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Volume 25, Number 1

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IJCP Group of Publications Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor

Volume 25, Number 1, June 2014 from the desk of THE group editor-in-chief

Dr Deepak Chopra Chief Editorial Advisor Padma Shri, Dr BC Roy National & DST National Science Communication Awardee

Dr KK Aggarwal Group Editor-in-Chief

Dr Veena Aggarwal MD, Group Executive Editor

IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty ENT Dr Jasveer Singh Dr Chanchal Pal Dentistry Dr KMK Masthan Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar Dr Rajiv Khosla Dermatology Dr Hasmukh J Shroff Dr Pasricha Dr Koushik Lahiri Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan Dr Vineet Suri Journal of Applied Medicine & Surgery Dr SM Rajendran, Dr Jayakar Thomas Orthopedics Dr J Maheshwari

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Road Safety should be Taken up on Priority by the Government KK Aggarwal

American Family Physician

Outpatient Diagnosis of Acute Chest Pain in Adults John R McConaghy, Rupal S Oza

13 Practice Guidelines 16 Photo Quiz Anesthesiology

18 Conscious Sedation: An Observation

Jayashree Sen, Bitan Sen

CARDIOLOGY

22 Perioperative Myocardial Infarction

Sudivya Sharma, Prashast Jain

26 Coronary Artery Air Embolism

Monika Maheshwari, Anand Agarwal

Community Medicine

31 Evaluation of Vitamin D3 Deficiency in a Tertiary Care Center

Arshad A, Vijai C, Sherin T, Udaya S, Nupur D, Vijaya V

CRITICAL Care

36 Invasive Monitoring in the Intensive Care Unit

LP Saikumar Doradla, M Vadivelan

Dentistry

41 Odontogenic Myxoma of Maxilla: Management and Follow-up of A Rare Case

Karuna Jindwani, Vilas Nevaskar, Deepak Agrawal

Dermatology

47 Accidental PUVA Burns Leading to Prurigo Nodularis: A Rare Complication of Phototherapy

Shyam Verma

ENT

50 Facial Necrotizing Fasciitis: A Rare Complication of Maxillary Sinusitis

N Gupta, S Varshney, P Gupta

53 Myeloid Sarcoma of Maxillo-Ethmoidal Sinus: An

Uncommon Presentation of Acute Myeloid Leukemia

Amar Ranjan, RK Chandoke, Pranay Tanwar, Ashutosh Kumar, MD Ray, KK Kshitiz, Nidhi Chauhan

HEMATOLOGY Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash, Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com

58 Thrombotic Thrombocytopenia Purpura Refractory to Plasmapheresis Treated Successfully with Rituximab

VH Shah, A Patel, RK Chavda

61 Coomb’s Negative Hemolytic Anemia in Wilson’s Disease

Printed at New Edge Communications Pvt. Ltd., New Delhi E-mail: edgecommunication@gmail.com

V Padma, Halleys Kumar

Neurology

63 Communication Between Musculocutaneous and Median

Nerve – Different Types and Their Incidence in North Indian Population

The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

Priti Chaudhary, Gurdeep Kalsey, Ranjan Singla, Kamal Arora

Obstetrics and Gynecology

73 A Comparative Study Between Cleavage Stage Embryo

Transfer at Day 3 and Blastocyst Stage Transfer at Day 5 in IVF/ICSI on Clinical Pregnancy Rates

Editorial Policies The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

P Kaur, ML Swarankar, M Maheshwari, V Acharya

Oncology

78 Prognostic Impact of CD3 Tumor Infiltrating Lymphocytes in Triple-negative Breast Cancer

Ankita Singh Rathore, Madhu Mati Goel, Annu Makker, Sandeep Kumar, AN Srivastava

Psychiatry

85 A Clinical Study in Management of Primary Insomnia: Hypnotic versus Anxiolytic

Sreekumar D, Santhosh Kumar M

UROLOGY

91 Nephrotic Syndrome: A Rare Presentation of AIDS

Note: Indian Journal of Clinical Practice does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

Prabhat Agrawal, Ashish Gautam, Manish Kumar Bansal, Ayush Agrawal

AROUND THE GLOBE

94 News and Views LIGHTER READING

96 Lighter Side of Medicine

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Road Safety should be Taken up on Priority by the Government Union minister for Rural Development Gopinath Munde died in a road accident on his way to the airport in New Delhi. We have witnessed deaths of prominent politicians in road accidents in previous years. ÂÂ Former Delhi CM and Union labour minister Sahib Singh Verma died in a road accident in 2007 on the highway

while returning to Delhi from Jaipur.

ÂÂ In 2000, senior Congress leader Rajesh Pilot died in a road accident in Dausa, about 50 km from Jaipur. ÂÂ In 1994, former President, Giani Zail Singh died following a car crash on the Fatehgarh Sahib–Chandigarh

highway.

All these politicians died within a radius of 250 km. Their deaths were sudden and unexpected. Postmortem report suggests that Gopinath Munde died of cervical cord injury and liver injury with collection of blood in the peritoneal cavity. The cervical "whiplash" syndrome is caused by a traumatic event with an abrupt flexion/extension movement to the cervical spine. Symptoms of whiplash include severe neck pain, spasm, loss of range of motion in the neck i.e., unable to move your neck or turn your head and headache, especially at the back of the head (occipital headache). The most common causes of spinal cord injury are trauma; car accidents being the most common, either when a person is riding as a passenger in the car or is struck as a pedestrian followed by falls, sports accidents, assault. Generally, the higher up the level of the injury to the spinal cord, the more severe the symptoms. Cervical cord injury is fatal only when fracture occurs at C1 and C2. If politicians too are not immune to road traffic accidents, then what about the general public? This means that the general public is not safe. The growth in the economy of India has seen an almost parallel and an impressive rise in the number of vehicles on the roads. And this number keeps on increasing daily, which translates into greater risk of accidents, increased pollution etc. India has a poor record of road safety with one of the highest road traffic accident rates in the world. In The Global status report on road safety 2013, the WHO has cited road traffic injuries as the eighth leading cause of death globally. By the year 2030, road traffic deaths are projected to become the fifth leading cause of death unless urgent action is taken.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

from the desk of THE group editor-in-chief The major contributing factors to this high road traffic accident rate are speeding, drunken driving, lack of use of safety helmets, seat belts and child restraints in vehicles. Inefficient law enforcement has only compounded the problem. Road traffic accidents are a preventable cause of disability and death. ÂÂ There is an urgent need for the government to formulate and enforce legislation to address these major causes

of road accidents.

ÂÂ Enforcement of speed limits, laws related to drunken driving is essential. ÂÂ Wearing a seat belt for drivers, the front seat occupants as well as the rear seat occupants should be made

compulsory.

ÂÂ The road infrastructure should be made safer for vehicles and the pedestrians as well. ÂÂ There should be regular and effective road safety education campaigns to develop a safe driving behavior.

Distracted driving i.e. talking on the phone, texting, talking to a passenger, eating, etc. should be avoided. These activities take the driver’s attention away from the road.

The tragic death of Shri Gopinath Munde again highlights the need for an urgent and a concerted action on the part of the government and the general public. ■■■■

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

American Family Physician

Outpatient Diagnosis of Acute Chest Pain in Adults JOHN R MccONAGHY, RUPAL S OZA

Abstract Approximately 1 percent of primary care office visits are for chest pain, and 1.5 percent of these patients will have unstable angina or acute myocardial infarction. The initial goal in patients presenting with chest pain is to determine if the patient needs to be referred for further testing to rule in or out acute coronary syndrome and myocardial infarction. The physician should consider patient characteristics and risk factors to help determine initial risk. Twelve-lead electrocardiography is typically the test of choice when looking for ST segment changes, new-onset left bundle branch block, presence of Q waves, and new-onset T wave inversions. For persons in whom the suspicion for ischemia is lower, other diagnoses to consider include chest wall pain/costochondritis (localized pain reproducible by palpation), gastroesophageal reflux disease (burning retrosternal pain, acid regurgitation, and a sour or bitter taste in the mouth), and panic disorder/anxiety state. Other less common but important diagnostic considerations include pneumonia (fever, egophony, and dullness to percussion), heart failure, pulmonary embolism (consider using the Wells criteria), acute pericarditis, and acute thoracic aortic dissection (acute chest or back pain with a pulse differential in the upper extremities). Persons with a higher likelihood of acute coronary syndrome should be referred to the emergency department or hospital.

Keywords: Chest pain, unstable angina acute, myocardial infarction, twelve-lead electrocardiography, acute coronary

syndrome

pproximately 1 percent of all ambulatory visits in the primary care setting are for chest pain.1 Cardiac disease is the leading cause of death in the United States, yet only 1.5 percent of patients presenting to a primary care office with chest pain will have unstable angina or an acute myocardial infarction (MI).2 The most common causes of chest pain in the primary care population include chest wall pain (20 percent); reflux esophagitis (13 percent); and costochondritis (13 percent),2 although in practice, costochondritis is often included in the chest wall pain category. Other considerations include pulmonary (e.g., pneumonia, pulmonary embolism), gastrointestinal (e.g., gastroesophageal reflux disease [GERD]), and psychological (e.g., anxiety, panic disorder) etiologies, and cardiovascular disorders (e.g., acute congestive heart failure, acute thoracic aortic dissection). Table 1 lists the differential diagnosis of chest pain.3-15

JOHN R. McCONAGHY, MD, CPE, FAAFP, is a professor, the associate residency director, and the practice medical director in the Department of Family Medicine at The Ohio State University, Columbus. RUPAL S. OZA, MD, MPH, is a clinical assistant professor in and the director of the Urban Family Medicine Residency Program at The Ohio State University. Source: Adapted from Am Fam Physician. 2013;87(3):177-182.

Initial Evaluation Algorithmic approaches to the diagnosis and workup of the patient presenting with chest pain in the office setting have not been specifically studied. Differentiating ischemic from nonischemic causes often is difficult, and patients with chest pain with an ischemic etiology often appear well. As such, the initial diagnostic approach should always consider a cardiac etiology for the chest pain, unless other causes are apparent.16 The first decision point for most physicians is whether or not the chest pain is caused by coronary ischemia.16 Acute coronary syndrome (ACS) is a constellation of clinical findings that suggests acute myocardial ischemia encompassing unstable angina and acute MI. Angina has been described as deep, poorly localized chest or arm discomfort (pain or pressure) that is reproducibly associated with physical exertion or emotional stress and is relieved promptly with rest or sublingual nitroglycerin.17 Unstable angina is defined as angina at rest, new-onset angina, or angina that has become more severe or longer in duration.18 Acute MI is defined as ST segment changes (elevation or depression) on electrocardiography (ECG) and positive laboratory markers of myocardial necrosis (e.g., troponin I).17 In office and ambulatory settings, the clinical impression is, in most cases, shaped by the presenting symptoms,

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

American Family Physician Table 1. Differential Diagnosis of Chest Pain Diagnosis

Clinical findings

LR+

LR–

Acute myocardial infarction3

Chest pain radiates to both arms

7.1

0.67

Third heart sound on auscultation

3.2

0.88

Hypotension

3.1

0.96

At least two of the following findings: localized muscle tension; stinging pain; pain reproducible by palpation; absence of cough

3.0

0.47

Gastroesophageal reflux disease5,6

Burning retrosternal pain, acid regurgitation, sour or bitter taste in the mouth; one-week trial of high-dose proton pump inhibitor relieves symptoms

3.1

0.30

Panic disorder/anxiety state7

Single question: In the past four weeks, have you had an anxiety attack (suddenly feeling fear or panic)?

4.2

0.09

Pericarditis8,9

Clinical triad of pleuritic chest pain (increases with inspiration or when reclining, and is lessened by leaning forward), pericardial friction rub, and electrocardiographic changes (diffuse ST segment elevation and PR interval depression without T wave inversion)

Pneumonia10,11

Egophony

8.6

0.96

Chest wall

Heart

pain4

failure12

Pulmonary

embolism13,14

Acute thoracic aortic dissection15

Dullness to percussion

4.3

0.79

Fever

2.1

0.71

Clinical impression

2.0

0.24

Pulmonary edema on chest radiography

11.0

0.48

Clinical impression/judgment

9.9

0.65

History of heart failure

5.8

0.45

History of acute myocardial infarction

3.1

0.69

High pretest probability based on Wells criteria

6.8

1.8

Moderate pretest probability based on Wells criteria

1.3*

0.7

Low pretest probability based on Wells criteria

0.1

7.6

Acute chest or back pain and a pulse differential in the upper extremities

5.3

Note: The higher the LR is above 1, the better it rules in disease (greater than 10 is considered good). Conversely, the lower the LR is below 1, the better it rules out disease (less than 0.1 is considered good). LR+ = Positive likelihood ratio; LR– = Negative likelihood ratio; NA = Not available. *Does not change posttest probability. Information from references 3 through 15.

physical examination, and initial ECG, combined with the patient’s risk of ACS.16,19 The initial goal is to determine if the patient needs to be referred for further testing (e.g., troponin I or stress testing, coronary angiography) to rule in or out a potentially catastrophic ACS and acute MI. One recent meta-analysis concluded that the history and physical examination were mostly not helpful in diagnosing ACS or acute MI in patients presenting with chest pain, especially in a low prevalence setting.20 Although individual characteristics may not rule in or out a diagnosis, a combination of signs and symptoms may increase diagnostic accuracy.21 Characteristics

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

traditionally associated with increased likelihood of acute MI include male sex plus age older than 60 years; diaphoresis; pain that radiates to the shoulder, neck, arm, or jaw; and a history of angina or acute MI.22 Predictability may be influenced by patient description of their symptoms. Patients often do not use the term pain to describe their symptoms, but frequently use other terms like discomfort, tightness, squeezing, or indigestion.16 Other clinical features that increase the likelihood of MI in patients with acute chest pain include pain that radiates to both arms (positive likelihood ratio [LR+] = 7.1), a third heart sound on auscultation

American Family Physician (LR+ = 3.2), and hypotension (LR+ = 3.1). Clinical features that decrease the likelihood of acute MI include pleuritic chest pain (negative likelihood ratio [LR–] = 0.2), sharp or stabbing chest pain (LR– = 0.3), and chest pain reproduced by palpation (LR– = 0.2 to 0.4).3 The presence or absence of comorbidities, such as diabetes mellitus, tobacco use, hyperlipidemia, or hypertension, as cardiac risk factors weakly predict ACS in patients older than 40 years (LR+ = 2.1 in persons 40 to 65 years of age; LR+ = 1.1 in patients older than 65 years)23; however, evaluating for presence or absence of comorbidities is still an important component of the initial assessment. One recently developed and validated clinical decision rule (Table 2) outlines five items that best predict coronary artery disease as the cause of chest pain: age/sex (55 years or older in men or 65 years or older in women); known coronary artery disease, occlusive vascular disease, or cerebrovascular disease; pain that is worse during exercise; pain not reproducible by palpation; and patient assumption that the pain is of cardiac origin.24 Among those with none or one of these clinical factors, only 1 percent had coronary artery disease, whereas 63 percent of the patients with four or five of the factors had coronary artery disease. The study results suggest that patients with chest pain and four or five of these factors require urgent workup. Physicians should consider applying a Table 2. Validated Clinical Decision Rule to Predict CAD as a Cause of Chest Pain Component

Points

Age/sex: men 55 years or older, women 65 years or older

Known vascular disease (CAD, occlusive vascular disease, cerebrovascular disease)

Pain worse with exercise

Pain not elicited with palpation

Patient assumes pain is of cardiac origin

Likelihood of CAD as Cause of Chest Pain Score

Positive likelihood ratio

Negative likelihood ratio

0 to 1 point

1.09

0.00

2 to 3 points

1.83

0.03

4 to 5 points

4.52

0.16

CAD = Coronary artery disease.

validated clinical decision rule to predict heart disease as a cause of chest pain.24 Twelve-lead ECG is typically the test of choice in the initial evaluation of patients with chest pain.19 ST segment changes (elevation or depression), newonset left bundle branch block, presence of Q waves, and new-onset T wave inversion increase the likelihood of ACS or acute MI.3,25 Concern based on the clinical impression (history, physical examination, risk factors, and 12-lead ECG) often will influence the physician’s decision regarding whether to refer the patient to a higher level of care (emergency department or hospital) for further workup and treatment, or to look for other possible diagnoses for the chest pain.16,19 Other Diagnostic Considerations If the initial evaluation indicates that a cardiac cause of ACS is less likely, other noncardiac causes of chest pain should be considered. Understanding that there are common conditions that often occur, with the clinical impression, will help lead to a correct diagnosis.

