4 weeks to determine whether the joint stability has improved. A Pavlik harness, traction, closed or open reduction, femoral or pelvic osteotomy, or total hip replacement are some of the therapeutic options available to treat DDH, depending on the particular age and nature of the instability

2.1.2

Legg-Calve-Perthes Disease

Legg-Calve-Perthes disease is an idiopathic hip disorder that leads to ischemia and necrosis of the femoral head. The nucleus of the proximal femoral epiphysis is predominantly affected, leading to abnormal growth of the physis and remodeling of the regenerating bone. The underlying etiology is an impediment in the normal blood supply to the epiphysis. Legg-Calve-Perthes disease presents with knee pain, joint effusion, and a limp in the early phases. Later, there is an antalgic gait due to reduced abduction and internal rotation of the hip. The late phase involves a Trendelenburg gait. The Trendelenburg gait, and the test for this condition, is due to weakness in the abductors of the hip, particularly the gluteus medius. The pelvis appears to sag inferiorly on the side opposite to the defect.

2.1.3

Slipped Capital Femoral Epiphysis

Slipped capital femoral epiphysis is most common among pre-teens and teenagers, especially in males. Approximately one-third of patients will have bilateral involvement, and the largest positive predictor of this class of injury is obesity in African American males and in those with endocrine dysfunction. Slipped capital femoral epiphysis is categorized into three grades. Grade I is characterized by an epiphyseal displacement of less than 30% of the femoral neck width. Grade II is a slip up to 60%, and a grade III slipped capital femoral epiphysis is notable by a slip greater than 60% of the width. Treatment of a slipped capital femoral epiphysis involves surgical intervention to internally fixate the capitus through a central percutaneous pin fixation and cannulated screws. Prophylactic surgery has also been used by various authorities since the majority of patients will eventually have bilateral involvement (up to 80% of all patients). The best treatment is to avoid the situation altogether by weight reduction and strengthening of the joint through exercise. Complications of this disorder and subsequent repair include aseptic necrosis, chondrolysis, degenerative joint disease, and inequality of the leg lengths.

2.1.4

Orthopedic Emergencies

There are a number of situations in orthopedics that require immediate and decisive action on the part of the physician. Common orthopedic emergencies include patients who present with open fractures, a dislocation that results in loss of pulse in an extremity, acute compartment syndrome, cauda equina syndrome, septic joint arthritis, and necrotizing fasciitis. Urgent evaluation and treatment is required in situations involving femoral neck fractures and joint dislocation.

2.1.5

Pulseless Dislocations

Pulseless dislocations require immediate reduction to avoid permanent injury to the extremity. Neurovascular assessment and x-rays are required prior to any intervention for proper assessment of the dislocation and injury to the extremity. A neurovascular assessment and repeat x-rays should be done following reduction of the joint.

285

Clinical Review for the USMLE Step 1 2.1.6

Compartment Syndrome

Compartment syndrome is a surgical emergency that requires immediate decompression of the affected compartment to prevent irreversible neuromuscular damage. It is the result of elevated interstitial pressure within closed fascial compartments following trauma, vascular insult/revascularization, chemotherapy, or surgery. It is commonly seen following crush injuries, tibial fractures, and reperfusion of dysvascular limbs. Symptoms of compartment syndrome include the 5 Pâ&#x20AC;&#x2122;s: PAIN, pallor, paresthesias, pulselessness, and paralysis. Pressures should be measured in all compartments of the affected limb. Classically, intracompartmental pressure > 30 mmHg indicates compartment syndrome. More recent studies recommend measuring DBP and compartment pressure (CP). If DBP â&#x20AC;&#x201C; CP is less than 30, then compartment syndrome is likely. Acute compartment syndrome typically presents with pain when the region of the extremity is narrowed, as when the muscle is stretched. The sine qua non is pain that is out of proportion to the injury. Paresthesias are also common, presenting as a tingling or burning sensation in the muscle. There is often a sensation of fullness or pressure within the affected compartment. Later stages are hallmarked with numbness or paralysis, indicating the start of tissue necrosis. Compartment syndromes can be thought of as occurring when the pressure in the extremity is similar to or exceeds the mean arterial pressure, thereby leading to tissue ischemia. Fasciotomy of all compartments of the affected limb is required to avoid ischemia and necrosis.

2.1.7

Fractures

Open fractures should be washed out at the bedside immediately, and debrided in the operating room as soon as the patient will tolerate surgery. Historically, debridement has been completed prior to definitive fixation, but recent evidence suggests that there is no difference in outcome if thorough debridement and definitive fixation are achieved in a single procedure. Delay in antibiotic therapy has been shown to increase the risk of infection. Type 1 and 2 fractures should receive a first generation cephalosporin. Type 3 fractures should receive a first generation cephalosporin and aminoglycoside. The presence of organic contamination should also be treated with penicillin. All open fractures need tetanus prophylaxis.

Spine A trauma patient with a normal CT of the spine but with motor or sensory deficits should get an MRI to rule out ligamentous injury, disc protrusion, and vascular compromise. A Jefferson fracture is a C1 fracture with 3 or 4 fracture lines causing anterior and posterior arch and lateral mass displacement. Hangmanâ&#x20AC;&#x2122;s fracture is a bilateral C2 pars articularis fracture with C2 spondylolisthesis, often presenting with cord compromise. Nondisplaced fractures are treated with a Miami J collar. Displaced fractures require halo-vest fixation due to joint instability. Displaced fractures with jumped facets require halo traction for reduction followed by C2-3 posterior fusion for definitive treatment. Dens fractures are separated into three types. Type 1 fractures occur at the tip and are treated with a Miami J collar. Type 2 fractures occur at the waist and require a halo-vest, ORIF, or posterior C1-2 fusion. Nonoperative treatment of type 2 fractures has a high rate of nonunion from disruption of the vascular supply. Type 3 fractures occur at the base and require a halo-vest. 286

Pathology Burst fractures through the anterior and middle columns of the thoracic or lumbar bodies are due to axial load and endplate disruption. These are generally treated nonoperatively unless kyphosis is greater than 30 degrees, height loss is greater than 40%, canal compromise is greater than 50%, or there is an associated neurologic deficit. Chance fractures are high energy fractures through all three columns of the thoracic or lumbar spine. These are unstable; one must look for injury to surrounding structures. These fractures are associated with a high risk of concomitant intra-abdominal injury. While Chance fractures may be treated in a TLSO, they are often require instrumented spinal fusion.

Clavicle Look for pneumothorax, neurovascular compromise, or skin tenting if a clavicular fracture is suspected. Most clavicular fractures are treated non-operatively in a sling. Indications for operative repair include pneumothorax, neurovascular compromise, open fractures, severely displaced fragments, polytrauma, impending skin breakdown, or greater than 2 cm of shortening.

Humerus Beware of radial nerve compromise with midshaft fractures of the humerus. Humerus fractures are often treated non-operatively via reduction and cast placement. Supracondylar fractures of the humerus may have entrapment of the median nerve and brachial artery. These are treated non-operatively if nondisplaced, or percutaneously pinned if displaced. Volkmannâ&#x20AC;&#x2122;s ischemic contracture of the forearm is caused by anterior interosseous artery compromise leading to forearm compartment syndrome, deep flexor atrophy, and contracture.

Distal Radius Collesâ&#x20AC;&#x2122; fracture is the most common fracture pattern of the distal radius and occurs at the corticocancellous junction. Median nerve function must be evaluated, as acute carpal tunnel syndrome can occur. Distal radius fractures are treated with elective ORIF unless there is evidence of neurovascular compromise.

Pelvis Pelvic trauma can lead to acute blood loss exceeding 1 L. If an unstable fracture pattern is identified with hypotension, immediate attenuation of the injury with a pelvic binder or sheet binder is necessary. Rectal and genital examination should be performed to assess for open fractures or urologic injury. A retrograde urethrogram should be obtained if there is suspicion for urethral injury; foley catheter placement is contraindicated until the patency of the urethral tract is confirmed. Embolize bleeding pelvic vessels in patients who are hemodynamically unstable with a binder in place; open operating intervention is a distant second option and instituted only if coil embolization fails. External fixation may be required in some cases to stop blood loss. ORIF is performed when the patient is hemodynamically stable.

Femoral Neck Fractures of the femoral neck constitute a surgical emergency in the young patient due to the risk of avascular necrosis and debilitating arthrosis from compromise of the femoral head blood supply. These fractures may be percutaneously pinned or undergo ORIF. Older patients are often treated with hemiarthroplasty or total hip arthroplasty. 287

Clinical Review for the USMLE Step 1 Femoral Shaft Femoral shaft fractures may be associated with unrecognized blood loss up to 3 L into the thigh. Plain films from the hip to the knee should be obtained to look for associated femoral neck fractures, which occur 10% of the time and are frequently subclinical. Fat embolism syndrome may occur either from the fracture or from the ORIF. Treatment includes skeletal traction until definitive fixation with intramedullary nail placement may be performed.

Tibia This is the most common open fracture due to a thin soft tissue envelope anteriorly that is unable to contain the fragmented bone. Flap coverage is often required. Treatment includes ORIF, typically with an intramedullary nail. Tibial fractures are associated with a high risk of compartment syndrome.

Ankle Ankle fractures are common. Immediate treatment includes reduction and splint fixation with documentation of a baseline neurovascular exam. ORIF is performed when the swelling decreases, typically by 7-14 days. Careful wound management is necessary.

Other Fractures A Monteggia fracture is a proximal ulnar fracture and radial head dislocation; ORIF of the ulna is needed. Galleazzi fractures are radial shaft and distal radioulnar joint disruption; treatment is ORIF of the radius.

2.1.8

Dislocations

Anterior dislocation of the glenohumeral joint can lead to axillary nerve injury. Hip dislocations should be urgently reduced to prevent femoral head vascular disruption. Knee dislocations should also be urgently reduced to avoid vascular trauma. Document thorough pulse exam before and after reduction and consider arteriogram if ankle brachial index is 0.9 or less. Peroneal nerve injuries are common with knee dislocations.

2.1.9

Carpal Tunnel Syndrome (CTS)

Carpal tunnel syndrome is an acquired disorder in which compression of the median nerve occurs as it passes under the flexor retinaculum. Compression of the nerve occurs in a classic repetitive stress injury (RSI) or following direct trauma to the region. Pregnant women are especially at risk due to the generalized edema of pregnancy. Presentation is with distal weakness, thenar atrophy, and tingling in the fingers. Phalen’s sign is positive in which paresthesia occurs in the distal extremity following 90 degree wrist flexion (“prayer hand”); Tinel’s sign is positive in which tapping on the region of the median nerve at the wrist elicits pain and tingling that radiates distally to the phalanges. Treatment is straightforward. RICE, or rest, icing, compression, and elevation are done to decrease inflammation. Steroids may be used on a temporary basis to alleviate symptoms. Surgery is the treatment of choice and is a relatively straightforward process in which the flexor retinaculum is incised and the carpal tunnel decompressed.

288

Pathology 2.1.10

Meniscal Injuries

Tears of the medial and lateral meniscus are the most common knee injury that requires surgery. The medial meniscus is three times more likely to be affected than the lateral meniscus, due to its strong attachment to the ligaments. Treatment is partial removal of the damaged portion of the meniscus, especially in central or radial tears or complex damage to the structure. Repair of the meniscus is possible in peripheral and longitudinal tears, and younger patients are more amenable to this type of repair.

2.1.11

Cauda Equina Syndrome

Saddle anesthesia, incontinence, sciatica, and loss of motor or sensory function in the lower extremities are the most common effects of lumbar and sacral root compression in cauda equina syndrome (CES). CES is commonly secondary to spinal stenosis, disk herniations, and tumor expansion. Treatment of CES involves resting on a hard surface at night and adequate pain control. Laminectomy may become necessary to alleviate severe pain and neurologic symptoms.

2.1.12

Pediatric Trauma

A slipped capital femoral epiphysis (SCFE) predominantly affects teenaged, overweight boys. SCFE presents with knee pain and a quarter of patients may exhibit bilateral involvement. Treatment is with percutaneous pinning. Osgood Schlatter lesions are avulsion of the tibial tuberosity at the insertion of the patellar tendon. It affects adolescent males and is due to overuse. Knee pain is worse with palpation of the anterior tibia and with climbing stairs. Treatment is rest and avoiding stress on the affected patellar tendon. Legg-Calve-Perthes disease is avascular necrosis of the femoral head secondary to poor vascularization. This defect may be self-limiting or lead to collapse with concomitant knee pain and limping. Males are affected more than females. Treatment is with abduction bracing or surgery to restore the anatomic angle at the femoral head and neck.

2.1.13

Low Back Pain

Lower back pain is a consequence of numerous etiologies. The leading causes of back pain include arthritis (such as osteoarthritis or rheumatoid arthritis), anatomical defects, trauma, infectious processes, osteoporosis, cancer, and stenosis of the spinal canal. It affects some 90% of all Americans at some point and the vast majority of cases end without identification of a particular trigger. Back pain may present as a radiation down the lower extremities, paresthesias of the extremities, and changes with activity or position. All back pain deserves a work-up to identify a cause, but particular attention should be paid to patients who have a history of recent trauma regardless of age, chronic steroid use, history of osteoporosis, patients over 70 (due to risk of osteoporosis), cancer, infection, a prior history of cancer, recent infection, high fevers, pain at rest, anorexia, and IVDA. Incontinence and abnormal neurologic exam both warrant a thorough work-up. Low back pain is the second most common reason for visiting a doctor. Evaluation includes inspection of the back in a patient who has disrobed and wearing only an examining gown. Signs of scoliosis, thoracic kyphosis, lumbar lordosis, and other etiologies are inspected. Costovertebral angle tenderness, paraspinal tenderness, and other signs of pathology are also examined. The straight leg raise test is also used for diagnostic purposes. The straight leg raise can produce pain from a number of etiologies, including myogenic pain, ischial bursitis, annular tears, hamstring constrictions, and herniated discs. 289

Clinical Review for the USMLE Step 1 The straight leg raise test is primarily used to determine the extent of irritation of the lumbosacral nerve root due to prolapse of an intervertebral disc. The test is performed by having a patient supine, and raising one leg while having the knee straight until pain is experienced in the buttock, thigh, and calf. A normal value is pain around 90 degrees, and patients with defects would have pain at more acute angles. Additional pain can also be elicited upon dorsiflexion of the foot at the highest angle, known as the sciatic stretch test. Low back pain is initially evaluated using a thorough history and physical exam. Plain radiographs are then used in individuals with low risk after six weeks, such as previously healthy adults. Radiographs are ideally used in individuals between the age of 18 and 50, in back pain of acute onset with no nighttime symptoms, no recent weight loss, and no neurologic signs or symptoms. Radiographs are usually obtained immediately in children with acute onset of back pain to rule out spondylolisthesis or in elderly patients to rule out fractures and degenerative disk diseases. A CT myelogram is used as a second imaging measure to assess the level of lumbar stenosis, and can also be used to detect lateral disc herniations. Finally, MRI of the spine can be used as the final imaging study. Treatment of low back pain is dependent on the diagnosis. In the absence of a solid diagnosis, the typical management is to use NSAIDs, several days of bed rest, and a physical therapy education program. Acupuncture, massage, manipulation, traction, braces, biofeedback, and heat / cold therapies have not been shown to have a significant benefit.

2.2. Metabolic Bone Diseases 2.2.1

Osteoporosis

Osteoporosis is the development of bone resorption leading to decreased integrity of the bony skeleton. Bones susceptible to fracture and damage are the result, leading to a significant amount of related morbidity and mortality. Osteoporosis affects some 10 million Americans; osteopenia affects nearly twice as many people. Internationally, osteoporosis can be found in 1 in 3 women and 1 in 8 men. Over a million fractures occur every year that are directly due to osteoporosis, leading to over 37,000 deaths annually from related complications. Few patients return to their baseline function after experiencing a fracture. Osteoporosis is most common in elderly patients, but a variant of osteoporosis can occur in any individual. Osteoporosis is the result of numerous distinct pathologies. More than one can be found in a patient with summative effects. While estrogen is protective in women prior to menopause, paucity afterwards can accelerate osteoporosis. Hypogonadism with low testosterone is a risk factor. Osteoblast defects, long term use of heparin, various antiseizure medications (such as phenytoin and carbamazepine), corticosteroid inhibition of new bone deposition, cyclosporine A, and aluminum-containing antacids have all been implicated as causing osteoporosis. Endocrinologic defects such as Cushing syndrome increase bone resorption. Alcohol and smoking have direct toxic effects on the bone. Cancer and lymphomas have been implicated as increasing bone resorption. Malabsorptive disorders such as anorexia or GI ailments can prevent proper absorption of calcium and essential vitamins. The summation of these risk factors along with various idiopathic causes leads to osteoporosis through decreased bone formation and increased bone resorption. Unopposed action of osteoclasts leads to removal of calcium and decreased bone mass and strength. Type 1 osteoporosis occurs mostly in postmenopausal women and is thought to be due to a shortage of estrogen (it can also occur in men from a testosterone decrease). Increased sensitivity to PTH with increased calcium loss contributes to osteoporosis in this population. Senile osteoporosis, which is type 2 osteoporosis, occurs due to decreased pro290

Pathology duction of 1,25(OH)2 D3 from the kidney. Decreased bone formation with increased loss is the result. Type 3 osteoporosis can occur in any person and is commonly due to medication-induced bone loss. Osteoporosis is an asymptomatic disease. Identifying risk factors and correcting any underlying etiology is the method of choice for preventing the onset of osteoporosis and minimizing its effects. The first symptom of osteoporosis is often fracture, which is most likely to occur spontaneously in the thoracic or lumbar spine, or after falls in the forearm, hip, and femur. Rib fractures are more common with chronic steroid use. Diagnosis of osteoporosis begins with blood tests to measure the level of calcium, phosphate, and alkaline phosphatase â&#x20AC;&#x201C; all of which are normal in primary osteoporosis. This test is done to rule out other more reversible etiologies. Thyroid function is tested. Imaging studies center on locating regions of potential fracture. Plain films of the vertebral column are mandatory. Bone mineral density (BMD) testing is more precise and is a better predictor of fracture risk. A BMD score between -1 and -2.5 indicates osteopenia. Scores less than -2.5 are diagnosed as osteoporosis. BMD can be measured with a dual-energy x-ray absorptiometry (DEXA) scan, which is preferred over CT. Osteoporosis is best treated by preventing the onset of the disease. Calcium supplements, regular exercise, hormone replacement as indicated, calcitonin, selective estrogen-receptor modulators (SERMs), bisphosphonates, low dose PTH, and vitamin D intake are all beneficial. The majority of treatment is effective in preventing additional bone resorption. Weight-bearing exercise is highly beneficial. Alendronate sodium has recently been shown to lead to increased bone strength over a long period of use.

2.2.2

Paget Disease

Paget disease is typically an asymptomatic abnormality in bone resorption and bone formation leading to extensive bone remodeling and overall weakening in the bony skeleton. Significantly more woven bone is formed through this remodeling, and a syndrome similar to osteoporosis develops. The underlying pathophysiology is due to defects in osteoclasts and osteoblasts that cause an increased turnover in bone. Fibrosis ensues and weakening of nearly all the bones in the skeleton is the result. Paget disease can affect nearly 10% of the elderly population with nearly 3 million persons affected overall. Paget disease affects primarily a single bone the most often, but is occasionally polyostotic. Lesions progress in the bones that are affected by Paget disease. Presenting symptoms are rare, other than occasional bone pain, until fracture occurs. Concurrent CHF, deafness, and weakness can occur in some patients. Physical signs in the affected bones include increased heat production over the affected region, gait abnormalities, and expansion or other physical changes. Kyphosis, spinal stenosis, cord compression, hearing loss, facial deformities, and fracture are some of the manifestations. Increased urinary deoxypyridinoline and N-telopeptide are found with Paget disease. Plain films are diagnostic, but bone biopsy can also be done. Treatment consists of reducing bone pain and decreasing progression of Paget disease. Bisphosphonates, NSAIDs, skeletal assistance, and treating any other manifestations of Paget disease form the standard of care. Joint replacement and amputation may be necessary, especially with the development of an osteosarcoma.

2.2.3

Osteomalacia

Many vitamin D disorders or by abnormal phosphorus metabolism may lead to osteomalacia over the long term. Bones become soft, brittle, and deformed. Osteomalacia is also occasionally caused by liver disease or cancer. Rheumatic pain, anemia, progressive weakness, and fractures are all signs of osteo291

Clinical Review for the USMLE Step 1 malacia. Nutritional supplements and supportive therapy are all treatments for osteomalacia.

2.3. Inflammatory 2.3.1

and Infectious

Disorders

Septic Arthritis

Inflammation of the synovial membrane with a concomitant purulent exudate into the joint capsule. Septic arthritis is typically caused by a bacterial infection such as Staphylococcus aureus and various Streptococci, and urgent treatment is required due to the rapid pace with which the joint can be damaged through bacterial erosion. Other complications of septic arthritis include osteomyelitis, fibrous ankylosis, sepsis, and eventually death if the infection is permitted to proceed without check. Young children up to two years of age tend to be infected by S. aureus and H. influenzae, while sexually-active persons are more likely to have Neisseria gonorrhea.

2.3.2

DeQuervain’s Tenosynovitis

DeQuervain’s tenosynovitis is an inflammation that leads to stenosis at the styloid process of the radius. Thickening of the synovial sheath due to inflammation leads to pain with motion of the tendon. DeQuervain’s tenosynovitis is most common in women of childbearing age. It is diagnosed with Finkelstein’s test, which is positive for exquisite pain over the region of the radial styloid when the patient makes a fist, flexes the wrist towards the ulna, and stress to the ulnar flexion is applied to the index metacarpal. Splinting and steroid injections are typically therapeutic, and surgical decompression can be used in the first dorsal compartment for additional benefit.

2.3.3

Flexor Tenosynovitis

Flexor tenosynovitis is the result of an infection that disrupts the normal function of the flexors of the hand. Flexor tenosynovitis can also be secondary to overuse injuries, diabetes, and arthritis. Infectious flexor tenosynovitis leads to four positive Kanavel signs, including fingers held in a slight flexion to minimize stretching of the tendons, fusiform swelling indicating of infection, tenderness along the flexor sheath, and pain with passive extension of the phalanges. Infectious flexor tenosynovitis is an orthopedic emergency due to the ability of the infectious process to rapidly destroy the mobility of the fingers. Penetrating trauma and inoculation by native skin flora is the most common cause, and S. aureus is the most commonly isolated microorganism on culture. Treatment is incision and drainage.

2.3.4

Osteomyelitis

Osteomyelitis is the progressive destruction of the bone due to infection by GBS, S. aureus, E. coli, S. pyogenes, HIB, gram-negative bacilli, Pseudomonas, Serratia, and various anaerobes. Inflammation of the bone and subsequent damage is followed by new bone formation. The tibia and femur are the most commonly affected bones, but the vertebrae are also commonly affected in adults. Onset of osteomyelitis includes sudden development of fever, various constitutional symptoms, reduction in limb usage, and signs of inflammation and infection. A superimposed cellulitis or ulcer may be present in certain types of patients, especially diabetics. Blood culture is typically collected along with plain films and CT, but a bone biopsy is the gold standard for identifying the offending agent. Osteomyelitis is treated by identifying the offending organism and tailoring therapy against it.

292

Pathology 2.3.5

Costochondritis

Costochondritis is the result of irritation and inflammation at the articulation between the ribs and mediastinum at the anterior chest wall. It can occur in trauma, following URI, and with overuse. Costochondritis presents as reproducible pleuritic chest pain at the level of the heart. Diagnosis is made by ruling out other etiologies and by reproducing the pain through palpation. Costochondritis is treated by NSAIDs for pain control and reducing any overuse.

2.3.6

Epidural Abscess

Abscess development can occur as a consequence of immunosuppression, IVDA in the elderly, or following epidural anesthesia for labor in pregnancy. Abscess formation can lead to circulation occlusion, nerve impingement, and spread to adjacent structures. It is commonly the result of infection by Staphylococcus aureus, gram-negative rods, and TB. An epidural abscess presents with fever, pain, progressive weakness, paresthesia, and a rise in WBCs. Epidural abscesses are treated with antibiotics after localizing the extent of the injury with MRI.

2.3.7

Osteoarthritis

Osteoarthritis is one of the most common arthritic conditions that afflict people, with over 20 million people affected in the US alone. Over half of the elderly population is affected by OA. OA is a progressive disorder that occurs over many decades and leads to gradual decreases in mobility. OA is the result of articular cartilage breakdown due to degeneration and inflammatory processes. Weight bearing joints are affected the most, in addition to the distal interphalangeal (DIP) and proximal interphalangeal (PIP) joints in the hands. Cartilage loss is striking, and bony osteophytes develop throughout the body. OA occurs due to increasing age-related stress, obesity, following trauma or serious systemic infections, in repetitive stress injuries (RSIs), following inflammatory arthritis, and in various metabolic disorders. OA begins with a breakdown in the cartilage due to inflammation and degeneration, followed by erosion of the surface of the collagen. Inflammation and synovitis occurs followed by changes to the joint, formation of excess bone in an attempt to remodel and stabilize the affected region, and additional inflammation and breakdown. OA presents with pain, decreasing mobility, morning stiffness and stiffness following extended periods of rest, and joint instability. The stiffness typically improves with exercise. Physical exam findings include joint effusions, bursal inflammation, muscular spasms, joint crepitus, PIP and DIP enlargement, and limited ROM. ESR and CRP are not changed, and there is little WBC infiltrate in the synovial fluid. Plain films indicate numerous osteophytes and bony spurs with joint space narrowing and cyst formation. Therapy for OA includes reducing stresses on the joints through weight reduction, exercise, physical therapy (PT) and occupational therapy (OT). Ice or heat application is sometimes beneficial. Pain control with NSAIDs and cyclooxygenase-2 (COX-2) inhibitors help alleviate symptoms. Narcotics may also be necessary in more severe OA. Osteotomy, removal of bony spurs, and arthroplasty are surgical options available in alleviating the sequelae of OA.

2.3.8

Rheumatoid Arthritis

Rheumatoid arthritis is a systemic inflammatory autoimmune disease that leads to symmetric arthritis and numerous systemic symptoms. About 1 in 100 persons are affected, and there appears to be a ge293

Clinical Review for the USMLE Step 1 netic predisposition toward developing RA; however, environmental influences appear to play a major role due to the relatively low concordance rate among twins. RA leads to significant morbidity over time with disability in 1 in 3 patients within 5 years. Male gender, a positive family history, and increasing age appear to have a particularly poor prognosis. Mortality is somewhat increased. All populations are affected, but females are 3 times more likely than males to develop RA. The precise cause of RA remains to be elucidated, but it has been postulated that an infectious etiology in the form of Mycoplasma, EBV, parvovirus, or rubella may contribute to the development of the disease. HLA-DR1 and HLA-DR4 have also been found to be a positive risk factor for the development of RA. An autoimmune reaction with T cells and B cells has been found, especially with the formation of RF. Inflammation and cellular damage occur over time as the disease progresses. Damage to the joints is the primary presentation of RA, but numerous systemic effects also occur. RA presents with morning stiffness that resolves with activity. Three Figure 4. Rheumatoid arthritis. distinct joints are affected with arthritis throughout the body. SwellCopyright Bernd Bragelmann. ing is typically present in the wrist, metacarpophalangeal (MCP) or Used with permission. PIP joint. Arthritis tends to be generally symmetrical. Subcutaneous nodules are present over joints, and titers of RF can be demonstrated. Plain films often indicate bone resorption and erosions in the distal upper extremities. Many of these aforementioned criteria must be present for diagnosis of RA. Numerous constitutional symptoms are present. RA may precipitate suddenly starting with arthralgia and weakness. Physical exam often detects interosseus muscle atrophy, ulnar deviation, bouton deformities, swan-neck deformities, hammer toes, and typically affected joints. Decreased ROM, warmth, and swelling are present over these joints. Specific manifestations in various organs includes rheumatoid nodules in the skin, pericardial effusions, pleural effusions with or without interstitial fibrosis and nodules (forming Caplan syndrome), bronchiolitis obliterans, Felty syndrome with RA, splenomegaly, and neutropenia, purpura, normocytic, normochromic anemia, CTS, and keratoconjunctivitis sicca. Diagnosis of RA is confirmed by a careful history and physical exam along with 4 of the 7 cardinal features of RA described above. ESR and CRP are typically increased and mirror the progression of the disease. Anemia is present, and inflammatory synovial aspirates with high WBC counts and neutrophils are present. Antibodies that can be demonstrated include RF, ANA, anti-RA33, anti-CCP, and others. Progression of the disease can be determined by plain films of the joints, CT, and MRI. HLA-DR4 is present in a number of patients. Treatment of RA involves significant PT and OT to maintain mobility for as long as possible. DMARDs including gold salts, D-penicillamine, chloroquine, hydroxychloroquine, sulfasalazine, methotrexate, azathioprine, cyclosporine A, minocycline, leflunomide, etanercept, and infliximab are the cornerstone of treatment. Glucocorticoids are an important part of treatment and can be used to decrease inflammation. NSAIDs are also highly successful in treatment. Analgesics such as acetaminophen are useful in decreasing pain. Early treatment is the key to inducing a remission and to improving the morbidity and mortality. Methotrexate, sulfasalazine, leflunomide, azathioprine, gold salts, and penicillamine may lead to liver 294

Pathology toxicity and bone marrow suppression (BMS). Cyclosporine A, gold salts, and penicillamine may lead to renal toxicity. Methotrexate may also cause an inflammation of the respiratory system. Skin reactions can occur with gold salts and sulfasalazine. Autoimmune reactions including drug-induced lupus can occur with penicillamine, sulfasalazine, and minocycline. Immunosuppressants such as cyclosporine A and azathioprine can lead to infections. Ocular toxicity may occur with antimalarials such as hydroxychloroquine. Antibody formation against infliximab and etanercept may occur, leading to drug-induced lupus. Contraindications to the use of TNF antagonists include malignancy, infection, and demyelinating disorders.

2.3.9

Spondyloarthropathies

Ankylosing Spondylitis Ankylosing spondylitis (AS) is a prototypical spondyloarthropathy, related to disorders such as reactive arthritis (known as Reiter syndrome [RS]), psoriatic arthritis, arthritis associated with inflammatory bowel disease (IBD), and other autoimmune arthritides. AS is the autoimmune condition related to HLA-B27, and may occur as a result of molecular mimicry related to Klebsiella pneumoniae infection. Chronic inflammation leads to fibrosis and bone formation throughout the vertebral column, leading to fusion of the column, development of kyphosis, and arthritis of numerous joints. Cardiovascular disease leading to AR can occur, along with pulmonary fibrosis and cauda equina syndrome. AS is greater in Caucasians and affects males more than females. Onset is typically in young adults or teenagers with full blown disease by age 40. AS presents with back pain, loss of vertebral mobility leading to morning stiffness, and arthropathy. Inflammatory back pain affects nearly all patients, beginning bilaterally with the sacroiliac joints and progressing superiorly. A â&#x20AC;&#x153;bamboo spineâ&#x20AC;? appearance is obvious on plain films and is virtually diagnostic of AS. Arthritis and inflammation occurs in a majority of patients and causes significant pain and disability. Kyphosis and lordosis are characteristic. Uveitis, aortitis, restrictive lung disease with fibrosis, amyloidosis, cauda equina syndrome, and metabolic bone disease are other manifestations of AS. Diagnosis centers around the physical exam findings, the presence of a normochromic normocytic anemia in some patients, elevated alkaline phosphatase in others, elevated ESR and CRP, and the presence of acute phase reactants. HLA-B27 is found nearly universally. Treatment of AS centers around slowing the progression of this disorder. NSAIDs are used for symptomatic treatment, sulfasalazine for preventing involvement of the peripheral joints, and immune suppressants for decreasing the damage and progression. Methotrexate, azathioprine, cyclophosphamide, cyclosporine, and corticosteroids are all beneficial. Uveitis is treated with TNF antagonists and corticosteroids. Prophylactic spinal fusion may be attempted in some patients to avoid kyphosis and lordosis; others may require joint replacement.

Reactive Arthritis Reactive arthritis, also known as Reiter syndrome, is a combination of urethritis, conjunctivitis, and arthritis commonly secondary to infection by Shigella, Salmonella, Campylobacter, Yersinia, or Chlamydia. HLA-B27 is commonly found in those afflicted, and reactive arthritis is member of the group of seronegative spondyloarthropathies. Reactive arthritis presents shortly after infection by one of the aforementioned bacteria and is due to an autoimmune reaction leading to antibody-antigen complex deposition and subsequent synovitis. Reactive arthritis typically resolves on its own after about a year, but may recur over time. A chronic disease can also become established and lead to joint destruction. Males are more affected than females, and most patients are young adults. 295

Clinical Review for the USMLE Step 1 Reactive arthritis presents with constitutional symptoms, urethritis, conjunctivitis, and arthritis. Circinate balanitis along with asymmetric arthritis, keratoderma blennorrhagica, and other ocular lesions may be present. Acute phase reactants (APRs) are present, including ESR and CRP, and IgA antibodies against specific bacterial antigens may be found. EKGs should be done on patients to rule out any cardiac complications such as conduction abnormalities. NSAIDs, corticosteroids, antibiotics against any infectious processes, and disease-modifying antirheumatic drugs (DMARDs) form the mainstay of treatment. DMARDs include sulfasalazine, azathioprine, and bromocriptine.

Psoriatic Arthritis Psoriatic arthritis is the development of an HLA-associated, self-reactive arthritis that presents with psoriasis. It is more common in patients with preexisting psoriasis, but up to 3 out of 100 persons are affected overall. It progresses in older adults to present with skin or nail manifestations, the formation of either an arthritis or arthritis mutilans in which bone resorption occurs and destruction of the normal joint shape occurs. Telescoping digits are common in arthritis mutilans. Spondylitis may also occur in psoriatic arthritis, but only in a minority of patients. Sausage-shaped digits are common, along with onycholysis and occasional ocular manifestations such as uveitis. Treatment of psoriatic arthritis involves NSAIDs, DMARDs including sulfasalazine and cyclosporine, TNF antagonists such as etanercept, infliximab, or adalimumab, and vitamin D3. Corticosteroids are not used to avoid worsening the psoriasis after drug cessation. Exercise and physical therapy are recommended.

Enteropathic Arthropathy Arthritis due to various GI infections is referred to as enteropathic arthropathy. An immunologic predisposition towards antigens in various bacteria leading to an uncontrolled immune reaction and the development of an autoimmune disorder are blamed as the pathophysiology. This type of molecular mimicry is found with Shigella, Salmonella, Campylobacter, Yersinia, Clostridium, Strongyloides stercoralis, Taenia saginata, Giardia lamblia, Ascaris lumbricoides, and Cryptosporidium spp. Enteropathic arthropathy affects some 20% of patients with IBD. Enteropathic arthropathy presents like most other types of arthritis â&#x20AC;&#x201C; an axial arthritis is present that is worse in the morning or with low activity. Peripheral arthritis may develop. Manifestations of IBD such as abdominal pain, hematochezia, aphthous ulcers, pyoderma gangrenosum or erythema nodosum, uveitis, and low grade fever are all prevalent. Symptoms similar to reactive arthritis may develop. Water diarrhea and abdominal pain are common in some patients. Treatment of enteropathic arthropathy involves modifying the underlying IBD, whether it is Crohn disease or ulcerative colitis. NSAIDs are sometimes used with caution, but sulfasalazine is more popular. Antagonists to TNF are used by some care providers.