Chest Wall Pain One prospective cohort study identified four clinical factors that predict a final diagnosis of chest wall pain in patients presenting to the primary care office with chest pain: localized muscle tension, stinging pain, pain reproducible by palpation, and the absence of a cough. Having at least two of these findings had a 77 percent positive predictive value for chest wall pain, and having none or one had an 82 percent negative predictive value.4

Costochondritis Often considered a subset of chest wall pain, costochondritis is a self-limited condition characterized by pain reproducible by palpation in the parasternal/ costochondral joints. It is sometimes called Tietze syndrome, which is distinguished from costochondritis by the presence of swelling over the affected joints.26 Costochondritis is a clinical diagnosis and does not require specific diagnostic testing in the absence of concomitant cardiopulmonary symptoms or risk factors.27

GERD Classic symptoms of GERD include a burning retrosternal pain, acid regurgitation, and a sour or bitter taste in the mouth.5 No useful physical examination maneuvers exist to assist in establishing the diagnosis,

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

American Family Physician and there is no standard test to rule it in or out. However, a one-week trial of a high-dose proton pump inhibitor is modestly sensitive and specific for GERD, with modest LRs (LR+ = 3.1; LR– = 0.3).6

Panic Disorder and Anxiety State Panic disorder and anxiety state are common. One in four persons with a panic attack will have chest pain and shortness of breath.28 Yet, concomitant panic disorder and chest pain are often not recognized, leading to more testing, follow-up, and higher costs of care.28,29 Panic may cause chest pain and vice versa.28 Several validated brief questionnaires are used to diagnose panic disorder and anxiety state. One question (In the past four weeks, have you had an anxiety attack [suddenly feeling fear or panic]?) is sensitive (93 percent) and modestly specific (78 percent) in detecting panic disorder (LR+ = 4.2; LR– = 0.09).7 Less Common, but Important, Diagnostic Considerations

Pericarditis Pericarditis is the clinical triad of pleuritic chest pain, pericardial friction rub, and diffuse electrocardiographic ST-T wave changes.8 ECG usually demonstrates diffuse ST segment elevation and PR interval depression without T wave inversion. Acute pericarditis should be considered in patients presenting with new-onset chest pain that increases with inspiration or when reclining, and is lessened by leaning forward.9

Pneumonia Community-acquired pneumonia is a cause of chest pain and respiratory symptoms in the outpatient setting. Common symptoms include fever, chills, productive cough, and pleuritic chest pain.30 Fever, egophony heard during auscultation of the lungs, and dullness to percussion of the posterior thorax are suggestive of pneumonia.10 Clinical impression is modestly useful for ruling in or out pneumonia (LR+ = 2.0; LR– = 0.24).10 The test of choice for diagnosing pneumonia is chest radiography,11 although it has been more recently recommended that it be performed only if other diagnoses are being considered in the uncomplicated outpatient setting.31

Heart Failure Most patients with heart failure present with dyspnea on exertion, although some will have chest pain.12 A history of heart failure or acute MI best

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Table 3. Wells Clinical Prediction Rule for PE Component

Points

Clinical signs of DVT (asymmetric leg swelling, palpable calf pain)

Diagnosis of PE is more likely than an alternative diagnosis

Heart rate greater than 100 beats per minute

1.5

Previous diagnosis of DVT or PE

1.5

Bed rest immobilization or surgery within the past four weeks

1.5

Hemoptysis

Malignancy within the past six months

Probability of PE Points

Risk of PE

Probability of PE (%)

0 to 1 point

Low

1.3

2 to 6 points

Moderate

High

Greater than 6 points

DVT = Deep venous thrombosis; PE = Pulmonary embolism.

predicts the presence of heart failure (LR+ = 5.8 and 3.1, respectively).12 Clinical impression/judgment is predictive of heart failure (LR+ = 9.9; LR– = 0.65), as is pulmonary edema on chest radiography (LR+ = 11.0).12

Pulmonary Embolism Diagnosing pulmonary embolism in the office based on signs and symptoms is difficult because of its highly variable presentation. Although dyspnea, tachycardia, and/or chest pain are present in 97 percent of those diagnosed with pulmonary embolism,32 there is no single clinical feature that effectively rules it in or out.33 The physician can estimate the patient’s likelihood of pulmonary embolism by using a validated clinical decision rule, such as the Wells criteria (Table 313,34), to determine if further testing should be performed (e.g., d-dimer assay, ventilation-perfusion scan, helical computed tomography of the pulmonary arteries).13,14,35

Acute Thoracic Aortic Dissection Patients with acute thoracic aortic dissection may present with chest or back pain.36 History and physical examination are only modestly useful for ruling in or out the condition; acute chest or back pain and a pulse differential in the upper extremities modestly increase the likelihood of an acute thoracic aortic dissection (LR+ = 5.3).15

American Family Physician REFERENCES 1. Hsiao CJ, Cherry DK, Beatty PC, Rechtsteiner EA. National ambulatory medical care survey: 2007 summary. Natl Health Stat Report. 2010;(27):1-32. 2. Klinkman MS, Stevens D, Gorenflo DW; Michigan Research Network. Episodes of care for chest pain: a preliminary report from MIRNET. J Fam Pract. 1994;38(4):345-352. 3. Panju AA, Hemmelgarn BR, Guyatt GH, Simel DL. The rational clinical examination. Is this patient having a myocardial infarction? JAMA. 1998;280(14):1256-1263. 4. Bösner S, Becker A, Hani MA, et al. Chest wall syndrome in primary care patients with chest pain: presentation, associated features and diagnosis. Fam Pract. 2010;27(4):363-369. 5. Zimmerman J. Validation of a brief inventory for diagnosis and monitoring of symptomatic gastro-oesophageal reflux. Scand J Gastroenterol. 2004;39(3):212-216. 6. Wang WH, Huang JQ, Zheng GF, et al. Is proton pump inhibitor testing an effective approach to diagnose gastroesophageal reflux disease in patients with noncardiac chest pain?: a meta-analysis. Arch Intern Med. 2005;165(11):1222-1228. 7. Löwe B, Gräfe K, Zipfel S, et al. Detecting panic disorder in medical and psychosomatic outpatients: comparative validation of the Hospital Anxiety and Depression Scale, the Patient Health Questionnaire, a screening question, and physicians’ diagnosis. J Psychosom Res. 2003;55(6):515-519. 8. Imazio M, Brucato A, Cemin R, et al.; CORP (COlchicine for Recurrent Pericarditis) Investigators. Colchicine for recurrent pericarditis (CORP): a randomized trial. Ann Intern Med. 2011;155(7):409-414. 9. Maisch B, Seferovic’ PM, Ristic’ AD, et al.; Task Force on the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology. Guidelines on the diagnosis and management of pericardial diseases executive summary. Eur Heart J. 2004;25(7):587-610. 10. Diehr P, Wood RW, Bushyhead J, Krueger L, Wolcott B, Tompkins RK. Prediction of pneumonia in outpatients with acute cough–a statistical approach. J Chronic Dis. 1984;37(3):215-225. 11. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA. 1997;278(17):1440-1445. 12. Wang CS, FitzGerald JM, Schulzer M, Mak E, Ayas NT. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA. 2005;294(15): 1944-1956. 13. Wells PS, Anderson DR, Rodger M, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected

pulmonary embolism presenting to the emergency department by using a simple clinical model and D-dimer. Ann Intern Med. 2001;135(2):98-107. 14. Tamariz LJ, Eng J, Segal JB, et al. Usefulness of clinical prediction rules for the diagnosis of venous thromboembolism: a systematic review. Am J Med. 2004;117(9):676-684. 15. von Kodolitsch Y, Schwartz AG, Nienaber CA. Clinical prediction of acute aortic dissection. Arch Intern Med. 2000;160(19):2977-2982. 16. Kontos MC, Diercks DB, Kirk JD. Emergency department and office-based evaluation of patients with chest pain. Mayo Clin Proc. 2010;85(3):284-299. 17. Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/nonST-elevation myocardial infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines [published corrections appear in Circulation. 2011;124(12):e337-e340, and Circulation. 2011;123(22):e625-e626]. Circulation. 2011;123(18): 2022-2060. 18. Braunwald E. Unstable angina. Circulation. 1989;80(2):410-414.

classification.

19. Cooper A, Timmis A, Skinner J; Guideline Development Group. Assessment of recent onset chest pain or discomfort of suspected cardiac origin: summary of NICE guidance. BMJ. 2010;340:c1118. 20. Bruyninckx R, Aertgeerts B, Bruyninckx P, Buntinx F. Signs and symptoms in diagnosing acute myocardial infarction and acute coronary syndrome: a diagnostic meta-analysis. Br J Gen Pract. 2008;58(547):105-111. 21. Bösner S, Becker A, Abu Hani M, et al. Accuracy of symptoms and signs for coronary heart disease assessed in primary care. Br J Gen Pract. 2010;60(575):e246-e257. 22. Rouan GW, Lee TH, Cook EF, Brand DA, Weisberg MC, Goldman L. Clinical characteristics and outcome of acute myocardial infarction in patients with initially normal or nonspecific electrocardiograms (a report from the Multicenter Chest Pain Study). Am J Cardiol. 1989;64(18):1087-1092. 23. Han JH, Lindsell CJ, Storrow AB, et al. The role of cardiac risk factor burden in diagnosing acute coronary syndromes in the emergency department setting. Ann Emerg Med. 2007;49(2):145-152, 152.e1. 24. Bösner S, Haasenritter J, Becker A, et al. Ruling out coronary artery disease in primary care: development and validation of a simple prediction rule. CMAJ. 2010;182(12):1295-1300. 25. Rude RE, Poole WK, Muller JE, et al. Electrocardiographic and clinical criteria for recognition of acute myocardial infarction based on analysis of 3,697 patients. Am J Cardiol. 1983;52(8):936-942.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

American Family Physician 26. Proulx AM, Zryd TW. Costochondritis: diagnosis and treatment. Am Fam Physician. 2009;80(6):617-620. 27. Disla E, Rhim HR, Reddy A, Karten I, Taranta A. Costochondritis. A prospective analysis in an emergency department setting. Arch Intern Med. 1994;154(21): 2466-2469. 28. Huffman JC, Pollack MH, Stern TA. Panic disorder and chest pain: mechanisms, morbidity, and management. Prim Care Companion J Clin Psychiatry. 2002;4(2):54-62. 29. Katerndahl DA, Trammell C. Prevalence and recognition of panic states in STARNET patients presenting with chest pain. J Fam Pract. 1997;45(1):54-63. 30. Watkins RR, Lemonovich TL. Diagnosis and management of community-acquired pneumonia in adults. Am Fam Physician. 2011;83(11):1299-1306. 31. Lim WS, Baudouin SV, Georbe RC, et al.; Pneumonia Guidelines Committee of the BTS Standards of Care Committee. BTS guidelines for the management for community acquired pneumonia in adults: update 2009. Thorax. 2009;64(suppl 3):iii1-iii55.

32. Perrier A, Desmarais S, Miron MJ, et al. Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet. 1999;353(9148):190-195. 33. Goodacre S, Sutton AJ, Sampson FC. Meta-analysis: The value of clinical assessment in the diagnosis of deep venous thrombosis. Ann Intern Med. 2005;143(2): 129-139. 34. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: Increasing the models utility with the SimpliRED d-dimer. Thromb Haemost. 2000;83(3): 416-420. 35. Qaseem A, Snow V, Barry P, et al.; Joint American Academy of Family Physicians/American College of Physicians Panel on Deep Venous Thrombosis/ Pulmonary Embolism. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med. 2007;5(1):57-62. 36. Klompas M. Does this patient have an acute thoracic aortic dissection? JAMA. 2002;287(17):2262-2272.

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Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

American Family Physician

Practice Guidelines ACIP Releases Influenza Vaccination Updates for 2013-2014 The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) has updated its annual guidelines for routine influenza vaccination in 2013-2014. Vaccination is recommended for all persons six months or older who do not have contraindications. No specific vaccine product is preferable to another if more than one product is appropriate for an individual patient. This year’s updates include changes to the U.S. trivalent influenza vaccine and the quadrivalent influenza vaccine, the availability of new recently licensed vaccine alternatives for specific populations, and a new vaccine option for adults with egg allergy. Table 1 lists the influenza vaccines available for 2013-2014; contraindications and precautions to the influenza vaccine are presented in Table 2. This season, the U.S. trivalent influenza vaccines include an A/California/7/2009 (H1N1)–like virus, an H3N2 virus antigenically like the cell-propagated prototype virus A/Victoria/361/2011, and a B/Massachusetts/2/2012–like virus. The quadrivalent vaccines include an additional virus strain, which is a B/Brisbane/60/2008–like virus.

There are several newly licensed vaccine alternatives expected to be available. A quadrivalent live attenuated influenza vaccine (Flumist) is anticipated to replace the trivalent formulation; it is appropriate for healthy, nonpregnant persons two to 49 years of age. Three quadrivalent inactivated influenza vaccines are available in addition to their previous trivalent formulations; Fluarix and Flulaval are indicated for persons three years or older, and Fluzone is indicated for persons six months or older. Finally, a trivalent cell culture–based inactivated influenza vaccine (Flucelvax) is indicated for persons 18 years or older, and a recombinant hemagglutinin vaccine (Flublok) is available for persons 18 to 49 years of age. Although this is the first season both the trivalent and quadrivalent inactivated influenza vaccines are available, the quantity of quadrivalent doses may be limited. The quadrivalent dose provides broader protection against circulating influenza B viruses during seasons when the B virus in the trivalent vaccine is not an optimal match. There is no preference between the trivalent and quadrivalent inactivated vaccines; therefore, if only the trivalent vaccine is available, it should be used so as not to delay vaccination. Additionally, the high-dose trivalent inactivated influenza vaccine (Fluzone High-

Table 1. Vaccines for the 2013-2014 Influenza Season Vaccine

Dispensing method

Mercury content (mcg per 0.5-mL dose)

Ovalbumin Approved content (mcg ages per 0.5-mL dose)

Route of administration

0.5-mL single-dose prefilled syringe

≤ 1.0

≥ 9 years*

Intramuscular†

5.0-mL multidose vial

24.5

≤ 1.0

≥ 9 years*

Intramuscular†

Fluarix

0.5-mL single-dose prefilled syringe

≤ 0.05

≥ 3 years

Intramuscular†

Flucelvax

0.5-mL single-dose prefilled syringe

Not included‡

≥ 18 years

Intramuscular†

Flulaval

5.0-mL multidose vial

< 25.0

≤ 0.3

≥ 3 years

Intramuscular†

Fluvirin

0.5-mL single-dose prefilled syringe

≤ 1.0

≥ 4 years

Intramuscular†

5.0-mL multidose vial

25.0

≤ 1.0

≥ 4 years

Intramuscular†

0.25-mL single-dose prefilled syringe

—§

6 to 35 months

Intramuscular†

0.5-mL single-dose prefilled syringe

—

≥ 36 months

Intramuscular†

0.5-mL single-dose vial

—

≥ 36 months

Intramuscular†

5.0-mL multidose vial

25.0

—

≥ 6 months

Intramuscular†

0.1-mL prefilled microinjection system

—

18 to 64 years

Inactivated influenza vaccine, trivalent, standard dose Afluria

Fluzone

Fluzone intradermal||

Intradermal¶ continued...

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

American Family Physician Table 1. Vaccines for the 2013-2014 Influenza Season (continued) Vaccine

Dispensing method

Mercury content (mcg per 0.5-mL dose)

Ovalbumin content (mcg per 0.5-mL dose)

Approved ages

Route of administration

—

≥ 65 years

Intramuscular†

Inactivated influenza vaccine, trivalent, high dose Fluzone High-Dose** 0.5-mL single-dose prefilled syringe Inactivated influenza vaccine, quadrivalent, standard dose Fluarix quadrivalent

0.5-mL single-dose prefilled syringe

≤ 0.05

≥ 3 years

Intramuscular†

Flulaval quadrivalent

5.0-mL multidose vial

< 25.0

≤ 0.3

≥ 3 years

Intramuscular†

—

6 to 35 months

Intramuscular†

0.5-mL single-dose prefilled syringe

—

≥ 36 months

Intramuscular†

0.5-mL single-dose vial

—

≥ 36 months

Intramuscular†

18 to 49 years

Intramuscular†

0 (per 0.2-mL dose)

< 0.24 (per 0.2mL dose)

2 to 49 years‡‡

Intranasal

Fluzone quadrivalent 0.25-mL single-dose prefilled syringe

Recombinant influenza vaccine, trivalent Flublok

0.5-mL single-dose vial

Live attenuated influenza vaccine, quadrivalent Flumist quadrivalent††

0.2-mL single-dose prefilled intranasal sprayer

Note: Immunization providers should check U.S. Food and Drug Administration–approved prescribing information for 2013-2014 influenza vaccines for the most complete and updated information, including (but not limited to) indications, contraindications, and precautions. Package inserts for U.S.licensed vaccines are available at http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093833.htm. *Age indication per package insert is 5 years or older; however, the Advisory Committee on Immunization Practices recommends that Afluria not be used in children 6 months to 8 years of age because of increased risk of febrile reactions noted in this age group with 2010 Southern Hemisphere trivalent inactivated vaccine. If no other age-appropriate, licensed inactivated seasonal influenza vaccine is available for a child 5 to 8 years of age who has a medical condition that increases the child’s risk of influenza complications, Afluria can be used; however, health care professionals should discuss with the parents or caregivers the benefits and risks of influenza vaccination with Afluria before administering this vaccine. Afluria may be used in persons 9 years or older. †For adults and older children, the recommended site of vaccination is the deltoid muscle. The preferred site for infants and young children is the anterolateral aspect of the thigh. Specific guidance regarding site and needle length for intramuscular administration may be found in the Advisory Committee on Immunization Practices General Recommendations on Immunization (Centers for Disease Control and Prevention. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices, 2011. MMWR. 2011;60[RR-2].). ‡Information not included in package insert. The total egg protein is estimated to be less than 50 femtograms (5 × 1014 g) total egg protein (of which a fraction is ovalbumin) per 0.5-mL dose of Flucelvax. §Available on request from Sanofi Pasteur (1-800-822-2463 or MIS.Emails@sanofipasteur.com). ||Inactivated influenza vaccine, intradermal: a 0.1-mL dose contains 9 mcg of each vaccine antigen (27 mcg total). ¶The preferred site is over the deltoid muscle. Fluzone intradermal is administered using the delivery system included with the vaccine. **Inactivated influenza vaccine, high dose: a 0.5-mL dose contains 60 mcg of each vaccine antigen (180 mcg total). ††It is anticipated that the quadrivalent formulation of Flumist will replace the trivalent formulation for the 2013-2014 season. Flumist is shipped refrigerated and stored in the refrigerator at 35°F to 46°F (2°C to 8°C) after arrival in the vaccination clinic. The dose is 0.2 mL divided equally between each nostril. Health care professionals should consult the medical record, when available, to identify children 2 to 4 years of age with asthma or recurrent wheezing that might indicate asthma. In addition, to identify children who might be at greater risk of asthma and possibly at increased risk of wheezing after receiving live attenuated influenza vaccine, parents or caregivers of children 2 to 4 years of age should be asked, “In the past 12 months, has a health care professional ever told you that your child had wheezing or asthma?” Children whose parents or caregivers answer “yes” to this question and children who have asthma or who had a wheezing episode noted in the medical record within the past 12 months should not receive Flumist. ‡‡Flumist is indicated for healthy, nonpregnant persons 2 to 49 years of age. Persons who care for severely immunosuppressed persons who require a protective environment should not receive Flumist given the theoretical risk of transmission of the live attenuated vaccine virus.

Dose) is approved for persons 65 years or older. Three prelicensure studies among persons in this age group showed that, compared with the standard dose, the high-dose vaccine elicited higher hemagglutination inhibition antibody titers against the three virus strains included in the seasonal influenza vaccine during the study period. However, there is no recommendation for using the high-dose vaccine vs. the standard-dose vaccine in this population.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Persons 18 to 49 years of age who have an egg allergy of any severity now have the option of receiving trivalent recombinant influenza vaccine, an egg-free vaccine. In persons who have no known history of egg exposure but who have received allergy test results suggestive of an egg allergy, consultation with a physician who has expertise in allergy management is recommended before vaccination. Figure 1 provides an algorithm for influenza vaccination in persons who report an allergy to eggs.