2.3.10

Crystalline Arthropathies

Gout Gout is the result of abnormalities with uric acid metabolism leading to arthritis and joint destruction. Excess stores of uric acid lead to tissue accumulation with subsequent urate crystal formation. Consumption of uncoated uric acid crystals by mediators of the immune system leads to an inflammatory 296

Pathology reaction, which can subsequently cause joint damage through oxidative injury and direct toxic injury. Gout affects about 1 in 100 persons, and is highly amenable to medical intervention. Untreated gout can lead to tophaceous gout with joint destruction. Diseases associated with hyperuricemia include hypertriglyceridemia and HTN. African Americans are somewhat more affected than others, and males more than women. Cyclosporin A administration has also been tied to the of gout. Gout may be exacerbated by alcohol abuse, starvation, trauma, bleeding, diuretics, allopurinol, Lesch-Nyhan syndrome with hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency, von Gierke Figure 5. Gout. Copyright Bob Galindo. Used with disease with glucose-6-phosphatase dehydro- permission. genase (G6PD) deficiency, and fructose-1-phosphate (F1P) deficiency. Overproduction of uric acid can occur in tumor lysis syndrome, psoriasis, obesity, hemolytic anemia, and lymphoproliferative disorders. Hypothyroidism, hyperparathyroidism, and renal insufficiency are other causes of gout. Gout presents as a monoarticular arthritis, especially affecting the lower extremities. The hallux is typically inflamed in a condition known as podagra, but this can be present in pseudogout and other arthritic conditions. Inflammation in gout reaches a maximum after about half a day with redness, swelling, and pain. Resolution of the initial attacks occurs within a couple of weeks, with recurrence over time. Polyarticular arthritis ensues over time with involvement of numerous other joints. A polyarticular arthritis develops over time and becomes chronic in course. Aspiration of synovial fluid and the demonstration of negatively birefringent crystals with sharp ends is diagnostic of gout. An elevated serum uric acid test is not diagnostic of gout, and asymptomatic hyperuricemia does not necessarily warrant treatment other than observation of renal function tests. Uric acid excess in a 24 hour urine sample is diagnostic of overproduction. Acute manifestations of gout are treated with NSAIDs, colchicine, and steroids. NSAIDs are the drug of choice, especially indomethacin. Colchicine is rarely used in the treatment of acute gout today due to its side effects and numerous contraindications. The chief complication of colchicine is granulocytopenia and so therefore requires WBC monitoring during administration. Gout prophylaxis involves the use of allopurinol or probenecid (absolutely contraindicated in acute attacks as they can precipitate gout). Colchicine is used as prophylaxis along with NSAIDs. With a second attack of gout, lowering uric acid is undertaken, starting with probenecid, then sulfinpyrazone, then allopurinol. Dietary changes include avoiding alcohol and having a low-fat, low-cholesterol diet to avoid the ancillary disorders associated with gout.

Calcium Pyrophosphate Deposition Disease Calcium pyrophosphate deposition disease (CPDD), also known as pseudogout, affects many people and increases in incidence with age. CPPD is a crystalline deposition within joints in the articular and fibrocartilage with subsequent chondrocalcinosis. Arthritis affecting the lower extremities is the result. The cause has been attributed to increased adenosine triphosphate (ATP) breakdown leading to a malformation in the cartilage around joints. CPDD presents in either an entirely asymptomatic form with only chondrocalcinosis found on plain 297

Clinical Review for the USMLE Step 1 films of the joints, or acute pseudogout with varying degrees of arthritis. Any joint may be involved, and nearly one-quarter of patients present with monoarticular arthritis. A neutrophil-laden synovial fluid aspirate is common; glucose levels are normal, and microscopic examination of the crystals yields rhomboid-shaped, positively birefringent crystals. In more severe forms, a pseudoarthritis can occur with features similar to osteoarthritis (OA) or rheumatoid arthritis (RA). Osteophytes can occur. Inflammation and tenderness with swelling of the joints is found on physical exam. Treatment of symptomatic CPDD involves reversing contributing conditions such as hyperparathyroidism or hemochromatosis. Joint aspiration with use of corticosteroids and NSAIDs form the mainstay of therapy. Colchicine is also an effective treatment. Supportive care is also offered to patients to maintain joint function.

2.3.11

Other Arthritis and Myopathy

Gonococcal Septic Arthritis Gonorrhea occasionally presents as a migratory polyarthritis due to disseminated infection. This type of infection is more likely in women, especially during pregnancy. Several days after a polyarthritis, a monoarthritis with a purulent buildup occurs due to local replication of Neisseria gonorrhea. Fever is typically present, but local symptoms in the genitourinary area are infrequently present. Skin lesions also develop in the form of necrotic pustules. The upper extremities are more commonly affected than the lower, especially the distal-most portions. Diagnosis is made by joint aspiration that indicates elevated WBCs; a positive blood culture is also often present. Treatment of gonococcal septic arthritis requires immediate medical attention to minimize additional destruction of the joint. Ceftriaxone works well. Surgical drainage is an option if the disease is refractory to the medication. Lack of response to the antibiotic should also begin a search for reactive arthritis and other arthropathies.

Nongonococcal Septic Arthritis Septic arthritis not due to infection by N. gonorrhea is typically present in patients with a prior history of trauma to the affected joint. This monoarticular infective arthritis is due to a bacteremia that colonizes a region that sustained previous damage. Common bacteria include S. aureus, GBS, and gramnegative rods in young adults. Patients with sickle cell anemia are more likely to be infected with and S. aureus. IC patients and IV drug abusers (IVDA) are likely to be infected by E. coli and Pseudomonas aeruginosa. There is an increased risk of contracting nongonococcal septic arthritis with increasing age, patients with RA, presence of prosthetic joints, and in those with an immunodeficiency. Septic arthritis presents with the cardinal signs of infection, including redness, heat, pain, and swelling. Fever is also present. The affected joint is typically painful to move, so a limited range of motion is present on physical exam. Diagnosis is made by clinical history, an elevated ESR, and positive blood cultures on joint aspiration. Arthrocentesis is a diagnostic and therapeutic maneuver that can identify the over one million WBCs that may be present in the region, the low glucose level indicative of a bacterial infection, and the presence of numerous PMNs. Arthrocentesis may also decrease the joint pressure and permit increased ROM. In conjunction with antibiotics tailored to the infective organism, resolution is possible with resumption of near normal joint function.

298

Pathology 2.3.12

Gas Gangrene

Gas gangrene refers to myonecrosis and soft tissue destruction through the production of toxins and gas by Clostridium perfringens, but other Clostridium spp. may also lead to infection. Low oxygen content and direct inoculation into the muscle make up the ideal conditions for infection. Numerous exotoxins are produced leading to destruction of collagen, hyaline membranes, fibrin crosslinks, lecithin, and overall hemolysis. The immune reaction is impeded through direct toxic injury to leukocytes and other mediators of inflammation. Vascular injury also impedes the ability of WBCs to enter the region of infection. Mortality can be very high, especially in spontaneous cases. Gas gangrene presents with sudden pain out of proportion to clinical findings. A history of trauma is often elicited, along with risk factors such as alcoholism, IVDA, or DM. Edema, erythema, tenderness, crepitus, discharge, and mental status changes are prevalent. Diagnosis is made by elevation of aldolase, potassium, LDH, CPK, and evidence of myoglobinuria. Anemia and metabolic acidosis may also be present. A positive sialidase test is also diagnostic. Treatment for gas gangrene involves hyperbaric oxygen exposure, debridement, IVF, and possible amputation to avoid death. Antibiotics are also used with penicillin, clindamycin, or chloramphenicol.

2.3.13

Polymyositis

Polymyositis is a connective tissue disorder (CTD) in which an autoimmune response occurs following infection by a virus. Implicated pathogens include Toxoplasma, influenza, and Coxsackie virus. Polymyositis leads to a bilateral proximal muscle weakness with dysphagia. Rising from a seated position and climbing stairs becomes very difficult. A related syndrome is dermatomyositis is a skin rash affecting the upper torso and face, along with an increased risk of malignancy. Diagnosis is made by elevated creatine phosphokinase (CPK) released from dying muscle fibers, abnormal EMG, and hypertrophy of the myofibrils. Laboratory tests are positive for ANA titers, ESR, CPK, LFTs, LDH, and aldolase. Muscle biopsy is definitive. Specific antibodies such as anti-Jo-1 may also be present. Polymyositis and dermatomyositis are differentiated from myasthenia gravis by the lack of ptosis. These two autoimmune diseases are treated with azathioprine and methotrexate in conjunction with corticosteroids to suppress the immune system. Exercises and physical therapy (PT) are prescribed to maintain ROM. This progressive disorder is eventually fatal, but survival is markedly improved with this therapy. A variant of polymyositis, known as inclusion body myositis, is refractory to immunosuppressive therapy.

2.3.14

Myasthenia Gravis (MG)

Myasthenia gravis is an autoimmune disorder that leads to weakness and fatigue due to antibodies versus the acetylcholine receptor (AChR) and neuromuscular junction (NMJ). MG is very rare, and mortality has decreased significantly with modern therapy. MG can occur at any age and affects females decades before it affects males. MG is typically idiopathic, but exposure to penicillamine can cause this disorder. MG is exacerbated by a number of drugs. MG presents as variable weakness worsened on exertion and improved with rest. Extraocular muscles (EOM) are weak and ptosis may be present in many patients. Facial muscle weakness is obvious on physical exam, along with weakness in the bulbar muscles, extremities, respiratory muscles, and ocular muscles. Antibodies against the AChR can be readily demonstrated in most patients. A false positive 299

Clinical Review for the USMLE Step 1 may be found with SCLC, thymoma, Lambert-Eaton syndrome, RA, and spontaneously in a minority of the population. Antibodies to striated muscle (anti-SM) are found in some patients with MG. CXR is used to rule out thymoma. Electromyography (EMG) is diagnostic, along with repetitive nerve stimulation (RNS). MG has no clear treatment. Inhibitors of AChE have been used with some effect; medications include pyridostigmine and neostigmine. Plasmapheresis and thymectomy are somewhat beneficial. Plasma exchange (PE) is useful in minimizing exacerbations. Immunomodulation with prednisone, azathioprine, and cyclosporine A (CsA) have some benefit.

2.3.15

Guillain-BarrĂŠ Syndrome (GBS)

Guillain-BarrĂŠ Syndrome is an inflammatory polyradiculoneuropathy leading to ascending weakness and diminished reflexes, and flaccid paralysis. It commonly occurs following infection by Campylobacter jejuni, and is the result of an autoimmune cascade leading to antibodies against GM1 and GD1b gangliosides found in peripheral nerve myelin. There are multiple variants of GBS with variable onset and severity. GBS affects 3 out of every 100,000 people and is more common with age. Death is the end result in 1 out of every 10 persons, and increases with age. Intercurrent illness is the most common cause with etiologies such as ventilator-dependent pneumonia, sepsis, ARDS, and autonomic dysfunction. Patients may be of any age. Vaccination, surgery, pregnancy, and trauma are identified triggers. Infection by CMV, EBV, Mycoplasma pneumoniae, HIV, influenza A and B, adenovirus, HSV, and VZV can also lead to GBS. GBS presents with an illness occurring several weeks prior to onset of weakness. This ascending, symmetrical weakness affects proximal muscles and progresses over time. Paresthesia is typically present, and cranial nerve involvement may lead to facial droop, diplopia, dysarthria, and dysphagia. The vast majority of patients also complain of pain symptoms. Various autonomic changes can also occur during the illness along with respiratory involvement. Remission occurs about a month after onset. On LP, an elevation in protein is found in the CSF but no WBCs are present. MRI and CT are occasionally used to rule out other etiologies. EMG is helpful in diagnosis. PFTs are used to gauge respiratory status. Treatment for GBS is done with inpatient therapy in about half of all persons. Supportive care is vital to ensure good outcome. Ventilatory support and close observation are typically done. Spontaneous resolution occurs over a month.

2.4. Cancer 2.4.1

Overview

The most common bony lesion is secondary metastasis from breast, lung, thyroid, kidney, and prostate cancers. Bone biopsy should be performed by the surgeon who will perform the definitive resection and reconstruction to ensure that the entire biopsy tract is resected in the event of malignancy. With regard to soft tissue masses, sarco- Figure 6. Osteosarcoma. Copyright Nephron. Used mas typically occur within fascial compart- with permission. ments. They are rapidly growing. Any mass 300

Pathology greater than 5 cm and deep to a fascial plane should prompt concern for sarcoma. Unlike carcinomas, sarcomas rarely metastasize to the lymphatic system. The most common site of metastasis is the lungs.

2.4.2

Osteosarcoma

Osteosarcoma is the most common malignant primary tumor of bone. It occurs most commonly in the second decade of life with a second peak of occurrence in the elderly; it affects males more than females. Osteosarcoma occurs “away from the elbow and toward the knee” – signifying that the distal femur, proximal tibial, proximal humerus, and distal radius are the most common sites of occurrence. Osteosarcoma leads to elevated alkaline phosphatase and LDH on laboratory analysis, a classic sunburst pattern (periosteal reaction seen on radiographs), and night pain. Treatment involves neoadjuvant chemotherapy followed by surgery. Survival rates are currently 80% with local control and no metastasis.

2.4.3

Ewing Sarcoma

Ewing’s sarcoma is the second most common malignant primary tumor of bone and is more common in children. It involves a chromosomal translocation t(11:22) and affects males more than females between the ages of 5 and 30. This tumor affects the diaphyseal region of long bones and appears as small round blue cells on histology and may mimic osteomyelitis. A bone marrow biopsy is part of the diagnostic workup due to metastasis within the marrow. Treatment includes neoadjuvant chemotherapy and surgery. Unlike many sarcomas, Ewing’s sarcoma responds to radiation therapy. Spinal Metastasis Figure 7. Ewing sarcoma. Copyright Nephron. Used with permission. Primary bone cancers are rare, and the most common cause of tumor in a bony region is due to metastatic cancer from a distal primary source. These tumors can include prostate cancer, breast cancer, lung cancer, kidney cancer, multiple myeloma, and lymphoma. Due to the convergence of the blood supply and proximity to several major organs, the thoracic spine is the most commonly affected region. Lesions tend to invade the marrow, causing a hypodense region noticeable on plain films. With sufficient damage, compression fractures can occur leading to paresthesia, paralysis, and other symptoms of spinal damage. Back pain is common, along with incontinence and lower extremity weakness. An upgoing Babinski sign may even be present. Diagnosis is typically made by CT and MRI. Management of significant tumors invading the spinal cord and vertebral column are often late stage cancers with little potential for cure. The key is to support the patient and make them comfortable. Inflammation of the spinal cord can be controlled with high dose corticosteroids. Radiation therapy is successful in minimizing these metastases and decreasing symptoms. Surgical decompression is also an option. The goal is to control pain and symptoms in the patient.

301

Clinical Review for the USMLE Step 1

3. Pharmacology Table 5. NSAIDs Drug

Indications

Mechanism of Action

Complications

Contraindications

Acetaminophen

Pain, fever, inflammation

COX-2 inhibition

Gastrointestinal hemorrhage, kidney damage, liver damage

History of GI bleed, liver disease, or kidney disease

Ibuprofen

Pain, fever, inflammation

COX-1 and COX-2 inhibition

Diarrhea, vomiting, gastrointestinal hemorrhage

History of GI bleed

Table 6. Muscle Relaxants Drug

Indications

Mechanism of Action

Complications

Contraindications

Cyclobenzaprine

Muscle spasm

Release of norepinephrine from locus ceruleus

Drowsiness, dizziness

Metaxalone

Muscle spasm

Depression of the CNS

Drowsiness, dizziness

Elderly patients

Methocarbamol

Muscle spasm

Depression of the CNS

Urine discoloration, drowsiness, dizziness

Elderly patients

Table 7. Anti-Gout Agents Drug

Indications

Mechanism of Action

Complications

Colchicine

Acute gout

Mitotic poison that inhibits tubulin / microtubules

Neutropenia, bone marrow suppression

Probenicid

Chronic gout

Increases uric acid secretion by kidneys

Multiple drug interactions

Allopurinol

Chronic gout

Xanthine oxidase inhibitor, decreased uric acid production

Hypersensitivity

Contraindications Renal failure

Pregnancy

Table 8. DMARDs Drug

302

Indications

Mechanism of Action

Complications

Hydroxychloroquine

Prevents lysosome degranulation and decreases neutrophil chemotaxis

Cinchonism

Methotrexate

Lymphocyte toxin prevents inflammation

BMS, crystalluria

Contraindications G6PD deficiency

Pharmacology

303

Section Editors Sapan S. Desai, MD, PhD

Danny O. Jacobs, MD, MPH

Assistant Professor Department of Surgery Duke University Medical Center

Professor and Chair Department of Surgery Duke University Medical Center

Contributors

RESPIRATORY

Judson Williams, MD

Charles Murphy, MD

Resident Assistant Professor Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center Thoracic Surgery (adapted from the Clinical Review of Surgery)

Sapan S. Desai, MD

Mark Williams, MD

Sapan Desai, MD, PhD

Michael Lidsky, MD

Assistant Professor Resident Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center

Luigi Pascarella, MD

Cynthia Shortell, MD

Resident Professor Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center Surgical Principles (adapted from the Clinical Review of Vascular Surgery)

John W. Hallett, MD

Joseph P. Hart, MD

Professor Assistant Professor Department of Surgery Department of Surgery University of South Carolina University of South Carolina Upper Extremity (adapted from the Clinical Review of Vascular Surgery)

Basic Science

1. Basic Science 1.1. Anatomy 1.1.1

Alveoli

Type I alveoli form the structure of the alveolar wall. Type II alveoli secrete surfactant to decrease the surface tension of water and permit gas exchange. Type III alveoli are immune cells that destroy foreign invaders. Figure 1. Alveoli. Copyright Mariana Ruiz. Used with permission.

1.2. Physiology 1.2.1

Oxygen-Hemoglobin Dissociation Curve

Table 1. Oxygen-Hemoglobin Dissociation Curve Factors Variable

Right Shift

Left Shift

Temperature

High

Low

2,3 DPG

High

Low

PCO2

High

Low

PCO

Low

High

Acidosis

Alkalosis

Hemoglobin

Adult hemoglobin

Fetal hemoglobin

1.2.2

Pulmonary Function Tests

Pulmonary function tests (PFTs) measure different aspects of lung volumes and flow rates. These reflect the mechanical properties of lung elasticity, recoil, and compliance. The specific measures include the total lung capacity (TLC), residual volume (RV), forced expiratory volume over 1 second (FEV1), forced vital capacity (FVC), and midmaximal forced expiratory flow (FEF). The diffusion capacity of carbon monoxide (DLCO) is a measure of the efficiency of gas exchange from alveoli to blood. The DLCO is decreased with interstitial lung disease and emphysema. DLCO levels less than 40% of predicted are associated with increased perioperative risk. Bronchial hyperreactivity is tested with a methacholine challenge test, and is contraindicated in asthmatics. FEV1 (or other PFT measures) may be expressed as an actual value such as 0.9 liter per second or as a percentage of the predicted values based Figure 2. Oxygen-hemoglobin dissoon height and weight in normal patients. By accounting for ciation curve. Copyright Wikimedia. body habitus, the percent predicted value is more accurate. Used with permission. 305

Clinical Review for the USMLE Step 1

Figure 3. Pulmonary function tests. Copyright Vihsadas. Used with permission. PFTs are required before lung resection and must have a predicted post-op FEV1 greater than 0.8. An FEV1 > 2 L is required prior to pneumonectomy, > 1 L for a lobectomy, and 0.6 L for a wedge resection. If the FEV1 is less than 60% predicted, then a quantitative xenon-133 ventilation-perfusion lung scan may be considered to quantify the contribution of each lung to overall pulmonary function and improve the accuracy of predicted postoperative pulmonary function. Table 2. Pulmonary Function Tests Total lung capacity

Residual volume

Force expiratory volume

Forced vital capacity

Midmaximal forced expiratory flow

Diffusability of carbon monoxide

Methacholine challenge

The TLC is the entire volume of air that the lung can retain with maximal inspiration. RV is the remaining volume after maximum expiration, and is a volume of air that is always present. The vital capacity (VC) is the difference in volume between the TLC and RV. The functional reserve capacity (FRC) is the volume that remains after a normal breath, in addition to the RV. The inspiratory capacity (IC) is the maximum inspiratory volume that can be taken in with a normal breath. The IC and FRC add up to the VC, and, as stated above, the VC plus the RV equal the TLC. With a normal breath, the inspiration is known as the tidal volume (VT). The additional volume that is available for inspiration is known as the inspiratory reserve volume (IRV), while the additional volume available for expiration is the expiratory reserve volume. The IRV plus VT plus ERV equal the VC. With a normal breath, the ERV is equal to the FRC. 306

Pathology TLC = RV + ERV + V T + IRV = FRC + V T + IRV = RV + VC VC = ERV + V T + IRV FRC = RV + ERV Expiratory flow rate = FEV1 / FVC The diffusing capacity of the alveoli (DLCO) is generally decreased with interstitial lung disease and emphysema.

1.2.3

Gas Exchange and Hypoxia

Disorders with gas exchange can lead to impaired oxygen delivery to vital tissues and present with symptoms of hypoxia. Oxygen transport relies on sufficient cardiac output and hemoglobin of sufficient saturation and quantity. In patients with poor CO or Hgb, giving the patient 100% oxygen does little to improve the oxygenation. Calculating oxygenation can be done with the alveolar-arteriolar gradient: PAO2 = 150 - PaCO2 / 0.8 A-a gradient = PAO2 - PaO2 Faulty gas exchange can manifest as hypoxia. Causes of hypoxia can be attributed to poor ventilationperfusion (V-Q) mismatch leading to poorly ventilated alveoli or ventilation of poorly perfused alveoli; a right to left cardiac shunt that moves poorly oxygenated blood into the systemic circulation; anemia that leads to decreased oxygen carrying capacity in the blood and subsequent poor oxygenation; poor perfusion from MI or shock; increased oxygen demand with poor increases in supply; impairment in oxygen delivery due to cyanide or carbon monoxide poisoning; and low inspired oxygen at higher altitudes. The most significant contributor to oxygen carrying capacity is hemoglobin. Increasing PO2 over 100 increases oxygen only slightly via increased dissolved oxygen in the blood. Fe3+ improves oxygen delivery. Oxygen delivery is defined as the amount of oxygen made available to the body in one minute. It is equal to the cardiac output times the arterial oxygen content. This is approximately 1 L O2 per minute. Oxygen consumption is the amount of oxygen used every minute. Approximately 25% of the arterial oxygen is used every minute (95%+ saturation of blood leaving the heart, about 70% saturation of venous blood returning to the heart). Oxygen extraction decreases with the volume of oxygen, as it becomes harder to remove oxygen from insufficiently populated hemoglobin molecules. SVO2 increases with an increase in cardiac output. Oxygen extraction increases with sepsis, leading to a greater A-V oxygen gradient.

2. Pathology 2.1. Congenital 2.1.1

and

Structural

Pneumomediastinum

Pneumomediastinum, sometimes referred to as mediastinal emphysema, is the result of air in the mediastinum. It is commonly due to rupture of the esophagus, alveolar rupture (with dissection of air retrograde along the airways rather than into the pleural space), or damage to the tracheobronchial tree. 307

Clinical Review for the USMLE Step 1 This diagnosis is established by air in the mediastinum on either plain films or CT scans of the chest. Hamman’s sign is present in 50% of the cases. The presence of pneumomediastinum should prompt a targeted work-up to look for the source. A patient with recent vomiting should undergo a gastrograffin swallow to rule out a leak. A blunt trauma patient would undergo bronchoscopy to rule out a tracheobronchial injury. The underlying cause of the pneumomediastinum should be corrected.

2.1.2

Thoracic Outlet Syndrome

The thoracic outlet is bound by the first ribs, clavicles, manubrium, and the first thoracic vertebra. It defines the transition between the root of the neck and the superior mediastinum. Hypertrophy of the anterior and middle scalene muscles, narrowing of the space between the clavicle and first rib, or the presence of a cervical rib may lead to compression of the brachial plexus, subclavian artery, or subclavian vein and lead to clinicallysignificant thoracic outlet obstruction. There are other rarer causes of obstruction, including the presence of fibrous bands, exostosis of the first rib, bifid clavicle, abnormalities of the omohyoid muscle, and enlargement of the C7 transverse process. Trauma to the upper extremity or chest can cause fractures of the clavicle or dislocation of the head of the humerus and present with disruption of the structures within the thoracic outlet. The brachial plexus and subclavian artery travel through the scalene triangle, while the subclavian vein passes through the costoclavicular space. The boundaries of the scalene triangle include the anterior scalene muscle (anterior border), middle scalene muscle (posterior border), and first rib (inferior border). The costoclavicular space is bound by the clavicle (superior border), first rib (inferior border), costoclavicular ligament (anterior border), and middle scalene muscle (posterior border). Thoracic outlet syndrome (TOS) is a constellation of conditions caused by compression of one or more components of the neurovascular structures passing 308

Figure 4. Venous TOS patient undergoing lytic therapy for acute axillo-subclavian vein thrombosis (Paget-Schrötter syndrome). Initial injection showing angiographic presence of “first rib collaterals” (A). After an initial period of lysis, the peripheral aspect of the axillary vein is better identified, though thrombus remains (B) and this was subsequently crossed with a lysis catheter for additional treatment. In a final view (C) after further treatment, the subclavian vein was recanalized and the patient was bridged on heparin to Coumadin anticoagulation with interval first rib resection for definitive treatment of extrinsic compression. Courtesy of Joseph Hart and J. Joseph Hallett.

Pathology Trapezius muscle

Thoracoacromial artery Pectoralis minor tendon (cut) Coracoid process Acromion Cephalic vein

Acromial branch Deltoid branch

Suprascapular artery and nerve Dorsal scapular artery and nerve Transverse cervical artery

Clavicular branch Pectoral branch

Musculocutaneous nerve

Axillary artery

Anterior circumflex humeral artery Axillary nerve and posterior circumflex humeral artey

Clavicle and subclavius muscle (cut)

Pectoralis major muscle (cut) Coracobrachialis muscle

Anterior scalene muscle Sternocleidomastoid muscle

Deltoid muscle

Phrenic nerve

Biceps brachii muscle

Omohyoid muscle

Musculocutaneous nerve

Brachialis muscle

Ulnar nerve Medial brachial cutaneous nerve Intercostobrachial nerve Circumflex scapular artery

Profunda brachii (deep brachial) artery Radial nerve Triceps brachii muscle Brachial veins Ulnar nerve Median nerve Brachial artery

Lower subscapular nerve Teres major muscle Subscapular artery Latissimus dorsi muscle Thoracodorsal artery and nerve Upper subscapular nerve

Medial antebrachial cutaneous nerve Basilic vein

Serratus anterior muscle

Subclavian artery and vein 1st rib Brachial plexus Superior thoracic artery

Lateral pectoral nerve Lateral thoracic artery and long thoracic nerve Ansa pectoralis Medial pectoral nerve Pectoralis minor (cut)

Figure 5. The thoracic outlet and its major neurovascular structures. Copyright NetterImages. Used with permission. to the upper extremity via the thoracic inlet. There are considered to be three types of TOS: neurogenic (95%), venous (4-5%) and arterial (<1%). Treatment strategies employed depend on the TOS type identified. Neurogenic TOS is the most common form of TOS, but is also the hardest type to conclusively 309

Clinical Review for the USMLE Step 1 diagnose and treat successfully. A small group of high volume centers have, however, reported excellent results with treatment of highly selected groups of neurogenic TOS patients. Table 3. Types of thoracic outlet syndrome: presentation and treatment. After Fugate et al. and Sanders et al. Type

Incidence

Cause

Symptoms

Physical Exam

Treatment

Finger paresthesia, neck pain, headache, and arm pain

Supraclavicular tenderness, reproduction of symptoms with arm in 90o AER

Preoperative PT and CT guided block, scalenectomy, and first rib resection

Neurogenic

95%

Congenital narrowing of thoracic inlet and trauma

Venous

Venous compression at costoclavicular space

Acute or chronic arm swelling, arm pain

Swelling, cyanosis, and anomalous distended veins over shoulder and chest

Thrombolysis or catheter thrombectomy, first rib resection, PTA, or operative repair of vein

<1%

Cervical rib or anomalous first rib

Digital ischemia, cold sensation, digital numbness, claudication, and rest pain

Decreased unilateral blood pressure, pulses, and digital pressures; pallor, digital gangrene

Repair arterial aneurysm, resect cervical rib or abnormal first rib

Arterial

90o AER = 90o abduction in external rotation test. BP = blood pressure.

Venous and arterial TOS present with venous thrombosis or arterial ischemia/embolization respectively and as such are more readily recognized by the clinician. Venous and arterial TOS can most often be diagnosed rapidly by history and physical exam with the addition of duplex ultrasound and ultimately angiography in patients regarded as candidates for interventional and/or surgical therapy. Thrombolysis may be utilized as the first step in restoration of normal blood flow in venous and arterial disease. To definitively treat vascular TOS, first rib resection with anterior scalenectomy and resection of any cervical or other rudimentary ribs inciting the initial vascular injury leading to thrombosis is required. In arterial TOS, the subclavian artery will usually require reconstruction. Various surgical and interventional approaches to venous reconstruction in venous TOS have been described, but these must only be utilized either after (or in some cases during) surgical decompression of the bony compression leading to the venous thrombotic event. Symptoms in each of the distinct syndromes are determined by the neurovascular component which is compressed: differences between the three types of TOS are delineated in the table above. The scalene triangle is the space of greatest importance in this entity with regard to the anatomic relationships between involved structures. The anterior and middle scalene muscles form the sides of this space, arising from the lower cervical spine. The first rib is the scalene triangleâ&#x20AC;&#x2122;s base. The subclavian artery and vein as well as the five roots of the brachial plexus must pass through the relative confines of the scalene triangle. The subclavius muscle which travels from the clavicle to the first rib may also compress this space and in particular may be hypertrophied in athletes presenting with effort thrombosis of the subclavian vein. Congenital and acquired factors may contribute to the development of TOS. Trauma, cervical ribs, long C7 transverse process, or bifid first ribs may all lead or contribute to TOS. Congenital fibromuscular bands are also often seen, particularly in neurogenic TOS. Up to 80% of TOS patients report a history of trauma to the neck or shoulder. Repetitive activity due to athletic or occupational activities is a highly significant patient history finding, especially in venous TOS. TOS, in all of its variants remains an enormously interesting and challenging clinical problem. There remains significant interest in pursuing national research protocols in research on management, surgery 310

Pathology and outcomes in TOS.

2.1.3 Atelectasis Collapse of a portion of the lung is one of the most common causes of early postoperative fever due to activation of alveolar macrophages and secretion of IL-1. Poor inspiratory effort in this period, lack of sufficient coughing and lung expansion, and failure to use devices that aid in inspiration and expiration have all been implicated in the development of lung collapse. Atelectasis presents with fever, tachycardia, dyspnea, tachypnea, and hypoxemia. Deviations of the trachea or elevations of the diaphragm may be present on CXR, while more significant atelectasis may have mediastinal shifts. Treatment of atelectasis involves incentive spirometry, inducing cough, and deep breathing in an attempt to re-expand the affected lung regions. Treating any concomitant pulmonary disorders is also necessary, along with removing any obstructions or foreign bodies via bronchoscopy. Early ambulation following surgery reduces the risk. Fever is induced by alveolar macrophages. Aspiration leading to atelectasis may be treated with nasotracheal suctioning and bronchoscopy. Positive end-expiratory pressure ventilation may be used to treat associated hypoxia.

2.1.4 Bronchiectasis Figure 6. Venous TOS patient undergoing lytic therapy for Paget-Schrötter Syndrome. Initial injection demonstrates presence of heavy axillosubclavian thrombus burden (A). After an initial period of lysis, the axillosubclavian vein is better delineated, though thrombus remains (B) and “first rib collaterals” are still present. After further treatment (C), the subclavian vein was recanalized, extrinsic compression is still apparent, and the patient was bridged on heparin to Coumadin anticoagulation with interval first rib resection for definitive treatment. Courtesy of Joseph Hart and J. Joseph Hallett.

The anatomic distortion of a conducting bronchi, often with permanent dilation due to elastic and muscular damage to the epithelium, results in bronchiectasis. This obstructive lung disease leads to dilation of the mediumsized bronchi and may be either acquired or genetic. Congenital bronchiectasis presents early in age and is due to a developmental disorder that affects the bronchi. Such disorders include cystic fibrosis (CF), ciliary dyskinesia (as in Kartagener syndrome) with concomitant situs inversus and sinusitis. Acquired disorders include early lung injury such as pneumonia, abscess, tuberculosis and other infections, and chronic lung injury with RSV or bacterial infection. Immunocompromised states leading to Mycobacterium avium complex (MAC) is another cause. Allergic bronchopulmonary aspergillosis, alpha-1-antitrypsin deficiency, autoimmune disease, and toxic gas exposure are rarer causes of bronchiectasis.

Bronchiectasis presents with fever, anorexia, hemoptysis, dyspnea, pleuritic chest pain, wheezing, and significant sputum production and a chronic, productive cough. A history of recurrent infections is typi311

Clinical Review for the USMLE Step 1 cally present in the acquired form, while obvious physical signs of any congenital form are also present in selected patients. On physical exam, crackles, wheezing, and signs of chronic hypoxia are also evident. Diagnosis is made by CXR that shows a tram-track appearance in later stages of the disease, CT, Polycythemia and elevated WBCs on CBC, sputum analysis, and PFTs. PFTs typically indicate irreversible obstruction. CT is the preferred diagnostic test due to its very high sensitivity. The most common cause of hemoptysis is bronchiectasis. Symptomatic management of bronchiectasis is the cornerstone of therapy. Smoking cessation is mandatory, along with vaccinations for influenza and pneumonia. Oxygen therapy, as with COPD, is also used as necessary. Antibiotic prophylaxis is used including amoxicillin, tetracycline, TMP-SMX, azithromycin, cephalosporins, and quinolones. Bronchodilators, physical therapy, and drainage of mucus are essential to reducing morbidity and hospitalization; special compressive devices are also available to help expel the mucus. Surgical resection is reserved for severe cases involving poor function or large hemoptysis. Lung transplantation is the ultimate option.

2.1.5

Asthma

Asthma is reversible airway hyperreactivity that leads to bronchoconstriction, inflammation, and increased secretion. Asthma is typically a lower airway disease with the formation of mucus plugs and edema. It typically occurs intermittently with interposed periods of normal airway, and is most common in children. Asthma usually spontaneously remits over time and 80% of adults who had asthma growing up are symptom-free. About half of all causes of asthma deal with non-allergenic causes, including exposure to cold, certain inhalants, exercise, and anxiety. This is known as intrinsic asthma, and typically heralds a poorer prognosis. On the other hand, extrinsic asthma is due to allergens that increase IgE and cause an immune reaction with increased eosinophils. Also known as atopic asthma, this form of asthma typically has a family history of sensitivity, and presents with rhinorrhea, eczema, and urticaria. Extrinsic asthma has a better prognosis than intrinsic asthma. Asthma is worsened with respiratory irritation as often occurs with infection, aspirin, and B-blockers. The typical individual who has aspirin-induced asthma often meets the criteria for Samterâ&#x20AC;&#x2122;s triad: nasal polyps, aspirin allergy, and asthma. Changes in the airway with asthma are due to bronchial smooth muscle spasms that lead to constriction of both large and small airways. Over time, hypertrophy of these cells also leads to symptoms. In extrinsic asthma, the release of vasoactive substances by eosinophils leads to edema and secretion of copious amounts of mucus. The result is plugging of the airway and obstruction leading to hypoxia. Such mediators include histamine, bradykinin, various leukotrienes, and various prostaglandins. Mast cells, lymphocytes, and eosinophils have all been implicated as playing a vital role in the inflammatory process. With extrinsic asthma, the early phase occurs with IgE-mediated effects leading to mast cell release of histamine. The late phase occurs with cytokine release. The signs and symptoms of an asthma attack are dependent on the severity of the attack. Mild asthma typically produces a transient dyspnea with tachypnea and tachycardia. Diffuse wheezing is sometimes evident. Moderate asthma may have both inspiratory and expiratory wheezing. Severe asthma presents with no wheezing, diminished breath sounds, chest tightness, significant dyspnea, shortness of breath, intercostal retractions, and a dry, nonproductive cough. Factors that herald a poorer prognosis include cyanosis, decreased wheezing, bradycardia, decreased breathing with diminishing breath sounds, pulsus paradoxus, and diaphoresis. On physical exam, chest wall retractions may be present indicating increased respiratory effort, inability to speak normally, and wheezing may all be obvious. Asthma is diagnosed by CXR, PFTs, ABG, and careful history and exam. CXR is typically nonspecific and is primarily useful in ruling out other etiologies. PFTs indicate an obstructive pattern in which 312

Pathology FEV1 is less than 80% of normal, or the ratio of FEV1: FVC is less than 65%. ABG shows an acute increase in pH and a decrease in PaCO2, while severe asthma may have a decrease in pH, decrease PaO2, and increased PaCO2. Decompensation in the asthmatic may have an ABG that shows a normal PaCO2, often a sign that intubation may be necessary due to impending respiratory failure. Allergen inhalation challenges, skin testing, and radioallergosorbent assay tests (RASTs) may be used to clinch the diagnosis of asthma, although these are not typically performed. A typical ABG in mild asthma is a pH of 7.48, PCO2 of 30, and PO2 of 60 (recall that normal is 7.4, 40, and 98 respectively). Severe asthma presents with a pH of 7.4, PCO2 of 40, and a PO2 of 55.

Staging and Treatment – Mild Intermittent Asthma staging is important for proper treatment of this potentially fatal disorder. Asthma is graded by severity as mild, moderate, or severe, and by frequency of symptoms as either intermittent, or persistent. Mild intermittent asthma (stage 1) presents with symptoms no more than twice a week with night-time symptoms less than twice a month. FEV1 is 80% or better with a less than 20% variation. Mild intermittent asthma is treated with short-acting bronchodilators and severe exacerbations are treated with systemic glucocorticoids.

Staging and Treatment – Mild Persistent Mild persistent asthma (stage 2) presents with daytime symptoms several times a week, but not on a daily basis. Nocturnal symptoms occur several times a month. FEV1 continues to be better than 80%, but variability is typically between 20% and 30%. Treatment of mild persistent asthma consists of daily low-dose inhaled glucocorticoids, short-acting bronchodilators as needed, and several alternative therapies that are occasionally prescribed. Inhaled cromolyn, leukotriene modifiers, nedocromil, and sustained-release theophylline are some of these alternatives.

Staging and Treatment – Moderate Persistent Stage 3 asthma is moderate persistent with daily symptoms. Nocturnal symptoms occur weekly, and FEV1 is between 60-80% of normal. Variation of FEV1 is more than 30%. Moderate persistent asthma is treated with inhaled glucocorticoids on a daily basis in combination with long-acting bronchodilators. Short-acting bronchodilators are also added to the regimen. Alternative therapies include increasing the dosage of inhaled glucocorticoids, and using a leukotriene modifier or theophylline.

Staging and Treatment – Severe Persistent Stage 4 asthma is severe persistent asthma, also known as continuous asthma. Daytime symptoms are always present, and nocturnal symptoms are common. FEV1 is less than 60% of normal, and variation is more than 30%. Treatment consists of high-dose inhaled glucocorticoids and long-acting beta-2 agonists given on a daily basis. Short-acting bronchodilators are given as necessary. Additional medications are added as needed, and include oral glucocorticoids and the regimens mentioned above. Asthma requires prompt treatment to resolve symptoms. The hypoxia is very real and results in over 5,000 deaths a year. Glucocorticoids are the mainstay of treatment and are used to reduce inflammation. Supplemental oxygen, nebulizer treatment, IV fluids, and ventilatory support are all used in asthma treatment. Smoking cessation is important, along with modification of environmental risk factors such as dust, animals, cockroaches, mold, and pollen. Immunotherapy is occasionally used with repeated injections of allergen into the body, and is highly effective. Omalizumab, an antibody to IgE, is also used in certain cases, especially in severe asthma. 313

Clinical Review for the USMLE Step 1 Table 4. Asthma Intrinsic asthma- Non-allergenic causes: exposure to cold, certain inhalants, exercise, and anxiety. Etiology

Extrinsic asthma- Due to allergens that increase IgE and cause an immune reaction with increased eosinophils, has a family history of sensitivity, and presents with rhinorrhea, eczema, and urticaria. Mild asthma - transient dyspnea with tachypnea and tachycardia. Diffuse wheezing is sometimes evident.

Presentation

Moderate asthma -may have both inspiratory and expiratory wheezing. Severe asthma-no wheezing, diminished breath sounds, chest tightness, significant dyspnea, shortness of breath, intercostals retractions, and a dry, nonproductive cough. On physical exam, chest wall retractions may be present indicating increased respiratory effort, inability to speak normally, and wheezing.

Differential diagnosis

Reactive airway disease, CHF, aspiration of a foreign body, pneumoconiosis, COPD, emphysema, pneumonia, PAN, sarcoidosis, tracheal stenosis, sinusitis, pulmonary HTN, lung cancer, and variants of asthma.

Diagnosis

CXR, PFTs, ABG, and careful history and exam. Allergen inhalation challenges, skin testing, and RASTs may be used to clinch the diagnosis of asthma.

Mild intermittent (stage 1) Mild persistent (stage 2) Moderate persistent (stage 3) Severe persistent

Treated with short-acting bronchodilators and severe exacerbations are treated with systemic glucocorticoids. Daytime symptoms several times a week, but not on a daily basis. Nocturnal symptoms occur several times a month. Daily low-dose inhaled glucocorticoids, short-acting bronchodilators as needed, and several alternative therapies are occasionally prescribed. Daily symptoms. Nocturnal symptoms occur weekly. Inhaled glucocorticoids on a daily basis in combination with long-acting bronchodilators. Short-acting bronchodilators are also added to the regimen.

(stage 4)

Daytime symptoms are always present, and nocturnal symptoms are common. High-dose inhaled glucocorticoids and long-acting beta-2 agonists given on a daily basis. Short-acting bronchodilators are given as necessary. Additional medications are added as needed, and include oral glucocorticoids.

General treatment

Glucocorticoids, supplemental oxygen, nebulizer treatment, IV fluids, and ventilatory support. Smoking cessation is important, along with modification of environmental risk factors. Immunotherapy is occasionally used with repeated injections of allergen into the body, and is highly effective, Omalizumab.

Inpatient treatment

Indications for intubation include severe dyspnea, hypoxia, tachypnea, and mental status changes indicating hypoxia. ABG is useful. Overventilation should not be done, and expiratory time should be prolonged.

Beta 2 agonists are administered through nebulizers or metered dose inhalers (MDIs). Ipratropium bromide is delivered by the same mechanism and is used to decrease airway secretions. Albuterol is an example of a short-acting medication, and salmeterol is an example of a long-acting medication. Glucocorticoids are used to decrease inflammation, and can be given by MDI, oral, or IV routes. Side effects of glucocorticoids include inhibited growth, weight gain, HTN, glaucoma, cataracts, diabetes, and osteoporosis. Leukotriene modifiers such as zafirlukast are used to prevent degranulation; another example is the mast cell stabilizer cromolyn sodium and nedocromil. Theophylline is used only in limited cases due to the number of side effects this medication has, including the ability to cause seizures and arrhythmia. Asthmatics may require intubation in order to ensure respiratory integrity. Indications for intubation include severe dyspnea, hypoxia, tachypnea, and mental status changes indicating hypoxia. ABG is useful in intubation, in that an ABG with normal PaCO2 in a patient who is laboring to breath (or has suddenly become very quiet) is an indicator for immediate intubation. Overventilation should not be done, and expiratory time should be prolonged.

314

Pathology 2.1.6

Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) includes emphysema and chronic bronchitis. A longstanding expiratory obstruction is present with decreases in FEV1. COPD is an irreversible airway obstruction and presents with significant anatomical and functional changes. Chronic bronchitis presents with a chronic productive cough for at least three months within a two year period. Emphysema presents with airway enlargement distal to the terminal bronchioles. COPD is more common in men and carries a greater mortality in Caucasians. The most common cause of COPD is smoking, followed by air pollution, infection, allergy, and alpha-1-antitrypsin deficiency. Up to 90% of patients with COPD are smokers. Alpha-1-antitrypsin deficiency is an autosomal recessive disorder that is more common in patients of Mediterranean descent. Liver abnormalities are commonly present in this disorder. The underlying pathophysiology of COPD is increased airway resistance in bronchitis, and decreased lung recoil in emphysema. Patients with chronic bronchitis are typically known as blue bloaters and present with right heart failure, polycythemia, and high PCO2 with low O2 on ABG. Patients with emphysema are typically known as pink puffers with a barrel chest, anorexic appearance, and a low PCO2 with normal PO2 on ABG. Congenital lobar emphysema is accompanied by compression of normal alveoli. The diagnosis of COPD is established by physical exam, CXR, and PFTs. Chronic bronchitis presents with ronchi and wheezes upon auscultation; emphysema presents with distant breath sounds. The CXR shows increased pulmonary markings with chronic bronchitis. Emphysematous changes on CXR include lung hyperinflation, flattening of the diaphragms, small heart size, and increased retrosternal space. PFTs indicate an increased TLC and RV, but a reduction in FEV1, FVC, and FEF. DLCO is decreased in emphysema. As COPD is irreversible, there is typically little change in FEV1: FVC after administration of bronchodilators. Obtaining PFTs is the diagnostic method of choice for COPD. COPD is primarily treated with oxygenation via home oxygen support. The goal is to maintain PaO2 over 60 and hemoglobin saturated over 90%. Vaccinations against influenza and Streptococcus pneumoniae are mandatory. Antibiotic treatment is given empirically against Haemophilus influenzae and Streptococcus pneumoniae to reduce hospitalization and acute symptoms. Inhaled beta agonists are used along with ipratropium bromide, and ste- Figure 7. COPD. Copyright James Heilman. Used with roids are used during exacerbations. Surgical permission. options are limited, but include lung volume reduction to improve FEV1. Lung volume reduction appears to benefit COPD patients with primarily upper lobe disease with decreased exercise tolerance. Lung transplantation is an option for selected patients. Regardless of what treatment is used, smoking cessation is mandatory to slow the progression. 315

Clinical Review for the USMLE Step 1 Survival in COPD is best predicted by FEV1, with a rapid decline indicative of increased morbidity and mortality. Dyspnea often occurs with exercise (DOE) when FEV1 drops below 50% predicted. FEV1 below 25% often portends dyspnea at rest.

2.1.7

Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a severe diffuse alveolar injury that leads to pulmonary infiltrates, hypoxemia, and failure of normal lung function. Increased permeability of the alveoli leads to fluid infiltration into the alveoli and subsequent damage to the sensitive epithelial cells. Damage occurs primarily to the vascular endothelium or alveolar epithelium, depending on the nature of the infiltrate. Vascular congestion occurs with alveolar collapse, inflammatory cell infiltration, and edema. Pulmonary edema occurs with destruction of type II pneumocytes. Longstanding damage leads to hypoxemia, pulmonary HTN, and in more severe cases, fibrosis with permanent and progressive pulmonary damage. Limited acute injury typically resolves. ARDS presents with acute onset of dyspnea and hypoxemia following an identifiable cause (i.e. drug overdose, sepsis, acute pancreatitis, aspiration). Physical findings include tachypnea, tachycardia, dyspnea, oxygen supplementation, signs of hypoxia, and signs of the underlying etiology. ARDS often occurs with sepsis and shock. Criteria Figure 8. Acute respiratory distress syndrome. Copyright for diagnosis include acute onset, bilateral pulmonary infiltrates on CXR, James Heilman. Used with permission. hypoxemia (i.e. PaO2 / FiO2 less than 200), and absence of cardiogenic pulmonary edema (PAWP < 18 mmHg). Treatment of ARDS is primarily supportive with treatment of the underlying etiology. Respiratory support may be necessary. Maintaining an FiO2 as low as possible is helpful. Permissive hypercapnia is a strategy often employed to achieve minimal ventilator settings. Utilizing a low tidal volume strategy of 6 ml/kg provides a survival benefit.

2.1.8

Sleep Apnea

Sleep apnea is the abrupt, recurring discontinuation of airflow for more than 10 seconds that occurs multiple times per night in a sleeping patient. Decreased oxygen saturation and increased pulmonary pressure account for the high complication rate of pulmonary HTN in this group of patients. Daytime sleepiness is common due to this sleep abruption, along with HTN and cor pulmonale. Obstructive sleep apnea (OSA) is secondary to poor airway integrity leading to airway collapse; positive pressure ventilation via nasal cannula (CPAP via NC) is necessary. Central sleep apnea is due to decreased respiratory drive by the CNS. Treatment of central sleep apnea is with administration of progesterone, 316

Pathology acetazolamide, and oxygen. Diagnosis is made by polysomnography

2.1.9

Idiopathic Pulmonary Fibrosis (IPF)

Progressive interstitial lung disease leading to inflammation and lung fibrosis is known as idiopathic pulmonary fibrosis (IPF). In this disease, repeated injury and healing leads to a rampant fibrotic process that destroys healthy lung tissue. The precise cause is unknown, but environmental allergens, various pneumoconioses, and aspiration from GERD have all been implicated. IPF presents with DOE, a nonproductive cough, and constitutional symptoms. Oxygen-dependence occurs early in the disease, and there is no remission. Progressive illness leads to worsening symptoms with eventual clubbing from hypoxia, pulmonary HTN, and RHF. Diagnosis is made by CT, which indicates pleural effusions, hilar adenopathy, densities, mediastinal lymph nodes, reticular and linear opacities, cystic air spaces, and ground-glass opacities. PFTs indicate a reduction in lung volume, and DLCO is used to determine the extent of the disease. PaO2 with ABGs classically decreases with exertion. A bronchoalveolar lavage (BAL) is occasionally performed. Biopsy is necessary to rule out other modalities. IPF is a diagnosis of exclusion. Treatment of IPF involves steroids and azathioprine to decrease the progression to full lung fibrosis and respiratory collapse. However, this is a progressive disease and total lung failure is irreversible.

2.1.10

Sarcoidosis

Sarcoidosis is a inflammatory disorder that affects multiple systems leading to the development of noncaseating granulomas. T cells are responsible for the development of sarcoidosis, and increased production of various cytokines with T cell propagation to various tissues leads to inflammation, B cell hyperreactivity, and fibrinogenesis. Sarcoid leads to death via respiratory failure and RHF. Sarcoid is especially common in African Americans and young adults. Sarcoidosis presents with a history of constitutional symptoms, pulmonary symptoms including DOE, chest pain, and cough; however, sarcoidosis can be entirely asymptomatic. Physical exam findings include exertional desaturation, bilateral hilar lymphadenopathy on CXR, and fibrosis. Erythema nodosum occasionally occurs, along with a facial rash, granulomas leading to impingement of the eyesight, and CNS changes. Diagnosis involves increased vitamin D secretion by the granulomas with hypercalcemia, elevated alkaline phosphatase from liver damage, increased ACE, documenting pulmonary changes, and PFTs that indicate decreased DLCO and a restricted pattern. Biopsy is used for confirmation. Sarcoid is a difficult disease to treat. Steroids are used with some benefit, but increased relapse may occur. Methotrexate, hydroxychloroquine, cyclosporine, azathioprine, and other medications are variably useful. Minimal disease affecting the lungs is typically only observed; treatment is instituted only with chronic disease with changes in oxygenation and PFTs.

2.1.11

Pneumoconiosis

Overview Pulmonary fibrosis stemming from toxic lung injury is known as pneumoconiosis. Repeated exposure to pulmonary irritants and toxins leads to fibrosis of the lung over many years. The disease begins with macrophages consuming the toxic compounds leading to inflammation. Early bouts of inflammation are typically resolved, but repeated toxic injury leads to rampant inflammation and fibrosis. Common 317

Clinical Review for the USMLE Step 1 causes include asbestos dust exposure, silica dust exposure, and coal dust exposure. There is typically no treatment for pneumoconiosis. However, bronchodilators have been used in certain etiologies with some benefit. Standard respiratory treatments (i.e. oxygen therapy, beta-agonists) are somewhat beneficial.

Asbestosis Asbestosis may occur in mining, milling, shipyard work, and repeated exposure to materials that contain high levels of asbestos (insulation, brake linings). Asbestosis presents with DOE, wheezing, cough, pleuritic chest pain, SOB, excess sputum production, clubbing, and respiratory failure. Hypoxemia is present along with a restrictive PFT. DLCO is decreased. CXR indicates pleural thickening with plaques and calcifications. Pleural effusions are typically present from the inflammation, especially in the lower lung region around the diaphragm. Asbestosis has been linked to bronchogenic adenocarcinoma. Smoking increases this risk by nearly 100 fold.

Silicosis Silica dust exposure may occur in mining, quarrying, glass production, and sandblasting. It presents similar to asbestosis, while significant exposure can lead to rapid respiratory failure. Hyaline nodules are typically present. Silicosis has been associated with tuberculosis, and prophylaxis for this infection is typically mandated.

Coal Miner’s Lung Coal dust exposure is especially common in miners. CXR signs include round densities in the upper lung. Coal miner’s lung is associated with increased IgA, IgG, C3, ANA, and RF. Massive progressive fibrosis typically results.

Farmer’s Lung Farmer’s lung is due to exposure to actinomycete spores leading to a hypersensitivity pneumonitis. Repeated exposures lead to fibrosis, while acute exposure presents as a hypersensitivity response that typically remits with steroid use.

2.1.12

Mediastinal Masses

Mediastinal masses present due to compression of mediastinal structures or are found incidentally. The most common masses by mediastinal compartment are as follows: •

Anterosuperior Mediastinum (thymus gland, lymph nodes, fat): Thymoma, thyroid enlargement, T-cell lymphoma, teratoma

•

Middle Mediastinum (heart, pericardium, great vessels, phrenic and vagus nerves, trachea/ bronchi, lymph nodes): Cysts, vascular lesions, enlarged lymph nodes

•

Posterior Mediastinum (esophagus, azygos/hemiazygos veins, thoracic duct, sympathetic chain, lymph nodes): Neurogenic tumors

Mediastinal masses are most commonly located in the anterosuperior mediastinum (54%), followed by the posterior (26%) and middle mediastinum (20%). In adults, mediastinal masses represent malignancy about 40% of the time. 318

Pathology

2.2. Inflammatory 2.2.1

and Infectious

Postnasal Drip

The most common cause of cough is due to postnasal drip, commonly the result of a URI, sinusitis, rhinitis, or allergic rhinitis. Pertussis, COPD, asthma, CHF, pneumonia, aspiration, and PE are other causes of postnasal drip. Presentation is with a feeling of nasal discharge into the back of the throat with drainage into the hypopharynx and subsequent elicitation of the coughing reflex. Treatment is to cure the underlying etiology, whether with antihistamines and decongestants for the common cold, or with corticosteroids and antihistamines if allergy-induced.

2.2.2

Otitis Media

Otitis media is a middle ear infection often due to a dysfunction of the Eustachian tube. Obstruction of this passage leads to negative pressure in the middle ear, which can cause fluid to migrate from the nasopharynx into the middle ear cavity. This environment is conducive to growth of the normal flora of the nasopharynx, especially Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Otitis media resolves completely in 50% of patients within 14 days. By the ten-week mark, nearly 90% of all patients have had complete resolution. Otitis media with effusion (OME) in adults, especially when unilateral, indicates that a thorough workup for a nasopharyngeal carcinoma and other disease processes in this region. Nasopharyngeal carcinoma, if not properly diagnosed, may eventually metastasize to cervical lymph nodes, cause osteomyelitis, and lead to various neuropathies. Endoscopic exam of the nasopharynx is required. Acute otitis media (AOM) can lead to mastoiditis and meningitis if not treated quickly. These serious complications are rare due to typically prompt treatment with antibiotics. Meningitis is most commonly due to blood borne transmission of Haemophilus influenzae. Other complications include rupture of the tympanic membrane due to elevated pressure from fluid collection. Treatment of otitis media from any of these three causes is primarily with amoxicillin or trimethoprim and sulfamethoxazole for a duration of ten days. A beta-lactamase may also be added to the regimen as dictated by resistance, especially by Streptococcus pneumoniae. A culture may be required for further treatment. Children, however, tend to cycle through repeated otitis media infections, a condition known as recurrent otitis media. Such patients often require small tubes to be placed through the tympanic membrane to help equalize the pressure between the middle ear and the outside atmosphere. Equalizing the pressure helps to prevent transudation of the contaminated fluid of the nasopharynx into the middle ear cavity. The tubes tend to fall out without medical intervention. With developmental changes of the eustachian, future bouts of otitis media are less likely. In the event of a perforation, treatment with a 0.3% solution of ofloxacin is indicated. Spontaneous repair of the Viral Pharyngitis The majority of pharyngitis is viral in nature and is often referred to as the common cold. Viral pharyngitis is commonly the result of infection by rhinovirus, adenovirus, EBV, HSV, influenza virus, parainfluenza virus, coronavirus, enterovirus, RSV, CMV, or HIV infection leading to inflammation in the oropharynx, hypopharynx, and tonsils. Viral pharyngitis is extremely common, and the typical person will experience several infections yearly. Presentation of viral pharyngitis is with a sore throat. Nasal discharge is common, leading to significant post nasal drip leading to a cough. A thick yellow discharge may occur with viral pharyngitis and a cough is nonproductive. A low grade fever is sometimes present. Adenovirus is particularly common in children and military personnel and may also present with conjunctivitis. EBV occurs more in young 319

Clinical Review for the USMLE Step 1 adults, along with HSV. The latter may lead to gingivostomatitis and decreased PO intake. Influenza can lead to pharyngitis in the winter months. Enteroviruses may present with significant odynophagia and a rash. RSV affects those with pulmonary conditions or at extremes of age. CMV tends to affect sexually active adults. Pharyngeal edema and erythema are typically present, and symptoms of nasal irritation may also be found on exam. Diagnosis of viral pharyngitis is made by CBC, which identifies a somewhat elevated WBC count, an occasional lymphocytosis, and negative rapid streptococcal antigen test and bacterial culture of the throat. Viral cultures are rarely done. Antibiotics are entirely unnecessary for viral infections, except as prophylaxis against bacterial infections in certain high risk individuals. Oral hydration, analgesics for throat irritation and pain, antipyretics, and relief from coughing are the standard of care. Influenza may be treated with amantadine or rimantadine within 2 days of onset; there is little efficacy against influenza B with these two agents. Ribavirin is also useful. Zanamivir and Oseltamivir have been shown to decrease the duration of infection with influenza. EBV is treated with acyclovir (ACV), ganciclovir (GCV), and interferon alpha. HSV is treated with ACV, famcyclovir (FCV), and valacyclovir (VCV).

2.2.3

Bacterial Pharyngitis

Bacterial pharyngitis makes up less than a quarter of all cases of pharyngitis, and occurs most during the winter months and early spring. The most common cause of bacterial pharyngitis is group A streptococcus (GAS), leading to nearly 10 million diagnosed cases of infection. Rapid identification and appropriate treatment of GAS pharyngitis is important in a clinical setting to reduce morbidity and mortality. Related sequelae can include rheumatic fever with subsequent valvular damage and cardiac dysfunction, poststreptococcal glomerulonephritis (PSGN) that may lead to hematuria, proteinuria, and end stage renal disease (ESRD), and related upper respiratory tract infections such as otitis media, abscess formation, and sinusitis. GAS pharyngitis presents with constitutional symptoms, which include fever, general malaise, chills, headache, nausea, vomiting, and abdominal pain. Sore throat is universal. However, there is rarely a related rhinorrhea or nasal discharge as seen with viral pharyngitis. As a result, post nasal drip does not occur and there is rarely a cough due to irritation. Conjunctivitis is also not present. Significant erythema and swelling of the pharynx occurs and patchy exudates may be apparent on physical exam. Diagnosis must be confirmed by a rapid antigen detection test (RADT), and further compared to a throat culture. A throat culture also serves to minimize the chance of a false negative from the RADT; the RADT is useful because immediate results can be obtained and treatment started promptly. There is no need for serum antibody tests with routine bacterial pharyngitis. Treatment of bacterial pharyngitis from GAS is with penicillin for ten days. Supportive therapy, as mentioned above for viral pharyngitis, may also be necessary. Delaying treatment may lead to RF; all diagnosed cases should be treated immediately.

2.2.4

Acute and Chronic Cough

Acute cough is present for less than 3 weeks and is most commonly due to postnasal drip. Chronic cough lasts more than 3 weeks and is commonly due to postnasal drip, asthma, GERD, bronchitis, bronchiectasis, pertussis, cancer, ACE inhibitors, and psychogenic causes.

2.2.5

Sinusitis

Sinusitis is a common cause of postnasal drip and cough, and is most commonly due to bacterial URI 320

Pathology with maxillary sinus obstruction, long-standing inflammation, allergic reactions, foreign bodies, cystic fibrosis, and asthma. Sinusitis presents with nasal discharge, fever, and tenderness with external palpation of the sinuses. CT is sensitive and is used only in severe cases. Treatment of bacterial sinusitis is with amoxicillin or TMP-SMX. Complications include extension into nearby anatomic structures leading to neurologic sequelae or ophthalmologic complications. Additional discussion of sinusitis and other related ear, nose, and throat disorders can be found in the Clinical Review of Otolaryngology.

2.2.6

Pertussis

Pertussis is the development of whooping cough in children, and a common cause of cough in adults due to Bordetella pertussis. Although pertussis is increasingly rare in children, due to aggressive vaccination, it is common in adults and teenagers as the vaccination wanes. Vaccines are given to children every two months for the first six months of life, then repeated at 18 months and between 4-6 years. Pertussis begins in the catarrhal stage that lasts between 1 and 2 weeks. This stage is hallmarked by a mild URI. The paroxysmal stage lasts up to a month and includes a prolonged cough that worsens at night. The convalescent stage has gradual improvement. Diagnosis of pertussis infection is made by nasopharyngeal swabs and culture. Pertussis is a reportable infection in many states, and the public health department must be informed. Treatment of pertussis includes erythromycin, which is effective if started within a few days of illness identification. If erythromycin is no longer an option, supportive therapy is recommended. Infected adults should be kept away from young children who have not yet had the vaccination.

2.2.7

Influenza

Influenza is the result of a viral infection that can cause significant morbidity and mortality, especially at the extremes of age. Epidemics due to infection by the influenza A and B viruses tend to occur in the winter months, but the extent of the morbidity and mortality often depends on the particular makeup of the viral architecture. Infection often affects millions in an epidemic, and tens of thousands may die. By gender, pregnant women late in the pregnancy are at the highest risk of developing complications. Extremes of age are also a risk factor for morbidity â&#x20AC;&#x201C; the elderly and the very young are the most susceptible. Flu pandemics are rare, and occur a few times every century. Recent major pandemics occurred between 1918-1919, and again in 1957. These â&#x20AC;&#x153;superinfectionsâ&#x20AC;? affected millions of people with higher rates of morbidity and mortality due to a change in the architecture of the capsid of the influenza virus. Influenza is a viral illness transmitted by the family of viruses known as orthomyxoviridae (singlestranded RNA viruses). Influenza types A, B, and C have been identified and they are structurally and biologically similar to each other. However, their precise genetic makeup varies. Influenza is distinct from viral infections that can cause the common cold (these viruses include rhinovirus, coronavirus, respiratory syncytial virus, and others). Influenza A and B are the most common viral subtypes that cause disease in humans. Influenza A has also been found to infect animals, and transmission from an animal host to humans may lead to outbreak of pandemics. In addition to humans, influenza A can affect birds, horses, pigs, seals, and other animals. Influenza A contains ten distinct proteins that compose its outer viral coat, and eight internal single stranded RNA segments. Influenza B differs by having eleven outer viral coat proteins. The surface proteins responsible for antigen recognition by the body include hemagglutinin and neuraminidase, and particular variations in influenza viruses are characterized by the composition and types of these surface proteins. A particularly subtype of influenza A virus, known as avian influenza, containing hemagglutinin type 5 and neuraminidase type 1, is responsible for the death of millions of birds in 321

Clinical Review for the USMLE Step 1 southeast Asia. It has resulted in the death of several dozen human beings, and currently appears to be transmissible from animal to human, but not between humans. An avian influenza of subtype H9N2 has also been described. Influenza presents as an abrupt onset of fever up to 104oF, severe sore throat, myalgia, headache, rhinitis, weakness, and in some, an acute encephalopathy. Constitutional symptoms are severe and debilitating. Hypoxia and fever can lead to a tachycardia, and pharyngitis may be severe enough to lead to dyspnea and odynophagia. Nasal discharge is typically minimal or nonexistent. Wheezing and ronchi may be apparent on physical exam. It should be noted that influenza may present with only minimal symptoms in some patients. Viral cultures can be done to identify the particular subtype of influenza infecting the patient, but such tests hold a more academic interest, as nearly a week may pass before the results are available. Direct immunofluorescence may be used along with serologic cultures to more rapidly identify the particular subtype of influenza. Several rapid tests are also available, but they are expensive and difficult to obtain. CXR should be done in high-risk patients to rule out concomitant pneumonia. Influenza is treated by avoiding the disease altogether â&#x20AC;&#x201C; all high-risk individuals should receive the annual flu vaccine. Amantadine and rimantadine are effective against influenza A, but viral resistance can rapidly develop against these two medications. Oseltamivir and Zanamivir can be used to reduce the duration of illness, but as with amantadine and rimantadine, these agents should be given early in disease. Supportive therapy is necessary in more severe disease.

2.2.8

Tuberculosis

Tuberculosis is the most common cause of death in the world. It is transmitted by Mycobacterium tuberculosis and the most common manifestation is with pulmonary tuberculosis. The majority of those infected are likely to be free of disease; however, about 5% develop TB within 2 years, and another 5% develop TB sometime in the course of their life. Patients most at risk include IC patients, HIV patients, IV drug users, persons from outside the US, prisoners, the homeless, and those who live in poorer areas of the US. People most likely to develop active TB once infected include those with HIV, IC, IV drug users, and those with abnormal CXR. TB presents with night sweats, hemoptysis, and constitutional symptoms. A positive PPD strongly raises the clinical suspicion of TB. The presence of an infiltrate on CXR, sputum positive for acidfast bacilli (AFB), and a positive culture clinch the diagnosis. The PPD is used as a screening test in those at risk, and typically yields a positive reaction within several days. The PPD is read within 2 or 3 days of placement, and the level of induration is measured. A positive result Figure 9. Tuberculosis. Copyright Centers for Disease Conmay indicate TB, but it may also be posi- trol and Prevention. Used with permission. 322

Pathology tive due to a vaccination with the Bacillus Calmette-GuĂŠrin (BCG) regimen or infection by another Mycobacterium spp. False negatives are common in up to Âź of all patients; a two step PPD is used in those with a high clinical suspicion of TB. Induration greater than 15 mm is considered positive in all patients. If more than 10 mm, it is considered positive in those at high risk of TB; if it is greater than 5 mm, only those patients with HIV, in close contact with others, and those with abnormal CXR are considered positive. Prophylaxis of TB is done with INH for twelve months. Prevention with INH is contraindicated for those with hepatic derangements or anyone over 35. Therapy for active TB includes six months of INH, rifampin, pyrazinamide, and ethambutol. Streptomycin may be substituted for ethambutol. Nine months of therapy are used for those patients who cannot use pyrazinamide. After treatment, for about 10 days and three negative AFBs, the patient is no longer considered to be infectious. Complications of treatment are numerous but generally preventable. INH is a bactericidal agent that can lead to a peripheral neuropathy if not given with pyridoxine. Seizures can occur with overdose. Hepatitis is also possible. Rifampin is another bactericidal agent that can lead to increased LFTs; rifampin discolors contacts and can cause a reddening of the urine, sweat, tears, and stool. Ethambutol is more of a bacteriostatic agent and can lead to loss of color vision and optic neuritis.

2.2.9

Bronchitis

Bronchitis is the result of an inflammation from a variety of causes including bacteria, viruses, parasites, or toxic injury from smoking or toxins. Local irritation leads to edema and hyperemia with a boggy mucous membrane. Mucus production increases significantly and leads to cough. Excess production for several months over a two year period leads to the diagnosis of chronic bronchitis, discussed earlier. Common bacterial causes include Mycoplasma spp., Chlamydia pneumoniae, Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae. Viral infections include influenza, parainfluenza, adenovirus, rhinovirus, and RSV. Bronchitis presents with constitutional symptoms such as fever and productive cough. Sore throat and rhinorrhea are common. Muscle aches and fatigue are also common. A low-grade fever may also be present. Sputum cultures are often obtained and a plain film performed. Symptomatic treatment is the key to handling this disease. Antitussive medication such as guaifenesin with dextromethorphan is commonly used. Antibiotics that are occasionally used include telithromycin, erythromycin, clarithromycin, azithromycin, tetracycline, cefditoren, TMP-SMX, amoxicillin, ciprofloxacin, and others.

2.2.10

Lung Abscess

A lung abscess is the formation of an infectious cavity with subsequent pulmonary damage. Infectious sources such as Staphylococcus, Streptococcus, Klebsiella, HIB, Actinomyces, Nocardia, and other sources. Morbidity drastically increases with rupture or developing in high-risk patients, such as those who are immunocompromised. Lung abscess presents with fever, productive cough, night sweats, and weight loss with a foul smelling sputum. Hemoptysis is sometimes present. Blood culture and sputum culture are often collected, and a bronchoscopy may be done. Plain films and CT are also done to precisely identify the location of the defect. Treatment involves clindamycin and specific coverage against identified agents.

323

Clinical Review for the USMLE Step 1 2.2.11

Mediastinitis

Inflammation of the mediastinum may be due to: (1) rupture of the esophagus; (2) anthrax infection leading to hemorrhage (nearly 100% fatal); (3) infection by TB or Histoplasma; (4) extension of infection from the neck (peritonsillar abscess); and as a (5) complication of cardiac surgery. Mediastinitis presents with symptoms including fever, chills, chest pain, and shortness of breath. Significant leukocytosis is usually present. CT scans of the chest may demonstrate fluid collections or air within the mediastinum. Needle aspiration of fluid collections may be helpful in some cases. Mediastinitis requires prompt medical and often surgical attention. The underlying etiology is rapidly treated with antibiotics and surgical drainage as necessary.

2.2.12

Pneumomediastinum (Mediastinal Emphysema)

Pneumomediastinum is the result of air in the mediastinum, commonly due to rupture of the esophagus, alveolar rupture, tracheal damage, or dissection of the neck or abdomen with an air leak. It is treated by reversing the underlying etiology. This disease is often found in asthmatics, those with DKA, and those with pernicious vomiting. Hammonâ&#x20AC;&#x2122;s sign is present in 50% of the cases. Confirmation is by radiography demonstrating gas within the mediastinal tissues.

2.2.13

Pneumonia

Pneumonia is commonly the result of infection by community-acquired sources such as Streptococcus pneumoniae or Haemophilus influenzae, or hospital acquired sources such as Pseudomonas aeruginosa, Staphylococcus aureus, and enteric organisms. Atypical sources of pneumonia include Chlamydia pneumoniae, Legionella pneumoniae, and Mycoplasma pneumoniae. A common cause of pneumonia in alcoholics, the elderly, and with blood products includes Klebsiella, especially if currant jelly sputum is present. Patients with chronic bronchitis are likely to be infected by Haemophilus influenzae. Immunocompromised (IC) patients are likely to be infected by Pneumocystis carinii pneumonia (PCP). Streptococcus pneumoniae presents with rust-colored sputum. It is also the likely cause of a complicated pneumonia arising after influenza. Patients with HIV and a CD4 count over 200 are likely to be infected by Mycobacterium. Those with a CD4 count between 50 and 200 are likely to have P. carinii, Histoplasma, or Cryptococcus neoformans. those with a CD4 count below 50 are likely to have either CMV or MAC. The most likely organisms in patients who have had a splenectomy are encapsulated bacteria, such as Klebsiella, S. pneumoniae, and H. influenzae. Alcoholics are likely to have similar infections. Those who use significant amounts of steroids may have Mycobacterium tubercu- Figure 10. Pneumonia. Copyright James Heilman. Used with perlosis or Nocardia. mission. 324

Pathology Pneumonia generally presents with fever, productive cough, and pleuritic chest pain. Pneumonia is equally likely to present with atypical symptoms, such as dry cough, constitutional symptoms, and generalized GI symptoms. On physical exam, rales and tactile fremitus are present. Diagnosis is made by telltale CXR signs including a lobular or segmental infiltrate (upper lobe if TB or Klebsiella), cavities (small in TB, large in others), and bilateral infiltrates (in PCP and TB). Gram stains are done on sputum samples. Encapsulated organisms may be detected, including Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella, and Neisseria meningitidis. Elevated LDH is indicative of PCP. No bacteria on smear may be indicative of Legionella and Mycoplasma spp. Inpatient treatment is necessary for patients at extremes of age, residents of nursing homes, hypotension, tachypnea, tachycardia, PaO2 < 60, and pleural effusions. Treatment consists of penicillins, cephalosporins, and quinolones. Atypical pneumonias get coverage with erythromycin; hospital-acquired pneumonias are covered for P. aeruginosa; and pneumonia in immunocompromised patients gets PCP coverage. Aspiration pneumonia is treated with nasotracheal suction and PEEP.

2.2.14

Pneumocystis Carinii

P. carinii infection is a serious concern in HIV patients with a CD4 T-cell count below 200 / mm3. Prophylaxis should be started in these and otherwise symptomatic patients with bactrim. Aerosolized pentamidine can also be given, although this has been associated with spontaneous pneumothorax and extrapulmonary pneumocystosis. Dapsone has also been shown to be an effective therapy.