American Family Physician Table 2. Contraindications and Precautions* to the Use of 2013-2014 Influenza Vaccines Inactivated, including trivalent, quadrivalent, and cell culture–based History of severe allergic reaction to any component of the vaccine, including egg protein, or after previous dose of any influenza vaccine Recombinant History of severe allergic reaction to any component of the vaccine Live attenuated History of severe allergic reaction to any component of the vaccine, including egg protein, gentamicin, gelatin, and arginine, or after a previous dose of any influenza vaccine Concomitant aspirin therapy in children and adolescents In addition, the Advisory Committee on Immunization Practices recommends against use in the following groups: Children < 2 years

Persons with asthma

Persons with egg allergy

Adults ≥ 50 years

Children and adults who have chronic pulmonary, cardiovascular (except isolated hypertension), renal, hepatic, neurologic/ neuromuscular, hematologic, or metabolic disorders

Close contacts and caregivers of severely immunosuppressed persons who require a protected environment

Children 2 to 4 years of age whose parents or caregivers report that a health care professional has told them during the past 12 months that their child had wheezing or asthma, or whose medical record indicates Children and adults who have a wheezing episode has occurred during the immunosuppression (including past 12 months (Table 1) immunosuppression caused by medications or by human immunodeficiency virus infection)

Pregnant women

Influenza Vaccination in Patients with Egg Allergy Can the person eat lightly cooked egg (e.g., scrambled egg) without reaction?* No After eating eggs or egg-containing foods, does the person experience only hives?

Yes Yes

No After eating eggs or egg-containing foods, does the individual experience other symptoms such as: Cardiovascular changes (e.g., hypotension) Respiratory distress (e.g., wheezing) Gastrointestinal symptoms (e.g., nausea, vomiting) Reaction requiring epinephrine Reaction requiring emergency medical attention

Yes

Administer vaccine per usual protocol Administer recombinant influenza vaccine, trivalent, if patient is 18 to 49 years of age or Administer inactivated influenza vaccine Observe for reaction for at least 30 minutes following vaccination Administer recombinant influenza vaccine, trivalent, if patient is 18 to 49 years of age or Refer to a physician with expertise in management of allergic conditions for further evaluation

*Persons with egg allergy might tolerate egg in baked products (e.g., bread or cake). Tolerance to egg-containing foods does not exclude the possibility of egg allergy. For persons who have no known history of exposure to egg but who are suspected of being egg-allergic on the basis of previously performed allergy testing, consultation with a physician who has expertise in the management of allergic conditions should be obtained before vaccination. Alternatively, recombinant influenza vaccine, trivalent, may be administered if the recipient is 18 to 49 years of age.

Figure 1. Algorithm for influenza vaccination in persons who report egg allergy.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

American Family Physician

Photo Quiz A Swollen Thumb A 78-year-old man with a history of diabetes mellitus and hypertension presented with a four-month history of progressively worsening, painless swelling at the base of his left thumbnail. The swelling was accompanied by a serosanguineous discharge at the cuticle. There was no history of trauma to the area. Treatment with levofloxacin, 500 mg, for 10 days was ineffective. Physical examination revealed hyperpigmented skin just below the cuticle of the left thumb with swelling (see accompanying figure). The base of the nail appeared fleshy with loss of the cuticle and dystrophy of the nail plate.

Question Based on the patient’s history and physical examination findings, which one of the following is the most likely diagnosis?

C. Herpetic whitlow.

A. Chronic paronychia.

D. Onychomycosis.

B. Felon.

E. Subungual hematoma.

Figure.

SEE THE FOLLOWING PAGE FOR DISCUSSION.

Source: Adapted from Am Fam Physician. 2014;89(8):663-664.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

American Family Physician cases. Resolution of chronic paronychia can take several weeks to months.4

Discussion The answer is A: chronic paronychia. Paronychia is inflammation of the nail fold secondary to a bacterial infection.1,2 Retraction of the proximal nail fold, nail disfigurement, and loss of the cuticle are common. Chronic paronychia lasts longer than acute paronychia, often more than six weeks, and is usually nonsuppurative. Predisposing factors include exposure of hands to a moist environment (e.g., bartending, dish washing, swimming), immunocompromise, diabetes, and repeated minor trauma (e.g., nail biting, thumb sucking). Treatment of chronic paronychia involves keeping the hands dry, wearing protective gloves if working in a moist environment, and keeping hands away from irritants. Medium- to high-potency topical steroids are the first-line treatment because chronic paronychia is thought to be primarily an inflammatory, eczematous process.3 Because colonization with Candida albicans is common, a topical antifungal cream can be added if there is no resolution. Surgery with proximal nail fold and nail plate excision may be indicated in refractory

Summary Table Condition

Characteristics

Chronic paronychia

Inflammation of the nail fold with retraction of the proximal nail fold, nail disfigurement, and loss of the cuticle

Felon

Acute subcutaneous pyogenic infection of the pulp space of the thumb and index finger, associated with minor trauma to the dermis overlying the finger pad

A felon is an acute subcutaneous pyogenic infection of the pulp space of the thumb and index finger commonly caused by Staphylococcus or Streptococcus species. Infection usually begins with minor trauma to the dermis overlying the finger pad. Felons that are untreated or incorrectly treated, or that have a prolonged course may lead to osteomyelitis. Herpetic whitlow is caused by herpes simplex virus infection. Herpes simplex virus 1 infection is usually the cause in children, whereas herpes simplex virus 2 infection is more common in adults. Patients with herpetic whitlow have a tingling or burning sensation and fluid-filled vesicles, usually without nail plate involvement. A Tzanck test can confirm the diagnosis.5 Onychomycosis is a fungal infection that may involve any portion of the nail unit. Discoloration and thickening of the nail plate are characteristic. Subungual debris may separate the nail plate from the nail bed.6 Subungual hematomas result from trauma to the nail plate that causes bleeding and pain. The nail may separate from the nail plate, although puncturing the nail plate with a handheld cautery device or heated needles relieves the pressure. Subungual hematomas usually cause a bluish or violaceous discoloration of the nail plate that remains until the nail plate grows out. REFERENCES 1. Tully AS, Trayes KP, Studdiford JS. Evaluation of nail abnormalities. Am Fam Physician. 2012;85(8):779-787. 2. Rockwell PG. Acute and chronic paronychia. Am Fam Physician. 2001;63(6):1113-1116.

Herpetic whitlow

Tingling or burning sensation and fluidfilled vesicles, usually occurs without nail plate involvement

3. UpToDate. Goldstein BG, Goldstein AO. Paronychia and ingrown toenails. May 10, 2012. http://www.uptodate. com/contents/paronychia-and-ingrown-toenails (sub scription required). Accessed February 15, 2013.

Onychomycosis

Discoloration and thickening of the nail plate, subungual debris separating the nail plate from the nail bed

4. Rigopoulos D, Larios G, Gregoriou S, Alevizos A. Acute and chronic paronychia. Am Fam Physician. 2008;77(3):339-346.

Subungual hematoma

History of trauma; bluish or violaceous discoloration under the nail plate, pain and separation of the nail from the nail plate may occur

5. Tintinalli JE, Stapczynski JS, eds. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. New York, NY: McGraw-Hill; 2011. 6. Rakel RE, ed. Textbook of Family Medicine. Philadelphia, Pa.: Saunders-Elsevier; 2007. ■■■■

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Anesthesiology

Conscious Sedation: An Observation JAYASHREE SEN*, BITAN SEN†

Abstract Conscious sedation is a drug-induced depression of consciousness while the patient remains awake to respond to the verbal commands. Certain diagnostic and therapeutic procedures can be carried out under local anesthesia with sedation and analgesia without any requirement for intervention of maintenance of cardiorespiratory function. The hemodynamic status and the level of consciousness needed for the procedures remain continuously under the vigilance and control of a qualified anesthesiologist. An essential component of conscious sedation or monitored anesthesia care, which is a planned procedure, is the assessment and management of a patient’s actual or anticipated physiological derangements or medical problems that may occur during the diagnostic or therapeutic procedure carried out under sedation.

Keywords: Sedatives, consciousness, procedures, monitoring

onscious sedation, as defined by the American Society of Anesthesiologists (ASA), is a specific anesthesia service for a diagnostic or therapeutic procedure done under local anesthesia along with sedation and analgesia. This ‘conscious’ sedation or monitored anesthetic care (MAC), is a drug-induced depression of consciousness. The process makes the patient calm while he remains awake and responsive to follow commands, either alone or accompanied by light tactile stimulation. No intervention is required for maintaining normal respiratory and cardiovascular function. Conscious sedation, as per the ASA, includes the nature of the procedure, clinical condition of the patient and/or the potential need to convert sedation to a general or regional anesthesia. Monitoring of the patient is done continuously by an anesthesiologist, of the anesthetic procedure, the vital signs and level of consciousness as required for the surgical technique. It incorporates varying levels of sedation, analgesia and anxiolytics as necessary. After the procedure is over, the anesthesiologist will discharge the patient fully awake and almost pain free.

*Associate Professor Dept. of Anesthesiology Goldfield Institute of Medical Sciences and Research, Chhainsa, Faridabad, Haryana †Junior Resident Emergency Medicine, Apollo Hospital, New Delhi Address for correspondence Dr Jayashree Sen Associate Professor Dept. of Anesthesiology Goldfield Institute of Medical Sciences and Research, Chhainsa, Faridabad, Haryana E-mail: jayashree_sen@rediffmail.com

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Purpose The purpose of conscious sedation or MAC is to provide the patient with relief of discomfort and anxiety associated with the proposed surgical or investigative procedure so that the patient remains motionless and can co-operate actively following verbal commands throughout the procedure. Indication Conscious sedation may be appropriate for: a) Diagnostic purposes such as gastrointestinal endoscopy or bronchoscopy; b) interventional pain procedures; c) ENT surgeries such as myringoplasty, ear-lobe reconstruction; d) ophthalmological procedures such as intraocular lens application, blepharoplasty; e) cardiothoracic procedures such as angiography, transvenous cardiac pacemaker surgery; f) neurological procedure such as stereotactic surgeries; g) gynecological procedures such as tubectomy or medical termination of pregnancy; h) urological surgeries such as stent application or stent removal; i) orthopedic procedures like removal of external fixators; j) radiological procedures like computerized tomography (CT) or magnetic resonance imaging (MRI) and k) some minor surgeries or liposuction for which the patient needs to lie still for more than a few minutes. Pre-requisites Conscious sedation includes a pre-procedure visit (preanesthetic check-up), intra-procedure care and postprocedure anesthesia management along with certain specific services:

Anesthesiology ÂÂ ÂÂ

ÂÂ ÂÂ ÂÂ ÂÂ ÂÂ

Explanation of the procedure and request to the patient for active co-operation. Administration of drugs such as sedatives, analgesics, hypnotics, anesthetic agents or other medications as necessary for patient safety. Maintenance of hemodynamics. Support of psychological aspects. Care of physical comfort. Diagnosis and management of clinical problems that might occur during the procedure.

infusion dose along with local anesthetic injection. Sedation can be deepened by more bolus dose at stimulating moments. Infusion dose titrated at the end of the procedure to make the patient awake to follow commands.

Provision of emergency management.

Ketamine

Technique The procedure begins once oxygen is given via nasal cannulae, the intravenous (IV) access established, skin sensitivity test for local anesthetic done, cardiopulmonary and other required monitors connected. Drugs Chosen Conscious sedation includes the use of drugs whose clinical effects can be modified according to the surgical requirements and which can induce amnesia so that the patient will not remember the procedure after it took place. Moderate sedation can be achieved using pharmacologic agents for sedation, anxiolysis and analgesia. The procedure can also be achieved using patient controlled sedation, target controlled infusion or continuous IV infusion.

Midazolam A short-acting, water-soluble benzodiazepine, an ideal agent for its amnestic and anxiolytic properties. Midazolam, with a half-life of 2 hours, has limited cardiovascular effects, allows for quick recovery and has no postoperative sequelae such as nausea and vomiting.

Slow administration maintains hemodynamics. Does not cause postoperative nausea or vomiting but may cause postoperative shivering. Dose: Bolus-0.5-1 mg/kg; infusion - 25 µg/kg/min.

Agent of choice as an analgesic in conscious sedation. Produces dissociated anesthesia. Psychotic reactions such as hallucination, serious cardiovascular adverse effects, seizures and postoperative shivering have been reported. Dose: 2 mg/kg IV or 6-10 mg/kg IM.

Dexmedetomidine Has both sedative and analgesic properties, does not cause respiratory depression, though hemodynamic parameters need to be closely monitored. Has a high incidence of postoperative dry mouth. Dose: 1μg/kg-1IV

Local Anesthetic Agent One percent lidocaine can be used either plain or with epinephrine (EPI) 1:2,00,000 or 1:1,00,000 for direct injection into the incisional site. Xylocaine, an amide, has a rapid-onset of the anesthetic effect while bupivacaine, another amide has a longer duration of action. Dose: Lidocaine 7.0 mg/kg with EPI; 4.5 mg/kg without EPI; duration: 30-60 minutes.

Dose: 0.05 mg/kg bolus IV

Bupivacaine (0.5% or 0.75% or 0.25%), 225 mg/dose with EPI; 175 mg/dose without EPI; duration: 30-90 minutes.

Fentanyl

Complication

A rapidly-acting narcotic analgesic, with little sedative effect. May cause depression of respiratory function. The patient may experience postoperative nausea and vomiting. Dose: Boluses of 25-50 µg increments for analgesia.

Propofol A rapidly-acting sedative and hypnotic agent having a quick recovery property. Can be used in bolus and

Complications due to use of sedatives include hypoxia, hypercarbia and cerebral hypoperfusion. Complications due to local anesthetic toxicity can manifest as local or systemic adverse effects. Localized reactions with local anesthetics present as urticaria, rash and/or allergic reactions including anaphylaxis. Prolonged or permanent paresthesia, anesthesia and motor weakness, local vasoconstriction effect resulting in necrosis may also occur.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Anesthesiology entropy monitoring, auditory8 evoked potentials, SNAP monitor and the Narcotrend monitor. But these are unreliable: 1) At extremes of age; 2) certain N-methyl-d-aspartate (NMDA) receptor antagonist agents such as nitrous oxide, ketamine or Xenon suppress the cortical EEG activity less and 3) affected by the interference from other biological potentials as electromagnetic (EMG) or external electrical signals as electrosurgery.

Systemic adverse effects can result in breathlessness, hypotension, angina pectoris, dysrhythmias and even cardiovascular collapse. The possible effects of central nervous system (CNS) toxicity with local anesthetics are disorientation, decreased responsiveness, auditory and visual hallucinations, respiratory and cardiovascular collapse including seizures and coma. Other less severe complications, not related to drugs, may be discomfort due to uncomfortable position or a member of the surgical team leaning on the patient, IV site extravasation, pruritus, hypothermia, hyperthermia, bladder distention, prolonged tourniquet inflation. Monitoring during Conscious sedation ÂÂ

Pulse oximetry: For O2 saturation.7 The predisposing factors for hypoxia other than sedatives include obesity, extremes of age, lithotomy position, pre-existing upper airway obstruction and respiratory disease. The respiratory events constitute the single largest source of adverse outcome as analyzed by the ASA Committee on Professional Liability.

ÂÂ

Capnography: For end-tidal carbon dioxide (EtCo2) measuring side stream capnograph using face masks, nasal airways or nasal cannulae is the procedure of choice.

ÂÂ

ECG and noninvasive blood pressure (NIBP) for cardiovascular system: The ECG lead II continuously should be displayed and NIBP measured and recorded at least every 5 minutes. The pulse should be monitored by palpation or oximetry. Use of precordial stethoscope is an inexpensive, effective, risk-free way of monitoring.

ÂÂ

Temperature: External and core body temperature for detecting inadvertent hypothermia, particularly in the elderlies during regional and conscious sedation techniques and also hyperthermia, which may be due to use of too much drapings during the procedure in a hot climate or malignant neuroleptic syndrome. Response to communication: For titration of sedation, continuous evaluation for response to verbal commands and tactile stimulation should be carried out. Other clinical findings as shivering, pallor, cyanosis or acute changes in neurological or cardiorespiratory status are to be observed. Depth of sedation: Monitoring can be done through bispectral index (BIS), electroencephalogram (EEG)

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Conscious sedation in pregnancy This can be considered medically necessary for certain procedures. Due to physiological changes in pregnancy, the doses of anesthetic or sedative agents also require alteration. Propofol however is taken as a safe agent. The American College of Obstetricians and Gynecologists (ACOG) has recommended that intermittent or continuous fetal monitoring during conscious sedation is a more sensitive and important indicator of placental perfusion and fetal oxygenation than observations of maternal hemodynamic stability.

Disadvantage The disadvantages of conscious sedation mainly are the lack of airway control and the risk of airway obstruction or aspiration. Thus to minimize the disadvantage, the medication should be selected and titrated under the hawk eyes of an anesthesiologist to maintain a spontaneous respiration and an anesthetic depth so that the desired and optimal intraoperative sedative effect and postoperative outcome obtained. Risk factors ÂÂ ÂÂ ÂÂ ÂÂ ÂÂ ÂÂ ÂÂ

ÂÂ

Unco-operative or acutely agitated individual with delirium, senile dementia, organic brain disease. Cognitive dysfunction, psychological impairment, or intoxication (unable to follow simple commands). Severe comorbidity (ASA III physical status or greater). Morbid obesity (body mass index [BMI] >40). Patients of extreme age. Documented sleep apnea. History or anticipated intolerance to standard sedatives, e.g., chronic opioid use/chronic benzodiazepine use/alcohol abuse. Patients with risk for airway obstruction due to: zz

Spasticity or movement disorder

Dysmorphic facial features, such as PierreRobin syndrome or trisomy-21

Anesthesiology

ÂÂ

Jaw abnormality (e.g., micrognathia)

Oral abnormalities (e.g., macroglossia)

Neck abnormalities (e.g., neck mass)

Stridor.

Patients who are pregnant.

Observation Fifty cases were observed in a teaching institute, in a period of time between January to December 2012, following a body weight (per kg) depended standard dose protocol of different drugs. Midazolam, fentanyl, propofol or ketamine was used either as a single agent (e.g., propofol) or in combination (e.g., midazolam + ketamine/midazolam + fentanyl) for conscious sedation in different patients. Drugs were administered in bolus with additional doses given when required for adequate sedation for the procedure concerned. ASA I and II groups within an age range of 18-60 years of either sex and BMI within 20-25 were accepted. The average procedural time was 90 minutes. Any complication was noted. Result The primary outcome recorded was respiratory depression of 7 (14%) patients requiring airway modification such as chin lift or mask ventilation for some minutes to those requiring no modification. No patient but required endotracheal intubation. Some cases had to be treated for nausea and postoperative pain. The patients received sedation, remained responsive to commands throughout the procedures and were monitored by a qualified anesthesiologist and thus the procedures met the definition of conscious sedation or monitored anesthesia care. Conclusion The use of conscious sedation has been increasing rapidly over the last decade, is the first choice in 10-30% of all diagnostic and therapeutic procedures and has been applied to patients with lower anesthetic

risk. A shared decision-making to weigh the risks and benefits of a patient is the recommendation by Liu and colleagues who studied the utilization of anesthesia services among low-risk patients (ASA I and II). The success of conscious sedation lies in the provider’s (anesthesiologist) ability to intervene to rescue a patient’s airway from any sedation-induced compromise and also management of post-procedure responsibilities such as relief of pain, side effects of medication used, adverse physiological responses as well as diagnosis and treatment of complications. Suggested reading 1. American Society of Anesthesiologists. Statement on nonoperating room anesthetizing locations. Amended October 22,2008. Available online at: http://www.asahq. org/For-Members/Standards-Guidelines-and-Statements. aspx. Last accessed March 6, 2013. 2. American Society of Anesthesiologists. Guidelines for ambulatory anesthesia and surgery. Amended October 15, 2008. Available online at: http://www.asahq.org/ForMembers/Standards- Guidelines-and-Statements.aspx. Last accessed March 6, 2013. 3. American Society of Anesthesiologists. 2009. Distinguishing monitored anesthesia care (“MAC”) from Moderate sedation/analgesia (conscious sedation). Retrieved 3/8/13 from http://www.asahq.org/ publicationsAndService/standards/35.pdf. 4. Sarmento KM Jr, Tomita S. Retroauricular tympanoplasty and tympanomastoidectomy under local anesthesia and sedation. Acta Otolaryngol 2009;129(7):726-8. 5. Gan TJ. Pharmacokinetic and pharmacodynamic characteristics of medications used for moderate sedation. Clin Pharmacokinet 2006;45(9):855-69. 6. Bailey PL, Pace NL, Ashburn MA, Moll JW, East KA, Stanley TH. Frequent hypoxemia and apnea after sedation with midazolam and fentanyl. Anesthesiology 1990;73(5):826-30. 7. Alhashemi JA. Dexmedetomidine vs midazolam for monitored anaesthesia care during cataract surgery. Br J Anaesth 2006;96(6):722-6. 8. Myles PS, Leslie K, McNeil J, Forbes A, Chan MT. Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial. Lancet 2004;363(9423):1757-63.

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In a new study, 5-year overall survival was significantly better in patients with gastric cancer who did not experience any perioperative complications than in those who did (43% vs 27%; P < 0.001). Preoperative characteristics associated with complications included older age, elevated American Society of Anesthesiologists class, previous gastrectomy, and upper gastrointestinal bleed.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

CARDIOLOGY

Perioperative Myocardial Infarction Sudivya Sharma, Prashast Jain

Abstract Myocardial infarction (MI) is defined by the World Health Organization Criteria, which includes typical ischemic chest pain, ECG criteria and raised cardiac enzymes. The perioperative period induces large, unpredictable and nonphysiological alterations in coronary plaque morphology, function and progression and may trigger a mismatch of myocardial oxygen supply and demand. Perioperative MI (PMI) is one of the most important predictors of short- and long-term morbidity and mortality associated with noncardiac surgery. Inability to fulfil the criteria, different symptomatology and numerous differential diagnoses makes PMI our subject of detailed discussion.1

Keywords: Perioperative myocardial infarction, plaque rupture, ischemia, risk stratification

he incidence of perioperative cardiac injury is a cumulative result of preoperative medical condition, the specific surgical procedure, expertise of the surgeon, the diagnostic criteria used to define myocardial infarction (MI) and the overall medical care at a particular institution. Patients with or at risk of cardiac disease have a 3.9% risk of suffering a major perioperative cardiac event. A perioperative MI (PMI) has an associated in-hospital mortality of 15-25% and an increased risk of subsequent cardiovascular death or MI.2,3 Most PMIs occur in the first 24-48 hours after surgery. They are mostly of silent type; ECG changes include ST depression, tachycardia and absence of Q waves and ST elevation. There is complete reversal of ECG changes to the baseline. The pain is masked by the analgesia and residual anesthesia provided intraoperatively. The prolonged stress-induced mismatch between oxygen supply and demand is the most likely cause of myocardial ischemia. A study of aortic surgical patients identiďŹ ed three patterns of troponin elevation. It was proposed by the authors that coronary plaque rupture was consistent with early PMI due to the rapidity of troponin change, while a sustained myocardial oxygen supply-demand imbalance in the postoperative period was consistent with delayed MI.4

PGIMS, Rohtak, Haryana Address for correspondence Dr Sudivya Sharma Flat No: 77, B-Wing, Mahavir Krupa building TJ Road, Sewri (W), Mumbai-400 015

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Pathophysiology One hypothesis supports sudden development of a thrombotic process associated with vulnerable plaque rupture. This hypothesis is based on postoperative autopsy studies and angiographic evidence of thrombus present in noncritically stenosed vessels. Endothelial injury at the site of a plaque rupture triggers the cascade of platelet aggregation and release of mediators including thromboxane A2, serotonin, adenosine diphosphate, platelet-activating factor, thrombin, and oxygen-derived free radicals. Aggregation of platelets and activation of other inflammatory and noninflammatory mediators potentiates thrombus formation and leads to dynamic vasoconstriction distal to the thrombus. The combined effects of dynamic and physical blood vessel narrowing cause ischemia and/or infarction. In the postoperative period, changes in blood viscosity, catecholamine concentrations, cortisol levels, endogenous tissue plasminogen activator concentrations, and plasminogen activator inhibitor levels create a prothrombotic state. Changes in heart rate and blood pressure as a result of the endocrine stress response can increase the propensity for plaque fissuring and endothelial damage. These MIs are preceded by tachycardia and ST depression, are often silent and present as non-STsegment elevation MI (NSTEMI). Patients with more severe coronary artery disease (CAD) are at greater risk. These observations support the other likely hypothesis that perioperative myocardial injury develops as a consequence of increased myocardial oxygen demand (increased blood pressure and heart rate) in the context of underlying compromised myocardial oxygen supply.

CARDIOLOGY The oxygen demand is increased perioperatively due to increased heart rate, heart wall tension, preload, afterload, and myocardial contractility. On the other hand, the oxygen supply is decreased due to decreased coronary blood flow, tachycardia, hypotension, hypocapnia, hypoxemia, anemia, etc. In combination, these factors can precipitate thrombus formation in an atherosclerotic coronary artery and lead to the development of STEMI (Q-wave). Thus, two different pathophysiologic mechanisms

Table 1. Clinical Predictors of Increased Perioperative Cardiovascular Risk Major Unstable coronary syndromes

Acute or recent MI with evidence of important ischemic risk by clinical symptoms or noninvasive study

nstable or severe angina U Decompensated heart failure

Significant dysrhythmias

High-grade atrioventricular block Symptomatic ventricular dysrhythmias in the presence of underlying heart disease

Supraventricular dysrhythmias with uncontrolled ventricular rate Severe valvular heart disease

Intermediate Mild angina pectoris Previous MI by history or Q waves on ECG Compensated or previous heart failure Diabetes mellitus (particularly insulin dependent) Renal insufficiency Minor Advanced age (older than 70 years) Abnormal ECG (left ventricular hypertrophy, left bundle branch block, ST-T abnormalities) Rhythm other than sinus Low functional capacity History of stroke Uncontrolled systemic hypertension (Adapted from Fleisher LA, Beckman JA, Brown KA, et al: ACC/AHA 2006 guideline update on perioperative cardiovascular evaluation for noncardiac surgery: Focused update on perioperative beta-blocker therapy: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2006;113: 2662-2674. with permission.)

can be responsible for PMI. One could be related to acute coronary thrombosis, and the other could be the consequence of increased myocardial oxygen demand in the setting of compromised myocardial oxygen supply. These processes are not mutually exclusive. However, one process or the other can predominate in a particular patient. Risk Stratification Tables 1-4 are guides to risk stratification for a patient, predicting likelihood of myocardial ischemia or infarction perioperatively. The severity of surgery, the functional capacity and present cardiac clinical signs and symptoms collectively determine the prognosis and outcome of surgery. These are also a guide for further delay or optimization of the patient. Figure 1 shows a step-wise approach to patients at risk.

Table 2. Revised Cardiac Risk Index in Patients Undergoing Elective Major Noncardiac Surgery High-risk surgery Abdominal aortic aneurysm Peripheral vascular operation Thoracotomy Major abdominal operation Ischemic heart disease History of myocardial infarction History of a positive exercise test Current complaints of angina pectoris Use of nitrate therapy Q waves on electrocardiogram Congestive heart failure History of congestive heart failure History of pulmonary edema History of paroxysmal nocturnal dyspnea Physical examination showing rales or S3 gallop Chest radiograph showing pulmonary vascular redistribution Cerebrovascular disease History of stroke History of transient ischemic attack Insulin-dependent diabetes mellitus Preoperative serum creatinine concentration > 2 mg/dL Adapted from Lee TH, Marcantonio ER, Mangione CM, et al: Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999;100:1043-1049 with permission.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

CARDIOLOGY Table 3. Metabolic Equivalents of Functional Capacity MET

Functional levels of exercise

Eating, working at a computer, dressing

Walking down stairs or in your house, cooking

Walking 1-2 blocks

Raking leaves, gardening

Climbing 1 flight of stairs, dancing, bicycling

Playing golf, carrying clubs

Playing singles tennis

Rapidly climbing stairs, jogging slowly

Jumping rope slowly, moderate cycling

Swimming quickly, running or jogging briskly

Skiing cross country, playing full-court basketball

Running rapidly for moderate to long distances

Step 1

Table 4. Cardiac Risk Stratification for Noncardiac Surgical Procedures Risk stratification

Vascular (reported yy Aortic and other major vascular surgery cardiac risk often yy Peripheral vascular surgery > 5%) Intermediate (reported cardiac risk generally 1-5%)

yy Intraperitoneal and intrathoracic surgery yy Carotid endarterectomy yy Head and neck surgery yy Orthopedic surgery yy Prostate surgery

Low (reported cardiac risk generally < 1%)

yy Endoscopic procedures yy Superficial procedure yy Cataract surgery yy Breast surgery yy Ambulatory surgery

Operating room

Perioperative surveillance and postoperative risk stratification and risk factor management

Evaluate and treat per ACC/AHA guidelines

Consider operating room

Yes (Class I, LOE C)

Need for emergency noncardiac surgery?

Procedure examples

No Yes (Class I, LOE B)

Step 2

Active cardiac conditions

Step 3

Low risk surgery

Step 4

Functional capacity â&#x2030;Ľ4 METs without symptoms.

Step 5

Proceed with planned surgery

Yes (Class I, LOE B)

Yes (Class IIa, LOE B)

No or unknown

3 or more clinical risk factors Vascular surgery

1-2 1-2 clinical clinical risk risk factors factor

Vascular surgery

Intermediate risk surgery

Proceed with planned surgery with HR control (Class IIA LOE B) or consider noninvasive testing (Class IIb LOE B) if it will change management

Figure 1. Risk stratification and management.

No clinical risk factor

Intermediate risk surgery

Class IIa LOE B Consider testing if it will change management

Proceed with planned surgery

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Class IIa LOE B

Proceed with planned surgery

CARDIOLOGY The goal is to identify patients with heart disease who are at high-risk for perioperative cardiac morbidity or mortality or those with modifiable conditions or risk. The guidelines for cardiac evaluation before noncardiac surgery published by the ACC/AHA have become the national standard of care. These guidelines were recently revised with a marked reduction in recommendations for preoperative noninvasive stress testing and revascularization. The substantial pullback of ACC/AHA recommendations advocating noninvasive stress testing and coronary revascularization before noncardiac surgery is due to the general lack of definitive benefit and risk reduction with this approach.5 Preoperative period is an opportunity to identify patients with CAD who will benefit from long-term risk modification with statins, aspirin, exercise and diet adjustment. Patients with symptoms consistent with ischemia (but without a diagnosis of CAD) or significant risk factors without medical management such as statins and aspirin may benefit from evaluation by a cardiologist regardless of whether they are having surgery. Preoperative evaluation should not simply focus on perioperative risk. Management The management of PMI is also different as thrombolytics cannot be given and anticoagulant use is with caution. The risk of life-threatening bleeding cancels thrombolytics as an option, hence a more conservative approach is recommended. So, the mainstay of treatment includes good pain control, β-blockers, statins, antiplatelets, nitroglycerine and unfractionated heparin.

Conclusion Many questions relating to perioperative pharmacological therapy to prevent PMI remain unanswered. Careful perioperative monitoring for ischemia, a low threshold for treating and preventing tachycardia while avoiding hypotension, decreased cardiac output and/or cardiac decompensation help prevent PMI. Coronary intervention is rarely indicated as the firstline of treatment and antithrombotic therapy may exacerbate bleeding. Future studies are needed to determine, which patients with PMI require intensified postoperative surveillance, medical therapy and/or coronary intervention to improve long-term survival. References 1. Priebe HJ. Perioperative myocardial infarction aetiology and prevention. Br J Anaesth 2005;95(1):3-19. 2. Devereaux PJ, Goldman L, Cook DJ, Gilbert K, Leslie K, Guyatt GH. Perioperative cardiac events in patients undergoing noncardiac surgery: a review of the magnitude of the problem, the pathophysiology of the events and methods to estimate and communicate risk. CMA J 2005;173(6):627-34. 3. Devereaux PJ. Can attenuation of the perioperative stress response prevent intermediate or long-term cardiovascular outcomes among patients undergoing noncardiac surgery? Anesthesiology 2009;111(2):223-6. 4. Le Manach Y, Perel A, Coriat P, Godet G, Bertrand M, Riou B. Early and delayed myocardial infarction after abdominal aortic surgery. Anesthesiology 2005;102(5):885-91. 5. Fleisher LA, Beckman JA, Brown KA, et al: ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery. J Am Coll Cardiol 2007;50:159-241.

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Be Cautious in Giving Painkiller to Patients with High Cholesterol Long-term non-steroidal anti-inflammatory painkiller drugs (NSAIDs) such as naproxen should not be prescribed to patients with high cholesterol. In a swine model study published in Surgery Dr Frank Sellke, chief of cardiothoracic surgery and research at Rhode Island Hospital found that a high-cholesterol diet reduced blood flow to the heart muscle in animal models with chronic heart disease when given daily naproxen. They also found reduced levels of prostacyclin, a compound that dilates blood vessels and prevents blood clots. These findings suggest that there may be a stronger risk of negative effects on the heart in patients who have high cholesterol levels and are taking NSAIDs as a form of pain or inflammation relief. Source: eMedinews

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

cardiology

Coronary Artery Air Embolism MONIKA MAHESHWARI*, ANAND AGARWALâ&#x20AC;

Abstract Coronary artery air embolization is a rare event leading to catastrophic hemodynamic compromise within seconds after introduction of air emboli within the coronary arteries. The management of massive air embolism should be extremely quick so as to save life of the patient. We present a case of a 35-year-old, diabetic and hypothyroid female who had massive air embolism in both LAD and LCX arteries during coronary angiography, which resolved within a few minutes with prompt treatment.

Keywords: Coronary artery air embolism, angiography, percutaneous interventions, hemodynamic compromise

oronary artery air embolization is a rare event, with overall incidence ranging from 0.2% to 0.8% during percutaneous interventions.1 Catastrophic hemodynamic compromise can occur within seconds after introduction of air emboli within the coronary arteries and may resolve within a few minutes if prompt treatment is undertaken, as we did in our case.

LCX

LAD

CASE REPORT A 35-year-old, diabetic and hypothyroid female with treadmill test (TMT) positive for inducible ischemia, was planned for coronary angiography. The right radial artery was cannulated with 5F tiger catheter. Engagement and initial injections of left coronary angiogram was uneventful showing a smooth, normal left anterior descending (LAD) and left circumflex arteries (LCX). However, while shooting subsequently RAO cranial view suddenly patient on table began to experience severe chest pain and ST segments in leads V1-V6 began to rise upto 3 mm in amplitude. Angiography demonstrated massive air embolism in both LAD and LCX arteries with no contrast flow beyond the mid-segments of both arteries (Fig. 1). The patient was soon hemodynamically unstable with hypotension and bradycardia. Immediately an attempt was made to suck out the air from the left coronary

*DM (Cardio) 3rd Year Resident â&#x20AC; DM (Cardio) Assistant Professor Dept. of Cardiology Jawaharlal Nehru Medical College Address for correspondence Navin Niwas, 434/10, Bapu Nagar, Ajmer - 305 001, Rajasthan E-mail: opm11@rediffmail.com

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Figure 1. Massive with no contrast flow beyond the midsegments of both arteries.