2.2.15

Pleural Effusion

Pleural effusions are fluid collections within the pleural cavity, classified as either transudative or exudative. Common causes of a transudative effusion are increased hydrostatic pressure or decreased oncotic pressure (as in CHF), cirrhosis, fluid overload, PE, lobar collapse, and nephrotic syndrome. Transudative effusions are likely to be due to systemic causes and tend to be bilateral in nature. Exudative effusions contain cells and are due to local processes such as cancer, infection, trauma, post-coronary bypass grafting, or pancreatitis. Exudative effusions tend to be unilateral. Pleural fluid has a turnover of 1-2 liters per day. Pleural effusions are diagnosed by thoracentesis and the LDH and protein titers are measured. An LDH > 200, a ratio of effusion LDH to serum LDH > 0.6, or a protein effusion to serum ratio > 0.5 are indicative of an exudative effusion. A parapneumonic effusion is considered if the leukocyte count is greater than 10,000 with a high PMN number; these are always exudative effusions due to the high cellular content. Blood in the effusion brings the differential to trauma, infection, aortic dissection, and malignancy. Low glucose in the effusion leads to the consideration of tuberculosis, empyema, rheumatoid arthritis, and malignancy. Finally, elevated amylase titers require ruling out pancreatitis, renal failure, esophageal rupture, and tumors. Transudative and exudative effusions should be treated by treating the underlying cause(s). Tube thoracostomy or thoracoscopic drainage with or without chemical pleurodesis may be needed for recurrent symptomatic effusions. Thoracotomy or thoracoscopy with mechanical pleurodesis or pleurectomy is used in cases refractory to all other measures.

325

Clinical Review for the USMLE Step 1

2.3. Vascular 2.3.1

Pulmonary Embolism

Pulmonary embolism (PE) is a challenging diagnosis that must be made to avoid potentially catastrophic outcomes. Untreated PE has a 30% mortality rate in the inpatient setting. PE is commonly due to deep vein thrombosis (DVT) from venous stasis, intimal injury, and hypercoagulability, which comprise Virchowâ&#x20AC;&#x2122;s triad. Most DVTs arise from the iliofemoral circulation. As thrombi become larger and veins become larger in the thigh and pelvis, propensity for dislodging increases. Specific risk factors for PE include use of oral contraceptives, cancer, thrombophilias (including factor V Leiden, antithrombin III (AT III) deficiency), protein C (PrC) deficiency, protein S (PrS) deficiency, and antiphospholipid antibody (APA). Respiratory effects of PE include hypoxemia, hyperventilation, and alveolar necrosis. Pulmonary infarction often occurs with untreated PE decreases lung integrity through surfactant loss in the affected region. Arterial hypoxemia is a common finding due to ventilation-perfusion (V/Q) mismatch, shunts, decreased cardiac output from increased pulmonary circulation pressure, and a patent foramen ovale (PFO). Infarction of the lung is rare due to collateral circulation from the bronchial arteries. Increased pulmonary vascular resistance leads to increased RV afterload with subsequent right heart strain. Sudden increases in load can lead to sudden cardiac death from excessive RV load. Large emboli may become lodged at the bifurcation of the pulmonary artery or major branches thereof, leading to a saddle embolus that leads to acute heart failure. The most common signs and symptoms of PE include tachypnea, rales, tachycardia, S4 gallop, and accentuated P2 heart sound. A sudden decrease in ETCO2 during surgical procedures likely indicates a pulmonary embolism. A large PE presents with circulatory collapse and death, and is a common cause of death in hospitalized postoperative patients, especially in the elderly. Smaller PEs can present with pulmonary infarction with pleuritic chest pain and hemoptysis. SOB, DOE, pallor, hypotension, and numerous atypical symptoms such as seizures, syncope, abdominal pain, wheezing, CNS changes, and atrial fibrillation complicate the picture. Signs of a PE Figure 11. Saddle pulmonary embolism. Copyright James Heilon EKG include ST-T wave changes, man. Used with permission. right-axis deviation, S waves in lead 1, Q waves in lead 3, and inverted T waves in lead 3 (S1-Q3-T3). PE diagnosis involves a host of exams and imaging studies with variable sensitivity and specificity. The diagnostic testing begins after a thorough history and physical exam are completed. ABG may indicate hypoxemia, hypocapnia, and alkalosis with a decreased A-a gradient. D-dimer is a nonspecific test that indicates fibrin breakdown; it should not be used alone for diagnosis but raises the clinical suspicion if 326

Pathology positive. In a low risk patient (outpatient with pleuritic chest pain and no risk factors), a normal D-dimer effectively removes PE from the differential diagnosis. D-dimer is rarely indicated in the postoperative period. CXR is normal in the acute phase, but later may show dilation of proximal pulmonary vessels, atelectasis, pleural effusions, and/or decreased pulmonary vascular markings peripherally (Westermark sign). A Hamptonâ&#x20AC;&#x2122;s hump is a wedge-shaped subpleural consolidation that is often discussed but rarely seen on CXR. V/Q scanning provides a meaningful diagnosis in many cases; segmental perfusion defects with normal ventilation are highly indicative of PE but many patients fall in the intermediate probability category. Additional testing is warranted, and includes ultrasound to detect a DVT. CT with contrast may be used to identify a significant pulmonary embolus (smaller ones are not detected), and is the most common modality employed when suspicion for PE is high. Pulmonary angiography is considered the gold standard but is an invasive study. Any patient with a high or medium clinical suspicion with a high-probability V/Q scan, or those with confirmed results by CT should be treated for PE. Anticoagulation therapy beginning with heparin followed by warfarin is used. Treatment is typically continued for at least 3 months with a goal INR of 2-3. The first occurrence of a DVT is typically treated with six months of anticoagulation, the second occurrence with one year of therapy, and a third occurrence requires lifetime warfarin therapy. Low-molecular-weight heparins (LMWH) are being used with increasing frequency and do not usually require routine laboratory evaluation; the level of anticoagulation is measured with anti-Xa assay or estimated by LMWH level. LMWH is the treatment of choice in pregnant patients. Thrombolytic therapy may be used in hemodynamically unstable patients and must be given shortly after the event to achieve maximal effectiveness. An inferior vena cava filter is placed in patients with contraindications to anticoagulation, fragile patients who cannot tolerate another PE, those with risk of recurrence, and patients who experience a significant PE while being anticoagulated. Table 5. Indications for IVC filter. DVT or PE in the presence of anticoagulation therapy DVT or PE with contraindications to anticoagulation therapy (i.e. trauma, head bleeds, GI bleeding) Persistent DVT or PE with maximum anticoagulation therapy s/p Pulmonary embolectomy

2.4. Trauma 2.4.1

Overview

Thoracic injuries and complications of chest trauma account for roughly 45% of all trauma-related deaths. Physical examination of the chest in any trauma patient is critical to identify life-threatening conditions amenable to immediate intervention, including cardiac tamponade, tension pneumothorax, massive hemothorax, flail chest, and open pneumothorax. CXR should be obtained following physical examination.

2.4.2

Rib Fractures

Fracture of 1-2 ribs without pleural or lung involvement may generally be treated on an outpatient basis. Poor pain control can lead to complications such as pneumonia or atelectasis due to inability to inspire deeply and cough. Elderly patients have twice the risk compared to younger patients. In the event of multiple rib fractures, an epidural catheter should be considered for pain management and an abdomi327

Clinical Review for the USMLE Step 1 nal CT should be obtained due to the risk of intra-abdominal injury (spleen, liver) from a fractured rib. Flail chest is paradoxical movement of the chest wall due to two or more fractures in three or more consecutive ribs.

2.4.3

Spontaneous Pneumothorax

Spontaneous pneumothorax is a potentially devastating disorder that leads to air in the pleural cavity from a sudden rupture of a pleural bleb. It is most likely to occur in tall and thin people, or in those who smoke. Other causes include COPD, cystic fibrosis, pneumonia, cancer, and illicit drug abuse. Spontaneous pneumothorax presents with pleuritic chest pain, SOB, and exam findings of decreased breath sounds. Hyperresonance due to increased conduction through the air is present on the affected side. Diagnosis includes upright expiratory CXR, where a collapsed lung may be found. ST changes may be present on EKG. Volume-control mode on ventilation will increase airway pressures in the event of a pneumothorax. Initial treatment includes oxygen and observation. A significant pneumothorax or an increasing space mandates placement of a catheter into the pleural space (tube thoracostomy). Most firsttime spontaneous pneumothoraces can be treated successfully with a chest tube. Recurrent pneumotho- Figure 12. Large pneumothorax. Copyright James Heilman. Used races should be treated with de- with permission. finitive therapy (bleb resection and pleurodesis) secondary to the risk of further recurrences.

2.4.4

Tension Pneumothorax

Tension pneumothorax occurs with air under pressure within the pleural space. Blunt or penetrating thoracic trauma and mechanical ventilation are situations in which tension pneumothoraces occur. Pneumothorax can also be an iatrogenic complication of central line placement. Tension pneumothorax presents similarly to spontaneous pneumothorax, with the addition of tracheal deviation away from the side of the pneumothorax, hypotension, and tachycardia. Diagnosis is made by clinical presentation, not by CXR. Beware of tension pneumothorax following central line placement. A tension pneumothorax exerts its physiologic compromise through vena cava compression, leading to decreased venous return. This leads to hypoxia, hypercapnia, hypotension, and sudden death. A sign of tension pneumothorax while on a mechanical ventilator includes increasing inspiratory pressures using 328

Pathology volume-controlled ventilation and decreased tidal volumes with pressure-control modes. Tension pneumothorax requires emergency management and is treated with needle decompression followed by tube thoracostomy. An 18 gauge needle is inserted into the second intercostal space at the mid-clavicular line. Trauma patients with a pneumothorax should be intubated first (preserve the airway first).

2.5. Cancer 2.5.1

Hodgkin Lymphoma

Hodgkin lymphoma (HL) is a distinct malignant lymphoma with a clonal B-cell population proliferating as Reed-Sternberg (RS) cells. These cells propagate the effects of HL while numerous inflammatory cells lead to local insult and injury. HL accounts for less than 1% of all cancers and has a good 5 year survival rate, if caught early. It is more common in Caucasian males. It has been postulated that infection by EBV is a predecessor to HL. HL presents with supradiaphragmatic lymphadenopathy (typically seen in the neck and axilla), numerous constitutional symptoms, chest pain, intermittent fever, and pruritus. Hepatosplenomegaly is typically evident on physical exam. On laboratory workup, ESR and LDH are elevated. CBC typically indicates an anemia of chronic disease. CT scans are used to identify the extent of disease, and flow cytometry is the key for diagnosis. The most common site for a single positive lymph node is the axilla. Stage 2B disease indicates presence of supraclavicular and mediastinal lymph nodes without abdominal disease in a symptomatic patient. Staging requires a laparotomy except in Stage I disease; however, this procedure is becoming less common with the advent of sensitive MRI and CT scans. Table 6. Hodgkin Lymphoma Staging Stage

Features

Stage I

Single lymph node or single extralymphatic site involvement

Stage II

Two or more lymph nodes on the same side of the diaphragm or one lymph node region and one contiguous extralymphatic site

Stage III

Involvement of lymph nodes on either side of the diaphragm (including spleen), or limited contiguous extralymphatic organ involvement

Stage IV

Disseminated disease in extralymphatic organs

HL is treated with radiation and chemotherapy. The MOPP or ABVD regimen is often used; MOPP stands for the trade names of mechlorethamine, vincristine, procarbazine, and prednisone and ABVD stands for adriamycin, bleomycin, vinblastine, and dicarbazine. Other regimens are also used for HL therapy. One side effect of bleomycin is pulmonary fibrosis. Adriamycin leads to DNA template disruption and the formation of free radicals. Vinblastine leads to inhibition of mitosis via tubulin binding and subsequent disruption of spindle formation. Bone marrow transplant is sometimes necessary. PET scans are used to assess the success of therapy and look for recurrence.

2.5.2

Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (NHL) is a lymphoid tumor with several distinct presentations. It may be due to malignant expansion of B cells, T cells, natural killer (NK) cells, or macrophages, but the majority are due to B cell expansion. NHL leads to over 25,000 deaths a year with over 50,000 new cases annu329

Clinical Review for the USMLE Step 1 ally. Patients tend to be middle-aged adults at the time of diagnosis. Causes of NHL include: (1) a chromosomal translocation that predisposes the patient to the development of lymphoma; (2) a history of infection by EBV, human T-cell leukemia virus (HTLV), HCV, or herpesvirus 8 (HHV 8); (3) exposure to certain environmental toxins or chemotherapeutic agent; (4) various congenital causes (severe combined immunodeficiency disease [SCID]); (5) a state of chronic inflammation; or (6) H. pylori infection. NHL usually presents as a painless peripheral adenopathy. Other presentations include pancytopenia caused by bone marrow extension, multiple constitutional symptoms, or extranodal manifestations. Bowel obstruction may occur. Significant growth of the lymphoma may lead to cranial nerve impingement. Hepatosplenomegaly is common, and more advanced disease may also present with testicular enlargement, skin lesions, or a mediastinal mass. Workup includes a CBC to detect the extent of the pancytopenia and lymphocytosis, an LDH (which is tied to prognosis), and various enzyme function tests to screen for involvement of other organ systems. Imaging studies help to identify the extent of the tumor. Stage IV disease is confirmed by bone marrow biopsy. Laparotomy is not indicated for staging for NHL; CT scanning is sufficient. Early stage NHL is treated with radiation therapy, but chemotherapy is sometimes used in high-risk patients. More advanced stages have both radiotherapy and chemotherapy with the CHOP regimen (trade names for cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone) or CVP (cyclophosphamide, vincristine, and prednisone). Monoclonal antibodies such as rituximab have been used with success. More aggressive tumors are treated with high dose chemotherapy, radiotherapy, followed by BMT.

2.5.3

Lung Cancer

The leading cause of cancer-related death is due to lung cancer, and is the number one killer in both men and women. Over 160,000 people die annually in the United States, surpassing the combined total number of deaths from breast, prostate, and colorectal cancer. Lung cancer has very high morbidity and mortality with only a fraction of patients surviving after five years. By the time tumors are found, metastasis has already occurred in most people with rapid spread through lymphatics and blood to the liver, adrenal glands, bones, and brain. The vast majority of lung cancer can be traced back to a longstanding history of smoking, and this invariably worsens the prognosis of lung cancer. About 95% of all lung cancers are either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Unusual varieties include carcinoid, lymphoma, metastatic cancers to the lung, and others. Of the NSCLCs, adenocarcinoma (adenoCA) and squamous cell carcinoma (SCC) are the most common. Overall, adenocarcinoma makes up 45% of all lung cancers, followed by squamous cell cancer at 30%, small cell cancer at Figure 13. Lung cancer. Copyright Lipothymia. Used with permission. 20%, and large cell cancer at 10%. 330

Pathology Without question, the most significant positive predictor of lung cancer risk is a history of smoking. The number of cigarettes smoked, the number of years of smoking, and the age that smoking started are specific positive predictors of risk. Other causes make up about 15% of all lung cancers, and include secondhand smoke, air pollution, chronic lung disease (including TB and COPD), exposure to heavy metals or asbestos, and a prior history of lung cancer. One affected oncogene is K-ras, which is transformed through point mutation. Lung cancer presents without symptoms in up to a quarter of patients at the time Figure 14. Distribution of lung cancer. Copyright Mikael of diagnosis. The remainder develops Haggstrom. Used with permission. a new, progressive cough (occasionally blood-tinged), pleuritic chest pain, SOB, wheezing, hoarseness, recurrent URIs, and systemic effects based on metastasis. Paraneoplastic syndromes can also occur with production of gastrin, ACTH, ADH, calcitonin, ANF, and PTHrP. Squamous cell and small cell cancers tend to occur centrally, while adenocarcinomas tend to occur peripherally. Lung cancer is diagnosed beginning with a careful smoking history and complete physical exam. CXR is typically the first test ordered, sometimes indicating the presence of a nodule or adenopathy, though in early cases (those potentially amenable to curative resection) the CXR may show no evidence of lung mass. CT and MRI are more sensitive and can detect smaller nodules, and are also useful for staging; a CT of the chest and abdomen is typically completed, along with the head as indicated. Biopsy, sputum cytology, and bronchoscopy are other methods of obtaining cells and tissue for additional analysis. Collection of fluid via thoracentesis, or open procedures such as thoracotomy may be necessary to collect an adequate tissue sample. Regional spread to lymph nodes is evaluated by mediastinoscopy. Approximately half of all lung cancers are metastatic at the time of diagnosis. PFTs with FEV1 > 0.8 is required prior to lung surgery. An FEV1 > 2Â L is required prior to pneumonectomy, > 1 L for a lobectomy, and 0.6L for a wedge resection. PCO2 > 60 and poor DLCO ratios are prohibitive risks for lung resection due to the elevated chance for permanent mechanical ventilation postoperatively.

Small Cell Lung Cancer SCLC accounts for 20% of lung cancers with 80% centrally located. SCLC tends to be more aggressive and rapidly growing than NSCLC. Histology often indicates dark nuclei with little cytoplasm, an oat-like appearance. SCLC produces gastrin, ACTH, ADH, ANF, and calcitonin, which can lead to a number of paraneoplastic effects. Treatment of SCLC involves radiotherapy and chemotherapy. Surgical resection is typically not possible because of extensive disease at presentation. SCLC has a 5 year survival of approximately 5%.

331

Clinical Review for the USMLE Step 1 Non-Small Cell Lung Cancer NSCLC includes adenocarcinoma, bronchoalveolar carcinoma, squamous cell carcinoma, and large cell carcinoma or the lung. NSCLC features cells with pleomorphic nuclei and large amounts of cytoplasm. Adenocarcinoma of the lung is the most frequent NSCLC, accounting for 45% of lung cancers, with 75% occurring peripherally. Adenocarcinoma tends to metastasize earlier than squamous cell carcinoma and more often to the CNS. Bronchoalveolar carcinoma is a subtype of adenocarcinoma and is associated with the best prognosis of all the types because it is more differentiated and spreads along alveolar walls. Squamous cell carcinoma (SCCA) accounts for 30% of lung cancers and 2/3 are located centrally. Squamous cell carcinoma may produce PTHrP. Surgical resection is the treatment of choice in early stage disease. Five year survival is better for NSCLC than for SCLC. Large cell undifferentiated carcinoma accounts for 10% of lung tumors. These tend to occur peripherally and metastasize relatively early.

Prognosis Palliative care is often the final outcome of therapy for lung cancer. This is due to the high rate of recurrence, in which many lung cancers are present again within 2 years. Pain management with hospice care involves the use of high dose opioids and NSAIDs as indicated. Oxygen administration is often the key to patient comfort. The primary method of avoiding the lethal pitfall of lung cancer is avoidance â&#x20AC;&#x201C; smoking cessation is the first and most important step to reducing the risk of lung cancer. Survival with stage I NSCLC is 70% at 5 years; stage II offers a 30% 5-year survival, stage III a 20% 5-year survival, and stage IV offers only a 9 month survival period. SCLC that is treated with chemotherapy has a 10% 5 year survival; advanced SCLC has a 6 month survival period.

Screening

Figure 15. Ferruginous bodies in lung Some institutions offer CT scans as a screening test in high cancer. Copyright Nephron. Used with risk patients; early data appears to indicate that CT scans permission. can detect lung cancer earlier, and in some patients, this may lead to earlier treatments and potential surgical resection before significant metastasis occurs. Whether this translates into less morbidity and mortality over a 5 year period remains to be determined.

Associated Syndromes Lung cancer is associated with numerous syndromes. Superior vena cava syndrome occurs due to compression of the SVC with swelling of the upper extremity, head, and neck. Cough, headache, epistaxis, and syncope are commonly associated symptoms. SVC syndrome is most likely due to lung cancer (90%). It is treated with radiotherapy. Horner syndrome 332

}

Stage IV (M1B - disseminated metastasis)

Stage IV (M1B - solitary metastasis)

} }

}

 Surgical resection, mediastinal node Bx - Reresect, chemorad, or RT if margin + - Adjuvant chemotherapy in high risk pt - Adjuvant chemotherapy for stage IIA/B  Neoadjuvant chemoradiation, followed by surgical resection, then adjuvant chemotherapy - Adjuvant chemotherapy + RT for stage N1/2 - Concurrent chemoradiation for N2-3  Palliative chemoradiation - Local therapy for exudate/serosanguinous  Resect solitary metastasis - Whole brain RT - Resect lung lesion - Consider adjuvant chemotherapy First line chemotherapy - Platinum-based (prolongs survival to 10 mo) - Add bevacizumab, cetuximab, erlotinib, or pemetrexed; ﬁrst two agents better - No systemic chemo if poor functional status Second line chemotherapy - Docetaxel suggested for most patients - Pemetrexed for adenoCA or large cell - Erlotinib as last line

Surveillance - CT chest Q4-6 mo for 2 yrs, then annually - Annual inﬂuenzae and pneumococcal vaccine

Notes - PCO2 (>45) > risk than PO2 - Postop FEV1 < 30% contraindication - Nonresectable if SVC syndrome, RLN or phrenic nerve paralysis, major MDC Cases vascular involvement, contralateral node - All stage IIB and III cancers involvement, supraclavicular node invol vement, malignant or bloody effusion, Biomarkers tracheal involvement, Horner syndrome, - EGFR - nonpredictor of survival, but can be or esophageal fistula. indication for erlatinib - Mediastinal node > 1.5 cm associated - K-ras - poor prognosis, failure of platinum with metastasis; 30% present w/ + nodes - ERCC - excision repair complex - poor - Mediastinoscopy = 2R/L, 4R/L, 7 prognosis and failure of platinum - Left parasternal = 5,6 - RRM - better prognosis but less response to - Chamberlain = 5,6 gemcitabine - VATS 5-9 (low 7) - Solitary nodule: < 3 cm (35% 1o, 25% Other 2o, increased risk with age - Adjuvant chemotherapy improves survival - Stable for 2 yrs or calcified = low risk - Neoadjuvant chemorad can destroy landmarks - PET/CT, bronch, or wedge - 25% increased risk of lung CA from secondhand - Resect metastatic tumors to lung - NLST looking at role of screening CT - i.e. melanoma, renal cell cancer - 50% of patients present with stage IV cancer

++  Brain  Resect  Evaluate lung   Biopsy of isolated metastasis  Adrenal  ± Resect, eval lung CA   PRN workup  

++ Thoracentesis or pericardiocentesis 

 Ipsilateral nodes −  Stage IIIA  ++  Contralateral nodes −  Ipsilateral nodes +   Conﬁrmation of T4 status by Bx  Contralateral nodes +    Metastatic disease  

++  Biopsy −  Stage I-IIIA  Conﬁrmation of N3 status by Bx  Biopsy +    Metastatic disease  

++

 Superior sulcus   ++  MRI of spine and thoracic inlet  Chest wall    Proximal airway    Metastatic disease  

}

+   Brain MRI Mediastinoscopy

} PFTs Bronchoscopy  ± Mediastinoscopy (gold standard) EBUS + LN  Bx on mediastinoscopy  Stage IIIA/B  PET/CT  − LN  

Stage IV (M1A - pleural/pericardial eﬀusion)

Stage IIIB (T4, N2-3)

Stage IIIB (T1-3 N3) - Mediastinal CT + - Contralat LN > 1 cm or - Palpable supraclavicular LN

Stage IIIA (T1-3 N2)

Stage IIB (T3 N0) Stage IIIA (T3,4 N1)

Stage IB (T2A N0) (T1AB N0 central) Stage IIA (T1AB N1), (T2A N1) (T2B N0) Stage IIB (T3 N0), (T2B N1) Mediastinal LN < 1 cm

Stage IA (T1AB N0 periph) Mediastinal LN < 1 cm

Nodal staging diagram from Mountain C F, Dresler C M. Regional lymph node classification for lung cancer staging. Chest. 1997; 111: 1718–1723. Staging table from The New Lung Cancer Staging System. Chest. 2009; 136. Survival graph based off National Cancer Database 5-year survival. Content based off NCCN NSCLC guidelines. Images and tables used used in accordance with 17 USC §107. Consult standard text. Not liable for erors / misprints. Prepared May 2010.

- H&P central (inner 2/3) - CT chest and abdomen  peripheral (outer 1/3) through adrenals - CBC, BMP - Smoking cessation

squamoid (better survival in late stage)

 adenocarcinoma, large cell, others - tend to metastasize to CNS N S CL C ( 8 5% -- non-squamous squamous  most common - subtypes = bronchoid (better survival in early stage))

Pathology

333

Clinical Review for the USMLE Step 1 presents with paralysis of the sympathetic nerve due to damage to the ganglion; it presents with ptosis, enophthalmos, miosis, and anhidrosis. Pancoast tumor presents with damage to the 8th cervical nerve, 1st and 2nd thoracic nerve, and damage to the ribs that leads to pain that radiates to the ipsilateral arm. Pancoast tumor can lead to Horner syndrome, vessel or nerve compression, and injury to underlying structures. SIADH presents with hyposmolality and hyponatremia. Eaton-Lambert syndrome occurs with an autoimmune reaction to nerve terminals leading to decreased release of acetylcholine (ACh). Trousseau syndrome is a hypercoagulable state that leads to venous thrombosis.

3. Pharmacology Table 7. Anticoagulants and Thrombolytics Drug

Indications

Heparin

Mechanism of Action

Complications

• Antithrombin III potentiation leading to prevention of clot formation • Inhibits factors II, IXa, Xa

HIT (early is benign; late is IgG mediated); treat with danaparoid sodium or lepriludin due to risk of thrombosis Can lead to white clot syndrome

Anticoagulation

Notes

Existing bleeding disorder Safe in pregnancy

Follow aPTT time Give protamine sulfate as antidote (beware of hypotension) Half-life: 90 mins Test factor VIII function if intrinsic elevation in PTT

Cleared renally

PTT is not followed

LMWH

Factor Xa inhibition

Warfarin

Inhibits epoxide reductase in liver to prevent formation of factors II, VII, IX, X, protein C, and protein S

Interacts with numerous medications (P-450) GI bleed Limb necrosis

Existing bleeding disorder; avoid in pregnancy; can lead to skin necrosis from lack of protein C – treat with heparin

Must monitor therapeutic index via PT/INR Half-life: 40 hours

Anticoagulation in PTCA

Prevents platelet aggregation and thrombus formation

TCP

Existing bleeding disorder

GPIIb/IIIa Ig inhibitor; similar to ticlodipine

Streptokinase

Fibrinolytic

Cleaves plasminogen to produce plasmin and breakdown clots

Allergic reaction on subsequent doses Bleeding

Hemorrhagic disorder

Usually given only once following MI Intrinsic elevation = malignancy

tPA

Fibrinolytic

Serine protease forms plasmin to breakdown clots

Bleeding

Hemorrhagic disorder

Used in MI and stroke within the first six hours of symptom onset

Hypercoagulability

Prevents platelet aggregation through ADP receptor blockade on platelets

Neutropenia TTP Hemorrhage

Safe in pregnancy

Plavix, MI and stroke risk Similar to ticlodipine

Hypercoagulability Fever

Increased bleeding time by impaired platelet release, inhibition of COX, and decreased thrombus formation Irreversible effects

Abciximab

Clopidogrel

Aspirin

334

Contraindications

Stop 7-10 days before surgery Prostacyclin inhibits platelet aggregation

Pharmacology Table 8. Decongestants, Cough suppressants, Expectorants, and Mucolytics Drug

Indications

Mechanism of Action

Complications

Notes

Pseudoephedrine

Decongestant / Cough Suppressant

Sympathomimetic amine; crosses blood-brain barrier

Tachycardia, anorexia, pulmonary edema

Do not use with serotonin or norepinephrine reuptake inhibitors

Oxymetazoline

Decongestant

Alpha-1 and -2 receptor agonist

Rebound congestion

Increases blood pressure

Guaifenesin

Expectorant / Mucolytic

Increases volume and decreases viscosity of respiratory secretions

Nausea, vomiting, nephrolithiasis

Dextromethorphan

Cough Suppressant

Serotonin reuptake inhibitor and NMDA receptor antagonist

Dissociative hallucinogen

Ephedrine

Does not function in children Codeine is no longer considered to be a cough suppressant

3.1. Endotracheal Intubation Indications for intubation include any patient unable to protect their airway, combative patients whose safety is threatened, and patients with falling GCS scores in the 7-9 range. Any patient undergoing general anesthesia or a major respiratory procedure requires intubation. Serious failure in accessing the airway by way of intubation may require a surgical airway, such as a tracheostomy or cricothyroidotomy.

3.1.1

Anesthetics and Analgesics

Contraindications to epidural analgesia include bleeding disorders, active infection, hemodynamic instability, and ileus. Epidurals are preferred with flail chest due to improved tidal volume, larger inspiratory force, and better pain control; there is no effect on FRC. Table 9. Anticholinergics – Nicotinic Antagonists Drug

Succinylcholine

Indications

Muscle paralysis Mechanical ventilation

Cisatracurium, Vecuronium

Mechanism of Action

Contraindications

Notes

Rapid onset, short duration with decrease in excitatory potential; noncompetitive Initial stage: prolonged depolarization > fasciculations, muscle pain. Second stage: repolarization but blockade of receptors.

Malignant hyperthermia with halothane; avoid in patients with increased ICP, burns, DMD, crush injury, MS, and hyperkalemia. May lead to arrhythmia and bradycardia.

Depolarizing NM agent Use neostigmine as second stage antidote. No antidote for first stage. Directly competes with acetylcholine.

Nicotinic receptor blockade

No cardiac effects with vecuronium; pancuronium leads to tachycardia

Use cisatracurium with renal or liver failure due to its Hoffman degradation.

Rocuronium

Facilitate tracheal intubation

Competes for cholinergic receptor at motor end-plates

Nondepolarizing NMJ agents. Reverse with neostigmine or edrophonium.

Dantrolene

NMS and malignant hyperthermia

Interferes with calcium ion release by sarcoplasmic reticulum

Active hepatic disease, OPD

Calcium channel blocker

Sildenafil

• ED • Pulmonary HTN • Raynaud phenomenon

PDE-5 blocker that increases cGMP

• • • •

• MI w/ nitrates • Do not use if Hx of MI, hypotension, renal or hepatic disease, and retinal disorders

Vasodilation Priapism MI Arrhythmia

335

Clinical Review for the USMLE Step 1 Malignant hyperthermia is a disorder of calcium metabolism with decreased reuptake by the sarcoplasmic reticulum leading to increased intracellular calcium. Increased end tidal CO2 (ETCO2) is an early sign of disease. The first physical finding is the presence of spasms in the masseter. ETCO2 may also increase in the setting of pulmonary embolism, or air embolism experienced during laparoscopic surgery. During general anesthesia, the muscle that is the last to be paralyzed and the first to recover is the diaphragm. A risk of general anesthesia in diabetes mellitus is hypoglycemia. Etomidate has few cardiovascular side effects. Use of nitric oxide permits lower concentrations of other anesthetics; it should not be used in patients with bowel obstruction or pneumothorax due to diffusion into closed spaces. Neostigmine can reverse muscular blockade. Flumazenil reverses benzodiazepines. Narcan reverses opioid overdose. Dantrolene treats malignant hyperthermia. Table 10. Sedatives and Hypnotics Drug

Indications

Mechanism of Action

Midazolam

Preanesthetic

Diazepam

Preanesthetic

Flumazenil

Reversal of sedative effects of benzodiazepines

Complications Myocardial depression

Notes Short-acting Long-acting

Competitively inhibits benzodiazepine receptor site

Seizures

Leads to amnesia, no analgesia

Table 11. Inhaled Anesthetics Drug

Indications

Complications

Notes

Halothane

Anesthesia

Bradycardia, hepatitis, malignant hyperthermia, arrhythmia, respiratory depression, increased ICP, cardiac and hepatic toxicity

Sevoflurane

Anesthesia

Bradycardia, respiratory depression, increased ICP

Rapid onset

Nitrous oxide

Anesthesia

Minimal

Lowest potency, combined with other agents

Desflurane

Anesthesia

Airway irritation, coughing, respiratory depression, increased ICP

Most rapid onset

Table 12. Intravenous Anesthetics Drug

Complications

Notes

Midazolam

Respiratory depression, amnesia

Benzodiazepine; reverse w/ flumazenil

Ketamine

CV, hallucinations, ICP

Amnesia, analgesia, muscle relaxation

Morphine

Substance abuse and dependence, respiratory depression (brainstem CO2 response), miosis, CNS depression, constipation, N/V (CTZ)

Opioid, good analgesia

Fentanyl

Muscle rigidity at high doses that impedes ventilation

Opioid, good analgesia. Tolerated in large doses due to lack of histamine response.

Propofol

Hypotension

No cumulative effects, strict aseptic technique must be maintained.

No tolerance to miosis or constipation.

Visceral pain is carried by C-fibers. Nociceptive stimuli are carried via afferent nerves of the spinothalamic tract. Ketamine may lead to hypertension in normal patients, and hypotension in patients in shock; it is a dissociative anesthetic and should not be used in patients with head injury. Meperidine is occasionally used due to its ability to prevent shivering. Morphine is preferred as it has no negative car336

Pharmacology diovascular side effects and improves venous capacitance. Fentanyl is used in patients with respiratory disorders as it does not cause bronchospasm. Propofol should not be used in obstetrical anesthesia due to neonatal complications. The major side effect is hypotension. Prolonged use can lead to bradycardia or asystole, rhabdomyolysis, metabolic acidosis, and renal failure. As a result, propofol should not be used for more than 48 hours and avoided in patients with CNS disease. Table 13. Local Anesthetics Drug

Complications

Notes

Lidocaine

Toxicity signs: lightheadedness, dizziness, metallic taste, tinnitus, circumoral paresthesia, numbness, seizure, arrhythmia, cardiac collapse

Bupivacaine

CV toxicity

• Greater amounts needed in infected tissue (acidic tissue) • Smaller fibers affected first, so pain is lost first, then touch • Give with epinephrine to increase local effects • No allergic cross reactivity between esters and amides. Long duration.

Spinal anesthetics are contraindicated when ICP is increased. Esters have a higher chance of causing a hypersensitivity reaction compared to amides. Use of local anesthetic leads to decreased pain in the postoperative period. The maximum safe dose for lidocaine is 3-5 mg/kg and should not exceed 300 mg. Epinephrine with lidocaine permits a dose of up to 7 mg/kg. Bupivacaine can be used up to 2.5 mg/ kg, or 3.0 mg/kg with epinephrine. Intravenous lidocaine may lead to cardiac arrest, but intraarterial injection has few side effects at low doses. Early signs of toxicity include metallic taste, vasovagal response, tinnitus and lightheadedness, followed by numbness, seizures, and loss of consciousness. Cardiopulmonary depression may then occur. Treat with oxygen, atropine, and ephedrine first, followed by midazolam or other benzodiazepines to stop seizure activity. A lipid rescue is possible with immediate administration of lipids such as TPN. Table 14. Typical Anxiolytics Drug

Indications

Contraindications

Notes

Clonazepam

Absence seizures

LFTs, glaucoma, pregnancy

Intermediate-acting

Diazepam

Sedation

Glaucoma, pregnancy, children

Longest acting Three active metabolites

Midazolam

Sedation Anesthesia

Shortest-acting benzodiazepine

Lorazepam is a long-acting sedative. Dexmedetomidine is used as a bridge for extubation due to low respiratory suppression. Droperidol is an anxiolytic and antiemetic drug with cardiac side effects. Midazolam is an anxiolytic, sedative, and amnestic agent and is preferred over diazepam as the latter leads to accumulation of metabolites.

337

Clinical Review for the USMLE Step 1 Table 15. Barbiturates Drug

Indications

Phenobarbital

• Anxiolytic • Hypnotic • Sedative

Mechanism of Action

Complications

Facilitates GABAA and increase length of chloride channel opening to decrease neuronal firing

• • • •

Induce tolerance Low therapeutic index Respiratory depression Myocardial suppression

Table 16. Cromolyn Drug

Indications

Cromolyn sodium

Asthma prophylaxis

Mechanism of Action

Notes

Stabilizes mast cell membranes to prevent histamine release

Used only for prophylaxis. No effect in active disease.