Figure 2. Showing TIMI-3 flow and no residual air embolism.

cardiology arteries via the guiding catheter. Cardiopulmonary resuscitation (CPR) was initiated with vigorous external cardiac massage. The patient was given 100% oxygen, intravenous (IV) atropine injections and was also put on IV dopamine. External cardiac massage and prompt aspiration was maintained for almost four minutes by which time the patient recovered both his heart rate and blood pressure with settled ST-segment on ECG monitor. After ascertaining that the patient was hemodynamically stable and had fully recovered her consciousness, left coronary angiogram was retaken, which showed TIMI-3 flow and no residual air emboli (Fig. 2). Discussion Air can be introduced in coronary vessels inadvertently by inadequate aspiration of the guiding catheters, rupture of balloon and leakage of air via a defective manifold system.2 The management of massive air embolism should be extremely quick so as to save life of the patient. Case reports have described mechanical methods in the treatment of an air embolus including disruption or dislodgement by the guidewire,3 forceful injection of saline1 to fragment the air embolus and allow dispersal distally. Such interventions may result in main vessel patency but have a potential to damage the distal microvasculature due to widespread, smaller embolizations. In contrast, aspiration aims at resolving the blockage by removing the air. Aspiration has been attempted with nondedicated devices such as over the wire (OTW) balloons4 or the angiography catheter itself.1 The lumen of such an OTW balloon system is just large enough to allow 0.014 inch wire passage and this may limit rapid aspiration. Use of the angiography catheter is limited by the ability to manipulate it

deeply enough to affect the distal embolus and the risk of damage while attempting this. In contrast, the export aspiration catheter is a dedicated system for coronary artery aspiration.5 As such, it has the favorable qualities of being a monorail system that has the flexibility and slenderness to reach distal lesions down tortuous vessels Dudar et al6 reported a case of massive air embolism in which AngioJet catheter was utilized to aspirate coronary air embolus with successful restoration of coronary blood flow. Along with these mechanical efforts, supportive measures with 100% oxygen, opoid analgesia, external cardiac massage (CPR), DC cardioversion and if needed intraaortic balloon support are warranted for life saving. Treatment has to be rapid and prompt as we did in our case. REFERENCES 1. Khan M, Schmidt DH, Bajwa T, Shalev Y. Coronary air embolism: incidence, severity, and suggested approaches to treatment. Cathet Cardiovasc Diagn 1995;36(4):313-8. 2. Dib J, Boyle AJ, Chan M, Resar JR. Coronary air embolism: a case report and review of the literature. Catheter Cardiovasc Interv 2006;68(6):897-900. 3. Inoue T, Yaguchi I, Mizoguchi K, Hoshi K, Takayanagi K, Morooka S, et al. Air embolism in the right coronary artery occurring during the left coronary angioplasty using the guiding catheter with a side hole. Catheter Cardiovasc Interv 2000;49(3):331-4. 4. Solodky A, Birnbaum Y, Assali A, Ben Gal T, Strasberg B, Herz I. Coronary air embolism treated by bubble aspiration. Catheter Cardiovasc Interv 2000;49(4):452-4. 5. Patterson MS, Kiemeneij F. Coronary air embolism treated with aspiration catheter. Heart 2005;91(5):e36. 6. Dudar BM, Kim HE. Massive air embolus treated with rheolytic thrombectomy. J Invasive Cardiol 2007;19(7):E182-4.

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New Way to Block Inflammation in Alzheimer’s, Atherosclerosis and Type 2 Diabetes Researchers at NYU Langone Medical Center have discovered a mechanism that triggers chronic inflammation in Alzheimer’s, atherosclerosis and type 2 diabetes. The results, published in Nature Immunology, suggest a common biochemical thread to multiple diseases and point the way to a new class of therapies that could treat chronic inflammation in these noninfectious diseases without crippling the immune system. Alzheimer’s, atherosclerosis and type 2 diabetes – diseases associated with aging and inflammation – affect more than 100 million Americans. (Source: Science Daily)

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Community Medicine

Evaluation of Vitamin D3 Deficiency in a Tertiary Care Center Arshad A*, Vijai C*, Sherin T†, Udaya S‡, Nupur D#, Vijaya V$

Abstract In India, vitamin D deficiency is epidemic, with a prevalence of 70-100% in the population. There is a growing awareness that vitamin D deficiency has serious health consequences and this highlights the need for assessment of the vitamin D nutritional status. The skeletal benefits of vitamin D are well-known, but the research into the extra-skeletal functions of vitamin D has been expanding in recent years. Vitamin D deficiency, probably plays an important role in the very high prevalence of rickets, osteoporosis, cardiovascular diseases, diabetes, cancer and infections such as tuberculosis in India. This paper highlights the functions of vitamin D, particularly the extra-skeletal functions, high prevalence in tropics due to changing lifestyles despite adequate sun exposure, and the necessary caution and care in diagnosing, treating and prevention of deficiency.

Keywords: Vitamin D deficiency, skeletal benefits, extra-skeletal functions, prevalence in tropics, prevention of deficiency

Background on Vitamin D

Material and Methods

Vitamin D is a unique nutrient in several ways. It regulates the functions of over 200 genes and is essential for growth and development of the body. Vitamin D is actually a prohormone that humans obtain from foods and dietary supplements, and by endogenous skin synthesis from 7-dehydrocholesterol with sunlight exposure. This endogenous synthesis produces vitamin D3 (cholecalciferol), which the vitamin D binding protein (DBP) transports to the liver. In foods and dietary supplements, vitamin D can exist in the form of either cholecalciferol or ergocalciferol (vitamin D2). Both are absorbed via the lymphatic system as part of chylomicrons, which are metabolized to remnant particles that then transport vitamin D to the liver. Vitamin D occurs naturally in a limited number of foods in highest amounts in fatty fish and in low amounts in meats and other animal food products; it is also available in fortified foods (including milk and milk products, margarines and breakfast cereals).

The study was conducted on 1,550 patients presenting to Apollo Hospital, Chennai, due to any ailment, whether the presentation was with or without symptoms referable to vitamin D3 deficiency. Patients were included in the study following informed consent and after explaining the cost of investigation.

Aims and objectives The aim of the study was to evaluate the deficiency of vitamin D3 in patients presenting to a tertiary care center. *Senior Consultant, Dept. of General Medicine †Head of the Department, Dept. of Biochemistry ‡Director of Preventive Medicine #Resident, Dept. of General Medicine Apollo Hospitals, Chennai $Medical Affairs, Strides Arcolab Ltd, Bangalore

In this study, a serum 25-hydroxyvitamin D3 [25(OH)D3] level <10 ng/mL was defined as deficiency. Serum 25 (OH)D3 levels were measured in the laboratory by chemiluminescence immunoassay. The patients were categorized according to their occupation, residential state, rural or urban background, sun exposure and presenting complaints. The study was conducted over a period of 1 year from January 2010 to December 2010. Results Amongst the total 1,550 (n = 1,550) patients studied, 927 (59.8%) were vitamin D3 deficient considering the reference values of the laboratory and 1,108 (76.12%) were deficient considering the international definition of vitamin D3 deficiency (<20 nmol/L) (Fig. 1). One thousand two hundred seventy-one (82%) patients belonged to urban background and 279 (18%) were from rural areas. Amongst 1,271 patients from urban areas 927 (73%) were deficient in vitamin D3, while 170 (61.1%) out of 279 patients from rural areas were deficient in vitamin D3 (Fig. 2).

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Community Medicine

80 70 60 50 40 30 20 10 0

Vitamin D3 Deficiency

76.12% 59.8%

Number of patients (%)

Vitamin D3 Deficiency

Based on lab reference values Based on international definition

Based on lab reference values

Based on international definition

73%

75 70 65

61.1%

Urban population Rural population

60 55 Urban population Rural population

Figure 1. Vitamin D3 deficiency based on laboratory reference values.

Figure 2. Vitamin D3 deficiency in urban and rural population.

Amongst the 927 patients deficient in vitamin D3, 323 patients (34.8%) presented with bone and joint pains and 604 patients (65.2%) presented with complaints other than bone and joint pains like lethargy, fatigue, fever of unknown origin (FUO) and asymptomatic patients who underwent routine check-up.

ÂÂ

Similar data have been obtained from Pakistan, most disturbingly from infants.

ÂÂ

In Bangladesh (24°N), hypovitaminosis D is common in women regardless of age, lifestyle and clothing.

Amongst the 927 patients deficient in vitamin D3, only 84 (9.06%) patients had occupations with ample sun exposure (farmers and field workers) and 843 (90.93%) had occupations confined to indoors for most of the day (software engineers, housewives and businessmen). On reviewing the literature for global prevalence of vitamin D3, we found that serum 25(OH)D levels below 75 nmol/L are prevalent in every region studied, while levels below 25 nmol/L are most common in regions such as South Asia and the Middle East. Older age, female sex, higher latitude, winter season, darker skin pigmentation, less sunlight exposure, dietary habits and absence of vitamin D fortification are the main factors that are significantly associated with lower 25(OH)D levels.

Europe7-10 ÂÂ

In the Netherlands, the Longitudinal Aging Study Amsterdam (LASA) showed a serum 25(OH)D <25 nmol/L in 8% of men and 14% of women, and <50 nmol/L in 45% of men and 56% of the women.

ÂÂ

Population-based study and the Swiss MONItoring of trends and determinants in CArdiovascular disease (MONICA) project.

ÂÂ

A study of Swiss Nursing Homes observed that 90% of elderly women had serum 25(OH) D levels <50 nmol/L compared to 57% in noninstitutionalized elderly women.

Latin America11

Discussion

An international epidemiological investigation conducted in postmenopausal women with osteoporosis from Mexico (n = 149), Chile (n = 115) and Brazil (n = 151) found lower values of 25(OH)D in Mexico than in Chile and Brazil. The percentage of persons with inadequate levels of 25(OH)D (<75 nmol/L) in the mentioned countries were 67%, 50% and 42%, respectively.

Global Vitamin D Status2

Middle East and Africa12-16

A similar study done by Viswanathan et al1 from Apollo Hospitals in software engineers showed significant vitamin D deficiency due to lack of sun exposure.

Asia3-6 ÂÂ

ÂÂ

In North India (27°N), 96% of neonates, 91% of healthy school girls, 78% of healthy hospital staff and 84% of pregnant women were found to have hypovitaminosis D. The criteria used for defining hypovitaminosis D in most of the studies was a serum 25(OH)D level <50 nmol/L.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

ÂÂ

The first study in adults from the region was conducted in university students and elderly from Saudi Arabia and revealed a mean 25(OH)D level ranging between 10 and 30 nmol/L.

ÂÂ

The proportion of subjects with vitamin D levels below specific cut-offs varied. It was 35% for a vitamin D level <25 nmol/L in a study of elderly subjects from a geriatric hospital in Israel; and between 60% and 65% in Lebanon, Jordan and Iran.

Community Medicine Table 1. Age-wise Distribution of 25(OH)D3 Levels Age groups (years) 1-5 20-49

25(OH)D3 cut-off (nmol/L) <37.5 <50 nmol/ L <75 nmol/L 2% 8% 50% 13% 29% 73%

70 years and older

11%

ÂÂ

27%

78%

In the elderly Lebanese, 37% of men and 56% of women had vitamin D levels <25 nmol/L.

North America17,18 In the USA, serum 25(OH)D levels have been assessed in a representative sample of 20,289 noninstitutionalized, civilian males and females in the National Health and Nutrition Examination Survey (NHANES) over the period of 2002-2004. The age-wise distribution of 25(OH)D3 deficiency levels at cut-off levels <37.5, <50 and <75 nmol/L are shown in Table 1. Oceania19,20 ÂÂ

ÂÂ

In a prospective study evaluating prevalence of vitamin D deficiency in older people in residential aged-care facilities in the northern Sydney area, vitamin D deficiency (serum 25(OH)D <28 nmol/L) was present in 68% of men and 86% of women, with a mean serum 25(OH)D level of 17 nmol/L. A case series of elderly patients (mean age 81 years) admitted with a hip fracture to Royal Hobart Hospital, Tasmania, found vitamin D deficiency (<28 nmol/L) in 67%.

Consequences of Vitamin D Deficiency on Calcium and Bone Metabolism1 Vitamin D deficiency causes a decrease in the efficiency of intestinal calcium absorption and results in a decrease in ionized calcium. The calcium sensor in the parathyroid glands immediately recognizes the decrease causing the parathyroid glands to increase the production and secretion of parathyroid hormone (PTH). PTH maintains serum calcium levels by increasing tubular reabsorption of calcium in the kidneys. Through its receptor on osteoblasts, PTH stimulates the formation of osteoclasts, which in turn dissolves the bone matrix and mineral to release the calcium into the extracellular space. This process, known as secondary hyperparathyroidism, can precipitate and exacerbate both osteopenia and osteoporosis, increasing risk of fracture. PTH also causes phosphorus loss in the urine resulting in a lownormal serum phosphorus level.

Figure 3. Schematic representation of the synthesis and metabolism of vitamin D for regulating calcium, phosphorus and bone metabolism.

The net result is an inadequate calcium-phosphate product necessary for the mineralization of the collagen matrix leading to osteomalacia. In children, poorly mineralized matrix and abnormal chondrocyte maturation leads to the classic skeletal deformities of rickets including the inward or outward bowing of the legs, widened epiphyseal plates at the end of the long bones and costochondral junctions, frontal bossing of the skull, craniotabes and a delay in tooth eruption. In adults, there is enough mineral in the long bones and the epiphyseal plates are closed; thus, there are no obvious skeletal deformities. However, the unmineralized matrix underneath the periosteal membrane that is heavily innervated with sensory fibers is hydrated and pushed upwards, often being perceived by the patient as throbbing aching bone pain. These patients are often misdiagnosed as having fibromyalgia, chronic fatigue syndrome or arthritis. Neither a skeletal X-ray, nor a bone-density scan can distinguish between osteomalacia, osteopenia and osteoporosis. They look the same i.e., decreased bone mineral (calcium) content that can increase risk of fractures.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Community Medicine Nonskeletal Functions of Vitamin D21 The association of living at upper (and lower) latitudes (i.e., above or below the 38th parallels of latitude) with increased risk of dying from cancer, type 1 diabetes, multiple sclerosis and hypertension is welldocumented. It has been assumed that living beyond the temperate zone at higher latitudes increases risk of vitamin D deficiency because of decreased sun exposure on account of longer winters and the angle of sun, which is such that there is decreased ultraviolet light effect. It is also recognized that every tissue and cell in the body including immune, brain, colon, prostate and breast cells, among many others, have a vitamin D receptor (VDR). Studies have revealed that upwards of 2,000 genes are either directly or indirectly regulated by 1,25(OH)2D. Initially, it was thought that increasing your vitamin D intake or exposure to sunlight raised your blood levels of 25(OH)D, which resulted in increased blood levels of 1,25(OH)2D, which in turn could interact with a wide variety of genes in a multitude of cells and organs to maintain cells and organ health and thereby reducing risk of chronic diseases. However, the conundrum was that the kidneys only produced a finite amount of 1,25(OH)2D that was tightly regulated by the serum calcium, phosphorus and PTH levels in the circulation. The realization that many tissues and cells in the body including among others the skin, breast, prostate, brain

Figure 4. Metabolism of 25(OH)D to 1,25(OH)2D for nonskeletal functions.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Figure 5. A schematic representation of the major causes for vitamin D deficiency and potential health consequences.

and activated macrophages have an enzymatic process that is identical to the kidneys converting 25(OH)D to 1,25(OH)2D, provided a new insight as to how vitamin D could have all of the other health benefits not related to calcium and bone metabolism. Conclusion and Recommendations Vitamin D deficiency and insufficiency is pandemic and is quite prevalent throughout the world, but it appears to be much worse in the countries of sunny South Asia, especially among children, women and elderly. There are many causes but lack of awareness on vitamin D deficiency has become a major public health interest with its association with osteoporosis, osteomalacia, fractures and more recently with prevention of cancer, diabetes, heart disease and other chronic illnesses. Regular sun exposure has decreased due to changing lifestyles and aggressive use of sun block creams by dermatologists has been a contributing factor to vitamin D3 deficiency. Vitamin D3 deficiency is especially prevalent in dark-skinned children and adults living in Northern latitudes, and obese children and adults. There is an increasing need to improve the vitamin D status worldwide and would have dramatic effects on public health, and reduces the healthcare costs for many chronic diseases. The most cost-effective solution to address the deficiency is to increase food fortification with higher levels of vitamin D3 along with sun exposure, and adequate vitamin D supplementation.

Community Medicine ultrasound of bone in the institutionalized elderly. Osteoporos Int 1998;8(2):115-20.

References 1. Viswanathan V, et al. Poverty amongst plenty. IJCP 2006;17(6):24-8. 2. Mithal A, Wahl DA, Bonjour JP, Burckhardt P, DawsonHughes B, Eisman JA, et al; IOF Committee of Scientific Advisors (CSA) Nutrition Working Group. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int 2009;20(11):1807-20. 3. Sachan A, Gupta R, Das V, Agarwal A, Awasthi PK, Bhatia V. High prevalence of vitamin D deficiency among pregnant women and their newborns in northern India. Am J Clin Nutr 2005;81(5):1060-4. 4. Puri S, Marwaha RK, Agarwal N, Tandon N, Agarwal R, Grewal K, et al. Vitamin D status of apparently healthy schoolgirls from two different socioeconomic strata in Delhi: relation to nutrition and lifestyle. Br J Nutr 2008;99(4):876-82. 5. Arya V, Bhambri R, Godbole MM, Mithal A. Vitamin D status and its relationship with bone mineral density in healthy Asian Indians. Osteoporos Int 2004;15(1):56-61. 6. Islam MZ, Akhtaruzzaman M, Lamberg-Allardt C. Hypovitaminosis D is common in both veiled and nonveiled Bangladeshi women. Asia Pac J Clin Nutr 2006;15(1):81-7. 7. Snijder MB, van Dam RM, Visser M, Deeg DJ, Dekker JM, Bouter LM, et al. Adiposity in relation to vitamin D status and parathyroid hormone levels: a population-based study in older men and women. J Clin Endocrinol Metab 2005;90(7):4119-23. 8. van Dam RM, Snijder MB, Dekker JM, Stehouwer CD, Bouter LM, Heine RJ, et al. Potentially modifiable determinants of vitamin D status in an older population in the Netherlands: the Hoorn Study. Am J Clin Nutr 2007;85(3):755-61.

11. Morales-Torres J, Gutiérrez-Ureña S; Osteoporosis Committee of Pan-American League of Associations for Rheumatology. The burden of osteoporosis in Latin America. Osteoporos Int 2004;15(8):625-32. 12. Sedrani SH, Elidrissy AW, El Arabi KM. Sunlight and vitamin D status in normal Saudi subjects. Am J Clin Nutr 1983;38(1):129-32. 13. Goldray D, Mizrahi-Sasson E, Merdler C, EdelsteinSinger M, Algoetti A, Eisenberg Z, et al. Vitamin D deficiency in elderly patients in a general hospital. J Am Geriatr Soc 1989;37(7):589-92. 14. Fuleihan GE, Deeb M. Hypovitaminosis D in a sunny country. N Engl J Med 1999;340(23):1840-1. 15. Hashemipour S, Larijani B, Adibi H, Sedaghat M, Pajouhi M, Bastan-Hagh MH, et al. The status of biochemical parameters in varying degrees of vitamin D deficiency J Bone Miner Metab 2006;24(3):213-8. 16. Mishal AA. Effects of different dress styles on vitamin D levels in healthy young Jordanian women. Osteoporos Int 2001;12(11):931-5. 17. Looker AC, Pfeiffer CM, Lacher DA, Schleicher RL, Picciano MF, Yetley EA. Serum 25-hydroxyvitamin D status of the US population: 1988-1994 compared with 2000-2004. Am J Clin Nutr 2008;88(6):1519-27. 18. Yetley EA. Assessing the vitamin D status of the US population. Am J Clin Nutr 2008;88(2):558S-564S. 19. Sambrook PN, Cameron ID, Cumming RG, Lord SR, Schwarz JM, Trube A, et al. Vitamin D deficiency is common in frail institutionalised older people in northern Sydney. Med J Aust 2002;176(11):560.

9. Burnand B, Sloutskis D, Gianoli F, Cornuz J, Rickenbach M, Paccaud F, et al. Serum 25-hydroxyvitamin D: distribution and determinants in the Swiss population. Am J Clin Nutr 1992;56(3):537-42.

20. Inderjeeth CA, Barrett T, Al-Lahham Y, Mulford J, Nicklason F, Reberger C. Seasonal variation, hip fracture and vitamin D levels in Southern Tasmania. N Z Med J 2002;115(1152):183-5.

10. Krieg MA, Cornuz J, Jacquet AF, Thiébaud D, Burckhardt P. Influence of anthropometric parameters and biochemical markers of bone metabolism on quantitative

21. Holick HF. The vitamin D deficiency pandemic: a forgotten hormone important for health. Pub Health Rev 2007;32(1):267-83.

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Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

CRITICAL Care

Invasive Monitoring in the Intensive Care Unit LP Saikumar Doradla*, M Vadivelan†

Abstract The purpose of monitoring of the patient in an intensive care unit (ICU) is to improve patient care, like bringing about a change in the treatment or transfer of the patient to a step-down unit. Monitoring also shows the extent of compliance with a formulated standard of care or the degree of deviation from the expected standard of care. The monitoring used for a patient admitted to an ICU can be invasive or noninvasive. Invasive monitoring in an ICU includes arterial blood pressure, transesophageal Doppler, central venous pressure (CVP) measurement, pulmonary artery catheterization, arterial blood gas (ABG) analysis and measurement of intracranial pressure (ICP) and intra-abdominal pressure (IAP). Monitoring of the physiologic parameters depends on the underlying illness of the patient and the availability of equipment in the ICU.

Keywords: Invasive monitoring, intensive care unit

atients admitted to an intensive care unit (ICU) require constant and intensive monitoring of their vital parameters. This helps in deciding about the future management of patients who have been stabilized and in modification of treatment in the acutely ill, unstable patient.

The components of invasive monitoring in the ICU are as follows: ÂÂ Invasive blood pressure (BP) monitoring ÂÂ Transesophageal Doppler (TED) ÂÂ Measurement of central venous pressure (CVP) ÂÂ Pulmonary artery catheterization ÂÂ Arterial blood gas (ABG) analysis ÂÂ Intracranial pressure (ICP) measurement ÂÂ Intra-abdominal pressure (IAP) measurement Invasive BP monitoring1

Indications Continuous ‘beat-to-beat’ BP monitoring is useful in patients receiving inotropic drugs and head injury patients. Both groups of patients require close control of BP, which can be achieved by this technique.

*Junior Resident †Assistant Professor Dept. of Medicine Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER) Pondicherry, Tamil Nadu Address for correspondence Dr M Vadivelan No. E-2, JIPMER Quarters, JIPMER Campus Dhanvantari Nagar, Pondicherry - 605 006, Tamil Nadu E-mail: mevadivelan@hotmail.com

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Advantages This method can be used in patients with gross peripheral edema, morbidly obese patients, patients in shock and patients who require repeated ABG analysis. It also allows measurement of cardiac output by pulse contour analysis of arterial pressure waveform. The origin of pulse contour method of measuring cardiac output is derived from variations in the pulse pressure waveform. Pulse pressure is directly proportional to stroke volume and inversely related to vascular compliance. Pulse contour analysis is calibrated to injection dilution method. Stroke volume is calculated and compared with stroke volume as determined by the dilution technique; and the cardiac output is then calculated. With beat-to-beat waveform analysis, cardiac output can be determined continuously. Lithium is the contrast agent most commonly used with the injection dilution method for external calibration of pulse contour analysis devices (lithium indicator cardiac output [LiDCO], pulsed-induced contour cardiac output [PICCO]). Lithium Indicator Dilution Cardiac Output2 It is a minimally invasive technique of arterial pulse analysis that allows continuous, real-time cardiovascular monitoring. It is safe, accurate and simple to use. It is contraindicated in patients with intracardiac shunts, patients with atrial fibrillation and those on lithium therapy or patients receiving muscle relaxants. Pulse-induced Contour Cardiac Output It is a pulse contour analysis with intermittent thermodilution measurement that enables continuous

CRITICAL Care hemodynamic monitoring using femoral or axillary artery catheter.

Complications

ÂÂ

Infection (But less frequent than venous lines) Local thrombosis Damage to local nerves Bleeding/hematoma formation

ÂÂ

Pseudoaneurysm formation

ÂÂ ÂÂ ÂÂ

TransEsophageal Doppler2 TED measures blood flow velocity in the descending aorta by a Doppler transducer (4 MHz continuous wave or 5 MHz pulsed wave) placed at the tip of a flexible probe. It estimates preload, myocardial contractility and vascular tone. A study has found 86% correlation between cardiac outputs as determined by esophageal Doppler and pulmonary artery catheterization.

Advantages ÂÂ

Minimally invasive Can be inserted rapidly

ÂÂ

Allows real time measurement

ÂÂ

Limitations ÂÂ ÂÂ ÂÂ

Interference occurs by nasogastric tube. Can get dislodged by movement which may result in loss of signal. Inability to obtain continuous reliable measurements of hemodynamic parameters.

Central Venous Cannulation

Indications

Air embolism zz Pneumothorax Delayed zz Infection zz Venous thromboembolism zz

ÂÂ

Pulmonary Artery Catheterization3 Flow-directed pulmonary artery catheters, also called Swan-Ganz catheters are used in the diagnosis and management of a range of conditions in critically ill patients. Pulmonary artery catheterization can yield direct measurements of central venous, right-sided intracardiac, pulmonary arterial and pulmonary capillary wedge pressures. Automated thermodilution techniques can be used to estimate cardiac output. Systemic and pulmonary vascular resistance can be calculated on the basis of vascular pressures and cardiac output.

Indications Despite the widespread use of pulmonary artery catheters in hemodynamically unstable patients, no study has definitively demonstrated improved outcome in critically ill patients managed using pulmonary artery catheterization. Role of invasive hemodynamic monitoring in critically ill patients is controversial as the pulmonary artery catheter is yet to be proven to improve patient outcome. Accepted indications for pulmonary artery catheterization have been generated largely on the basis of clinical experience. The decision to place a pulmonary artery catheter should be based upon a specific question regarding a patient’s hemodynamic status that cannot be answered satisfactorily by clinical or noninvasive assessment. If the answer could change management, then placement of the catheter is indicated.

ÂÂ

Patients requiring rapid resuscitation by infusion of fluids or blood.

ÂÂ

Patients requiring measurement of CVP.

ÂÂ

Patients requiring long-term drug administration.

Diagnostic Uses

ÂÂ

Patients undergoing hemodialysis.

ÂÂ

Patients undergoing plasmapheresis.

ÂÂ

Patients requiring placement of pacemaker.

Complications ÂÂ

Immediate zz Bleeding zz Arrhythmia

ÂÂ

To differentiate between mechanisms of pulmonary edema (cardiogenic and noncardiogenic). To diagnose left-to-right intracardiac shunt.

ÂÂ

To measure intracardiac pressures.

Therapeutic Uses ÂÂ Management of perioperative patient with unstable cardiac status. ÂÂ Management of patients following cardiac surgery.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

CRITICAL Care Complications There are three categories of complications related to the use of pulmonary artery catheters: ÂÂ Complications related to insertion of the pulmonary artery catheter. ÂÂ Sustained ventricular arrhythmias occur in upto 3% of patients. ÂÂ Right bundle branch block (RBBB) develops during approximately 5% of catheter insertions. Complications Related to Maintenance and Use of Catheter ÂÂ Pulmonary artery perforation is the most feared complication. It has a mortality of >30% and usually requires emergent thoracotomy for management. Self-limited pulmonary hemorrhage following perforation can result in the formation of a pulmonary artery pseudoaneurysm. Risk factors for pulmonary artery rupture are pulmonary hypertension, advanced age, mitral valve disease, hypothermia and anticoagulant therapy. ÂÂ Migration of the catheter may result in pulmonary infarction. ÂÂ Thromboembolic events may occur with catheters acting as a nidus for thrombus formation. ÂÂ Catheter-related infections with possible bloodstream infection. Complications Related to Data Interpretation Under ideal conditions, the tip of the catheter sits in zone 3 of the lung, where the arterial pressure exceeds the venous pressure and the venous pressure exceeds the alveolar pressure, thereby creating a continuous column of blood from the catheter tip to the left atrium (LA) when the balloon is inflated. Also, the LA pressure is similar to left ventricular end-diastolic pressure (LVEDP). These conditions may not necessarily apply in many settings, and can result in hemodynamic data, which can be inaccurate. Sources of error are improperly calibrated pressure monitors, transduction of airway pressures under non-zone 3 conditions and over estimation of pulmonary capillary wedge pressure (PCWP) due to incomplete pulmonary artery branch occlusion. Also, inter-observer variability in the interpretation of hemodynamic data among ICU physicians and anesthesiologists can lead to misinterpretation of accurately measured data. ABG Analysis Analysis of ABG gives an idea about the oxygenation status and allows the clinician to assess the elimination

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

of carbon dioxide and metabolic parameters of the critically ill patient. The information obtained from ABG analysis allows better goal directed management of the ICU patient. Parameters reflected in the ABG report are pH, PO2, PCO2, SaO2, bicarbonate (HCO3⁻) and base excess.4 ÂÂ

pH: Normal arterial blood pH is 7.35-7.45. pH <7.35 indicates acidosis and pH >7.45 indicates alkalosis.

ÂÂ

PO2: Normal range is 75-100 mmHg. Values of PO2 <60 indicate the need for mechanical ventilation in the patient.

Conditions with low PO2 in ICU are:4 Hypoventilation; impaired diffusion; perfusion mismatch and shunting.

ventilation-

PaO2/FiO2 ratio (P/F):4 Normal ratio >500 Ratio between 300-500 - Mild hypoxemia Ratio between 200-300 - Acute lung injury (ALI) Ratio <200 - Acute respiratory distress syndrome. (ARDS). PaO2/FiO2 ratio (P/F) is used for evaluating the severity of lung involvement in ALI/ARDS.4 Oxygen index (OI) accounts better for the influence of ventilator pressures on oxygenation value. In patients with ARDS, OI >8.1 is usually in agreement with P/F < 200. However, patients with ALI having an OI of 5.3-08.1 frequently had P/F <200.6 ÂÂ

PCO2: Normal range is 35-45 mmHg. A high value is indicative of respiratory acidosis and suggests hypoventilation, while a low value indicates respiratory alkalosis due to hyperventilation.

ÂÂ

SaO2: Normal range is 95-100.

ÂÂ

HCO–3: Normal range is 22-30 mEq/l. Low HCO–3 value indicates metabolic acidosis whereas a high HCO3 value is suggestive of metabolic alkalosis.

Oxygen index (OI)5 = ÂÂ

Mean airway pressure × FiO2 × 100 PaO2

Base excess (BE): Normal range is –2 to + 2 mEq/l. BE may indicate tissue acidosis. But, it is a crude indicator of tissue dysoxia. Tissue hypoperfusion may occur in the absence of a significant change in the BE.7

ICP Monitoring Normal ICP is in the range of 10-15 mmHg.

CRITICAL Care Indications for ICP Monitoring

ÂÂ

Head injury Intracerebral hemorrhage Subarachnoid hemorrhage Hydrocephalus Cerebrovascular stroke Cerebral edema

ÂÂ

Brain tumors

ÂÂ ÂÂ ÂÂ ÂÂ ÂÂ

Devices for ICP Monitoring ÂÂ ÂÂ ÂÂ

Intraventricular catheter (Gold Standard) Epidural catheter Subdural catheter

Measurement of ICP is useful in the calculation of cerebral perfusion pressure (CPP).

Indications for IAP Monitoring ÂÂ ÂÂ

Severe acute pancreatitis. Intra-abdominal bleeding (rupture of abdominal aortic aneurysm).

The risk of developing intra-abdominal hypertension is minimal in:9 Mechanically ventilated patients with positive endexpiratory pressure (PEEP) < 10 cm H2O and PaO2/FiO2 ratio >300. ÂÂ

Patients with body mass index (BMI) <30 kg/m².

ÂÂ

Patients without pancreatitis, hepatic failure, cirrhosis of liver with ascites, gastrointestinal bleeding or in patients undergoing laparotomy and the use of vasopressors/inotropes on admission.

Cerebral perfusion pressure = Mean arterial blood pressure-intracranial pressure.

Presently, there are no clear guidelines to select the patients in whom IAP measurements should be performed.9

Normally, CPP is more than 60 mmHg.

CONCLUSION

Newer Fiberoptic ICP Monitors8

In critical care, monitoring is essential in the daily care of ICU patients as the optimization of the patient’s hemodynamic parameters, ventilation, temperature and metabolism is the key to improving patients’ survival.

Advantages ÂÂ They have a smaller diameter, so they cause less damage to brain tissue. ÂÂ Allow simultaneous measurement of ICP and local cerebral blood flow by using Doppler flowmetry. ÂÂ Also measure brain tissue oxygen pressure, CO2 pressure, pH and other metabolic parameters. Disadvantages ÂÂ Cannot be used for cerebrospinal fluid (CSF) drainage. ÂÂ Cannot be recalibrated in situ. IAP Monitoring Studies have shown that there is no correlation between abdominal girth and IAP measurements. Sensitivity of physical examination for intra-abdominal hypertension has been estimated to be 40-60% approximately. Normal IAP value ranges between 0 and 5 mmHg. Direct measurements of IAP with an intraperitoneal catheter are precise. However, the less invasive and inexpensive technique of intravesical manometry is the recommended standard. There are 4 grades of intra-abdominal hypertension: ÂÂ Grade I: IAP is between 12-15 mmHg ÂÂ Grade II: IAP is between 16-20 mmHg ÂÂ Grade III: IAP is between 21-25 mmHg ÂÂ Grade IV: IAP is g >25 mmHg

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

REFERENCES 1. Gupta B. Update in Anaesthesia. Vol. 21, World Federation of Society of Anaesthesiologists. December 2007. 2. Marik PE, Baram M. Non-invasive hemodynamic monitoring in the intensive care unit. Crit Care Clin2007;23:383-400. 3. Weinhouse GL. Pulmonary artery catheterization: indications and complications. In: UpToDate, Basow DS (Ed.), UpToDate. Waltham, MA, 2012. 4. Kipnis E, Ramsingh D, Bhargava M, Dincer E, Cannesson M, Broccard A, et al. Monitoring in the intensive care. Crit Care Res Pract 2012;2012:473507. 5. Brochard L, Martin GS, Blanch L, Pelosi P, Belda FJ, Jubran A, et al. Clinical review: Respiratory monitoring in the ICU - a consensus of 16. Crit Care 2012;16(2):219. 6. Van Haperen M, Van der Voort PH, Bosman RJ. The Oxygenation Index compared with the P/F ratio in ALI/ ARDS. Critical Care 2012;16(Suppl 1):91. 7. Marik PE. The optimal endpoint of resuscitation in trauma patients. Crit Care 2003;7(1):19-20. 8. Batra. Invasive monitoring in an intensive care unit. In: Manual of Medical Emergencies. 3rd edition, Grover A, Aggarwal V, Gera P, Gupta R, (Eds.), Pushpanjali Medical Publications Pvt. Ltd.: New Delhi 2007:p.40. 9. Starkopf J, Tamme K, Blaser AR. Should we measure intra-abdominal pressures in every intensive care patient? Ann Intensive Care 2012;2 Suppl 1:S9.

Dentistry

Odontogenic Myxoma of Maxilla: Management and Follow-up of A Rare Case Karuna Jindwani*, Vilas Nevaskar†, Deepak Agrawal‡

Abstract Odontogenic myxoma is a slow growing benign, locally malignant tumor, notorious for recurrence. It represents a broadspectrum of lesions of uncertain histogenesis with a characteristic histologic appearance. We report a rare case of odontogenic myxoma in a 10-year-old male patient and present the respective strategy for the management of a huge myxoma of right-side of maxilla via an intraoral approach after a brief review of its clinical and radiological features.

Keywords: Odontogenic myxoma, resection, intraoral approach

dontogenic myxomas (OMs) are benign tumors derived from the primitive mesenchymal structures of a developing tooth including the dental follicle, dental papilla or periodontal ligament.1 World Health Organization (WHO) defines OM as a benign, locally invasive neoplasm characterized by rounded and angular cells lying in an abundant mucoid stroma that replaces the cancellous bone and expands the cortex.2 It is an uncommon lesion and is unusual for a bone other than maxilla or mandible to be the site of origin of a true OM.3 The evidence for its odontogenic origin arises from its almost exclusive location in the tooth bearing areas of the jaws, its occasional association with missing or unerupted teeth and occasional presence of odontogenic epithelium.4 There are only a few reports on the relative frequency and incidence of OM in the available literature. However, in Asia, Europe and America relative frequencies between 0.5 and 17.7% have been reported.5 This tumor may present at any age but is most frequently discovered in the 2nd to 4th decades and occur more frequently in the mandible than in maxilla with marked female prediclection.6

*Senior Resident Dept. of Dentistry, SS Medical College and SGM Hospital, Rewa, Madhya Pradesh †Professor and Head ‡Associate Professor Dept. of Oral Surgery, Government College of Dentistry, Indore, Madhya Pradesh Address for correspondence Dr Karuna Jindwani Behind Vidya Bhawan Near HPO, Rewa - 486 001, Madhya Pradesh E-mail: jindwanikaruna@yahoo.co.in

Clinical presentation involves a slow growing painless, site-aggressive mass causing marked asymmetry of face. Pain and paresthesia are uncommon, thus the lesion can reach considerable size before the patient becomes aware of its presence and seeks treatment.7 Enlargement of the mass commonly leads to cortical expansion and even perforation. Maxillary myxomas often extend into the sinus.8 Loosening and displacement of the teeth are likely to occur in time, but root resorption is less frequently seen.9 Radiologically, the appearance may vary from a unilocular radiolucency to multilocular lesion with well-defined or diffuse margins with fine, bony trabeculae within its interior structure expressing a ‘honey-combed’, ‘soap bubble’ or ‘tennis racket’ appearance. This typical appearance can not be observed in all patients with OM.1,4,6,10 Histologically, the tumor is noncapsulated which promotes infiltration into the adjacent medullary bone.11 OM in maxilla is less frequent but behaves more aggressively than that of the mandible. The treatment of choice for this infiltrative lesion varies from simple enucleation, curettage and excision (0.5 mm from apparent normal bony margin) and resection (1 cm from apparent normal bony margin) to more aggressive resection with disarticulation, excision of tumor with dentoalveolar segment and preservation of the mandibular lower border and maxillectomy.12 When associated with teeth, their removal is usually necessary. We present a rare case of OM of maxilla in a 10-yearold male patient including the management and long asymptomatic 2-year follow-up of the patient.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Dentistry CASE REPORT In March 2009, a 10-year-old male patient was referred to the Dept. of Oral and Maxillofacial Surgery, Government College of Dentistry, Indore, MP for the evaluation and management of a painless swelling on right side of the face. The physical examination showed a well-developed child in no acute distress. His medical history revealed a gradual increase in the swelling on right half of the face in a span of approximately two years to the present size of approximately 3 inches diameter from a small pea-sized growth. However, he noticed rapid increment in its size in the last five months. He consulted many private clinics and institutions but was finally referred to our department for the management. The medical history, family history and a review of systems of the patients were noncontributory.