Table 17. Corticosteroids Drug

Indications

Mechanism of Action

Complications

Notes

Asthma prophylaxis Immunosuppression Prednisone

Nephrotic syndrome Crohn disease Organ rejection

Dependency Suppresses cytokine production and decreases TNF-α action

Addisonian crisis if sharp cessation Hyperglycemia

Autoimmune disease

Table 18. Antileukotriene Drug Zileuton

338

Indications Asthma prophylaxis

Mechanism of Action Inhibits 5-lipoxygenase to inhibit leukotriene synthesis

First line for chronic asthma

Pharmacology

339

CARDIOVASCULAR

Section Editors Sapan S. Desai, MD, PhD

Danny O. Jacobs, MD, MPH

Assistant Professor Department of Surgery Duke University Medical Center

Professor and Chair Department of Surgery Duke University Medical Center

Contributors Sapan S. Desai, MD, PhD

Michael Lidsky, MD

Assistant Professor Resident Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center

Luigi Pascarella, MD

Cynthia Shortell, MD

Resident Professor Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center Surgical Principles (adapted from the Clinical Review of Vascular Surgery)

Judson Williams, MD

Charles Murphy, MD

Resident Assistant Professor Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center Thoracic Surgery (adapted from the Clinical Review of Surgery)

David A. Peterson, MD

Mani Daneshmand, MD

Fellow Resident Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center

G. Chad Hughes, MD

Richard L. McCann, MD

Associate Professor Professor Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center Arterial Aneurysms (adapted from the Clinical Review of Vascular Surgery)

Introduction

1. Introduction Cardiovascular disease spans topics that cover the heart and the entire vascular system. Basic science principles are frequently tested on the USMLE, especially the physiology and pharmacology aspects of cardiovascular disease. There are numerous equations and drugs that appear on the exam, and familiarity with all of these topics is vital for earning a top score. This section on cardiovascular disease also includes a brief overview of epidemiology and preventive medicine as it appears on the USMLE.

2. Epidemiology 2.1. Causes

Death

The most common cause of death depends on the average age of the patient. Neonates are most likely to die from congenital defects, VLBW/LBW complications, and SIDS. Children tend to die from injuries, cancer, and congenital defects. Young adults die from injuries, homicide, and suicide. Middle-aged adults die from cancer, heart disease, and injuries. The elderly die from heart disease, cancer, and stroke. According to the 2005 National Division of Vital Statistics, the overall top ten causes of death for both males and females are heart disease, cancer, cerebrovascular disease, chronic obstructive pulmonary disease, unintentional injuries / accidents, diabetes mellitus, influenza and pneumonia, Alzheimer disease, nephritis, nephrotic syndrome and nephrosis, and septicemia. Together, these top ten causes of death account for nearly 80% of all death in the United States of America. It is important to understand the relevance of this list. The top ten causes of death listed do not imply that these ten causes deserve the greatest amount in public health resources â&#x20AC;&#x201C; quite often, some causes of death that are not ranked are of great importance to physicians and public health authorities. Some such causes that did not make the list include tracheal cancer, lung cancer, and motor vehicle accidents. Overall, death may be attributed to heart disease in about 29% of all cases. Cancer comes in at 23%, and stroke leads to about 7% of all deaths. The top three categories account for nearly 60% of all causes of death. The top three cancers by incidence are prostate / breast cancer, lung cancer, and colorectal cancer. The top three cancers by death are lung cancer, prostate / breast cancer, and colorectal CA.

2.2. Preventive Medicine Preventive medicine deals with the branch of medicine dedicated to avoiding disease and promoting sound and healthy practices for well-being. Preventive medicine is responsible for the eradication of small pox in 1977, vaccines for typhoid, diphtheria, and cholera, and a treatment for rabies in the late 1800s. Preventive medicine has three levels of prevention: primary prevention is to avert the onset of illness in healthy people; secondary prevention is to prevent the progression of a disease in people who are already afflicted; and tertiary prevention is directed towards reducing disability from a disease. Preventive medicine has fronts in routine health screening and education, cancer screening, substance abuse, domestic violence, obesity, malnutrition, immunization, and more. Table 1. Preventive Medicine Primary level

Avert onset of illness in healthy people.

Secondary level

Prevention of progression of disease in already afflicted.

Tertiary level

Reducing disability from a disease.

341

Clinical Review for the USMLE Step 1

2.3. Use

Tests

Screening tests are tools for the discriminating physician to use in preventive health care. Some screening tests reach their full efficacy only after a certain age, or in certain populations. For example, young adults have little benefit for yearly colonoscopy due to the rare incidence of colon cancer in an individual with no family history or risk factors; in fact, the risk of perforation and side effects from the procedure far outweigh the chance of detecting a malignant lesion. The best screening tests have guidelines that have been tested in randomized, double-blind, placebo-controlled, multicenter trials â&#x20AC;&#x201C; a tall order for many research studies. As a result, the guidelines proposed by various institutions are based on the best available evidence and some groups frankly state that there is no preponderance of evidence indicating a good utility for certain screening tests. Realize that routine screening for disease is typically done with the best interest of the patient and population in mind â&#x20AC;&#x201C; medicine is more than treating the individual, it is also improving the overall health of society.

2.4. Routine Screening Routine screening tests should be carried out at every visit to a physician. For examination purposes, the correct answer to what a physician should do next may sometimes be to carry out an appropriate screening exam for that patient population. Generally, young adults (defined in this section as those less than 40 years of age) should receive physical exams every 3-5 years, blood pressure and weight measurements every 2 years, cholesterol measured every 5 years, glaucoma screens at least once, and a Pap smear in women every 1-3 years. The screening guidelines in middle-aged adults (defined here as those between 40 and 65) should continue with the screening recommendations for young adults and start having fasting blood sugars measured every 3 years, mammography yearly for women, and colon cancer screening every 5 years. Vision screening should increase in frequency to every 3 years. Older adults (those over 65) should receive yearly physical exams, periodic hearing tests, and vision screening yearly. A digital rectal exam should be done yearly after age 50 with tests for occult bleeding. The United States Preventive Services Task Force (USPSTF) comes out with yearly screening guidelines. Table 2. Routine Screening Schedule Young adults (Under 40)

Physical exams every 3-5 years; BP and weight every 2 years; cholesterol levels every 5 years; glaucoma and pap tests every 1-3 years.

Middle age (40-65)

Same as young adults plus fasting blood sugars every 3 years, mammography yearly in women, colon cancer screen every 5 years, vision every 3 years Digital, yearly rectal exam after 50.

Older adults (over 65)

Yearly physicals, periodic hearing tests, yearly vision test.

2.5. Cancer Screening 2.5.1

Breast Cancer

Breast cancer is the second most common cause of death in women. Screening tests recommend self breast exams every month about a week after the onset of menses. Annual exams by a physician should be made at least once a year, but even this examination is controversial up until the age of 40 or 50. The American Cancer Society recommends clinical breast exams every three years, then yearly after the age of 40. Mammograms are recommended every 1-2 years from ages 40-49, then yearly. The data to conduct mammograms in the 40s is currently controversial. Mammograms should not be conducted earlier than age 35 due to the density of the breast shadow and limited clinical utility of this test in younger women. However, a large multicenter trial with 40,000 women completed in 2005 suggests that mam342

Epidemiology mograms using digital imaging might be appropriate for younger women. It is believed that as digital imaging solutions replace current x-ray film technology, more and more women would be eligible for the diagnostic benefits of mammography.

2.5.2

Cervical Cancer

Screening for cervical cancer is done with Papanicolaou (Pap) smears. Cervical cancer is commonly associated with certain human papillomavirus (HPV) types. Screening is generally recommended with yearly Pap smears starting at the age of 18 or when sexual activity begins, whichever is sooner. Pap smears may be performed every 3 years following 3 normal smears one year apart. Pap smears typically continue until the age of 70 in any woman who has a cervix. Ovarian cancer is the fourth most common cause of death in women. Risk factors include positive family history and having a pregnancy later in life. There are no screening tests.

2.5.3

Colorectal Cancer

Colorectal cancer screens are somewhat controversial. Most groups recommend fecal occult blood testing (FOBT) with digital rectal exams (DRE) every year after the age of 50. Flexible sigmoidoscopy should be done every 5 years or colonoscopy every 10 years. Some physicians recommend conducting colonoscopy in lieu of sigmoidoscopy, and some studies have discounted the benefits of FOBT. DRE should be done in all patients as up to 50% of all colon cancers may lay within reach of the clinicianâ&#x20AC;&#x2122;s finger.

2.5.4

Prostate Cancer

Adenocarcinoma of the prostate is the third leading cause of death in men. Most groups prefer to individualize the screening process, but generally recommend yearly DRE and prostate specific antigen (PSA) tests in individuals over the age of 50. Significant elevations in PSA should be tested with a transrectal ultrasound (TRUS) of the prostate gland to confirm the clinical suspicion. Due to the increased risk of prostate cancer in African American males, some clinicians may choose to begin screening for prostate cancer earlier in this population.

2.5.5

Testicular Cancer

Testicular cancer screening tests also have little supporting evidence in the literature. The ACS recommends testicular exams with every physical exam for cancer screening. Table 3. Cancer Screening Breast

Self exam every month, clinical breast exam every 3 years until 40. Mammograms every 1-2 years between 40-49.

Cervical

Yearly Pap smear starting at 18 or when sexually active. May be performed every 3 years following 3 normal smears one year apart. Typically continue until 70.

Colorectal

FOBT with DRE every year after 50. Sigmoidoscopy every 5 years or colonoscopy every 10 years.

Ovarian

No screening tests. Family history important as is late in life pregnancy.

Prostate

DRE and PSA yearly after 50. African American males earlier than 50.

Skin

Physical exam of skin every 3 years until age 40, then yearly.

Testicular

With every physical exam.

343

Clinical Review for the USMLE Step 1

3. Basic Science 3.1. Embryology The heart is derived from the mesoderm. The mesothelium gives rise to the pericardium, the myocardium gives rise to the musculature, and the endothelium gives rise to the blood vessels and inner lining of the heart. Fusion of the cardiac growth plates is completed by three weeks, and the heart begins to beat not long after. The cardiac stem cells migrate to form a single tube, which later separates into an anterior-posterior axis to allow formation of the chambers. This tube undergoes a twisting motion, followed by septation and valve formation. Septation is dependent upon the neural crest and defects in this process lead to persistent truncus arteriosus, transposition of the great arteries, tetralogy of Fallot, and stenosis of the aorta of pulmonary ateries. The atrium is divided into the right and left sides through formation of the septum primum, which eventually fuses with the endocardial cushion. The foramen primum exists temporarily during this fusion process - defects here can lead to large septal defects. A second septum begins to develop and eventually forms the foramen ovale, which typically closes after birth. Defects in this process can lead to atrial septal defects and a persistent foramen ovale. As the atria continue to mature, the bicuspid and tricuspid valves develop from the atrial canal, itself derived from the endocardial cushions. The interventricular septum develops toward the endocardial cushion during this period. A foramen that forms here is eventually closed by the muscular septum. Defects in this process can lead to ventricular septal defects.

3.2. Anatomy 3.2.1

Heart

The heart is made of four chambers, including two atria and two ventricles. The flow that occurs throughout the pulmonary vasculature and systemic vasculature is due to the action of the muscular ventricles, while the atria serve primarily to store blood during diastole. One atrium works in conjunction with a ventricle, and the two systems are separated by a septum. The atrioventricular valves control flow of blood from the atria to the ventricles. The right atrium and ventricle are separated by the tricuspid valve, and the left atrium and ventricle are separated by the bicuspid (mitral) valve. The SA node is located at the junction of the right atrium and superior vena cava.

3.2.2

Vasculature

The internal mammary artery is the first branch off the subclavian artery. The left internal mammary artery has the best patency for a CABG. The subclavian artery is located between the anterior and middle scalene muscles. The majority of the vasculature was discussed in â&#x20AC;&#x153;3. Anatomyâ&#x20AC;? on page 155. The blood supply to the heart consists of the coronary arteries. The left coronary artery (LCA) supplies the left side of the heart, and the left anterior descending (LAD) branch of the LCA supplies the anterior wall of the left ventricle and anterior 2/3â&#x20AC;&#x2122;s of the interventricular septum of the heart. The left circumflex (LCX) branch supplies the lateral wall of the left ventricle and posterior portions of the heart. The LCA arises distal to the posterior aortic sinus of Valsalva. The right coronary artery (RCA) supplies the inferior wall of the left ventricle and the SA and AV nodes of the heart. The RCA also gives off the marginal artery, which supplies the right atrium and right ventricle. The RCA arises directly from the aorta immediately distal to the anterior aortic sinus of Valsalva. 344

Basic Science

Figure 1. Anatomy of the heart. Copyright Mikael Haggstrom. Used with permission.

Figure 2. Conduction system of the heart. Copyright Madhero88. Used with permission.

345

Clinical Review for the USMLE Step 1 •

SA node

RCA via sinus node branch

•

AV node

RCA via sinus node branch

•

RA RCA via sinus node branch and atrial branch

•

RV RCA via acute marginal and RV branches

•

LA LCA via circumflex; RCA and LCA directly

•

Anterior LV

LCA via LAD

•

Lateral LV

LCA via diagonal branches

•

Posterior LV

LCA via obtuse marginal, posterolateral, and posterior descending

•

Anterior septum

LCA via LAD and septal branches

•

Posterior septum

RCA via posterior descending (right dominant)

•

Apex LCA via LAD and IV branches

3.2.3

Thoracic Duct

The thoracic duct terminates at the junction of the left subclavian vein and the left internal jugular vein.

3.3. Physiology 3.3.1

Fluid Dynamics

Fluid dynamics is the study of fluids and how they behave in motion. An appreciation of fluid dynamics is essential to understanding the complex processes of arteriosclerosis, aneurysm formation, and peripheral vascular disease. Blood is a type of fluid that deforms and flows under pressure. The physical principles that guide fluid energy and how it reacts within a tube (i.e. blood vessel) are well studied. Several traits can be applied to vascular surgery in order to afford a better understanding of the intricate processes that underlie aneurysmal rupture, lead to claudication, as well as many other pathologies that ultimately lead to morbidity and mortality.

3.3.2

Fluid Energy

As for other physical principles of movement, the motion of blood relies on a particular force, pressure. While pressure is the most important factor contributing to the motion of blood within the vascular system, other forms of energy may also play a role. The combination of all of these forces results in the total fluid energy, in which differences guide the directionality of blood flow. Applying this notion, fluid flows from regions of high pressure to regions of low pressure, and more accurately is determined by the difference in total fluid energy at any two points. This total fluid energy is, however, a factor of pressure, combined with the potential and kinetic energy of that fluid. The potential energy of a fluid represents nothing more than the ability of that fluid to do work based on its height above a given point, and the kinetic energy is the work done by a fluid in motion. When these physical characteristics of fluid are combined, the total energy of fluid (E) is equal 346

Basic Science to the sum of the hydrostatic pressure (P), potential energy (rgh), and kinetic energy (1/2rv2): E = P + rgh + 1/2rv2.

3.3.3

Bernoulli’s Principle

Bernoulli’s principle states that an inviscous fluid in a steady flow state or streamline maintains a constant energy at any given point along that particular streamline. The individual characteristics that make up the total fluid energy do not necessarily need to be equal, but rather the sum of these characteristics must be equivalent between two points. For example, for two points in a streamline to have equal total energies, the combination of hydrostatic pressure, potential energy, and kinetic energy must change accordingly based on the following relationship: P1 + rgh1 + 1/2rv12 = P2 + rgh2 + 1/2rv22.

3.3.4

Poiseuille’s Law

Bernoulli’s principle is difficult to apply to human physiology, in that blood flow requires mechanical energy that is converted to heat when it moves from one point to another. This dissipation of energy is related primarily to the viscosity of blood, which is defined as resistance to flow. This resistance, or friction, is not only between fluid particles themselves, but also between those particles and the vessel wall. The viscosity of fluid, combined with characteristics of the vasculature as well as pressure (P) gradients, determine flow according to the following relationship: Q = DPpr4/8Lh. The radius (r) exerts the most significant effect on flow, but viscosity also plays a role, determined by the viscosity coefficient (h). It is important to keep in mind, however, that Poiseuille’s law only applies to laminar, non-pulsatile flow.

3.3.5

Turbulence

Turbulence is nothing more than a disturbance in flow. However, an understanding of this concept is much more complex. Sir Osborne Reynolds studied this concept by injecting dye into a cylindrical tube and observing characteristics of flow. In streamline states, the dye was seen to travel in a discrete, laminar pattern. On the other hand, turbulent states caused the dye to fill the tube. The difference be-

Figure 3. Derivation of Bernoulli’s principle. Copyright Manny Max. Used with permission.

347

Clinical Review for the USMLE Step 1 tween streamline and turbulent states was determined to be the velocity of flow. Reynolds concluded that therein lays a critical velocity at which a particular fluid loses its streamline characteristics and becomes distorted. The so-called Reynolds number, which is the point that fluid flow states transition from streamline to turbulent, can be described by the ratio of inertial forces to viscous forces acting on the fluid: Re = rvr/h (Re = Reynolds number; r = density; v = critical velocity; h = viscosity). When the Reynolds number approaches 2000, laminar flow is disturbed and becomes turbulent. It is the generation of turbulent flow that results in the transfer of energy from the blood to the vessel wall, which is a likely etiology of vascular pathology.

3.3.6

Laplace’s Law

The Law of Laplace describes tension (T) as a factor of pressure (P) and radius (r): T = Pr. While this law could potentially describe the stress on an arterial wall that leads to rupture, for example, an arterial aneurysm, it more accurately applies to the stress of thin walled structures (i.e. soap bubbles, alveoli). However, the Law of Laplace was applied by Roy in the early 1900s to describe tension length relationships. Roy discovered that as blood vessels are stretched, they resist stretch more strongly; this lead to the implementation of Young’s modules, which increase with increasing stretch.

3.3.7

Young’s Modules of Elasticity

Young’s modules of elasticity (E) is determined by the ratio of the stress applied (t) to the resulting strain (e): E = t/e. Roy applied this concept in his studies where he cut circumferential strips of vessel wall and stretched them with weights. However, one must be skeptical of Roy’s initial results because it is unclear as to how much resistance to stress a vessel possesses when it is not challenged in its natural anatomical configuration; that is, when the entire circumferential unit is not stressed as a congruent unit. Therefore, tension-length relationships were determined using pressure-volume relationships by applying the Law of Laplace. Although the Law of Laplace allows us to create more accurate tension-length diagrams to illustrate the forces and stresses on vessel wall, it should not be used to describe the true stresses on an arterial wall.

3.3.8

Wall Tension

To better understand why large aneurysms rupture more often than small aneurysms, a different relationship can be applied. The stress exerted on a vessel wall (t) is related to the transmural pressure (P), the inner radius of the vessel (ri), and the wall thickness (d): t = Pri/d. Remember that the transmural pressure is the difference between the intraluminal pressure and the extravascular pressure. Aneurysms rupture at a point within the vascular wall where the tangential stress within the wall overcomes the tensile strength of the wall (t > T).

3.3.9

Vascular Hemodynamics

Peripheral Vascular Resistance Peripheral vascular resistance relies on the tone of the vasculature. Both intrinsic and extrinsic mediators regulate the overall tone within a vascular bed. Peripheral vessels are predominantly found in the skin as well as muscle beds. Sympathetic tone is primarily responsible for the peripheral vascular resistance in the skin and superficial tissue, and responds to body temperature. Activation of the sympathetic nervous system results in vasoconstriction peripherally, an attempt to conserve heat. On the other hand, when body temperature rises, a vasodilation reflex occurs as sympathetic tone is withdrawn.

348

Basic Science The vasculature found within a muscle bed is innervated by not only a system that vasoconstricts, but also one that vasodilates. Postural changes elicit vasoconstriction of the arterial system in an attempt to maintain blood pressure. However, in times of stress (i.e. exercise), metabolites build up, and combined with ischemia of exercise, the vascular bed vasodilates in an attempt to increase peripheral blood flow. The balance of vasodilator and vasoconstrictive mediators is responsible for the overall peripheral vascular resistance.Â

Autoregulation Autoregulation is responsible for maintaining constant and consistent blood flow to a target region or organ as perfusion pressure increases and decreases. Conceptually, as blood pressure rises and falls, resistance vessels constrict or dilate, respectively, to ensure a constant level of flow through that vessel. This is particularly important in the cerebral vasculature, in that a rising blood pressure elicits a constrictive response to protect the brain from hypertension. Autoregulation, mediated by local and sympathetic mediators, preserves blood flow over a range of blood pressures.

Venous Hemodynamics Veins are thin, compressible, valve-containing structures that contain a significant percentage of the bodyâ&#x20AC;&#x2122;s blood supply. Both the deep and superficial veins in the periphery are responsible for returning blood to the heart, and do so in a fluctuant manner. This rapidly changing flow through the venous system can be explained by the forces that act on blood within the system: dynamic pressure transmitted through the vasculature from the contractile force of the heart, hydrostatic pressure that is affected by gravity, and filling pressure that varies with venous elasticity. Given that the contractile forces of the heart are transmitted through the arteries and capillaries, it may be negligible at the venous level. Hydrostatic pressure, on the other hand, varies depending on where it is measured with regards to the heart, with the greatest hydrostatic pressure being found at the point most inferior to the heart in an upright individual. Lastly, in applying what we know about orthostatics, the venous system alone does not constrict in response to the increased blood volume (i.e.,Â when a patient is moved from supine to upright), which corresponds to a relatively innate filling pressure. The characteristic filling pressure is what is responsible for the great capacitance of the venous system that separates it from the arterial system. Understanding each entity is important, but it is the combination of these factors within the venous system that generates the overall venous pressure.

Respiratory Flow Variation Respiration has significant impact on flow through the venous system. Not only does venous return rely on the dynamic pressure transmitted through the arterial system from the heart as well as the pumping effect of the muscles, there is significant pull generated by changes in pressure within the thoracic and abdominal cavities. Inspiration involves descent of the diaphragm into the abdomen, which in turn increases the intraabdominal pressure. This increase in pressure impedes venous flow from the legs into the central venous system because the pressure gradient between the two systems is diminished. On the other hand, during expiration, the diaphragm ascends back into the chest, decreasing intraabdominal pressure, thereby allowing increased flow into the vena cava. This concept also applies to venous flow from the upper extremities and head, in that inspiration and the resultant descent of the diaphragm decreases the intrathoracic pressure, and venous blood is then drawn into the chest.

349

Clinical Review for the USMLE Step 1 Cardiac Hemodynamics EF = (EDV-ESV)/EDV = SV/EDV CO = HR x SV The compensatory reaction for mild, normovolemic anemia is via increased cardiac output. Mean arterial pressure is 2/3s of the diastolic pressure plus 1/3 of the systolic pressure. MAPs should be kept above 60. Components of the MAP are cardiac output and peripheral vascular resistance. Oxygen delivery is affected by cardiac output, hemoglobin, and oxygen saturation. Per Starlingâ&#x20AC;&#x2122;s rule, cardiac output increases with left ventricular end diastolic volume. Left heart valve disorders lead to distortions in pulmonary capillary wedge pressure. A significant discordance in PCWP and central venous pressure indicate right heart failure. Myocardial oxygen consumption is proportional to ventricular wall tension. A pulmonary artery catheter (PAC, also known as a Swan-Ganz catheter) is an excellent method for measuring pulmonary vascular resistance. Indications include hypovolemia with significant fluid management issues, and low urine output following an operation. A fixed reading on the pulmonary artery catheter with loss of respiratory variation is an indication for malposition.

3.4. Vasoactive Mediators 3.4.1

MMPs

3.4.2

Nitric Oxide

Pathology vates SERCA, which removes calcium from the intracellular space, thus reducing calcium ions available for contraction. Therefore, nitric oxide leads to vasodilation be relaxing vascular smooth muscle cells within the vessel wall.

3.4.3

VEGF, EGF, and Angiogenesis

4. Pathology 4.1. Basic Topics 4.1.1

Atherosclerosis

Plaque formation occurs in a three step process starting with deposit of lipid within the vessel wall, known as fatty streaks. This stimulates recruitment of macrophages that attempt to resorb this lipid, leading to the formation of foam cells. Intimal hyperplasia sets in with smooth muscle cell proliferation. This is followed by sudden plaque rupture, causing embolism. Significant atheroma formation can lead to peripheral arterial occlusive disease. Stenosis of over 50% often leads to significant arterial flow disruption, while symptoms are typically present with over 75% stenosis. However, friable plaques and anatomic location play a major role in the risk assessment of stenotic disease; for example, symptomatic patients with carotid stenosis over 50% will undergo a carotid endarterectomy. Atherosclerosis is related to inflammation, a process that is accelerated by fatty streak formation and macrophage recruitment. The inflammatory process leads to damage via free radical formation and damage to the underlying endothelium. Recruitment of monocytes, platelets, neutrophils, and macrophages eventually leads to a cycle of inflammation and repair with subsequent calcification. This process is amplified by a high concentration of VLDLs and LDLs and is worsened by a low concentration of HDLs as there will be an insufficient mechanism for cholesterol removal. Once formation of the plaque has occurred, gradual stenosis of the vessel occurs from growth of the plaque. Expansion of the lipid component occurs gradually, but there is also a level of fibrosis under the intima as a reaction to the inflammation. The extent of the lipid component is related to overall plaque instability and contributes to the risk of sudden rupture of the plaque. A high fibrotic component leads to stenosis and may eventually lead to occlusion. Separation of the fibrotic capsule from the fatty plaque forms a thrombogenic surface susceptible to acute vessel occlusion. A variety of risk factors contribute to atherosclerosis, including hyperlipidemia, diabetes, hypertension, smoking, increasing age, and male gender. Treatment of reversible risk factors can lead to a decrease in atherosclerosis. The combination of risk factor control with medical management can help stabilize plaques and reduce the risk of plaque rupture.

351

Clinical Review for the USMLE Step 1

Figure 4. Atherosclerosis. Copyright Grahams Child. Used with permission.

4.1.2

Pathologic Heart Sounds

Table 4. Pathological Heart Sounds Diagnosis

Etiology

4.1.3

S1: Wide splitting. Loud S1 S2 Pulmonic valve closes before the aortic valve and is especially noticeable upon inspiration. S1: Splitting=RBBB; Loud S1=mitral stenosis S2: Hypertrophic cardiomyopathy, aortic stenosis, left bundle branch block.

Causes of Chest Pain

Chest pain can be attributed to a number of causes, and although a particular pain syndrome may be classic for a specific etiology, some of the most serious causes of chest pain can atypically present with 352

Pathology little or no pain. The common causes of chest pain are divided into those due to gastroesophageal reflux disease (GERD) and disorders of the esophagus,(which typically presents as a burning sensation, dysphagia, and general symptoms similar to a myocardial infarction). Pneumonia presents as pleuritic chest pain that is accompanied by cough and worsens with deep inspiration. Pulmonary embolism (PE) is associated with a coagulopathy and the presence of a deep vein thrombosis (DVT), and presents with tachypnea, tachycardia, and acute chest pain. Costochondritis is one of the more common causes of chest pain, and is a localized, sharp pain that is reproducible upon physical exam. Pericarditis presents as a chest pain that radiates to the shoulder, back, or neck and is relieved by leaning forward. Aortic dissection presents with a tearing sensation, chest pain that radiates to the back, and discordant pulses and blood pressures between arms. Finally, MI and angina present with substernal pain and pressure that radiates to the left arm, jaw, or shoulder. Other causes of chest pain that should be on the differential diagnosis include peptic ulcer disease (PUD), hiatal hernia, hepatobiliary disease, herpes zoster, pneumothorax, pulmonary hypertension, and various psychiatric conditions.

4.2. Congenital Heart Defects Table 5. Congenital Heart Defects Type

Tetralogy of Fallot

Transposition of great vessels

Truncus arteriosus

Etiology

Pathophysiology

Abnormal neural crest migration leading to displacement of anterosuperior infundibular septal development.

Pulmonary stenosis, RVH, overriding aorta, and VSD leads to RàL shunt and mixing of blood.

Aorta comes from R heart, pulmonary artery comes from L heart – requires PDA or other RàL shunt to be compatible with life.

Defect in neural crest migration leads to septal malformation.

Presentation RàL shunt w/ cyanosis, clubbing, boot-shaped heart, syncope.

Notes If aorta is from RV, then known as Taussig-Bing malformation; Tet spells in ToF.

Risk factor includes diabetes.

Single great vessel leaving heart due to failure of septum development from faulty neural crest migration. Infantile: Aortic stenosis proximal to end of aortic arch

Aortic coarctation

Adult: Aortic stenosis distal to end of aortic arch.

Infantile occurs in Turner syndrome.

Presents with notching of ribs, UE HTN, cerebral hemorrhage, infective endocarditis. Patent ductus arteriosus

Machine-like murmur.

Indomethacin closes; PGE1 keeps open.

VSD

High or low-pitched murmur (low or none = bad).

Most common heart defect – mostly in membranous portion of heart.

ASD

Loud S1 and fixed S2.

Typically a secundum type defect – less common.

353

Clinical Review for the USMLE Step 1 Eisenmenger syndrome occurs later in life with long-term RVH that eventually reverses a left to right shunt and makes it right to left. Occurs with PHTN and requires heart-lung transplant. When shunt reverses it leads to cyanosis, hypoxia, clubbing, and polycythemia.

4.3. Coronary Heart Disease 4.3.1

Overview

Coronary heart disease (CHD), also known as coronary artery disease (CAD), is a serious public health problem that affects nearly 14 million Americans. CHD is the result of years of fatty acid deposition, calcification, and subsequent plaque formation within the coronary arteries. Narrowing of the artery lumen by the plaque leads to decreased blood to the myocardium, followed by symptoms of angina and chest pain. Sudden complete blockade of the lumen, as can occur with the rupturing of the plaques, leads to signs and symptoms of an MI. Coronary heart disease is a significant cause of death in the United States. There are a number of risk factors for the development and progression of CHD. Atherosclerosis is the most significant cause, and this disease may be exacerbated by a positive family history, smoking, elevated titers of low-density lipoprotein (LDL), decreased titers of high-density lipoprotein (HDL), hypertension (HTN), central obesity, diabetes mellitus (DM), elevated C-reactive protein (CRP), elevated homocysteine levels, and increase in the circulation of fibrinogen. Lack of regular exercise, poor diet, high levels of emotional stress, and a typical type A personality also contribute to the development of CHD. Anemia and carbon monoxide poisoning can significantly decrease the oxygen-carrying capacity of the blood and exacerbate CHD. A family history for CHD is considered positive if relatives have experienced a MI prior to the age of 45 in men, and 55 in women. The major causes of CHD are discussed below. CHD that presents with decreased blood supply and oxygen to the heart is often referred to as ischemic heart disease (IHD).

4.3.2

Dyslipidemia

Normal lipid transport relies on a number of particles to carry lipids between various organs of the body. Derangements in this transport, or overloading certain carriers, results in deposition of this lipid into the arteries and can lead to CHD over time. Lipid transport begins with digestion of fatty acids and their breakdown within the small intestine. Digested cholesterol is transported via chylomicrons. Fatty acids are removed from chylomicrons for use in normal tissue function by lipoprotein lipase (LPL) in the liver. The remnants of the chylomicrons are converted into very low-density lipoprotein (VLDL) and secreted by the liver. VLDL carries fatty acids and cholesterol in the bloodstream to various tissues, which metabolize the VLDL to form intermediate-density lipoprotein (IDL). The IDL is metabolized to form LDL, and continues to transport the cholesterol-laden vesicles throughout the body. Once metabolism of LDL is complete, the now high-density molecules, HDL, are transported from various tissues back to the liver for further metabolism and excretion. Elevated LDL is the single most important risk factor for dyslipidemia, while elevated HDL titers (>60) indicate good metabolic function and diminished risk of dyslipidemia and subsequent CHD. Dyslipidemia is the cause of nearly half of all CHD, and most cases have a significant familial component. The types of dyslipidemias are broken down into five distinct types. Causes of isolated elevated cholesterol titers are typically due to type IIa, which includes familial hypercholesterolemia, familial defective apo B100, and polygenic hypercholesterolemia. The total cholesterol titers vary, but are often between 250 and 500 with elevated LDL but normal VLDL and chylomicron levels. Hypertriglyceridemia may occur by itself with familial hypertriglyceridemia and elevated VLDL (type IV disease), familial 354

Pathology lipoprotein lipase deficiency or familial apo CII deficiency, both with elevated chylomicrons (type I and V disease). Diabetes with poor glucose control can also present as type I or type V disease. A combined hyperlipidemia occurs with elevations in VLDL and LDL in type IIb disease, while a dysbetalipoproteinemia with elevated VLDL and IDL occurs in type III disease. The highest cholesterol concentrations are found in type I, IV, and V disease. Very high triglyceride levels may lead to pancreatitis as a complication. Dysbetalipidemia presents with obvious signs and symptoms only in very severe disease. Severe hypercholesterolemia may present with xanthelasmas, which are yellow-colored swellings on the eyelids, and xanthomas, which are red papules on the exposed portions of the skin. Diagnosis of dyslipidemia is made by a lipid profile after fasting overnight. Repeated testing may be required in pregnancy, recent weight loss, following surgery, and in severe illness. Testing done within the first few hours following an MI will be indicative of pre-MI lipid levels, while those performed thereafter may be the result of disease. Total cholesterol (TC) is considered normal if it falls below 200. Cholesterol below 240 is considered borderline, while greater than 240 is high. Normal HDL is between 30 and 100, although recent guidelines prefer an HDL greater than 60 in order for HDL to be cardioprotective. LDL should be around 100, with 130-159 borderline, 160-189 high, and 190 or more considered to be very high. Dyslipidemia is treated with immediate changes to dietary intake and increased exercise. A Step 1 diet is tried for the first few months and includes decreasing total fat intake to less than 30% of all caloric intake, keeping saturated fats below 10%, and reducing dietary cholesterol to less than 300 mg per day. A step 2 diet is used thereafter by further decreasing the saturated fat intake to less than 7% of total caloric intake, and reducing dietary cholesterol to less than 200 mg per day. Successful implementation of a step 2 diet can reduce total cholesterol by more than 10%, and exercise can be cardioprotective by raising HDL. Failure of diet by six months typically heralds the use of medications to improve the lipid profile. Treatment for dyslipidemia begins after the failure of diet and exercise to return a lipid profile to within normal limits (WNL). The use of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, such as statins, reduces the conversion of acetyl-CoA to LDL, and increases the formation of HDL. Statins are among the most successful medications for decreasing LDLs, which can be nearly 35%, and raising HDL by nearly 10%. The use of bile acid sequestrants such as cholestyramine and colestipol are sometimes used to decrease LDL by 20%; these medications function by binding to bile acids in the intestine and preventing their reuptake. Nicotinic acid, or niacin, is used to prevent the synthesis of cholesterol and prevents the liberation of fatty acids from adipose tissue, leading to a gradual 20% decrease in LDL. Fibrates are useful for increasing HDL by up to 30%, although their success varies. Thus far, the use of vitamin E appears to have a negative effect on the lipid profile, plant stanols have been shown to decrease cholesterol absorption, calcium blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and alpha-adrenergic blockers have no effect on lipids, beta-receptor blockers and diuretics worsen the lipid profile, and fish oils such as omega-3 fatty acids (FA) decrease triglycerides and increase HDL.

4.3.3

Hypertension

The formal diagnosis of hypertension is made after confirmation of an elevation in systolic blood pressure (SBP) over 140 or diastolic blood pressure (DBP) over 90. HTN is divided into an idiopathic cause (90% of all cases), and secondary HTN attributable to a specific medical condition. Secondary HTN can be due to renal artery stenosis (RAS), Cushing or Conn syndrome leading to hyperaldosteronism, pheochromocytoma, eclampsia / preeclampsia, aortic coarctation, and parenchymal disease of the kid355

Clinical Review for the USMLE Step 1

Figure 5. Factors affecting blood pressure. Copyright Wikimedia. Used with permission. ney. HTN is broken down into four stages: stage I HTN has a SBP below 150 and a DBP below 100; stage 2 disease has SBP below 180 and DBP below 110; stage 3 disease has SBP below 210 and DBP below 120; and stage 4 disease is any SBP above 210 or DBP above 120. The highest blood pressure determines the stage. HTN affects nearly 1/3 of the adult American population. Hypertension is the result of increased systemic vascular resistance (SVR) with a normal cardiac output. This results in an increase in work by the heart in order to have the same stroke volume (SV) with every heartbeat. Risk factors for HTN include a high salt diet, obesity, smoking, diabetes, family history, African American race, and male gender. Hypertension presents with few, if any symptoms unless severe. Such symptoms may include epistaxis, hematuria, blurred vision, chest pain, light-headedness, headache, and congestive heart failure (CHF). The diagnosis of HTN is made by testing the BP in both arms and finding symmetrically abnormal readings of at least stage 1 HTN. Ophthalmoscope exam is typically positive for papilledema, arteriovenous (AV) nicking, and punctate hemorrhages. Renal artery bruits may be present with renal disease or RAS, and hematuria may be present on urinalysis (UA). Renal disease may be tested with kidney function tests, with abnormalities in the BUN) to creatinine ratio, and elevations in serum potassium. Finally, an electrocardiograph should be done in all patients with long-standing HTN to diagnose any cardiac conduction dysfunction. Hypertension requires a reduction in fatty-acid intake similar to the step 1 and step 2 diets of dyslipidemia. Weight loss and exercise are required to improve cardiac function and reduce SVR. Improved mortality has been found with the use of beta-receptor blockers and thiazide diuretics. The use of ACE inhibitors is especially effective in Caucasians and diabetics. African American patients benefit more from calcium-channel blockers. Patients with dyslipidemia should avoid beta-blockers. Pregnant patients should avoid diuretics and ACE inhibitors, and should be treated with alpha-methyldopa and hydralazine. Diabetics should avoid beta-blockers, as should asthmatics and patients with vascular disease. Patients with gout should avoid diuretics, and elderly patients are most likely to benefit from diuretics, ACE inhibitors, and calcium channel blockers to reduce the isolated SBP commonly found in this group.