Figure 1. Frontal view.

A nontender, bony hard swelling of the right maxilla was seen on extraoral examination extending from right corner of the mouth anteriorly till the tragus of the right ear posteriorly. Superiorly, the swelling extended from right infraorbital margin and rested inferiorly till the body of mandible measuring approximately 4 x 3 inches (Figs. 1 and 2). The intraoral examination of the maxillary arch revealed a nontender, bony hard expansile lesion extending from upper right lateral incisor till maxillary tuberosity, thereby obliterating the right buccal vestibule. All the associated teeth in the mixed dentition stage showed a low-degree of morbidity. The tumorous growth was soft and shiny involving the expansion of both buccal and palatal cortical plates (Fig. 3). The alveolar bone in the area appeared soft on palpation. However, the entire mucosa overlying the area was intact.

Figure 2. Lateral view.

Computed tomography (CT) showed the evidence of lytic destruction of maxilla causing expansion of right maxilla with erosion of alveolar bone (Fig. 4) and disclosed its extension into the sinus and zygomatic buttress. The left nasal and orbital cavities were intact. Three dimensional reconstruction confirmed the extent of the tumor (Fig. 5). The patients blood type was determined and crossmatched for 1 unit of whole blood. On admission to the hospital for the surgery, a routine physical examination, laboratory tests (complete blood count and urinalysis) and radiographs of the chest and limbs showed no abnormalities. The differential diagnosis included odontogenic keratocyst, ameloblastoma, odontogenic myxoma, central giant cell granuloma and osteosarcoma. Fine needle aspiration was performed to rule out odontogenic cyst and the result was negative.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Figure 3. Intraoral view showing buccal and palatal cortical plate expansion.

Dentistry

Figure 4. Computed tomography showing the extent of growth.

Figure 5. Three-dimensional reconstruction depicting the lytic lesion.

Figure 7. Operated site after en bloc resection.

resection of the tumor was planned. The surgical management involved a solo intraoral approach to the massive growth under general anesthesia by way of left nasal endotracheal intubation. Vertical releasing and gingival crevicular incisions helped us to raise a full thickness mucoperiosteal flap for approaching the tumorous mass. The partial en block excision of the maxilla was done with a margin of normal tissue. The specimen was removed completely in one piece with all associated teeth embedded in the mass (Fig. 6). The operated site was irrigated with copious amounts of saline and betadine solution (Fig. 7) and packed with an iodoform gauze before partial closure. The resected specimen was sent for histopathological analysis, which confirmed it to be an OM. The postoperative course of the patient and early healing of the wound were uncomplicated (Figs. 8a and 8b). The patient was discharged on the seventh postoperative day. The wound was irrigated and the iodoform gauze dressing changed regularly during the first four weeks after surgery. Impressions were taken of maxillary arch and a partial acrylic denture was constructed to protect the healing surgical site from repeated exposures during meals. The dressing was removed and the defect treated with simple irrigation.

Figure 6. Specimen of growth.

Thereafter, an incisional biopsy was performed under local anesthesia and submitted for histopathological examination. The material submitted revealed the lesion to be an OM. Based on the incisional biopsy report, progressive nature of the lesion and cortical expansion, radical

The patient was regularly seen in the our department for six months (Figs. 9a and 9b) on a monthly basis and then every third month. The patient has been followed for two years since the surgical resection of tumor (Figs. 10a and 10b). Radiographic and clinical examination confirm that the healing phase was uneventful with no evidence of recurrence. Periodical evaluation and surgical reconstruction of the edentulous region is to be planned for complete rehabilitation of the patient.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Dentistry

Figure 8a. Immediate postoperative view.

Figure 8b. Immediate postoperative intraoral view.

Figure 9a. Postoperative view after six months.

Figure 9b. Postoperative intraoral view after six months.

Figure 10a. Postoperative view after two years.

Figure 10b. Postoperative intraoral view after two years.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Dentistry DISCUSSION Odontogenic myxoma (OM) is a rare benign neoplasm derived from embryonic mesenchymal tissue associated with odontogenesis. The prevalence of this lesion is principally quoted between 0.04% and 3.7%.13 In Asia, Europe and America, relative frequencies between 0.5% and 17.7% have been reported.5,14 There was lack of uniformity in the most common age group studies of OM, but the previous studies by Noffke et al, refer the incidence of OM in an age group of 11-70 years.15 However, it is rarely seen in patients younger than 10 years of age and older than 50.5,16 The mandible appears to be more frequently affected than maxilla in most of the studies.6,7 However, Zimmermann and Dahlin17 reported in their study that OM could be found in both jaws with an equal frequency. Odontogenic maxillary myxoma were first mentioned in the literature by Thoma and Goldman in 1947.18 A marked female predilection has been reported in several studies.6,7 The male patient presented in this report approached our department at the age of 10 years involving right side of the maxilla with a previous history of swelling for the last two years. This is usually rare and differs from the prevalence reported in the literature. OM is commonly reported as a slow growing tumor that is generally symptomless, although some patients present with progressive pain in lesions involving surrounding structures with eventful neurological disturbances.19 Our case presented with a painless swelling without signs of paresthesia in the mentioned area which is almost in conformity with the reported literature. These tumors usually show variable radiographic features ranging from small unilocular lesions to large multilocular lesions. Varying radiographic descriptions reported in literature are ‘honey comb’, ‘soap bubble’, ‘tennis racket’ ‘Wispy’ and ‘spider-web’ appearance.1,4,6,10 CT in the present case presented with a multilocular osteolytic expansile lesion in the right maxilla involving the right maxillary sinus and zygomatic buttress region. The aggressive nature of OM is well-documented in the literature. It is now well-established that for the management of OM a surgical approach is the treatment of choice.11,12,20 It is also generally agreed upon that the radiation therapy is of no value in the management of these tumors as OM is not radiosensitive.7,12,17 The nonencapsulated nature and infiltrative growth pattern is responsible for high rate of recurrence when conservative modes like enucleation and curettage

are performed.5,11,21 Hence, radical treatment of block resection is advised over conservative therapy by most authors.9,11,13 In agreement with the available literature, the tumor was completely removed by en bloc resection and no recurrence was reported even after two years of the surgery. Prognosis in the present case after excision was excellent in this two year follow-up period. Postoperatively, patients should be closely follow-up for the period of 2-year in which the recurrence is most likely.22 However, CS Columbo and Y Boivin in their study recommended a minimum of five years of surveillance to confirm that the lesion healed,23 and periodical clinical and radiographic followed-up should be maintained indefinitely irrespectively of treatment modality applied to treat OM.11,23 CONCLUSION A rare case of OM in a 10-year-old boy is presented in this report, which illustrates the resective strategy for the treatment of a huge maxillary OM via an intraoral approach. A close follow-up of the patient was maintained for two years to confirm an uneventful healing in the present case. Hence, it is summarized that with adequate surgical excision, long-term survival without recurrence can be anticipated. However, one should be cautious in drawing general conclusions on the basis of a single case. REFEReNCES 1. Halfpenny W, Verey A, Bardsley V. Myxoma of the mandibular condyle. A case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;90(3):348-53. 2. Kramer IRH, Pindborg JJ, Shear M. Histological Typing of Odontogenic Tumours. 2nd edition, Springer Verlag: Berlin 1992:p.23. 3. Shafer WG. Cysts, neoplasms, and allied conditions of odontogenic origin. Semin Roentgenol 1971;6(4):403-13. 4. Stout AP. Myxoma, the tumor of primitive mesenchyme. Ann Surg 1948;127(4):706-19. 5. Simon EN, Merkx MA, Vuhahula E, Ngassapa D, Stoelinga PJ. Odontogenic myxoma: a clinicopathological study of 33 cases. Int J Oral Maxillofac Surg 2004;33(4):333-7. 6. Kaffe I, Naor H, Buchner A. Clinical and radiological features of odontogenic myxoma of the jaws. Dentomaxillofac Radiol 1997;26(5):299-303. 7. Farman AG, Nortje CJ, Wood RE. Oral and Maxillofacial Diagnostic Imaging. Mosby: St Louis 1993:p.257-60. 8. Brannon RB. Central odontogenic fibroma, myxoma (odontogenic myxoma, fibromyxoma), and central odontogenic granular cell tumor. Oral Maxillofac Surg Clin North Am 2004;16(3):359-74.

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Dentistry 9. Peltola J, Magnusson B, Happonen RP, Borrman H. Odontogenic myxoma - a radiographic study of 21 tumours. Br J Oral Maxillofac Surg 1994;32(5):298-302. 10. Regizi JA, Sciubba JJ, Jordan RC (Eds.). Oral Pathology: Clinical - Pathologic Correlations. 4th edition, WB Saunders Company Ltd: Philadelphia 2003:p.278-9. 11. Lo Muzio L, Nocini P, Favia G, Procaccini M, Mignogna MD. Odontogenic myxoma of the jaws: a clinical, radiologic, immunohistochemical, and ultrastructural study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82(4):426-33. 12. Reddy SP, Naag A, Kashyap B. Odontogenic myxoma: Report of two cases. Natl J Maxillofac Surg 2010;1(2): 183-6. 13. Slootweg PJ, Wittkampf AR. Myxoma of the jaws. An analysis of 15 cases. J Maxillofac Surg 1986;14(1):46-52. 14. Lu Y, Xuan M, Takata T, Wang C, He Z, Zhou Z, et al. Odontogenic tumors. A demographic study of 759 cases in a Chinese population. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86(6):707-14. 15. Noffke CE, Raubenheimer EJ, Chabikuli NJ, Bouckaert MM. Odontogenic myxoma: review of the literature and report of 30 cases from South Africa. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104(1):101-9.

16. King TJ 3rd, Lewis J, Orvidas L, Kademani D. Pediatric maxillary odontogenic myxoma: a report of 2 cases and review of management. J Oral Maxillofac Surg 2008;66(5):1057-62. 17. Zimmerman DC, Dahlin DC. Myxomatous tumors of the jaws. Oral Surg Oral Med Oral Pathol 1958;11(10):1069-80. 18. Reichart PA, Philipsen HP. Odontogenic Tumors and Allied Lesions. Quintessence Publishing Co Ltd: Illinosis; 2004. 19. Hernández Vallejo G, Cohn C, García Peñín A, Martínez Lara S, Llanes Menéndez F, Montalvo Moreno JJ. Myxoma of the jaws. Report of three cases. Med Oral 2001;6(2): 106-13. 20. Thoma KH, Goldman HM. Central myxoma of the jaw. Am J Orthod Oral Surg 1947;33:532-40. 21. Leiser Y, Abu-El-Naaj I, Peled M. Odontogenic myxoma - a case series and review of the surgical management. J Craniomaxillofac Surg 2009;37(4):206-9. 22. Moshiri S, Oda D, Worthington P, Myall R. Odontogenic myxoma: histochemical and ultrastructural study. J Oral Pathol Med 1992;21(9):401-3. 23. Colombo CS, Boivin Y. Myxoma of the jaws. Oral Surg Oral Med Oral Pathol 1966;21(4):431-6.

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New Report Concludes that Dental Implants can Save Costs and Improve Quality-of-life A report published as the lead article in the International Journal of Oral & Maxillofacial Implants shows that dental implants offer a cost-effective alternative to traditional treatments for tooth replacement. The report, which is also cited on PubMed, the US National Library of Medicine located at the National Institutes of Health, is based on a systematic review of all available studies published in English between 2000 and 2010 relating to the cost-effectiveness of various tooth-replacement options. In total, 14 studies on long-term costs were included in the final review, which yielded the following conclusions.

MTA Beat CaOH in a Direct Dental Pulp Capping Trial Mineral trioxide aggregate (MTA) fails less often when used for direct pulp capping than calcium hydroxide (CaOH), according to a new study published in a clinical supplement to the Journal of Dental Research. In the study, 24.6% of pulp caps made with CaOH failed within two years compared with only 13.6% of those made with MTA. (Source: Medscape)

ADA/AAOS Look at Joint Implant Infections after Dental Care The first evidence-based clinical practice guideline to be codeveloped by a both the American Academy of Orthopedic Surgeons (AAOS) and the American Dental Association (ADA) suggest that prophylactic antibiotics might not always be needed for routine dental procedures in patients with joint implants, that the jury is still out on the usefulness of topical antibiotics during dental procedures, and that patients with joint implants should be particularly careful about oral hygiene. The recommendations from the AAOS/ADA working group were published in the April 17 issue of the Journal of Bone and Joint Surgery. (Source: Medscape)

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Dermatology

Accidental PUVA Burns Leading to Prurigo Nodularis: A Rare Complication of Phototherapy Shyam Verma

Abstract Medical treatment function vitiligo aims to restore color to use depigmented patches. Psoralen + ultraviolet-A (PUVA) may be used if there is extensive vitiligo. Possible long-term adverse effects of PUVA therapy include accelerated skin aging with wrinkle formation, telangiectasias, lentigines, elastosis, xerosis and pigmentary changes. Accidental burns during photochemotherapy have been reported though nodular prurigo has never been reported. Vitiliginous skin is more rone to burns.

Keywords: Vitiligo, PUVA burns, prurigo nodularis, hyperkeratotic nodules, itching Case Report A 50-year-old woman presented with severely pruritic nodules (PN) and plaques on her legs and breasts. She developed vitiligo at the age of 18 years for which she was treated unsuccessfully with many drugs. In 1991, she was treated with home psoralen + ultraviolet-A (PUVA) radiation therapy using 20 mg of oral methoxsalen. The light source used was a set of 4 tube lights of 100 W emitting UVA between 315-350 nm wave length and she exposed the areas for 3 minutes three times a week. There was marked improvement in the vitiligo on her legs in about 5 months with total clearing of the lesions on the face except the lips. Around this time, she accidentally fell asleep during her PUVA session and woke up after 60 minutes with blistering burns on her breasts and legs, which took a month to heal. During the healing stage, she started developing thickened skin, nodules and plaques on her legs and breasts, which were intensely itchy. She was given emollients, topical steroids, antihistamines, individually and in combination but with little benefit. Many nodules coalesced to form scaly plaques. Her homoeopath husband then started treating her with some homoeopathic medication, which apparently caused resolution of lesions for many years only to reappear in 2004. Several physicians and

Consultant Dermatologist, Vadodara Gujarat

dermatologists diagnosed her condition as psoriasis and post burn keloids. She was prescribed oral steroids by a private practitioner for a few months, which was later stopped as she developed diabetes. She now has excruciating itching, which has severely affected her quality-of-life. On examination, she had vitiligo on her breasts and lower extremities showing perifollicular pigmentation. Her legs were studded with thick, horny, hyperkeratotic nodules with a rough surface, many of them coalescing to form plaques on the anterior aspect (Fig. 1). She had severely pruritic erythematous nodules on the breasts (Fig. 2). Her skin was otherwise normal. She was diabetic, hypothyroid and took metformin and thyroxine daily. Her blood work up and serum chemistry was normal except an IgE of 700 IU/mL with no history, signs or symptoms of atopy like chronic itching, eczema, allergic rhinitis or asthma. A skin biopsy taken from the nodule showed a superficial perivascular lymphocytic infiltrate with moderate irregular epidermal hyperplasia. The papillary dermis was thickened with papillomatosis and showed thickened bundles of collagen in vertical array. The capillaries in papillary dermis were increased in number and thick walled. The granular layer was thickened and stratum corneum showed marked compact orthokeratosis. One of the sections showed abundant deposit of amyloid in papillary dermis. The histological diagnosis was PN with lichen amyloidosis (Fig. 3). We started her on gabapentin 900 mg daily with topical halobetasol and petrolatum with about 20% relief in itching reported in 30 days.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Dermatology Discussion

Figure 1. Multiple coalescing erythematous excoriated nodules on both legs.

We report a case of PN occurring in the sites of PUVA burns in a patient of vitiligo. Oral PUVA side effects include short-term and long-term. Short-term adverse effects include erythema, swelling, dry skin, pruritus, axillary freckling, increased recurrence of herpes simplex virus and rarely, phototoxic blisters. Possible long-term adverse effects include accelerated skin aging with wrinkle formation, telangiectasias, lentigines, elastosis, xerosis and pigmentary changes. High cumulative PUVA exposure is associated with a dose-related increase in the risk of nonmelanoma skin cancer, particularly genital and cutaneous squamous cell carcinoma in Caucasians only. However, nodular prurigo has never been reported. Accidental burns during photochemotherapy have also been reported, which includes self-treatment as seen in this patient. Bothersome pruritus following burns per se is a known phenomenon though there is a paucity of long-term prospective studies documenting the course and magnitude of this phenomenon. Burns are known inducers of neuropathic itch. A study by Van Loey et al documented itching at 3, 12 and 24 months post burns and recorded mild-to-severe itching in 87%, 70% and 67% of patients. However, this appears to be the first case of PN developing in a case of accidental PUVA burns.

Figure 2. Erythematous nodules on vitiliginous skin of breast.

Figure 3. Massive hyperorthokeratosis associated with hypergranulosis and acanthotic epidermis with masses of amyloid in papillary dermis (H&E 40x).