356

Pathology 4.3.4

Malignant Hypertension

Malignant HTN is severe BP increases that result in end-organ damage. Damage is typically found in a fundoscopic exam, but damage may also occur within the renal parenchyma, central nervous system, heart, and elsewhere with signs such as neurologic changes, papilledema, heart failure, renal failure, and cerebrovascular accident (CVA). Treatment of malignant HTN is to reduce the mean arterial pressure (MAP), and IV agents should be used in emergency situations. Such agents include nitroglycerin, nitroprusside, and labetalol. Pheochromocytoma is often controlled with phentolamine, and pre-eclampsia is controlled with hydralazine or alpha-methyldopa. Magnesium sulfate is also given for pre-eclampsia. Nitroprusside is preferred with CNS changes, while nitroglycerin is preferred with coronary changes.

4.3.5

Angina

Angina is chest pain associated with decreased oxygen flow to the myocardium leading to temporary, reversible ischemia. There are three major types of angina â&#x20AC;&#x201C; stable angina, unstable angina, and Prinzmetal angina. Angina presents with a retrosternal pain that radiates to the left shoulder, arm, or jaw. Angina lasts a few minutes and is intermittent in nature. The pain is typically a heavy pressure sensation, sometimes described as a squeezing or tightening inside the chest. Angina typically does not last more than 15 minutes â&#x20AC;&#x201C; if it does, the clinician should seriously consider angina evolving into an MI. Angina is precipitated by factors that affect cardiovascular stability or increase cardiac work; these factors typically include vasoconstriction due to cold or exertion, psychoactive factors such as anxiety, and eating large meals. Angina also presents with shortness of breath (SOB), nausea and vomiting (N/V), diaphoresis, and palpitations. Angina is relieved by nitroglycerin within a few minutes; resting also ameliorates the symptoms of angina. Physical signs of angina include tachycardia with or without an S4 gallop. Stable angina is due to ischemia of the myocardium leading to episodic pain. Stable angina is chronic in nature and does not progress over time. Stable angina occurs with predictive changes to myocardial oxygen consumption, such as with strenuous exercise. Stable angina is relieved with rest. This disease may evolve into unstable angina. Unstable angina is any new-onset angina that progresses over time with respect to location, frequency, or severity. Unstable angina can occur at rest, and typically requires increasing amounts of medication to have relief from symptoms. Unstable angina requires treatment to avoid evolution into an MI. Prinzmetal angina is a rare variant of angina that is due to vasospasms of the coronary arteries. Prinzmetal presents as a chronic, intermittent chest pain unrelated to exertion, and tends to occur at predictable times in the morning. The pain wakes up the patient at night. Prinzmetal angina presents with ischemic changes and ST elevations on EKG during exacerbations. Diagnosis of Prinzmetal is done with angiography. Diagnosing angina proceeds by ruling out other causes of chest pain by carefully obtaining a history, completing a physical exam, and running an EKG. EKG changes may be normal, or present with ST changes (depression or elevation), and T wave inversions. An exercise stress test (treadmill stress echocardiogram, or TSE) is done to determine the type of angina that occurs and its severity. A TSE with thallium is done in patients with valvular defects, arrhythmia, young women, and those with acute ischemic changes. Other examinations available to diagnose and determine the prognosis of angina include dobutamine stress echocardiogram (DSE), persantine echocardiogram, and thallium imaging. Stress tests should not be performed on individuals with unstable angina due to the risk of evolution to MI. 357

Clinical Review for the USMLE Step 1 Patients with aortic stenosis (AS), hypertrophic subaortic stenosis, chronic obstructive pulmonary disease (COPD), congestive heart failure, aortic dissection, ischemic changes on EKG, uncontrolled HTN, and those with general contraindications to exercise should also not receive a stress echocardiogram. Angina is initially treated by lifestyle and dietary modifications. Patients with stable angina should receive sublingual nitroglycerin (SLN) during exacerbations, percutaneous transluminal coronary angioplasty (PTCA) or a coronary artery bypass graft (CABG), beta blockade to reduce oxygen demand by the myocardium, and aspirin (ASA) to decrease the risk of evolution to MI. Those with unstable angina should also receive SLN, PTCA and CABG as indicated, and should also be monitored in a cardiac care unit (CCU) due to the risk of MI. Heparin or low molecular weight heparin (LMWH) should be used in conjunction with ASA to decrease the risk of thrombosis. Finally, those patients with Prinzmetal angina should receive calcium channel blockers and nitrates to reduce coronary artery spasms; beta-blockers are contraindicated in this population.

4.3.6

Myocardial Infarction

Myocardial infarction (MI) is the development of myocardial necrosis following prolonged ischemia. MI is typically attributed to sudden rupture of a plaque leading to coronary artery blockade, an embolism from a secondary source, shock leading to impaired cardiac perfusion, and coronary vasospasm. Hypercoagulable states such as thrombocytosis and polycythemia vera can contribute to embolism, and direct embolisms can occur from atrial myxoma and coronary thrombi. Spasms of the coronary arteries are common in cocaine abuse and in Prinzmetal angina. Finally, inflammation of the vasculature can lead to MI, as in systemic lupus erythematosus (SLE), polyarteritis nodosa (PAN), Takayasu arteritis, and Kawasaki disease. Risk factors for MI include males over 55 years of age, postmenopausal women, smokers, HTN, hyperlipidemia, DM, and atherosclerosis. The typical MI is a progressive process that leads to significantly greater damage to the myocardi-

Figure 6. ST elevations seen on an EKG in a patient with an acute myocardial infarction. Copyright Moody Grove. Used with permission. 358

Pathology um with the passage of time. If therapy is not immediately started after coronary vasocculsion, permanent damage to the myocytes sets in within 20 minutes. Coagulation necrosis begins within about 6 hours with the influx of PMNs. Total coagulative necrosis sets in after a day or two, and granulation tissue starts to form around 3-7 days. It is during this time that the destroyed myocytes are being cleared and fibrotic tissue is being formed. Rupture through the heart wall can occur, leading to cardiac tamponade and significant morbidity and mortality. Acute MI (AMI) can occur as a transmural lesion, which is typically accompanied with Q waves. A subendocardial infarct is confined to the innermost portion of the ventricular wall and does not present with Q waves; regardless of the cause of the MI, the subendocardial tissue of the left ventricle is the most susceptible to damage due to the tenuous oxygen supply from lack of direct arterial flow. The typical MI presents with symptoms of severe, retrosternal chest pain for more than 20 minutes. This severe crushing pressure or squeezing sensation leads to nausea and vomiting, diaphoresis, weakness, and anxiety. Shortness of breath develops with failure of heart function. In order to compensate for Figure 7. The components of the EKG and how it relates to changes the ischemic changes taking elsewhere in the cardiopulmonary system. Copyright Anthony Atplace, tachycardia ensues with kielski and Daniel Chang. Used with permission. an S4 gallop. Cardiogenic shock with hypotension, jugular venous distention (JVD), and S3 gallop, and rales may develop if more than half of the myocardium has been compromised. Depending on the severity of the damage, arrhythmias and septal rupture may occur. Inferior MIs may present with bradycardia. Typically, an MI will present as pain that radiates to the left arm or shoulder, or the jaw. It is most likely to occur in the early waking hours as this is when the blood pressure can be the highest. MI may be entirely silent in diabetics, the 359

Clinical Review for the USMLE Step 1 elderly, patients with HTN, and in postsurgical patients. Psychological symptoms include a feeling of impending doom. The initial test in diagnosing an MI is the use of an EKG. In inferior wall MI, there will be an STe in leads II, III, and aVF. Anteroseptal MI has STe in leads V1-V3. Lateral wall MI has STe in V4-V6, and posterior wall MI has STd in V1 and V2. New onset of Q waves is indicative of a transmural MI, and is the most common EKG finding after an ST elevation MI (STEMI). Flattening of the ST segment typically does not progress to Q waves, and this is known as a non-ST elevation MI (NSTEMI). A new LBBB is also diagnostic of MI. Echocardiograms in order to demonstrate hypokinesia of the ventricular wall are used in patients with nondiscernable EKGs but who otherwise fit the clinical picture of MI. The EKG changes that occur immediately upon onset of MI include sharp, peaked T waves and STe, followed by Q waves, then T wave inversions (Twi) after several hours. The Q waves may remain as an indicator of prior MI, and the Twi may remain for several years. Table 6. EKG Findings Inferior wall MI

STe in leads II, III, and aVF

Anteroseptal MI

STe in leads V1-V3

Lateral wall MI

STe in V4-V6

Posterior wall MI

STd in V1 and V2

Transmural MI

Q waves after an ST elevation MI (STEMI)

The progression of an MI leads to a predictable rise in cardiac markers of myocardial damage. Some of these markers are specific, others sensitive, and some useful only as early markers of disease. Myoglobin is typically one of the earliest markers to become serologically positive with elevations within one hour of experiencing an MI; however, myoglobin is found in numerous tissues and so is not very specific. Rises in CPK occur within 6 hours, but this marker is similar to myoglobin in that it is not specific. Troponin T (TnT) and troponin I (TnI) rise within 3-4 hours, remain elevated for up to a week, and are highly sensitive markers for even minimal myocardial damage (so called microinfarcts). Creatine kinase, MB fraction (CK-MB) is a highly specific and sensitive marker for cardiac damage that is positive within 4-6 hours and remains so for at least one or two days. The CK-MB fraction rises only with myocardial necrosis, but CK itself may rise with general cardiac trauma or manipulation with resuscitation procedures. Lactate dehydrogenase (LDH) is rarely used as a marker for cardiac damage due to its lack of specificity and sensitivity, but it tends to be positive after 12 hours and remains elevated for up to two weeks. Most centers in the United States now measure serial cardiac enzymes in patients suspected of MI (especially in ruling out MI). Cardiac enzymes including CK-MB, TnT, and CPK are typically collected every 6 hours three consecutive times along with EKG tracings. A patient typically rules out for MI with lack of EKG signs and no increases in cardiac enzymes. Table 7. Diagnosis with Cardiac Enzymes

360

Myoglobin

One of the earliest markers within one hour of experiencing an MI; Not very specific.

CPK

Occurs within 6 hours. Not specific.

TnT, TnI

Rise within 3-4 hours, remain elevated for up to a week, and are highly sensitive markers.

CK-MB

Highly specific and sensitive marker for cardiac damage that is positive within 4-6 hours and remains so for at least 1 or 2 days. The CK-MB fraction rises only with myocardial necrosis, but CK itself may rise with general cardiac trauma or manipulation with resuscitation procedures.

Pathology Treatment of MI involves a series of medication and procedural orders. Aspirin, or its alternative, clopidogrel, are administered, immediately given evidence that aspirin can reduce mortality from MI by over 25% through decreased clot formation. Beta-blockers have also been shown to decrease mortality by limiting the extent of damage; metoprolol is typically given three times every 5 minutes and stopped if the heart rate falls below 60. If given in the first few hours after an MI, thrombolytic therapy has also been shown to decrease mortality by breaking up clots; agents Figure 8. Cardiac enzymes in MI. Copyright J. Heuser. Used include streptokinase and alteplase. Heparin is given to prevent the furwith permission. ther development of clots. Oxygen is given to increase oxygen saturation and for patient comfort. Nitroglycerin is also given to relieve symptoms by dilating coronary arteries and reducing cardiac oxygen demand through decreased preload. Morphine is given to reduce pain and anxiety, and thereby further decrease oxygen demand by the damaged myocardium. PTCA can be done on an emergent basis and within an hour or two of MI onset to restore the patency of the coronary arteries, especially if there is multiple vessel disease. Angioplasty is preferred in patients with contraindications to normal thrombolytic therapy, have CHF or poor EF, risk of dangerous arrhythmia development, and patients who fail thrombolytic therapy. Cardiac pacing may be required if arrhythmias develop as a result of damage to the heart. Patients should also be counseled with regard to dietary changes and exercise as discussed above for dyslipidemia and HTN. MI is broken down into four classes with specific clinical findings and objective signs that are indicative of mortality. Class I MI presents with no pulmonary symptoms, indicating reasonable cardiac function without heart failure. The cardiac index (CI) is greater than 2.2, and the pulmonary capillary wedge pressure (PCWP) less than 15. The hospital mortality is less than 1%. Class II MI presents with pulmonary congestion, CI greater than 2.2, and PCWP more than 15. There is a 10% hospital mortality. Class III MI has systemic hypoperfusion with CI less than 2.2, PCWP less than 15, and a hospital mortality of about 20%. Class IV MI has pulmonary congestion with systemic hypoperfusion, CI less than 2.2, PCWP more than 15, and a hospital mortality exceeding 50%. Table 8. Staging of MI Class I Class II

Presents with no pulmonary symptoms, CI is greater than 2.2, and the PCWP less than 15. Presents with pulmonary congestion, CI greater than 2.2, and PCWP more than 15.

Class III

Systemic hypoperfusion with CI less than 2.2, PCWP less than 15.

Class IV

Pulmonary congestion with systemic hypoperfusion, CI less than 2.2, PCWP more than 15.

Complications arising from MI include those leading to arrhythmias, dysfunction leading to pump failure, ischemic changes, pericarditis, and sudden cardiac death. Arrhythmias that develop following an MI include bradycardia that may require the use of atropine to prevent ectopic foci from developing and the use of a pacemaker, if the bradycardia is severe enough. Premature atrial contractions (PACs) 361

Clinical Review for the USMLE Step 1 or premature ventricular contractions (PVCs) can develop, although these tend to be benign, if isolated. Supraventricular tachycardia (SVT) can occur with the development of atrial fibrillation, atrial flutter, or a junctional focus. Ventricular tachycardias (VT) can also occur, which heralds a more dismal prognosis, especially with ventricular fibrillation. Hemiblocks and bundle branch blocks can also occur, in addition to first, second, and third order atrioventricular (AV) blocks. Heart failure is an all too common occurrence following a significant heart attack, and can present with either mechanical disruption due to anatomic failure, or with contractile dysfunction due to failure of normal expansion and contraction from direct muscle damage. In addition, the conduction system of the heart can become dissociated from the targets it innervates. Ischemia can continue and even progress following an MI. Extension of the infarct site can also occur, and is especially common if there is a sustained increase in myocardial oxygen demand but without the concomitant increase in supply. Thrombolytics should be used along with measures to ensure vessel patency prior to discharge. Dressler syndrome is the development of a pericarditis following an MI. Dressler syndrome may occur between a few days to a few months following an MI, and is due to an inflammatory process that runs rampant and leads to damage to otherwise healthy cells. Dressler syndrome may also complicate other heart disorders, especially those that require open surgical management. It is a rare complication of MI, affecting fewer than one in a hundred patients. Dressler syndrome is treated with NSAIDs and steroids. MI can lend to a pro-thrombotic state due to relative stasis of blood residing in a now dysfunctional portion of the heart. This meets one of the three requirements of Virchowâ&#x20AC;&#x2122;s triad for vascular thrombosis (the other two being endothelial damage and a hypercoagulable state). These clots can go on to cause pulmonary dysfunction in a right-sided MI, or systemic complications such as stroke and renal destruction in a left-sided MI. Immobilization immediately after an MI can also predispose an individual to deep vein thrombosis (DVT) and subsequent PE. Rupture of the papillary muscles can lead to mitral regurgitation and sudden cardiac decompensation following a posteroinferior MI. It tends to occur approximately 3-5 days after an MI and presents with a loud holosystolic murmur. Echocardiography demonstrates a valve leaflet moving around with the flow and regurgitation. Septal rupture is more likely in anterior MI and occurs 3-5 days afterwards. It presents with a loud holosystolic murmur that radiates to many locations, and also tends to have a palpable thrill. Echocardiography is used for diagnosis. Sudden cardiac death is occasionally a result of a fatal arrhythmia that develops following an MI, such as ventricular tachycardia and ventricular fibrillation. Repeated myocardial ischemia is the largest positive predictor of risk for arrhythmias leading to sudden cardiac death. Patients who have had an MI should receive a stress echocardiogram prior to discharge to ensure reasonable cardiac function. Left ventricular function may be assessed using a multigated acquisition (MUGA) scan. Patients should be advised to continue ASA and beta-blockers, and patients with poor EF should be started on ACE-inhibitors. Close management of existing risk factors such as HTN, DM, hyperlipidemia, and poor lifestyle habits should be done to minimize these contributing causes and avoid a repeated MI. Patients at particular risk of continued cardiac dysfunction should be evaluated for PTCA and CABG. Post-MI patients should achieve at least 70% of their ideal target rate on a stress test

362

Pathology 4.3.7

Congestive Heart Failure

Congestive heart failure is the loss in the heartâ&#x20AC;&#x2122;s ability to properly replenish the systemic or pulmonary blood volume. Right-sided CHF (RHF) leads to overflow in the systemic circulation leading to systemic venous congestion. Left-sided CHF (LHF) leads to pulmonary symptoms due to pulmonary venous congestion. The most common cause of CHF is following MI and the resultant ischemic changes. Abnormalities in myocardial cells also contributes to CHF; for example, cardiomyopathy arising from substance abuse, diseases such as sarcoidosis or hemochromatosis, and intrinsic cardiopulmonary diseases such as pulmonary HTN or aortic regurgitation can all lead to symptoms of CHF. Structural abnormalities such as valvular heart disease, congenital heart disease, CAD, constrictive pericarditis, restrictive cardiomyopathy (RCM), and high-output failure (such as wet beriberi) can exacerbate CHF. CHF can also be worsened with a high salt diet, arrhythmias that compromise the proper dynamics of heart function, infection (such as systemic infections or pneumonia), renal failure, high fluid loads, anemia, thyrotoxicosis, PE, and excessive exercise. The most common cause of right-sided CHF is left-sided CHF. CHF can present with either a diastolic dysfunction or a systolic dysfunction. Diastolic dysfunction leads to decreased cardiac output (CO) due to elevated systolic pressure (SBP) with normal EF. EF is allowed to remain approximately normal as both SV and EDV decrease proportionately. The decrease in EF due to decreased SV leads to a decrease in CO in the absence of any change in HR. The EF in diastolic dysfunction can be measured with echocardiography. In systolic dysfunction, there is decreased contractility leading to decreased EF. The decrease in EF is proportional to changes in SV and inversely proportional to changes in EDV. As a result, decreased EF leads to decreased SV, which in the absence of changes to HR, leads to decreased CO. In both diastolic and systolic dysfunction, congestion in either the pulmonary or systemic circulation is the end result. As indicated by the formula for CO, the output per beat is directly proportional to HR and SV. With decreases in SV as found in CHF, the first compensatory mechanism is to increase the HR in order to return CO to baseline. The heart can also function along its Frank-Starling curve by increasing stretch, leading to ventricular dilation and thereby increasing EDV. While the heart is along its Frank-Starling curve, it is able to compensate for the increased EDV by increasing its contractility, leading to a return of SV to baseline but at higher pressures. Myocardial hypertrophy results from the increased pres-

Figure 9. Frank Starling Curve. Copyright Sapan Figure 10. Changes in dilated cardiomyopathy. Desai. Used with permission. Copyright Sapan Desai. Used with permission. 363

Clinical Review for the USMLE Step 1 sures, and after some time, the heart decompensates, falls off the Frank-Starling curve, and any further dilation only leads to worsening CHF. A systemic compensation can also occur by way of decreased activation of stretch receptors in the heart and carotid artery, leading to increased systemic vascular resistance, increased afterload, and decreased SV. In other words, the systemic compensation is hardly helpful to restoring normal cardiac function. The kidneys also attempt to compensate for the decreased renal perfusion pressures. The renin-angiotensin-aldosterone (RAA) system is activated, leading to vasoconstriction and the retention of sodium chloride and water. This increased volume load leads to an increase in preload, which worsens the congestion as the heart is unable to compensate for the increased stretch by increasing its contractility â&#x20AC;&#x201C; the reason is that by the time the kidneys attempt to compensate for the failing heart, the heart has already fallen off its Frank-Starling curve and can no longer adequately compensate for changes in EDV. CHF presents differently depending on whether it is right-sided CHF or left-sided CHF. Right-sided CHF presents with hepatic congestion due to backing up of fluid from the right heart to the vena cava. The resultant hepatomegaly can lead to RUQ pain, distention of the jugular veins (JVD), ascites, peripheral edema, cyanosis, and a hepatojugular reflex (HJR). The HJR is increased distention of the jugular veins with gentle upward abdominal pressure due to a fluid wave that travels superiorly. Left-sided CHF presents with signs and symptoms of dyspnea on exertion (DOE), paroxysmal nocturnal dyspnea (PND), orthopnea, rales, nocturia, diaphoresis, an S3 gallop, and tachycardia. Both RHF and LHF can present with ankle edema, white sputum with flecks of blood, and cardiomegaly. Dyspnea is a complaint in CHF, and can present with a restrictive lung defect (RLD) demonstrable by pulmonary function tests (PFTs). Diagnosis of CHF is made by plain films of the chest demonstrating cardiomegaly, congestion of the pulmonary vasculature, Kerley B lines, and pulmonary effusion. Echocardiography can be used to demonstrate abnormalities in ventricular wall motion and diminished EF. EF can also be evaluated using a MUGA scan. A urinalysis (UA) will demonstrate oliguria (from activation of the RAA axis), increased specific gravity (SG), hyaline casts, and proteinuria. Diastolic dysfunction will present with normal EF and decreased CO; systolic dysfunction will present with decreased EF and decreased CO. SBP is increased in diastolic dysfunction. Diastolic dysfunction is typically treated with surgical options as medical options such as diuretics and negative inotropes have limited utility. Diuretics are recommended in situations of volume overload, while beta-blockers and calcium-channel blockers are used decrease the inotropic activity of the heart. Digoxin and vasodilators are not used. The main treatment for CHF is to decrease preload through sodium restriction, furosemide diuresis, and venodilation with nitrates. Afterload reduction is typically accomplished with ACE inhibitors. The Caucasian population responds best to ACE inhibitors and beta blockers, while African Americans respond best to calcium-channel blockers. The elderly respond better to thiazides, and diabetics respond better to ACE inhibitors. The cornerstones of treatment involve decreased cardiac oxygen demand, improving cardiac function, and reducing vascular load. Systolic dysfunction is primarily treated by reversing dietary trends such as excessive salt intake, and decreasing major stressors (physical and mental) for the patient. Medical treatment is essential, and is composed of diuretics and vasodilators such as ACE-inhibitors and hydralazine or nitrates. Beta-blockers such as carvedilol or metoprolol are used. Other agents that are often added to manage systolic dysfunction include spironolactone (which reduces mortality), digoxin, dobutamine, and amrinone (which decrease symptoms but have no effect on mortality), and ARBs. Surgery and heart transplant are the final options when all other recourses are exhausted. 364

Pathology Acute pulmonary edema is the result of cardiac decompensation leading to fluid collection in the perivascular, peribronchial, and alveolar spaces. It is commonly the result of CHF, arrhythmia, MI, severe HTN, PE, adult respiratory distress syndrome (ARDS), uremia, shock, anaphylaxis, and drug reactions. APE presents with tachypnea, pink sputum discharged with cough, cyanosis, dyspnea, rales, ronchi, wheezing, and crackles. CXR indicates Kerley B lines, pulmonary effusion, Cardiomegaly, and prominent, congested pulmonary vessels. Early ABGs indicate respiratory alkalosis, and later evolve into respiratory acidosis. Treatment of pulmonary edema involves nitroglycerin for preload reduction, oxygen with positive end expiratory pressure (PEEP), morphine, aspirin, and diuretics to further reduce preload. Amrinone may be used to increase inotropy and cause vasodilation, dobutamine can be used to further increase inotropy, and dopamine to cause an inotropic action with vasoconstriction. PND is the development of difficulty in breathing that awakens a person. During night, the volume of blood that was redistributed to the dependent extremities begins to flow superiorly to the head and chest. This increased fluid load is initially handled by the heart as it stays on the Frank-Starling curve, but the heart in CHF is already at its limits in terms of how much more it can increase contractility in response to increased EDV. The heart falls off the Frank-Starling curve, contractility ceases to keep pace with EDV, and the volume backs up into the lungs. Over a few hours, increasing pulmonary congestion occurs leading to pulmonary edema and impaired oxygen exchange. Hypoxia and dyspnea are the result. PND is treated by having the patient stand up, walk a few paces, and attempt to sleep sitting up. Standard CHF therapies are also used such as vasodilators and volume reducers.

4.4. Valvular Heart Disease Valvular heart disease is a significant cause of morbidity and mortality. However, with advances in the technique and timing of surgical interventions, patients are experiencing improved outcomes after being diagnosed and treated. The standard for diagnosis and assessment is echocardiography. Asymptomatic patients are typically observed on a regular basis, while those with clinical functional abnormalities may receive surgery to correct the defect in cardiac function. Valvular heart disease incorporates deficits in mitral stenosis (MS), mitral regurgitation (MR), mitral valve prolapse (MVP), aortic stenosis (AS), aortic regurgitation (AR), tricuspid stenosis (TS), and tricuspid regurgitation (TR). Pulmonary valve disease is similar to that for aortic valve deficits with the appropriate corrections made for the right side of the heart. Rheumatic heart disease (RHD) is also discussed due to the immunologic effects of rheumatic fever (RF) on the valves of the heart. Figure 11. Heart sounds in various valvular defects. Copyright Madhero88. Used with permission. 365

Clinical Review for the USMLE Step 1 4.4.1

Mitral Stenosis

Mitral stenosis is the development of a narrowing between the left atrium and left ventricle. Abnormalities of the valvular leaflets are the typical cause, and most cases are secondary to RF and subsequent RHD. The majority of patients are female, and congenital causes of MS are rare. Deficits in the valve leaflets and narrowing of the outflow tract lead to impaired LV function (LVF). There is increased pressure in the LA as a result of outflow tract failure, and this causes pulmonary edema and finally RHF. MS presents over a period of time with onset of cough, DOE, hemoptysis, RHF with ventricular failure, hoarseness from laryngeal nerve impingement by the expanding LA, and thromboembolic phenomenon in the systemic vasculature due to hemostasis in the LA. Orthopnea, PND, fatigue, hepatomegaly, ascites, and peripheral edema are other symptoms and are especially likely in the later stages of MS. On physical exam, a significant precordial thrust can be palpated with a sternal lift, atrial fibrillation may be present on EKG, and auscultation may yield a loud S1 with an opening snap. Decreased pulse pressure and a typical apical diastolic rumble may also be present. Physical exam signs of an apical diastolic murmur with an S1 that has an opening snap is indicative of MS. A CXR may indicate a straight left edge of the heart due to LAH, and Kerley B lines may be present as a result of the pulmonary congestion; a large pulmonary artery and pulmonary HTN may also be indicated on CXR. EKG typically indicates RVH, atrial fibrillation, and LAH. Echocardiography demonstrates thickened mitral valve leaflets and LAH. Treatment of MS starts with prophylaxis for endocarditis by beginning regimens typically used for CHF, controlling any arrhythmia that is present, beginning anticoagulation therapy (especially in the presence of atrial fibrillation), and considering balloon valvuloplasty or open surgical repair with significantly narrowed outflow tracts. Balloon valvuloplasty is more successful in MS than in AS. Specific medications include digitalis, diuretics, and warfarin.

4.4.2

Mitral Regurgitation

Mitral regurgitation (MR) is the result of ischemic changes leading to dysfunction of the papillary muscles, sudden rupture of the chordae tendineae, damage secondary to RHD, progressive changes from MVP, endocarditis, HCM, congenital defects, and severe LV dilation. MR leads to the return of blood during systole from the LV to the LA. MR is more common in men. MR leads to a compromise of systolic function by causing the left ventricle to exert more energy than necessary against a greater volume load in order to pump blood throughout the systemic circulation. Due to a relative patency in the mitral valve, part of the SV pumped during systole is transmitted into the LA instead of into the systemic circulation. Preload increases, and with the increase in EDV, there is an increase in myocardial contractility, abnormally high EF to compensate for part of the volume going to the LA, and eventual damage to the myocardium from the abnormally high work load Figure 12. Mitral regurgitation. Copyright J. as the MR continues to worsen. Heuser. Used with permission. 366

Pathology MR presents with the development of thromboemboli from the relative stasis in the LA, dyspnea, fatigue and weakness, orthopnea, PND, and RHF with pulmonary HTN. A displaced point of maximal impulse (PMI) with a palpable thrill and diminished carotid upstroke, a holosystolic apical murmur that radiates to the axilla, an S3 from rapid LV filling with a split S2 that worsens with inspiration, and JVD. Diagnosis of MR includes the presence of the physical symptoms, LAH on CXR and EKG, and valvular dysfunction on echocardiogram. LA overload is obvious on catheterization. Medical treatment is typically of low utility, but is the only option available until surgical correction can be achieved. The goal of treatment is to maintain LV function, which heralds a good prognosis. To this extent, diuretics are used to decrease preload, anticoagulation is used to minimize thromboembolic phenomenon, vasodilators such as ACE inhibitors are used to decrease afterload and attempt to shunt the blood away from the bicuspid valve, and digitalis is occasionally used as an inotropic agent. Replacement of the valve is done as soon as possible. Criteria for surgery include symptomatic heart failure due to severe MR.

4.4.3

Mitral Valve Prolapse

Mitral valve prolapse (MVP) is most commonly seen in Marfan disease and other connective tissue diseases. It is also common in women, RHD, IHD, and ASD. MVP is a congenital valve defect that leads to mild regurgitation. MVP is typically asymptomatic, but may occasionally present with atypical chest pain, a mid-systolic click, lightheadedness, syncope, palpitations, fatigue, SOB, and the development of arrhythmias. A late, high-pitched systolic murmur is evident and loudest at the apex, and the S2 is widely splitting. Diagnosis is made with echocardiography, and demonstrates displacement of the bicuspid valve leaflets and subsequent meeting at some point distal to the valve opening. As most cases are asymptomatic, little treatment is required. Medical management is necessary with increasing MR and includes those agents similar to that of MR. Chest pain and arrhythmias are controlled with beta-blockers, and prophylaxis for endocarditis is started in all individuals. Surgical replacement is rarely required. Close observation is required to avoid complications leading to CHF, infective endocarditis, valvular calcification, transient ischemic attacks (TIAs), and sudden cardiac death.

4.4.4

Aortic Stenosis

Aortic stenosis (AS) is the result of a congenital disorder, abnormal calcification of the valve leaflets in an otherwise normal adult, presence of a bicuspid valve that predisposes to fibrosis and calcification, or secondary to RHD. AS leads to increased afterload due to difficulty with transmitted blood through the aortic orifice. In order to avoid the decrease in SV that occurs as a result of the afterload elevation, there is increased contractility of the ventricle in order to maintain CO. Hypertrophic cardiomyopathy (HCM) occurs. Until cardiac decompensation takes place, SV is maintained and CO remains normal. Unfortunately, the hypertrophy that occurs in the ventricle leads to increased oxygen demand, but this is confounded by the elevated pressures within the ventricle that decrease oxygen supply. AS can therefore lead to angina through ischemia. Subsequent failure of the LV can lead to backflow congestion into the lungs and cause pulmonary edema. The high pressures generated within the LV lead to an S4 gallop. Syncope, angina, and DOE are all symptoms of AS. Angina and syncope are particularly noted for being worse with exertion. This triad 367

Clinical Review for the USMLE Step 1 eventually leads to CHF. None of these symptoms occur until late in the course of AS â&#x20AC;&#x201C; the early presentation is asymptomatic. Survival after development of angina is typically about five years; after syncope it is about 3 years; and after heart failure, it is typically about one year. The differential diagnosis of AS includes HCM, MR, and pulmonary stenosis (PS). HCM presents with Q waves on EKG, has a bifid carotid upstroke, and has a murmur that decreases with squatting and increases with the Valsalva maneuver. MR presents as a holosystolic murmur that radiates to the axilla. PS presents as a murmur that worsens with inspiration and is loudest along the left upper sternal border Figure 13. Aortic stenosis. Copyright Sapan Desai. Used (LUSB). Echocardiography is the definiwith permission. tive procedure to distinguish all of these causes. With regard to maneuvers, the Valsalva maneuver decreases the murmur of AS but increases that of HCM; squatting increases the murmur of AS but decreases that of HCM. Diagnosis of AS is made with physical signs of an aortic ejection click, harsh systolic ejection murmur (SEM) leading to a palpable thrill, especially at the PMI, and S4 gallop, split S2, narrow pulse pressure, and a carotid thrill. The SEM may radiate to the carotids. On echocardiography, a pulsus tardus et parvus may be present â&#x20AC;&#x201C; a specific waveform of blood flow velocity that occurs distal to the AS and has a prolonged early systolic acceleration and flattening of the systolic peak (a late pulse that is wider than normal). EKG changes indicate LV stain, and echocardiography demonstrates the damaged aortic valve. CXR can detect calcification of the aortic valve, along with cardiomegaly and pulmonary HTN. AS requires endocarditis prophylaxis. The standard therapy, as defined by the American Heart Association, for dental procedures, esophageal procedures, and pulmonary procedures is to administer amoxicillin one hour prior to the procedure. Patients who cannot take oral medications are given ampicillin. Those who are allergic to penicillins are given clindamycin, cephalosporins, or azithromycin. Prior to gastrointestinal or genitourinary (GU) procedures, ampicillin and gentamicin should be given; if the patient is allergic to penicillins, vancomycin plus gentamycin should be administered. Surgery via balloon valvuloplasty to correct the aortic valve defect is done with severe symptoms, but the rate of restenosis is very high and may eventually require replacement of the entire valve. Patients should be advised to avoid exercise.

4.4.5

Aortic Regurgitation

Aortic regurgitation (AR) is commonly the result of RHD, but may also occur in infective endocarditis, in dilations of the aortic root due to HTN, collagen vascular disease (CVD), or Marfan syndrome, in proximal dissections of the aortic root (as in cystic medial necrosis), syphilis, pregnancy, Turner syndrome, in conditions that affect the ascending aorta (such as aortic dissection), ankylosing spondylitis, and trauma. 368

Pathology AR leads to its effects through volume overload of the LV. The increased fluid load leads to increased EDV, which in turn increases preload and causes increased myocardial contractility in order to meet the same EF. This attempt to maintain SV and CO leads to overstretching of the myofibrils, and eventually, decompensation by the LV, as it can no longer stretch enough to have a sufficiently forceful contraction. Acute presentations of AR present with very high LV EDP due to lack of sufficient compensation by the ventricle to generate the necessary contractile force. Sudden AR can even lead to unexpected cardiac death by total heart decompensation and cessation of contractions due to fatal EDP. Acute AR leads to decreased CO and a narrow aortic pulse pressure (PP). Figure 14. Aortic regurgitation. Copyright Sapan Desai. Used with permission. AR presents with dyspnea, orthopnea, and PND. Angina is common from decreased circulation and increased oxygen demand in the myocardium. There is typically a wide pulse pressure, a bounding pulse known as Corrigan pulse, a bisferiens pulse with a dicrotic pulse (two fluid waves), and a rapid femoral pulse (referred to as a pistol-shot pulse). Compression of the femoral artery leads to a bruit, known as Duroziez sign; the Hill sign is SBP that is higher in the lower extremities (LE) than the upper extremities (UE); Quincke sign is fingernail color that changes with the heartbeat; and De Musset sign is bobbing of the head in synchrony with the HR. Other manifestations include a diastolic decrescendo murmur, a systolic flow murmur, and S3, and an Austin-Flint murmur ( in which blood enters the LV simultaneously from the aorta due to AR),and from the mitral valve (normal flow). Diagnosis of AR is made by physical exam (in which a blowing diastolic murmur is worsened by leaning the patient forward). A2 is accentuated, the PMI is displaced laterally and inferiorly, EKG demonstrates LVH with narrow Q waves in the left precordial leads, and echocardiography demonstrates regurgitation. CXR demonstrates LVH and aortic dilation. Treatment of AS involves prophylaxis against endocarditis, treating LV failure with preload and afterload reduction, digitalis for positive inotropy, and valve replacement with cardiac decompensation.

4.4.6

Tricuspid Stenosis

Tricuspid stenosis (TS) is commonly secondary to RHD, carcinoid, and congenital malformations. It presents with JVD, peripheral edema, and signs of hepatic congestion leading to hepatomegaly, ascites, and jaundice. TS is diagnosed as a low-pitched, rumbling, diastolic murmur. A thrill is palpable at the LLSB, and there is a RV thrust present. Treatment requires surgical repair. TS is distinguished from MS in that TS worsens with inspiration.

369

Clinical Review for the USMLE Step 1 4.4.7

Tricuspid Regurgitation

TR is the result of LHF or mitral valve deficits leading to increased pressure from the pulmonary artery. Stretching of the RV, for example from RHF or infarction, can also lead to TR from failure of leaflet coaptation, and direct lesions to the valve leaflets can account for TR. It presents with signs and symptoms of liver congestion, JVD, and RHF. TR is a holosystolic, blowing murmur loudest along the LLSB. Like TS, it worsens with inspiration. EKG signs indicate RVH, and atrial fibrillation tends to occur with TR. As RHF is most commonly due to LHF, treating LHF is usually the treatment of choice. Preload reduction should be attempted and finally surgical repair. Any diseased valve should herald the use of endocarditis prophylaxis to avoid infective endocarditis. Table 9. Summary Diagnoses of Murmurs Diagnosis

Murmur

Clinical Findings

Mitral stenosis

Apical diastolic rumble

Loud with opening snap

Normal

Murmur worsens with exercise

Mitral regurgitation

Holosystolic murmur

Soft

Split S2

S3 with strong carotid upstroke

Mitral valve prolapse

Mid systolic murmur with click

Normal

Murmur worsens when standing

Aortic stenosis

Mid systolic murmur, soft when severe

Normal

Paradoxical split

S3, S4, and diminished carotid upstrokes

Aortic regurgitation

Blowing diastolic murmur

Soft

Normal

Wide pulse pressure, SBP elevated

Pulmonary stenosis

Systolic

Single

Prominent “a” wave in the JVP, right ventricular lift, ejection click.

Pulmonary regurgitation

Inaudible in the absence of pulmonary HTN

Widened splitting

Usually related to the underlying disease process.

Tricuspid stenosis

Murmur upon inspiration

Tricuspid regurgitation

Systolic

4.4.8

Louder at lower left sternal border

Large jugular “a” wave with a slow Y descent. Often occurs with RHD. Atrial enlargement, ventricular hypertrophy, echocardiography is descriptive.

Rheumatic Fever

Rheumatic fever (RF) is due to a streptococcal pharyngitis leading to an autoimmune process. RF can develop into rheumatic heart disease (RHD) leading to deposition of immune complexes on valve leaflets and subsequent damage to the anatomy of the heart. The mitral valve is most commonly affected, but the tricuspid and aortic valves are also occasionally damaged. Rheumatic fever is diagnosed by serology that finds positive antistreptolysin-O (ASLO) titers and an elevated erythrocyte sedimentation rate (ESR). There are major criteria and minor criteria for diagnosis; two major criteria, or one major and two minor criteria must be present for the diagnosis of RF. The major criteria include myocarditis or other inflammation of the heart, migratory arthritis affecting multiple joints, erythema marginatum, Sydenham chorea, and subcutaneous nodules. Minor criteria include fever, elevated ESR, arthralgia, history of streptococcus pharyngitis, and a prolonged PR interval on EKG. 370

Pathology

Figure 15. Rheumatic fever and rheumatic heart disease. Copyright Oxynthes. Used with permission. RHD is treated with penicillin to eradicate any continuing infection by streptococcus and resolve existing pharyngitis. ASA is given for relief from arthritis and general pain relief, and steroids are used to emergently reduce the inflammation to the heart tissues. Chronic RHD is treated with continuing penicillin treatment with medications and surgery as indicated. Valve replacement may become necessary with continuing RHD. Anyone with a history of RF requires prophylaxis prior to undergoing any dental or GI procedures.

4.5. Cardiomyopathy Cardiomyopathy is disease of the myocardium leading to deficits in function. There are numerous distinct causes, but most cases of primary cardiomyopathy can be attributed to HTN, valvular heart disease, CAD, or congenital defects. Cardiomyopathy is divided into three main types, known as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and restrictive cardiomyopathy (RCM). DCM is sometimes referred to as congestive cardiomyopathy, and is the most common form. Myocarditis is also discussed at the end of this chapter.

4.5.1

Dilated Cardiomyopathy

DCM is the enlargement of the RV or LV with the loss of normal contractility. The end result is CHF, arrhythmia, and a predisposition towards thromboembolic phenomenon. It typically involves both ventricles, and is the most common cause of cardiac transplant. Causes Figure 16. Dilated cardiomyopathy. Copyof DCM include viral infections, alcohol abuse, cocaine right Sapan Desai. Used with permission. 371

Clinical Review for the USMLE Step 1 abuse, heavy metal poisoning, doxorubicin poisoning, endocrine disease (such as hypothyroidism or hyperthyroidism), pheochromocytoma, CTD, glycogen storage disease (GSD), neuromuscular disease (DMD), pregnancy, metabolic disorders (such as hypocalcemia and hypophosphatemia), inherited disorders (such as Fabry disease or Gaucher disease), and genetic predilections. Dilation of the ventricles leads to regurgitation through failure of coaptation of the valve leaflets. The combination of poor cardiac contraction, decreased EF, increased preload, and poor valvular function leads to CHF. Relative stasis of blood predisposes individuals to developing thromboembolisms. Finally, the dilation may impinge upon the conduction system and lead to arrhythmia. DCM is distinguished with decreased CO due to decreased SV and EF, an increase in ventricular filling pressure, increase in ventricular volume, and decreased compliance. DCM presents as heart failure. Angina is typically present due to increased oxygen demand and poor supply. Diagnosis of DCM is by CXR that indicates cardiomegaly and pulmonary edema, EKG that indicates LVH with LBBB or RVH with RBBB, and confirmation with echocardiography that demonstrates a dilated ventricle, wall motion abnormalities, and valve regurgitation. Physical exam often yields an S3 and S4 murmur, rales, and regurgitation murmurs. DCM is symptomatically treated as CHF, with preload and afterload reduction and volume reduction through diuretics and vasodilators, and positive inotropic agents such as digoxin. Pacemaker implantation may be necessary with arrhythmia, especially if rhythm suppressants such as procainamide and quinidine fail. The definitive treatment is heart transplant. All patients require lifelong anticoagulation.

4.5.2

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the thickening in the heart wall with narrowing of the intraventricular (IV) septum and sporadic obstruction of the outflow tract. Causes of HCM include generally idiopathic conditions (about half of all cases), and genetic causes (the remainder of all cases). The genetic defects are typically on chromosome 14 with the familial form, and autosomal dominant (AD) with variable penetrance. HCM is sometimes referred to as idiopathic hypertrophic subaortic stenosis (IHSS). HCM leads to decreased ventricular compliance but an increase in CO, as the heart function moves along the Frank-Starling curve due to volume changes. Diastolic dysfunction may occur as the heart is unable to relax. HCM is exacerbated with inotropic agents, tachycardia, preload reduction, and afterload reduction. HCM is improved with B-blockers, calcium-channel blockers, preload Figure 17. Hypertrophic cardiomyopathy. Copyright Sapan De- increases, afterload increases, and alpha-adrenergic stimulation. HCM sai. Used with permission. is distinguished by normal CO due 372

Pathology to increased SV and EF, an increase in EDP, and a decrease in chamber size. HCM has decreased compliance. HCM presents with syncope and angina, but may proceed directly to sudden cardiac death. Syncope often occurs following exercise, arrhythmia, and CHF. Angina may occur at rest, is not responsive to nitrates, but may improve by lying down. Angina may be due to outflow obstruction, but the precise cause remains to be elucidated. It is the development of arrhythmia that leads to sudden death in HCM. Clinical findings may include palpitations, paradoxical S2 splitting, bifid carotid pulse, S4 gallop, SEM along the LLSB that decreases with squatting and increases with exercise, decreased LV EDV, and regurgitation murmurs. HCM diagnosis is by EKG (which indicates arrhythmia including PVCs), atrial fibrillation, Q waves, ST changes, and T wave changes. Echocardiography is definitive with septal hypertrophy, LVH, reduced LV EDV, and midsystolic aortic valve closure. A CXR indicates LVH with a dilated LA. HCM is treated with arrhythmia suppressants such as amiodarone, beta-blockers decrease HR and permit increased filling time, increasing ventricular space with septal myomectomy, replacement of the mitral valve to reduce obstruction, pacemaker or defibrillator implantation, and avoiding exercise. Heart transplantation is required in most cases. HCM with a resting obstruction is often medically treated with dipyramide, beta-blockers, and calcium-channel blockers; surgical interventions replace the mitral valve or do a ventriculomyotomy. HCM with latent obstruction is treated first with beta-blockers, then by calcium-channel blockers and disopyramide; mitral valve replacement is the surgical procedure of choice. HCM without obstruction is treated with calcium-channel blockers and beta-blockers, and surgery is usually not required.

4.5.3

Restrictive Cardiomyopathy

RCM is the result of fibrosis and infiltrative changes to the myocardium, leading to decreased compliance and filling of the ventricles. Causes of RCM include fibroelastosis, amyloidosis, sarcoidosis, hemochromatosis, carcinoid, and cancer. Primary endocardial fibroelastosis is most likely to affect infants and has a thickened aortic and mitral valve with cardiac dilation and hyperplasia. Endomyocardial fibrosis is more common in Africa. Lรถffler endocarditis typically follows inflammation of the arteries and has an eosinophilia associated with it. Scleroderma (and the CREST syndrome), radiation exposure, GSD, and Becker disease are other causes of RCM. Becker disease occurs mostly in southern Africa with fibrosis of the papillary muscle, con- Figure 18. Restrictive cardiomyopathy. Copyright Sapan Desai. comitant necrosis of the endocar- Used with permission. dium, and dilation of the ventricles. 373

Clinical Review for the USMLE Step 1 RCM leads to scarring of the ventricles and thereby decreases compliance. The rigid myocardium retards filling and leads to abnormalities in diastole. While systolic function is also compromised to some extent, RCM is primarily a diastolic disorder. It must be differentiated from constrictive pericarditis (discussed below), and biopsy is usually done for confirmation of RCM. Upon physical exam, an S3 and S4 gallop with mitral valve regurgitation are evident. Low voltage EKG with ST and T wave changes and conduction changes are present. Echocardiography reveals large atria and thickened ventricular walls; some regurgitation is also present. Biopsy clinches the diagnosis. RCM is treated with heart transplantation. Medical treatment is effective only in reversible causes such as hemochromatosis (treat with phlebotomy and deferoxamine).

4.5.4

Myocarditis

Myocarditis is the inflammation of the myocardium, commonly due to Coxsackieâ&#x20AC;&#x2122;s B virus infection. Other viruses that can lead to myocarditis include Coxsackieâ&#x20AC;&#x2122;s A, CMV, Epstein-Barr virus (EBV), hepatitis B virus (HBV), echovirus, HIV, and adenovirus. Bacterial causes include group A streptococcus (GAS) leading to RF, corynebacterium, meningococcus, Borrelia burgdorferi, and Mycoplasma pneumoniae. Parasitic infections include Chagas disease from Trypanosoma cruzi, Toxoplasma, Trichinella, and Echinococcus. Arteritis from Kawasaki disease, general inflammation, sarcoid, SLE, cocaine abuse, and drug allergies to penicillin and sulfonamides can also lead to myocarditis. Idiopathic causes are the most common. Myocarditis is often associated with pericarditis due to the inflammatory changes taking place. Regurgitation and pericardial friction rubs can occur as a result of the infiltrate of PMNs and other mediators of inflammation and infection; this can also lead to conduction abnormalities. Myocarditis is a progressive disease that requires immediate hospitalization and treatment. Myocarditis presents with fever, fatigue, chest pain, and syncope. CHF may also be present due to diminished myocardial function. A history of URI may be present. Diagnosis of myocarditis is definitively made by biopsy. Serology raises the clinical suspicion with elevated ESR, WBC count, and cardiac enzyme elevations. Echocardiography indicates wall motion abnormalities, a generally dilated heart, and pericardial effusions. CXR is typically normal, and EKG changes sometimes find ST changes, arrhythmia, and may be low voltage. On physical exam, an S3 and S4 murmur is present along with regurgitation murmurs; a pericardial friction rub may also be heard. Presentation of symptoms prior to 30 years of age heralds a poor prognosis and increased risk of sudden death. Severity of symptoms is not correlated with increased risk of sudden death. Myocarditis is treated with supportive therapy, antibiotics and antivirals as indicated, and treatment of the heart failure and arrhythmia. The patient should be observed in the ICU. Immunosuppressive agents should not be used. Intravenous immunoglobulin (IVIG) may be beneficial.

4.6. Pericardial Disease 4.6.1

Introduction

Nearly all forms of pericardial disease are accompanied by pericardial effusion. Analysis of the fluid helps distinguish the underlying cause of the disease. A transudative effusion has a low specific gravity and is primarily composed of fluid bereft of proteins and cells; transudative effusion is most common in CHF, excessive hydration, and hypoproteinemia. Exudative effusions are more common with direct injury to the pericardium. Serosanguineous effusions are indicative of TB and cancer, while bright red 374

Pathology blood should immediately begin a search for aortic dissection and rupture. Other causes of blood within the pericardium include direct trauma, rupture of the heart several days after MI, and coagulopathies. Rapid accumulation of fluid may lead to pericardial tamponade.

4.6.2

Pericarditis

Pericarditis is the inflammation of the pericardium leading to chest pain and a friction rub. Pericarditis is commonly a result of various infectious causes, primary tumors from the breast or lung, a complication of MI, uremia, radiation, Gaucher disease, immunologic disorders, allergic reactions to drugs (such as hydralazine), INH, and procainamide, CVD, thyroid disturbances, trauma, and idiopathic in nature. Recent viral infections can grow into pericarditis; bacterial causes include tuberculosis, streptococci, and staphylococci. Pericarditis presents as substernal, pleuritic chest pain relieved by leaning forward. SLN has no effect on ameliorating the symptoms. Upon auscultation, a pericardial friction rub is commonly heard â&#x20AC;&#x201C; it is highly specific to pericarditis, but not always present. EKG changes indicate STe; STe in children is

Figure 19. EKG changes in pericarditis. Copyright James Heilman. Used with permission.

most commonly due to pericarditis. CXR may indicate an enlarged cardiac silhouette due to pericardial effusion. Echocardiography may be used to confirm the effusion. Pericarditis is treated by symptomatic management, including the use of NSAIDs, and steroids for Dressler syndrome. The underlying etiology should be treated to control progression of pericarditis.

4.6.3

Pericardial Tamponade

Tamponade is the result of a rapid pericardial effusion leading to fluid constriction around the heart and impeding normal cardiac function. It is typically the result of severe pericarditis, direct trauma, rupture of the heart wall following an MI, and dissection of the aorta with subsequent rupture. Cardiac filling is impaired, CO reduced, and systemic cardiovascular decompensation can lead to death. Numerous other causes also exist, such as uremia, radiation therapy to the chest, CVD and CTD, infection, and 375

Clinical Review for the USMLE Step 1 cancer. Pericardial tamponade leads to decreased ventricular volume due to increased external cardiac pressure from the pericardial effusion. The decreased filling leads to decreased SV and CO, with a subsequent drop in SBP. The body attempts to compensate for these changes by increased PVR, increasing HR, increased blood volume, and increasing contractility. However, as the effusion increases, the heart is not able to compensate for these changes and cardiac failure ensues with circulatory collapse. Pericardial tamponade presents with Beckâ&#x20AC;&#x2122;s triad, which includes JVD, muffled heart sounds, and hypotension. Other common symptoms include dyspnea, tachycardia, narrow pulse pressure, fatigue, and orthopnea. Pulsus paradoxus is present with a drop in SBP with inspiration (this finding can also occur in other heart failure causes, asthma, and lung disease). Tamponade is diagnosed by auscultation, a low voltage EKG that shifts over time, CXR that shows enlargement of the cardiac shadow, and echocardiogram that demonstrates the effusion. Pericardiocentesis and surgical drainage are the treatments of choice, and must be done on an emergent basis.

4.6.4

Constrictive Pericarditis

Constrictive pericarditis is the result of scarring and granulation tissue within the pericardium that limits CO. The subsequent diffuse thickening of the pericardium leads to abnormal diastole. Most causes are idiopathic, but open-heart procedures, radiation, and viral infections have all been attributed. Constrictive pericarditis presents similar to pericardial tamponade but without the rapid circulatory collapse. Orthopnea and dyspnea are the most common signs. Kussmaul sign with continuing JVP during inspiration is a common sign. A pericardial knock manifesting similar to an S3 gallop is typically present, along with distant heart sounds. Pericarditis is diagnosed through auscultation of distant heart sounds, calcification within the pericardium evident on CXR, low voltage EKG with inverted T waves in V1 and V2 and notched P waves, CT or MRI demonstrating a thickened pericardium, and confirmation of these findings with echocardiography. Treatment of pericarditis is to remove the pericardium. Sodium restriction and diuretics typically fail with more severe disease.

4.6.5

Endocardial Disease

Endocarditis is most commonly the result of infection by bacteria leading to infection of the endocardium and subsequent cardiac dysfunction and systemic phenomenon. It is especially likely in individuals with a pre-existing heart defect, those with a history of RHD, and in the elderly with a history of calcific AS. Non-infectious endocarditis is the result of iatrogenic damage to a heart valve followed by the development of infectious endocarditis. Rarer causes of endocarditis include complications of systemic lupus erythematosus (SLE) leading to Libman-Sacks endocarditis (LSE), and nonbacterial thrombotic endocarditis (which is typically a late-stage finding in numerous autoimmune disorders), chronic infections, and systemic illnesses.

4.6.6

Infective Endocarditis

Endocarditis is typically the result of an infective process leading to vegetation on the leaflets. Both acute bacterial endocarditis (ABE) and subacute bacterial endocarditis (SBE) can occur. Infective endocarditis is rare, but is increasing in incidence in children with congenital heart defects, especially those with tetralogy of Fallot (TOF), VSD, and AS. 376

Pathology The deposition of platelets and fibrin in regions of endothelial injury provide a region for bacteria to implant and multiply. Dental procedures, oral manipulation, esophageal procedures, respiratory procedures, GI procedures, and GU procedures all require prophylaxis as they may inadvertently allow bacteria to enter the blood (bacteremia), which may permit seeding of the damaged endocardium. About 80% of all cases are attributable to gram-positive bacteria such as Streptococcus viridans and Staphylococcus aureus. IV drug abusers and those with indwelling catheters are more likely to have fungal causes such as Candida. Patients with ABE are likely to have had normal, healthy valves and are typically infected with S. aureus. Death is likely within a month unless treatment is obtained. Patients with SBE have a history of heart damage, and are most likely to have S. viridans. The mitral valve is most likely to be affected in these patients. Infection by S. bovis should raise the suspicion for colon cancer. Most infection by S. viridans, group D streptococci, nonenterococcal group D streptococci, HACEK (Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kinkae) organisms, and fungi tend to cause subacute disease. Group B streptococcus, Staphylococcus aureus, and Pseudomonas tend to cause acute disease. Infective endocarditis should be suspected in any patient with a fever of unknown origin (FUO). Common signs and symptoms include fever, anorexia, headache, arthralgia, and a new heart murmur (common finding that strongly raises the clinical suspicion). ABE in particular presents with acute onset of infection, a new murmur, and infections in other parts of the body from bacteremia leading to meningitis and pneumonia. SBE presents with gradual onset of infection and has splenomegaly. Patients with a right-sided endocarditis should be suspected of IV drug abuse, and septic PE may be the result from the tricuspid infestation. However, left-sided endocarditis is the most common type of endocarditis overall. Objective findings of infective en- Figure 20. Infective endocarditis. Copyright Centers for Disease docarditis include multiple pete- Control and Prevention. Used with permission. chiae on the chest and mucous membranes, Osler nodes, Janeway lesions, splinter hemorrhages, Roth spots, and hemorrhage. Osler nodes are tender subcutaneous nodules on the distal extremities. Janeway lesions are hemorrhagic, nontender nodules on the distal extremities. Splinter hemorrhages are found in the nail bed, while Roth spots are points of retinal hemorrhage. Three positive blood cultures (BCx) are required for diagnosis. Vegetation on valve leaflets is pathognomonic and can be demonstrated best by TEE. Elevations in ESR, CRP, and WBCs are common, and the UA may have hematuria. CXR may indicate a water-bottle configuration. The primary treatment of infective endocarditis is prophylaxis, as discussed above with antibiotic treatment prior to major procedures. Following infection, treatment with ceftriaxone for one month is required for streptococcus infection and oxacillin for a month with staphylococcus infection. Vancomycin is used for resistant strains.

377

Clinical Review for the USMLE Step 1 4.6.7

Libman-Sacks Endocarditis (LSE)

Libman-Sacks endocarditis (LSE) is a consequence of SLE and leads to sterile, verrucous vegetations. The mitral and aortic valves are most commonly involved, and the abnormalities are typically clinically silent. Valvular regurgitation can occur, but embolic phenomenon is typically reserved for infective endocarditis (which is more likely with LSE). About half of all fatal SLE leads to LSE, and nearly Âž of all patients with SLE can be demonstrated, by echocardiography, to have vegetation present on their valve leaflets. The precise pathogenesis is unknown, but in the presence of the antiphospholipid antibody (APA), phospholipids in the endothelial cell membranes may be targeted. LSE is more common in African American patients and Hispanic women, and young women in particular tend to be affected by cardiac valvular lesions. Patients are typically asymptomatic, but may develop signs and symptoms similar to infective endocarditis. Thromboembolic phenomenon is rare, unless a superinfection leading to infective endocarditis occurs. SLE symptoms are universally present, along with APA. Physical exam is typically normal, and TEE may be required for diagnosis. Treatment is best done by supportive therapy and treating the underlying SLE. It is unclear what the role of steroid therapy is. Prophylaxis for infective endocarditis is mandatory, and anticoagulation therapy may also be necessary.

4.6.8

Nonbacterial Thrombotic Endocarditis (NBTE)

Nonbacterial thrombotic endocarditis (NBTE) is often the late manifestation of numerous chronic infections, autoimmune disorders, and wasting diseases that lead to a degenerative series of endocardial lesions. Deposition of fibrin is the general underlying cause. NBTE appears to be related to DIC, and the underlying cause may be a variety of neoplasms and systemic infections. Prolonged time in elevated altitudes has been demonstrated to be a causative factor by one study. NBTE is difficult to detect prior to death, but TEE provides the best chance of identifying this disease. There is no known treatment.

4.7. Arrhythmia 4.7.1

Introduction

Normal electrical conduction within the heart begins with the sinoatrial (SA) node, located in the RA. This natural pacemaker of the heart receives innervation from both the parasympathetic nervous system (PNS) and sympathetic nervous system (SNS), and responds to the bodyâ&#x20AC;&#x2122;s need for heart rate modulation as in exercise or in combating illnesses. The impulses leave the SA node and travel to the AV node, where they are briefly delayed to permit atrial contraction and ventricular filling. Once the impulses are transmitted from the AV node, they travel via the bundle of His and the Purkinje fibers to reach the ventricles and cause ventricular depolarization and contraction. The intact conduction system is referred to as normal sinus rhythm (NSR). Abnormal heartbeats due to electrical abnormalities are known as arrhythmia. Arrhythmias are classified by where they begin.

4.7.2

Premature Contractions

Premature atrial contractions (PACs) and premature ventricular complexes (PVCs) are early electrical impulses that cause a premature contraction of the heart. They are typically benign and disappear on their own.

378

Pathology 4.7.3

Sinus Bradycardia

Sinus bradycardia is a regular heart beat with normal P waves and regular PR intervals but with a rate less than 60 beats per minute (BPM). It is caused by excessive vagal tone, which in turn may be due to vasovagal syncope, MI, carotid sinus pressure, vomiting, parasympathetic agonists such as edrophonium, cardiac glycosides, and Valsalva maneuvers. Overmedication with beta-blockers and calcium-channel blockers also contribute. Increased intracranial pressure (ICP), hypothyroidism, and hypothermia are other causes. Sinus bradycardia may be an entirely normal finding, especially in athletes. It is typically asymptomatic. Symptomatic patients are typically treated with atropine. Continuing bradycardia with symptoms requires the use of a pacemaker. A dopamine drip may also be used in an emergent situation.

Figure 21. Components of the normal electric conductance. Copyright Anthony Atkielski. Used with permission.

4.7.4

Sinus Tachycardia

Sinus tachycardia is a sustained HR over 100 BPM, commonly due to fever, low BP, stress, medications, and hyperthyroidism. It may also occur for a short period of time following the cessation of beta-blocker therapy. Treatment often involves carotid sinus massage and otherwise increasing vagal tone.

4.7.5

Paroxysmal Atrial Tachycardia

Paroxysmal atrial tachycardia (PAT) is the result of a premature supraventricular beat leading to an AV nodal re-entry rhythm with a rate greater than 130 BPM. It is typically treated by increasing vagal tone, using calcium-channel blockers or adenosine, beta-blockers, and cardioversion. 379

Clinical Review for the USMLE Step 1 4.7.6

Atrial Flutter

Atrial flutter is a regular atrial rhythm of about 300 BPM and a 2:1 block through the AV node leading to a ventricular rhythm of 150 BPM. It is commonly the result of COPD, PE, MVP, ETOH, and thyrotoxicosis. Treatment involves cardioversion, calcium-channel blockers, and digoxin. Atrial flutter is distinguished from atrial fibrillation by its regular rate and rhythm.

4.7.7

Atrial Fibrillation

Atrial fibrillation is the development of impotent atrial contractions as a result of chaotic electrical activity through the conduction system. It is commonly found in patients with dilated atria, CHF, valvular heart disease, elderly patients, CAD, cardiomyopathy, ETOH abuse, sepsis, RHD, and thyrotoxicosis. Atrial fibrillation presents with palpitations, missed heart beats, fatigue, chest pain, and TIAs due to thromboembolic phenomenon likely in this condition. Atrial fibrillation is diagnosed as an irregularly irregular pulse, and nondistinct P waves on EKG. Atrial fibrillation has been described as having a â&#x20AC;&#x153;bag of wormsâ&#x20AC;? appearance. Atrial fibrillation is treated with thromboembolism prophylaxis using warfarin. Patients with a HR greater than 100 BPM may receive IV beta-blockers or calcium-channel blockers, digoxin, and cardioversion. Unstable patients receive cardioversion followed by maintenance therapy. Quinidine or procainamide may also be used with variable effect.

4.7.8

Atrioventricular Block

Atrioventricular (AV) block can be divided into three distinct classes: first-degree heart block, seconddegree heart block, and third-degree heart block. First-degree heart block is a PR interval greater than 0.20 s at a normal resting HR. It is commonly due to AV conduction system degeneration with aging, excessive vagal tone, inflammation, ischemia, and digoxin toxicity. Second-degree heart block is divided into Mobitz I and Mobitz II. Mobitz I second-degree heart block, also known as Wenckebach rhythm, is a progressive increase in the PR interval with shortening of the RR interval until a ventricular beat is dropped. It is typically due to AV nodal block in conduction, and this may occur due to poor perfusion. Mobitz II second-degree heart block is a prolonged but stable PR interval with regularly dropped beats. The site of blockage is usually infranodal. Third-degree AV block arises from discontinuity between the atria and ventricles, and leads to independent activity in the atria compared to the ventricles. Thirddegree heart block is also known as complete heart block, and the source of ventricular rhythm is an ectopic focus distal to the point of conduction blockade. Complete heart block is typically attributed to Lenegre disease, which is age-related degeneration in the conduction system. Other causes include inferior or posterior MI, infection, inflammation, digoxin toxicity, and ankylosing spondylitis. HLA-B27 is linked with the development of complete heart block. First-degree and second-degree heart blocks are typically asymptomatic. Third-degree heart block may present with intermittent CHF, transient ventricular arrhythmias leading to circulatory failure (known as Adams-Stoke attacks), and bradycardia which can worsen CHF. First-degree heart block is diagnosed by EKG with the characteristic prolonged PR interval. Mobitz I second-degree heart block is diagnosed by progressive PR prolongation with intermittent dropped QRS complexes. Mobitz I may worsen with increased vagal tone, while atropine may ameliorate this condition. Mobitz II second-degree heart block has a stable and prolonged PR interval with predictable

380

Pathology dropped beats. Atropine has no effect. Third-degree heart block is diagnosed by independent activity of the atria and ventricles. First-degree heart block is typically asymptomatic and not treated. Mobitz I is treated with atropine and pacing. Mobitz II typically requires a pacemaker. Complete heart block requires epinephrine or isoproterenol to establish a sustainable ventricular rate, then maintenance with a pacemaker.

4.7.9

Ventricular Arrhythmias

Ventricular arrhythmias are composed of ventricular tachycardia (VT), ventricular fibrillation (VF), WPW, and Torsade de Pointes (the latter two are discussed separately below). VT is a serious condition due to its degeneration into VF. VF is incompatible with life and patients with VF lasting more than a few seconds will lose consciousness. VT is an organized depolarization of the ventricles from a focus of ventricular origin that leads to more than 120 BPM. VT is characterized as having bizarre QRS complexes, and typically has some level of AV dissociation. VT is common in patients with MI, cardiomyopathy, metabolic changes, and digoxin toxicity. WPW and antiarrhythmic agents can also lead to VT. VF is the end result of a chaotic electrical activity within the ventricles leading to haphazard depolarization of the ventricles and an impotent contraction. VT presents with hypotension, CHF, syncope, and cardiac failure. SBP varies over time, and extra heart sounds may be present. Cannon waves may be present in the JVP due to simultaneous contraction of the chambers of the heart. There is also wide splitting of S1 and S2. VF presents with syncope and leads to death if no emergent interventions are taken. Increasing voltage cardioversion is used to restore normal heart rhythm, followed by epinephrine, and repeated cardioversion. Amiodarone, lidocaine, magnesium, and procainamide are given with cardioversion repeated between each medication administration. If successful, maintenance therapy includes pacemaker implantation, an implanted cardioverter and defibrillator (ICD), and ablation of any bypass tracts.

4.7.10

Wolff-Parkinson-White Syndrome

Wolff-Parkinson-White (WPW) syndrome is a pre-excitation syndrome characterized by an accessory pathway that bypasses the delay in conductance at the AV node. Narrow-complex reentry occurs with anterograde conduction between the bundle of His and Purkinje fibers and back up the accessory pathway. Simultaneously, a wide-complex reentry starts with conduction down the accessory pathway and retrogrades through the Purkinje fibers and His fibers. The end result is premature activation of parts of the ventricle. WPW is especially common in congenital heart defects such as Ebstein anomaly associated with the tricuspid valve and transposition of vessels (ToV). It can also occur in CHF, HCM, SVT, PAT, and atrial fibrillation. EKG typically shows a wide QRS wave with a delta wave indicating early depolarization of the ventricle via the bypass tract. The bypass is identified through electrophysiological tests and cardiac catheterization, and subsequently ablated with radio waves. Cardioversion may be required in emergent cases and with destructive arrhythmias. Maintenance therapy of WPW may be instituted until radioablation can take place; the medications used include amiodarone, flecainide, procainamide, or sotalol. Adenosine, beta-blockers, calcium-channel blockers, and digoxin are absolutely contraindicated due to the potential to block normal AV conduction.

381

Clinical Review for the USMLE Step 1 4.7.11

Torsade de Pointes

Torsade de Pointes is characterized by a prolonged QT and a QRS complex that rotates 180 degrees about its long axis. It is caused by hypokalemia, hypomagnesemia, tricyclic antidepressants (TCAs), procainamide, disopyramide, psychotropic agents (including lithium and phenothiazines), CVA, congenital QT syndrome, quinidine, bradycardia, complete heart block, and idiopathic causes. The arrhythmia itself may be initiated by a PVC leading to abnormal ventricular repolarization. Torsade de Pointes presents with syncope and may degenerate into ventricular fibrillation. It may also be initiated by sudden auditory stimuli. Long QT syndrome presents with recurrent lightheadedness and syncope. Treatment of torsade includes treating the underlying etiology, using magnesium to stabilize the heart rhythm, overdriving the heart, and using beta-blockers for maintenance. Pacing may be necessary.

4.8. Aortic Diseases 4.8.1

Introduction

The largest artery in the body is an elastic blood vessel composed of three layers of tissue: the innermost tunica intima, the middle tunica media, and the outermost tunica adventitia. The beginning of the aorta is known as the aortic root, followed by the ascending aorta that continues to the brachiocephalic, left common carotid, and left subclavian branches. The part that gives off these three branches is known as the aortic arch. The descending aorta travels through the diaphragm and into the abdomen, where it is referred to as the abdominal aorta. Numerous diseases affect the aorta â&#x20AC;&#x201C; the most common and clinically significant ones include aortic dissection, and aortic aneurysm. Mesenteric ischemia is included in this section due to its relation to vascular disorders.

4.8.2

Aortic Dissection

Aortic dissection is the result of a transverse tear through the intima and media of the aortic wall leading to extravasation of blood, potential compromise of flow to other arterial branches, and the possibility of rupture and hemorrhage. Aortic dissection is attributable to HTN, congenital heart defects, CTD, syphilis, pregnancy, coarctation of the aorta (as in Turner syndrome), abuse of cocaine, and trauma. The Treponema pallidum organisms of syphilis cause aortic dissection through infection of the vasa vasorum with subsequent irritation by the inflammatory and immune reaction. Aortic dissection is classified by the DeBakey system into three types: type I involves the ascending aorta and part of the distal aorta, and is the most common of the three types; type II involves only the ascending aorta; and type III involves only the descending aorta. The Stanford system classifies aortic dissections into the type A class if the ascending aorta is affected, and the type B class if the descending aorta is affected. Aortic dissection presents as a tearing sensation with severe chest pain that radiates to the back. HTN is typically present, discordant pulses between extremities can be measured, and AR is typically present. Diagnosis is made by CXR that indicates loss of the aortic knob and a widened mediastinum, CT with IV contrast or TEE that demonstrates an intimal flap with extravasation of blood, and angiogram as the gold standard. A CXR should be obtained in all patients suspected of MI, as the thrombolytic therapy used in MI is absolutely contraindicated in aortic dissection. Aortic dissection is treated with BP control, immediate surgical repair for type A / type II dissections, and medical management for type B / type III dissections. Complications of treatment include the development of MI, stroke, and tamponade. 382

Pathology 4.8.3

Arterial Aneurysms

Introduction Arterial aneurysms are defined as greater than 50% dilation in artery diameter compared to the adjacent normal artery. The most frequent site for the development of aneurysms is in the infrarenal abdominal aorta. Aortic aneurysms are classified by location as each is treated differently. Ascending aortic aneurysms may involve the aortic root (sinus of Valsalva segment), tubular ascending aorta above the sinotubular junction, or both. Arch aneurysms involve the aorta between the innominate (brachiocephalic) and left subclavian arteries and treatment must provide for continued Figure 22. Crawford classification of thoracoabdominal aortic perfusion of the great vessels. Deaneurysms. Reprinted with permission from McGraw Hill, NY. scending thoracic aortic aneurysms Coselli JS, LeMaire SA. Descending and Thoracoabdominal are the second most common aneuAortic Aneurysms. Cohn LH, ed. Cardiac Surgery in the Adult. rysm type and begin distal to the orCopyright 2008:1277-1298. Used with permission. igin of the left subclavian artery and end before the takeoff of the celiac axis. Thoracoabdominal aortic aneurysms involve a variable extent of the descending thoracic aorta and abdominal aorta below the diagram. The classification system developed by Dr. E. Stanley Crawford is used to describe the location of thoracoabdominal aortic aneurysmal pathology. Abdominal aortic aneurysms (AAA), are located either inferior to or at the level of the renal arteries, and may extend into the iliac arteries as well.

Etiology and Pathophysiology There are many causes of aneurysm formation including connective tissue disorders, infectious (mycotic), pseudoaneurysm, inflammatory, and most commonly, degenerative etiology, the pathophysiology of which remains poorly understood. While atherosclerosis may play some role in the development of degenerative aneurysms, not all degenerative aneurysms are found in patients with atherosclerosis. Matrix metalloproteinases are a family of digestive enzymes implicated in aneurysm pathogenesis. Matrix metalloprotease-9, in particular, has a strong correlation with degenerative aneurysms, and a randomized trial evaluating the effectiveness of the MMP inhibitor and antibiotic doxycycline on aneurysm progression is ongoing. Independent of matrix metabolism, histologic analysis of the infrarenal aorta has shown a marked age-related decrease in aortic elastin, resulting in decreased tensile strength. Connective tissue disorders should be excluded in any young patient with aortic aneurysmal disease. Marfan syndrome is caused by a heterozygous mutation in the gene encoding for the extracellular matrix protein fibrillin-1 (FBN1). In the autosomal dominant condition Loeys-Deitz syndrome (LDS), mutations occur in either of the 2 genes that encode the TGF-b receptor (TGFbR1 and TGFbR2). The skin, joint, and vascular manifestations of LDS can show similar phenotypes with the vascular form of 383

Clinical Review for the USMLE Step 1 Ehlers-Danlos syndrome, a disorder caused by mutations in the type III collagen gene (COL3A1). LDSII has features of an LDS and Ehlers-Danlos syndrome phenotype and is associated with mutations in the TGFbR genes. Independent of disorders associated with specifically identified genetic mutations, there appears to be a familial component to the development of aortic aneurysm disease. For example, twenty per cent of the first order male relatives of aneurysm patients will also have the disease. Aneurysms are four times more common in men than women, and occur more often in Caucasians than African or Asian Americans.

Natural History and Pathophysiology Aneurysms are the 13th leading cause of death in the United States. Death is caused by rupture which occurs precipitously and unpredictably. Most patients who rupture die suddenly and only a few whose rupture is contained are able to be saved by emergency surgery. In accordance with the Law of LaPlace, the risk of rupture increases exponentially with increasing diameter of the aneurysm sac. The risk of rupture of the abdominal aorta begins to exceed the risk of surgical repair at about 5 cm for fusiform aneurysms, and thus preemptive elective repair in this location is considered after the sac reaches 5 to 5.5 cm in diameter. In all patients, however, individual risks and benefits must be taken into consideration when deciding whether or not to perform aneurysm repair. On average the normal diameter of the ascending aorta is 20 mm, 20 mm in the descending aorta, and 16 mm in women and 18 mm in men in the infrarenal aorta. The principal clinical concern in patients with aortic aneurysm is the risk of rupture. Rare complications include aneurysm thrombosis and embolization of the thrombus that lines the aneurysm sac causing downstream ischemia. The incidence of thoracic aortic aneurysms and abdominal aortic aneurysms are 10 and 50 per 100,000 person-years in the United States, respectively.

Abdominal Aortic Aneurysms The majority of abdominal aortic aneuryms (90%) are located in the infrarenal position, with an additional 10% in the juxtarenal or pararenal position. A juxtarenal aneurysm is defined as an aneurysm that extends up to, but does not involve the renal arteries, while a pararenal aneurysm involves the origins of the renal arteries with aortic dilation. An additional variant of abdominal aortic aneurysm is an inflammatory aneurysm, defined on CT scan as an aneurysm with a 1 cm or greater inflammatory rind surrounding the infrarenal aorta. Clinical features associated with inflammatory aneurysms are fever, elevated erythrocyte sedimentation rate, back or flank pain, and hematuria. Preoperative identification of the presence of an inflammatory component is critical, as the operative approach may be different in these patients. The size threshold at which aneurysm repair is recommended is influenced by the risk of rupture compared to the risk of repair. The risk of rupture increases exponentially with sac diameter. An epidemiologic study of Olmsted County, Minnesota residents showed the 384

Figure 23. Three-dimensional reconstruction of CAT scan derived data in a patient with AAA. This data is essential for precise planning for endovascular therapy. Used with permission from TeraRecon (San Mateo, CA).

Pathology risk of rupture was negligible below a diameter of 5 cm.9 In 1950, Estes reported that most patients with aneurysms over 6 cm would die from rupture if untreated. The Aneurysm Detection and Management (ADAM) trial in the US and the UK small aneurysm trial both demonstrated no mortality benefit to treating abdominal aneurysms less than 5.5 cm; however, both of these trials have been criticized as nearly two thirds of the patients in the observation arm came to operation during the study because they met expansion criteria. The ADAM study was a VA-based trial enrolling 1163 men with 4 to 5.4 cm aneurysms. This study demonstrated no survival benefit to patients undergoing early surgery for 4 to 5.4 cm aneurysms. Studies of the natural history of small aneurysms suggest that abdominal aneurysms expand at an average rate of about 0.25 cm/year. However this rate is quite variable and it is not known if the predominant pattern is slow continuous growth or if growth occurs in a staccato fashion. Most practitioners follow patients with small aneurysms at annual or semi-annual intervals depending on aneurysm size to assess for growth to a size that warrants consideration of surgical repair and/or rapid growth rate (greater than 0.5 cm over six months). The threshold for repair is also influenced by the medical condition of the patient. The morbidity and mortality of aneurysm repair increases with the presence of severe heart, renal and pulmonary disease regardless of whether an open or endovascular technique is chosen. Since most aneurysms are asymptomatic in the absence of rupture or rapid expansion, they are usually discovered incidentally while looking for other pathology or on physical examination by an astute practitioner. Imaging is paramount for the diagnosis and treatment of AAA. Ultrasound is accurate for diagnosing abdominal aneurysms and determining the sac size but does not provide enough anatomic definition to be useful for planning either open or endoluminal aneurysm repair. Multichannel CT angiography is the current standard for preoperative imaging and treatment planning. Three dimensional reconstructions of CT-derived aortic data are optimal for comprehensive pre-operative endograft planning, and are becoming standard of care. When AAA rupture does occur, it is estimated that 50% of patients die before reaching the hospital and 50% of patients who reach the hospital die despite treatment. Poor prognosis for survival is associated with hypotension at time of presentation, cardiac arrest, need for intraoperative transfusion, and advanced age.

4.9. Vascular Disorders 4.9.1

Introduction

A number of vasculitides affect patients with rheumatic illnesses. Several have already been discussed in the renal section, including polyarteritis nodosa and Wegener granulomatosis. The rest of the major vascular disorders, including Churg-Strauss and Takayasu, are discussed below. Avascular necrosis of the hip is also mentioned for completeness.

4.9.2

Churg-Strauss Disease

Churg-Strauss disease affects medium-sized arteries. Churg-Strauss leads to granulomatosis and systemic necrotizing vasculitis with a number of nonspecific and constitutional symptoms. Overall, bronchospasm leading to asthma is common. Maculopapular rashes also develop throughout the body, along with purpura and nodules. Treatment of Churg-Strauss disease is to use corticosteroids, azathioprine, and cyclophosphamide to control the immune reaction.

385

Clinical Review for the USMLE Step 1 4.9.3

Takayasu Arteritis

Takayasu arteritis is an autoimmune complex that affects medium and large-sized arteries. It is especially common in Asian women. Takayasu arteritis is also known as pulseless arteritis because it leads to a loss of a palpable pulse in the upper extremities and carotid vessels. Raynaudâ&#x20AC;&#x2122;s phenomenon occurs as a result of this decreased flow, along with decreased perfusion of the brain and the resultant sequelae. Mesenteric ischemia leading to abdominal pain also occurs. Diagnosis of Takayasu arteritis is made by arteriography. Takayasu arteritis is treated with corticosteroids and methotrexate to induce remission.

4.9.4

Wegener Granulomatosis

Wegener granulomatosis is the formation of necrotizing granulomas in the respiratory tract and renal parenchyma. The result is the development of a glomerulonephritis, disseminated vasculitis, and pulmonary disease. Cytoplasmic antineutrophil cytoplasmic antibodies (C-ANCA) have been associated with Figure 24. Takayasu arteritis. CopyWegener granulomatosis, and implicate an autoimmune cause. right Wikimedia. Used with permisLeukocyte release of inflammatory cytokines and toxic oxygen sion. radicals leads to organ damage. Wegener granulomatosis presents with inflammation of the respiratory tract, vasculitis of smaller vessels, and focal glomerulonephritis. Some of the manifestations of this potentially devastating disease are: septal perforation, otitis media, hearing loss, facial paralysis, oral ulcerations, subglottic stenosis, pulmonary symptoms such as cough, hemoptysis, and pleuritis, renal involvement with focal glomerulonephritis and ESRD, conjunctivitis, uveitis, arthralgias, myalgias, petechiae, peripheral neuropathy, and GI symptoms. Diagnosis is by clinical history, elevated C-ANCA, and Figure 25. Wegenerâ&#x20AC;&#x2122;s granulomatosis. Copyright Nephron. confirmation by biopsy. Wegener granuUsed with permission. lomatosis tends to present with the triad of sinusitis, pulmonary infiltrates, and nephritis. Wegener granulomatosis is treated with glucocorticoids to achieve immunosuppression. Cyclophosphamide and methotrexate are used in more serious disease. TMP-SMX has been used to avoid relapse, but the Mechanism of Action of this agent is unknown. Survival is dismal without treatment and death is likely after only a few months due to renal failure.

386

Pathology 4.9.5

Henoch-Schonlein Purpura

Henoch-Schonlein purpura is aggregation of IgA and deposition of this immunoglobulin within vessel walls and the renal mesangium. Abnormalities with IgA1 have been implicated, with an inflammatory response resulting after abnormal deposition of these antibody complexes. The release of various inflammatory mediators by activated lymphocytes leads to the vasculitis seen in this disease. An allergic reaction to foods, insects, cold exposure, and various medications (penicillins, erythromycin, and quinidine) have been implicated as being the basis for the faulty immune reaction and IgA release. Figure 26. Henoch-Schonlein Purpura. Copyright Okwikikim. Used Other causes include infections with permission. by EBV, VZV, parvovirus B19, GAS, HCV, and SBE, and vaccinations including those for typhoid, measles, cholera, and yellow fever. HSP carries high morbidity but mortality is rare. A symmetrical erythematous macular rash begins on the lower extremities followed by the development of purpura. Edema of the scalp and distal extremities occurs. Abdominal pain, bloody diarrhea, arthralgias, and acute renal damage occur. Eosinophilia is often present along with IgA. Ultrasound, plain films, and MRI are used to confirm the findings, and a renal biopsy often clinches the diagnosis. The distinguishing feature of HSP is the presence of arthralgias. Treatment of HSP is primarily supportive management of renal failure and abdominal complications. Corticosteroids have been used with some benefit.

4.9.6

Polyarteritis Nodosa

PAN is the development of a systemic vasculitis with necrotizing inflammatory changes to medium and small arteries and subsequent infarction of organs. The kidney vasculature is especially affected, along with the intestines, peripheral nerves, joints, and skin. PAN is occasionally a consequence of viral infections such as HBV, but an autoimmune cause has yet to be ascertained. The complications of PAN include skin ulceration, gangrene of the distal extremities, infarction of the bowel, liver, and kidney, renovascular HTN, and internal hemorrhage. Peripheral neuropathy is often present. PAN may be a complication of RA and SjĂśgrenâ&#x20AC;&#x2122;s syndrome. Diagnosis of PAN is difficult as ANCA is rarely present, and biopsy is typically required to detect the focal necrotizing arteritis. Treatment of PAN involves glucosteroids to suppress the immune reaction. Seroconversion in patients with HBV is sometimes done through granulocyte-macrophage colony-stimulating factor (GM-CSF). 387

Clinical Review for the USMLE Step 1 4.9.7

Thrombotic Thrombocytopenic Purpura

TTP, and its related syndrome, hemolytic uremic syndrome (HUS) are the consequence of vascular injury from inflammatory or toxic damage. Platelet responses, subsequent release of free radicals, and loss of prostacyclin leads to amplified damage. TTP occurs in adults, while HUS occurs in children. TTP presents with widespread capillary thrombosis that primarily affects the kidney and brain. Microinfarction and petechial hemorrhages occur. HUS presents with mostly subendothelial capillary damage and affects the kidneys with necrotizing renal artery thrombosis only in older children. HUS appears to be due more to circulating Escherichia coli type 2 verotoxin. Binding of this verotoxin to the renal parenchyma may result in additional renal damage. HUS is responsible for as much as 1 in 10 cases of HTN in children. The prognosis with TTP and HUS remains guarded, with TTP having a higher mortality. HUS primarily affects children under five, TTP affects adults in their 30s. TTP has been related to RA, PAN, SLE, and SjĂśgrenâ&#x20AC;&#x2122;s syndrome. TTP evolves over a week with early fever and skin purpura. Hematuria and hematochezia are present with hemorrhage in the mucosal membranes and retina. Pancreatitis, arthralgia, and CNS changes also evolve. HUS may be preceded by a viral or bacterial prodrome; viruses include echovirus, adenovirus, Coxsackie virus, and bacteria include E. coli, Salmonella, Shigella, Streptococcus, and Yersinia. E. coli O157:H7 is the most common cause of HUS, and poorly cooked hamburger meat is the implicated cause. HUS presents with weeks of abdominal pain, nausea and vomiting, diarrhea, hematochezia, GI bleeding, ARF, uremia, HTN, CNS changes, blindness, high fever, and pallor. A microangiopathic hemolytic anemia with hematuria and proteinuria can be demonstrated in both TTP and HUS. Treatment of TTP involves plasmapheresis, fresh frozen plasma (FFP), and corticosteroids. Splenectomy is sometimes beneficial in TTP. HUS requires blood transfusions in most patients. Dialysis is necessary in about half of all patients due to the severe ARF. Fluid and electrolyte management is required, and reduction of HTN is necessary. Anticoagulation, thrombolysis, plasmapheresis, and prostacyclin infusion are necessary in some cases. Mesenteric infarction leading to ischemia of the colon in HUS may necessitate bowel resection.

4.9.8

Avascular Necrosis

The blood supply to the scaphoid bone of the wrist and the head of the femur are particularly limited and therefore susceptible to distal ischemia, if the perfusion is disturbed. Wrist fractures in the anatomical snuff box and fractures of the head of the femur must therefore be managed quickly and efficiently to prevent avascular necrosis (AVN). Other conditions that can lead to avascular necrosis of the hip include use of steroids, radiation therapy, alcoholism, sickle cell anemia, and Gaucher disease. AVN of the hip presents as referred pain to the knee and is worsened with internal rotation of the hip. It is for this reason, and many other related conditions, that all knee pain elicits a full examination of the entire lower extremity, including the hip. Diagnosis of AVN of the hip or scaphoid is made by MRI or bone scans. Plain films are nonspecific early in the disease. If surgical repair cannot be done and the blood supply reestablished to the ischemic region, total replacement of the joint may become necessary.

388

Pharmacology

5. Pharmacology 5.1. Nitrates The use of nitrates is a mainstay regimen for the treatment of numerous cardiac disorders. In low doses, nitrates dilate veins and thereby reduce preload. Larger doses lead to a reduction in afterload, and eventually lead to dilation of the coronary arteries to permit increased oxygenation of a heart that now has lower stresses. Side effects of nitrates stem from their vasodilation, causing orthostatic hypotension, reflex tachycardia, headaches, and facial flushing. Nitrates are contraindicated in individuals with low SBP. There is a risk of syncope and methemoglobinemia with nitrates; methemoglobinemia is treated with methylene blue. Table 10. Nitrates Drug

Indications

Mechanism

Complications

Contraindications

Notes

HTN Nitroglycerin

Fast acting medication available in sublingual and IV formulation

Angina PE HTN

Isosorbide dinitrate

Angina

Fast acting medication

PE Malignant HTN Nitroprusside

PE Hydralazine

Fast acting medication

Angina â&#x2020;&#x2018;GMP

â&#x2020;&#x2018;HR, HA, dizziness

Malignant HTN

Do not combine with sildenafil due to risk of sudden death Causes vasodilation more than venodilation

CHF HTN Nitrous oxide

Angina

Fast acting medication

PE HTN Diazoxide

Angina PE

5.2. Adrenergic Agents

and

Antihypertensives

Beta-blockers are used to decrease oxygen requirements by the myocardium through decreased heart rate, blood pressure, and contractility. They improve morbidity and mortality following an acute MI and in CHF. Side effects of beta-blockers include fatigue, depression, worsening of the lipid profile, bronchoconstriction, sexual dysfunction, and insomnia. Beta-blockers are contraindicated in individuals with severe asthma, and should be used with care in individuals with DM. Relative contraindications include poorly controlled DM, coexisting use of calcium channel blockers, in 1st degree heart block, and severe peripheral vascular disease.

389

Clinical Review for the USMLE Step 1 Table 11. Non-catecholamine adrenergic agonists. Drug Alpha-methyldopa

Indications HTN

Mechanism

Complications

Contraindications

Notes

Sedation, hemolytic anemia, liver disorders

CNS

PTSD Opioid withdrawal Clonidine

ADHD

α2 agonist in CNS α2, CNS

Consult MD before discontinuing

Tourette syndrome HTN Asthma Ephedrine

Nasal decongestant

Clinical use declining due to better options.

α, β

Urinary incontinence Nasal decongestant Phenylephrine

SVT

α1

Headache, cardiac irregularity

Cardiac arrhythmias

Mydriasis Metaproterenol

Bronchospasm

β2 > β1

Methylxamine

SVT

α1

Table 12. Alpha adrenergic antagonists Drug

Indications

Mechanism

Pheochromocytoma

390

Complications Orthostatic hypotension

Notes

Phenoxybenzamine

Peripheral vascular disease

α1, α2

Prazosin

HTN, BPH

α1

Orthostatic hypotension on first dose, dizziness, syncope, and HA

Dilates arterioles and venules

Terazosin

HTN, BPH

α1

Orthostatic hypotension on first dose, dizziness, syncope, and HA

Dilates arterioles and venules

Doxazosin

HTN, BPH

α1

Orthostatic hypotension on first dose, dizziness, syncope, and HA

Dilates arterioles and venules

Reflex tachycardia

Irreversible

Pharmacology Table 13. Beta adrenergic antagonists Drug

Indications

Propranolol

HTN Angina pectoris

Mechanism

Akathisia, HTN, angina, migraine, IHSS

Complications

β1, β2

Sedation, hyperlipidemia

β1

Sedation, hyperlipidemia

β1

Hyperlipidemia

Metoprolol

Atenolol

SVT

Esmolol

CHF

SVT

β1

Sedation

Glaucoma

Pheochromocytoma and malignant HTN

α1, β1, β2

Sedation

Labetalol

HTN

Contraindications

Notes Also used for performance anxiety and thyrotoxicosis

Impotence, asthma, CV disease, CNS disease, diabetes (relative)

Table 14. General antihypertensives Drug

Indications

Complications

Contraindications

Thiazide diuretics

HTN

Hypokalemia, hyperuricemia, hypercalcemia, hyperglycemia

Avoid in patients with arrhythmia

Loop diuretics

HTN

Hypokalemia, metabolic alkalosis, ototoxicity

Avoid in patients with arrhythmia

Clonidine

HTN

Xerostomia, sedation, rebound HTN

Alpha-methyldopa

HTN

Sedation

Guanethidine

HTN

Orthostatic hypotension, sexual dysfunction

Prazosin

HTN

Orthostatic hypotension

Beta-adrenergic receptor blockers

HTN

Asthma, CNS changes, CV effects, impotence

ACE-inhibitors

HTN

Cough, teratogenic

Avoid in pregnancy

ARBs

HTN

Hyperkalemia

Avoid in pregnancy

391

Clinical Review for the USMLE Step 1 Table 15. Calcium channel blockers Drug

Indications

Mechanism

Complications

Contraindications

Notes Most effective in smooth muscle

Nifedipine

HTN Angina

L-type calcium channel blockade

Strong arteriolar vasodilation leads to reflex increase in HR and decreased AV conduction

↓CV, edema, dizziness

Similar to the effect of nitrates Also a class IV antiarrhythmic

Verapamil

Diltiazem

Amlodipine

HTN Angina

HTN Angina HTN Angina

Nimodipine

Subarachnoid hemorrhage

Nicardipine

HTN

L-type calcium channel blockade

↓CV, edema, dizziness

Depressed cardiac function, AV conduction problems, those taking digoxin

Most effective in cardiac muscle

Sick sinus syndrome, 2nd & 3rd degree AV block, severe hypotension, acute MI.

Also a class IV antiarrhythmic

Dilates coronary vessels and arterioles with decrease in contractility Similar to the effects of betablockers

L-type calcium channel blockade

↓CV, edema, dizziness

L-type calcium channel blockade

↓CV, edema, dizziness

L-type calcium channel blockade

↓CV, edema, dizziness

None known

No vasospasm

↓CV

Advanced aortic stenosis

Short term treatment

Dilates coronary vessels and arterioles with decrease in contractility Long-acting agent

5.3. ACE-Inhibitors Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the mortality and morbidity following an MI due to the reduction in the progression of complications. ACE-inhibitors decrease cardiac load and permit improved oxygenation and myocardial function. ACE-inhibitors should be avoided in patients with renal artery stenosis, renal disease, and pregnancy.

5.4. Aspirin Aspirin is used to decrease the incidence of clot formation and provide some risk aversion to the development of MI. Aspirin is also one of the first medications given following an MI, and can reduce mortality by one-quarter. The major side effect of aspirin is gastrointestinal bleeding. Aspirin is renally secreted.

5.5. Heparin The use of heparin and low molecular weight heparin is necessary in minimizing further clot formation, especially after MI and in numerous coagulopathies. Heparin administration requires monitoring of PT and PTT; LMWH does not require such monitoring. Contraindications to heparin administration include active bleeding diatheses (such as GI bleeds), tendency towards hemorrhage (as in severe liver disease), immediately following a major surgery, in patients with severe HTN, and in those with infective endocarditis. LMWH is given subcutaneously (SC).

392

Pharmacology

5.6. Streptokinase

and

Alteplase

Among the thrombolytics are streptokinase, urokinase, alteplase, anistreplase, and reteplase. These medications are used to actively break up existing clots and are best if given within a few hours of MI onset. Contraindications to thrombolytic therapy include patients with a history of stroke in the past year, any history of significant hemorrhage, aortic dissection, severe HTN, and an active bleed. Relative contraindications include patients with recent surgical interventions, those with a bleeding disorder or coagulopathy, active PUD, and those who had cardiopulmonary resuscitation (CPR). Streptokinase cannot be used more than once every few months due to its immunogenic potential.

5.7. Digoxin The cardiac glycosides are used for the treatment of CHF, atrial fibrillation, and atrial tachycardia. Although they do not have any effect on mortality in CHF, digoxin does have a role in decreasing hospitalization and making the patient more comfortable. Digoxin works by promoting increased intracellular calcium through decreased calcium-sodium exchange and inhibition of the Na+/K+-ATPase. The increase in calcium leads to the positive inotropic activity of the cardiac glycosides; this in turn leads to increased stroke volume and improved cardiac output. Digoxin administration is confounded by hyperkalemia, which decreases the potency, and hypokalemia, which can lead to toxicity. Digoxin toxicity can occur in other disorders such as ESRD, electrolyte disturbances, hypothyroidism, hypoxemia, interaction with multiple drugs, HCM, WPW, intrinsic heart diseases, arrhythmia, and in the elderly. Medications that potentiate the effect of digoxin include quinidine, calcium-channel blockers, and numerous diuretics. Digoxin effect is decreased with bile acid sequestrants. Digoxin toxicity can lead to nausea and vomiting, blurred vision with a yellow halo around objects, gynecomastia, and arrhythmia (especially paroxysmal atrial tachycardia). Digoxin toxicity is treated by cessation of the medication, administration of potassium to decrease the effect of digoxin through calcium competition, digibind for significant overdoses, and lidocaine and phenytoin. High bioavailability with long half-life. Table 16. Cardiac glycosides Drug Digoxin

Indications

Mechanism of Action

Complications

Increases contractility through Na/K ATPase inhibition with a subsequent inhibition of the secondary active Na/Ca antiport. The net effect is an increase in intracellular calcium.

CHF

N/V/D. Yellow vision. Hypokalemia leading to arrhythmia.

Notes Positive inotrope. No change in mortality, but reduces hospital admissions.

5.8. Antihyperlipidemics Table 17. Bile acid resins Drug

Indications

Mechanism

Complications

Contraindications

Notes

Cholestyramine

Elevated LDL

Bile acid sequestration by binding and forcing excretion

GI discomfort

Cholelithiasis

Lead to an increase in the LDL receptor

Colestipol

Elevated LDL

Bile acid sequestration by binding and forcing excretion

GI discomfort

Cholelithiasis

Lead to an increase in the LDL receptor

Prior to administration of these lipid-lowering agents, the first line is to change the diet and lifestyle of the patient whenever possible. Antihyperlipidemics should be continued indefinitely once started. 393

Clinical Review for the USMLE Step 1 Table 18. HMG-CoA reductase inhibitors Drug

Indications

Mechanism

Simvastatin

Elevated LDL, TG

Increase LDL receptor expression to decrease LDLs

Fluvastatin

Hypercholesterolemia,

Competitive inhibitor of HMG-COA

Mixed dyslipidemia

reductase

Complications

Contraindications

Notes

Myositis, SLE

Hepatic disease

Some increase in HDL, increase in LDL receptor, thought to decrease MI risk

Rhabdomyolysis

Elevated liver enzymes

Decreases cholesterol synthesis

Table 19. Fibrates Indications

Drug

Mechanism

Complications

Contraindications

Notes

Gemfibrozil

Elevated TG

Increase lipoprotein lipase to decrease LDL, increase HDL, and significantly decrease TGs

Increase LFTs, myositis, Hepatic disease gallstones

Some increase in HDL

Clofibrate

Elevated TG

Increase lipoprotein lipase to decrease LDL, increase HDL, and significantly decrease TGs

Increase LFTs, myositis, Hepatic disease gallstones

Some increase in HDL

Table 20. Other agents Drug Ezetimibe

Niacin

394

Indications Elevated LDL

Elevated LDL, TG Improve HDL

Mechanism Prevents absorption of cholesterol by binding to it in the GI tract to decrease LDL

Complications Dumping syndrome

Contraindications

Notes

Caution in hepatic disease Significant improvement in HDL

Directly inhibits VLDL synthesis to cause lipolysis, decrease TGs, and decrease LDL with a subsequent rise in HDLs

Facial flushing

Vitamin B3 Use aspirin to avoid facial flushing

Probucol

Lower Type IIA, B hypercholesterolemia

Unknown

GI SX, prolongs QT interval

Cholestyramine

Lower serum lipoprotein

Binds bile acids and salts

GI SX, impaired fat soluble vitamin absorption

Colestipol

Lower serum lipoprotein

Binds bile acids and salts

GI SX, impaired fat soluble vitamin absorption

Dipyridamole

TIA or stroke

Inhibition of platelet aggregation

Atropine

Bradycardia, heart blocks

Parasympatholytic agent

Should not consume alcohol with this drug

Pharmacology

5.9. Antiarrhythmics Table 21. Class IA antiarrhythmics Drug

Indications

Mechanism of Action

Suppress ectopic rhythms from abnormal pacemaker cells

Amiodarone

Decrease phase 4 depolarization and increase firing threshold State-dependent effects target abnormal pacemaker cells

Phase 3 and 4 effects

Procainamide

Complications

Suppress ectopic rhythms from abnormal pacemaker cells

Decrease phase 4 depolarization and increase firing threshold State-dependent effects target abnormal pacemaker cells

Phase 3 and 4 effects

Notes

AV block, ventricular arrhythmia

Sodium channel blocker

SLE, AV block, ventricular arrhythmia

Sodium channel blocker

Table 22. Class IB antiarrhythmics Drug

Lidocaine

Mechanism of Action

Indications Ventricular arrhythmia Phase 3 and 4 effects

Complications Local anesthesia

Decrease AP duration

Notes Also used in digitalis toxicity

CNS changes

Targets ischemic and depolarized tissue

↓CV, Proarrhythmic

Table 23. Class IC antiarrhythmics Drug

Indications

Flecainide VT and VF

Mechanism of Action

Complications

Increase threshold of firing and decrease phase 4 depolarization

Proarrhythmic

Table 24. Class II antiarrhythmics Drug Metoprolol

Indications Suppress ectopic focus, HTN

Mechanism of Action ↓cAMP with ↓Ca2+ current Leads to ↓phase 4 in AV node with ↑PR

Complications Proarrhythmic, impotence, asthma, CV and CNS effects, masks hypoglycemia

Table 25. Class III antiarrhythmics Drug Amiodarone

Indications Last line for arrhythmia

Mechanism of Action ↑AP, ↑ERP, ↑QT, ↓IK

Complications Pulmonary fibrosis, hepatotoxicity, smurf skin, photodermatitis, CNS and CV effects, change in thyroid function

Notes Long half-life, very toxic

395

Clinical Review for the USMLE Step 1 Table 26. Class IV antiarrhythmics Drug Diltiazem

Indications

Mechanism of Action

Complications

↓conduction velocity to ↑ERP and ↑PR due to calcium-channel effects

SVT

Flushing, constipation, CV effects

Notes Targets AV node Ca2+ channel blocker

Generally, class IA and IC decrease phase 0 depolarization to slow conduction, class IB decrease phase 3 repolarization to slow conduction, class II suppresses phase 4 depolarization, class III prolongs phase 3 repolarization, and class IV shortens the action potential to make reaching threshold more difficult. Table 27. Atypical antiarrhythmics Drug Adenosine

Indications SVT Ectopic focus

Potassium

Magnesium

Digoxin toxicity Torsade de pointes Digoxin toxicity

5.10. Pressors

Mechanism

Complications

Decreases cAMP

Arrhythmia

Normalizes potassium and repolarization

Arrhythmia

Substitutes for calcium effects without depolarization

Arrhythmia

Contraindications

Hyperkalemia

Notes

Insulin can be given as a temporary antidote in hyperkalemia

and Inotropes

Table 28. Pressors and inotropes Drug Dopamine

Indications Shock with renal protection CHF

Norepinephrine

Shock

Mechanism D1, D2 β1

Complications

Contraindications

Notes Given IV due to significant first pass effects

Nausea, HTN, arrhythmia.

Given IV due to significant first pass effects

α1, α2, β1, β2

Open angle glaucoma Acute asthma Epinephrine

Anaphylactic shock Increase local anesthetic duration

Dobutamine

396

CHF

α1, α2, β1, β2 Closed angle glaucoma

Given IV due to significant first pass effects

β1

Atrial fibrillation.

Given IV due to significant first pass effects

Don’t use with MAOIs, anuria, liver disorders

Hemolytic anemia and liver disorders may occur

Increases aqueous humor outflow

Methyldopa

Hypertension

α2

Milrinone

Increase cardiac contractility

Phosphodieserase inhibitor

Mydriasis

Increased mortality, no beneficial effects

Pharmacology

5.11. Studies 5.11.1

and

Procedures

Electrocardiogram

Deflections between 180 and -90 degrees are commonly due to emphysema, hyperkalemia, transposition of leads, cardiac pacing, and ventricular tachycardia. Deflections between -90 and -30 can be normal in children and thin adults, or due to right ventricular hypertrophy (RVH), chronic lung disease, anterolateral myocardial infarction (MI), left posterior hemiblock, pulmonary embolism (PE), WolffParkinson-White (WPW) syndrome, atrial septal defect (ASD), or ventricular septal defect (VSD). Deflections between 90 and 180 degrees are due to left anterior hemiblock, inferior MI, cardiac pacing, emphysema, hyperkalemia, WPW, tricuspid atresia, ostium primum ASD, and left coronary artery (LCA) contrast injection. Table 29. Electrocardiogram (EKG) Detected abnormalities Short PR segments (less than .2 sec)

Wolff-Parkinson-White (WPW) syndrome, LGL syndrome, DMD, and Pompe disease.

Long PR intervals

First degree heart block.

QRS complex (not less than .12 sec)

Hyperkalemia, bundle branch blocks.

Increase in QT interval

MI, myocardial disease, hypocalcaemia, hypothyroidism, CVA, or in Romano Ward syndrome.

ST segment (flat or elevated)

MI, acute pericarditis, depressed in myocardial ischemia, digoxin toxicity, ventricular hypertrophy, acute posterior MI, PE, or LBBB.

Tall T waves

Hyperkalemia, very recent MI, and LBBB.

Flat or inverted T waves

May be idiopathic, LVH, digoxin, PE, RBBB, deficits in electrolytes.

QRS axis deviations (between 180 & -90 deg.)

Commonly due to emphysema, hyperkalemia, transposition of leads, cardiac pacing, & ventricular tachycardia.

QRS axis deviations (between -90 & -30 deg)

Can be normal in children and thin adults, or due to RVH, chronic lung disease, anterolateral MI, left posterior hemiblock, PE, WPW syndrome, ASD, or VSD.

QRS axis deviations (between 90 & 180 deg)

Left anterior hemiblock, inferior MI, cardiac pacing, emphysema, hyperkalemia, WPW, tricuspid atresia, ostium primum ASD, and LCA contrast injection.

Tall S waves in V1 & V2 & tall R waves in V5 & V6.

LVH

R wave taller than the S wave in V1

RVH

Peaked P waves

RAH

T wave inversions

Ischemic changes (in leads I, II, and V2-V6).

Elevated ST segments

Myocardial injury.

Elevated Q wave

Infarct

Abnormal V1 & V2

Anteroseptal injury.

Changes in V3 & V4

Anterior injury

Changes in V5 & V6

Anterolateral injury.

Leads II, III, & a VF

Indicate damage to the inferior wall.

Leads I and a VL

Lateral wall damage.

397

Clinical Review for the USMLE Step 1 5.11.2

Echocardiogram

Echocardiograms use sound waves in order to conduct real-time visualization of the heart anatomy and function. There are two non-stress versions, the transthoracic echocardiogram (TTE) and transesophageal echocardiogram (TEE). The TTE is preferred as the initial study as it is less invasive; it is better in thin patients as there is less tissue between the heart and the instrument. The TEE is the next test that is often utilized due to significantly more detail and the ability to assess the great vessels. Echocardiography is used for a multitude of heart diseases, including assessing wall motion abnormalities in MI, identifying ventricular function and ejection fraction (EF) in congestive heart failure (CHF), determining the severity of valvular disease, assessing pericardial effusions, identifying tears in aortic dissection, detecting increased right-sided pressure in pulmonary embolisms (PE), observing bubbles leaking through a patent foramen ovale (PFO) after administering air through a peripheral intravenous (IV) line, and identifying anatomic defects in congenital heart disease (CHD).

5.11.3

Treadmill Stress Echocardiogram (TSE)

A TSE is used to detect the severity of coronary artery disease (CAD) and other heart disease (HD). The treadmill echocardiogram has patients walking on a treadmill that increases in difficulty to allow the patient to reach 85% of their maximum heart rate. Concurrent EKG monitoring detects ischemic changes, arrhythmias, and other signs and symptoms of heart disease. CAD is often diagnosed following EKG changes including ST depression (STd) or ST elevation (STe), and decreased blood pressure (BP). The patient must be able to walk on a treadmill in order to successfully have a diagnostic TSE. Contraindications to TSE may permit stress testing via a dobutamine stress echocardiogram (DSE).

5.11.4

Thallium Imaging

The use of radio-labeled molecules, such as thallium 201 or technetium 99, permit imaging the heart and determining proper cardiac functioning. Nuclear medicine scans (NMS) using the aforementioned molecules permit gauging myocardial perfusion and EF, and also permit an analysis of the end diastolic volume (EDV) and end systolic volume (ESV). Together with heart rate (HR), the cardiac output (CO) can be determined, along with the mean stroke volume (SV). Specific defects in cardiac function can be identified with careful analysis of NMS.

5.11.5

Cardiac Catheterization

Catheterization through the femoral vessels permits the diagnosis and treatment of several major heart defects and the right heart structures can be accessed and manipulated. In addition, the left heart can also be accessed. Balloon angioplasty, known as percutaneous transluminal coronary angioplasty (PTCA), can be used to dilate a stenosis in a major coronary artery and to place a stent. PTCA is often used as an emergent procedure immediately following certain types of MI and in unstable angina. Manipulation of the heart structures, such as valvuloplasty in valvular heart disease, radiofrequency ablation of ectopic foci in arrhythmia, biopsy of the heart wall in certain heart diseases, and closing patency such as an ASD, VSD, or PFO can all be done through catheterization.

398

Pharmacology Table 30. Cardiac Tests

Echocardiogram

Wall motion abnormalities in MI, ventricular function and EF in CHF, determining the severity of valvular disease, assessing pericardial effusions, identifying tears in aortic dissection, detecting increased right-sided pressure in pulmonary embolisms, observing bubbles leaking through a PFO, and identifying anatomic defects in CHD.

TSE

Detect the severity of CAD.

Thallium imaging

Myocardial perfusion and EF, also permit an analysis of EDV & ESV.

Cardiac catheterization

Via the femoral vein: the right heart structures can be accessed and manipulated. The left heart can also be accessed. Balloon angioplasty coronary PTCA can be used to dilate a stenosis in a major coronary artery and place a stent. PTCA can also be used as following certain types of MI and in manipulation of the heart structures, such as valvuloplasty, radiofrequency ablation of ectopic foci, biopsy of the heart wall, and closing patency.

399