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

We propose the following logical sequence. Vitiliginous skin is more prone to burns. The accidental PUVA burns due to gross overdose initiated the itch in this patient, who also had atopic diathesis indicated by a high serum IgE. Itching is known to induce hyperplastic cutaneous response and this probably would have led to development of PN in this patient. There is a report of a bomb blast injury causing PN-like lesions. The diagnosis of PN is based upon family and personal history, typical clinical presentation and distribution of the lesions along the cleavage lines (Langerâ&#x20AC;&#x2122;s lines) of skin and was confirmed by histopathology. The amyloid deposit seen in some sections could be due to the chronic scratching of PN. Highly characteristic for PN is the presence of thick compact orthohyperkeratosis; the hairy palm sign (folliculosebaceous units in nonvolar skin in conjunction with a thick and compact cornified layer, like that of volar skin), irregular epidermal hyperplasia or pseudoepitheliomatous hyperplasia, focal parakeratosis, hypergranulosis, fibrosis of the papillary dermis

Dermatology with vertically arranged collagen fibers, increased number of fibroblasts and capillaries, a superficial, perivascular and/or interstitial inflammatory infiltrate of lymphocytes, macrophages and to a lesser extent, eosinophils and neutrophils. Histological analysis of lesional and nonlesional skin in PN has demonstrated a reduced density of nerve endings, findings suggesting a cutaneous neuropathy. Interestingly, the itch induced by burns, which would have played a major role in development of PN is also neuropathic in origin. The rationale of using gabapentin is that it has been tried with varying success in burns-induced itching as well as in PN. We believe, we are reporting the first case in dermatological literature of accidental PUVA burns developing PN.

Suggested Reading 1. Abdel Naser MB, et al. Clin Exp Dermatol 2004;29(4): 380-2. 2. Murase JE, et al. Int J Dermatol 2005;44(12):1016-21. 3. Herr H, et al. Burns 2007;33):372-5. 4. Sulliman MT, et al. Burns 2005;31(8):1063. 5. Goutos I, et al. J Burn Care Res 2009;30(2):221-8. 6. Van Loey NE, et al. Br J Dermatol 2008;158(1):95-100. 7. Ghosh SK, et al. Clin Exp Dermatol 2009;34(7):e471-2. 8. Weigelt N, et al. J Cutan Pathol 2010;37(5):578-86. 9. Schuhknecht B, et al. Br J Dermatol 2011;165(1):85-91. 10. Gencoglan G, et al. Dermatol Ther 2010;23(2):194-8. 11. Ahuja RB, et al. Burns 2011;37(2):203-7.

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Very Potent Steroids Most Effective Against Chronic Scalp Psoriasis Very potent steroids in topical solution may be the most effective first-line treatment of chronic plaque psoriasis of the scalp, according to a new meta-analysis published online June 24 in the British Journal of Dermatology. Those options include the very potent steroid clobetasol propionate, followed by the potent steroid betamethasone dipropionate, then the vitamin D3 analogue calcipotriol. Also, calcipotriol combined with a potent steroid may be more effective than a potent steroid alone. (Source: Medscape)

Psoriasis Patients should be Screened for Type 2 Diabetes Patients with psoriasis are at increased risk of type 2 diabetes, especially those with psoriatic arthritis, a new meta-analysis confirms. (Source: Medscape)

Eczema: Antibiotic Exposure in Infancy may up Risk Antibiotic exposure in the first year of life, but not prenatally, may predispose children and young adults to eczema, according to a systematic review and meta-analysis published online June 20 in the British Journal of Dermatology. (Source: Medscape)

Methotrexate Effective as Adjuvant for Treating Pemphigus Vulgaris Methotrexate allows discontinuation of steroids in many patients with pemphigus vulgaris, a retrospective study suggests. (Source: Medscape)

Malignant Melanoma Risk 4-fold Higher in Parkinson's A new study suggests that patients with Parkinson's disease (PD) have about a 4-fold increased risk for development of malignant melanoma, underscoring the importance of dermatologic screening in PD, the researchers say. (Source: Medscape)

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

ENT

Facial Necrotizing Fasciitis: A Rare Complication of Maxillary Sinusitis N Gupta*, S Varshney†, P Gupta‡

Abstract Necrotizing fasciitis is an uncommon infection of the fascia and subcutaneous tissue, which is extremely rare in head and neck region because of high vascularity. Necrotizing fasciitis arising as a complication of maxillary sinusitis is exceptionally rare. We present the case of a 50-year-old female patient who was immunocompetent and developed facial necrotizing fasciitis as a sequel of maxillary sinusitis. She was effectively managed by surgical debridement and antibiotics. To the best of our knowledge, this is the second case report in English literature presenting as necrotizing fasciitis secondary to maxillary sinus infection.

Keywords: Maxillary, sinusitis, facial, necrotizing, fasciitis

axillary sinus lies close to the orbit superiorly, nasal cavity medially, teeth inferiorly, pterygopalatine fossa posteriorly, and facial skin anteriorly. Complications occurring as a sequelae of maxillary sinusitis can involve all these structures but with the advent of highly effective antibiotics, it is rare to see them in the modern era.1 Necrotizing fasciitis of facial region is even a rarer occurrence, especially in an immunocompetent patient. The most common causes of cervicofacial necrotizing fasciitis are of odontogenic origin.2 Maxillary sinusitis is an uncommon cause of necrotizing fasciitis. The onset is often insidious in the form of nonspecific regional facial swelling, erythema, and fever. Thus, clinical distinction from more benign inflammatory conditions of the neck, such as cellulitis, may be impossible at an early stage. Without immediate surgical treatment, however, necrotizing fasciitis of the head and neck invariably leads to mediastinitis and fatal sepsis.3 Therefore, it is important to establish the correct diagnosis at an

*Assistant Professor Dept. of ENT Government Medical College and Hospital, Chandigarh, Punjab †Professor and Head Dept. of ENT All India Institute of Medical Sciences, Rishikesh, Uttarakhand ‡Lecturer Dept. of Orthodontics Subharti Dental College, Meerut, Uttar Pradesh Address for correspondence Dr Nitin Gupta Dept. of ENT Government Medical College and Hospital, Sec 32, Chandigarh, Punjab E-mail: nitinent123@gmail.com

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

early stage. Contrast-enhanced computed tomography (CECT) scan is the investigation of choice to evaluate the extent of the disease. The diagnosis of necrotizing fasciitis should be suspected if the inflammatory signs on CT scan are not limited to cellulitis, but include widespread fasciitis of the superficial and deep fascia.4 Antibiotic treatment alone is insufficient; prompt and aggressive surgical exploration and debridement are imperative to prevent a fatal outcome. Case Report A 50-year-old female presented in the ENT OPD with swelling over right cheek and upper lip for the last 3 days. Swelling was sudden in onset, rapidly progressive in size, associated with severe pain and fever for 2 days and black discoloration of the skin. Patient also complained of obstruction and purulent discharge in right nasal cavity. There was no history of diabetes, any drug reaction, or insect bite. There was swelling and pain over right eyelid. Examination of the patient revealed temperature of 100.3°F, tachycardia (pulse rate 104/min). On local examination, there was a swelling on right cheek, upper lip, and partly extending to lower lip with patchy black discoloration. Swelling was tender, 4 × 6 cm in size and temperature over surface raised, diffused with ill-defined margins, soft in consistency, and nonfluctuant (Fig. 1). There was edema over the right eyelid while the left eyelid was normal in texture and function. Anterior rhinoscopy and diagnostic nasal endoscopy were suggestive of purulent discharge in middle meatus of right nasal cavity. Vision and examination of cranial nerves was

ENT

Figure 2. CECT scan of the nose and PNS showing features of acute right-side sinusitis and soft tissue swelling of right cheek with marked thickening of fascia. Figure 1. Patient showing diffuse swelling over right cheek and lips.

normal except for hypoesthesia over right cheek. The patient was hospitalized and started on broad-spectrum intravenous antibiotics (Ceftriaxone, Gentamycin, and Metronidazole) along with analgesics, antipyretics, and nasal decongestants. Pus was sent for culture and sensitivity. Routine blood examination was suggestive of leukocytosis while other tests (urine, random blood sugar, and serum creatinine) were within normal range. Enzyme-linked immunosorbent assay (ELISA) test for human immunodeficiency virus (HIV) was negative. CECT scan of the nose and paranasal sinus (PNS) was done, which revealed air–fluid level in right maxillary sinus along with mucosal thickening in bilateral maxillary, ethmoid, and frontal sinuses, and a soft tissue swelling of right cheek extending to temporal region. There was marked thickening of superficial and deep fascia of this region (Fig. 2). Considering the clinical and CT scan findings, a diagnosis of necrotizing fasciitis was made. The patient was posted for emergency surgery where debridement of the wound and followup wound care was done. Pus culture revealed growth of b-hemolytic streptococci Group A, Pseudomonas spp., and Staphylococcus aureus that were sensitive to the prescribed antibiotics. Surgery and postoperative period was uneventful. Pain and swelling subsided considerably after 48 h. Histopathological examination of the tissue was suggestive of acute abscess. A postoperative CT scan done 5 days after surgery was normal and had no inflammatory signs (Fig. 3).

The patient was discharged on the sixth postoperative day. Patient has been on a regular follow-up for the last 4 months with no recurrence of disease. Discussion The term “necrotizing fasciitis” is used to describe a severe, acute and potentially life-threatening inflammatory condition caused by streptococcal or mixed bacterial infection and propagating continuously within soft tissues.5 Necrotizing fasciitis is a rare infection of the fascial planes, which is less common in head and neck because of higher vascularity in the region. The most common causes of necrotizing fasciitis are dental infections (dental abscess, gingivitis, and pulpits), blunt trauma, radiotherapy and tonsillitis.6 Maxillary sinusitis is an uncommon cause of necrotizing fasciitis. The predisposing factors for the development of necrotizing fasciitis are diabetes, hypertension, obesity, malnutrition, peripheral vascular diseases, severe liver disease, alcoholism and acquired immunodeficiency syndrome (AIDS).7 Although necrotizing fasciitis has been described mainly in elderly and immunocompromised patients, it recently has been observed increasingly in young, otherwise healthy, individuals. Normally, infection progresses rapidly and can involve the vascular structures causing small vessel thromboses. The most common clinical presentations are painful edema, erythema, warmth, tenderness and crepitation. Patients can develop mediastinitis and consequent septic shock.8

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

ENT surgical intervention. The mortality rate reported in the literature ranges from 19% to 40%.5 The higher mortality rate is related to pre-existing systemic illness, late surgical intervention, septicemia within 24 h, old age and mediastinal and thoracic extension of the infection. References 1. Stamenkovic I, Lew D. Early recognition of potentially fatal necrotizing fasciitis. The use of frozen-section biopsy N Engl J Med 1984;310(26):1689-93. 2. Raboso E, Llavero MT, Rosell A, Martinez-Vidal A. Craniofacial necrotizing fasciitis secondary to sinusitis. J Laryngol Otol 1998;112(4):371-2. 3. Banerjee AR, Murty GE, Moir AA. Cervical necrotizing fasciitis: a distinct clinicopathological entity? J Laryngol Otol 1996;110(1):81-6. Figure 3. Postoperative CT scan showing normal nose and PNS.

CT scan has been advocated for detecting gas, identifying the spread of infection in vascular sheaths, and detecting the extension of infection to remote areas (mediastinitis and pleural or pericardial effusions). Necrotizing fasciitis is a polymicrobial infection; the most common pathogens are Streptococcus spp., but S. aureus and anaerobes are also present in large proportion of cases. Effective treatment and management of necrotizing fasciitis is based on early recognition aggressive surgical intervention, use of broad-spectrum antibiotics, and supportive therapy. It is important to explore and drain all involved fascial planes. Hyperbaric oxygen was found to be useful by some authors.9 The morbidity and mortality seems to be related to the promptness of medical and

4. Becker M, Zbären P, Hermans R, Becker CD, Marchal F, Kurt AM, et al. Necrotizing fasciitis of the head and neck: role of CT in diagnosis and management. Radiology 1997;202(2):471-6. 5. Bahu SJ, Shibuya TY, Meleca RJ, Mathog RH, Yoo GH, Stachler RJ, et al. Craniocervical necrotizing fasciitis: an 11-year experience. Otolaryngol Head Neck Surg 2001;125(3):245-52. 6. Krespi YP, Lawson W, Blaugund SM, Biller HF. Massive necrotizing fasciitis infections of the neck. Head Neck Surg 1981;3(6):475-81. 7. Zbaren P, Rothen HU, Läng H, Becker M. Necrotizing fasciitis of soft tissues of the face and neck. HNO 1995; 43(10):619-23. 8. Vaid N, Kothadiya A, Patki S, Kanhere H. Necrotizing fasciitis of the neck. Indian J Otolaryngol Head Neck Surg 2002;54(2):143-5. 9. Kantu S, Har-El G. Cervical necrotizing fasciitis. Ann Otol Rhinol Laryngol 1997;106(11):965-70.

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Harvard Six Ways to Ease Neck Pain ÂÂ

Don’t stay in one position for too long.

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Make some ergonomic adjustments. Position your computer monitor at eye level so you can see it easily. Use the hands–free function on your phone or wear a headset. Prop your touch–screen tablet on a pillow so that it sits at a 45° angle, instead of lying flat on your lap.

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If you wear glasses, keep your prescription up-to-date.

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Don’t use too many pillows.

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Know your limits. Before you move a big armoire across the room, consider what it might do to your neck and back, and ask for help.

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Get a good night’s sleep.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

ENT

Myeloid Sarcoma of Maxillo-Ethmoidal Sinus: An Uncommon Presentation of Acute Myeloid Leukemia Amar Ranjan*, RK Chandoke, Pranay Tanwar, Ashutosh Kumar, MD Ray, KK Kshitiz, Nidhi Chauhan

Abstract Introduction: Myeloid sarcoma (MS) is a rare localized extramedullary tumor of myeloid precursor cells. Short clinical history: An 11-year-old male presented with nasal bleed, two days; breathlessness and loss of appetite, one month and bilateral nasal blockade for two months. There was no fever. On clinical examination, bilateral cervical lymphadenopathy and hepatosplenomegaly was found. On opening mouth, a pink mass hanging behind the soft palate was noted. Magnetic resonance imaging of head and neck revealed a nasopharyngeal mass in maxillo-ethmoidal sinus. Gross pathology: Excised mass was greenish pink, measuring 2 × 2 × 2 cm. Microscopic examination: Hemogram revealed total leukocyte count 1.2 lac/mm3, hemoglobin 10.1 g/dl, and platelet count 41,000/mm3. Differential count showed 24% blasts with marked left shift. Bone marrow aspirate revealed 27% blasts. No auer rod seen. Cytochemistry showed myeloperoxidase (MPO) positivity. Trephine biopsy showed myeloid hyperplasia with excess blasts. Histopathological examination of lymph nodes and soft tissues showed leukemic infiltration. Immunohistochemistry showed blasts positive for MPO and negative for CD3. On multicolor flow cytometry blasts were positive for MPO, CD34 and CD45, and negative for CD3 and CD79a. A diagnosis of MS with acute myeloid leukemia (AML) was made. Discussion: It is rare in children (1 month-89 years). Any site of body, most commonly skin, lymph node, bone, etc. are affected. Prediction of first appearance of MS or AML was difficult in this case. MS may progress to AML simultaneously or may remain localized, never progressing to AML. Conclusion: Any extramedullary tumor showing myeloid precursor cells, should be investigated for MS, easily misdiagnosed as solid tumors.

Keywords: Paranasal sinuses, malignant tumors, myeloid leukemia, granulocytic sarcoma

yeloid sarcoma (MS) is a rare malignant extramedullary neoplasm of myeloid precursor cells. Etiology is acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN). It is called ‘chloroma’, because of its green color on cut-section. This is believed to be caused by myeloperoxidase (MPO),1 an enzyme present in myeloid cells. This disorder may occur in concomitance with AML or precede the development of AML by months-to-years. On the other hand, it rarely develops in asymptomatic patients of leukemia. Here, a case of maxillo-ethmoidal chloroma has been described, which developed during the course of AML, although it is difficult to predict, which one appeared first.

*Assistant Professor Laboratory Oncology Unit, BRA Institute-Rotary Cancer Hospital All India Institute of Medical Sciences, Ansari Nagar, New Delhi Address for correspondence Dr Amar Ranjan A-369D, DDA Flats, New Ranjit Nagar Opp. Satyam Cinema, New Delhi - 110 008 Email: dr.amarranjan@rediffmail.com

Case Report An 11-year-old male presented to ENT clinic with difficulty in breathing and loss of appetite for one month, bilateral nasal blockade for two months and nasal bleed for two days. There was no history of fever, weight loss or night sweats. Liver was just palpable and spleen was 4 cm below the costal margin. No history of blood transfusion or hematinic intake was present. On clinical examination of mouth, a pink lobulated soft tissue mass was seen hanging behind soft palate. There was bilateral cervical lymphadenopathy, largest lymph node measuring 2.5 cm in diameter. On routine investigations, he had total leukocyte count (TLC): 1.2 lac/mm3, hemoglobin: 10.1 g/dL and platelet count: 41,000/mm3. Peripheral smear showed 24% blasts. Radiological investigations magnetic resonance imaging (MRI) of head and neck region revealed a large mass lesion occupying the nasopharynx. It was nonenhancing type and had no intracranial or intraocular extension. The impression of ? lymphoma and ? lymphoid hyperplasia was made.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

ENT

Figure 1. FNAC of cervical lymph nodes, May-GrunwaldGiemsa stain, 60x. The smear shows massive infiltration by blasts.

Figure 4. Trephine biopsy H&E stain, 40x. The section shows massive infiltration by blasts.

Figure 2. Peripheral blood smear (PBS), May-GrunwaldGiemsa stain, 40x. The smear shows massive infiltration by blasts.

Figure 5. Histopathological section of nasopharyngeal mass showing massive infiltration by blasts.

of differentiated lymphoid cells. The impression of leukemic infiltration was given (Figs. 1 and 2). Bone marrow aspirate (BMA) examination revealed 27% blasts with opened up chromatin, occasional conspicuous nucleoli and scant cytoplasm. MPO stain was positive, confirming AML. No auer rod seen (Fig. 3). B/L trephine biopsy showed hypercellular marrow spaces with myeloid hyperplasia and excess of immature cells present diffusely. Erythroid and megakaryocytic series were reduced (Fig. 4).

Figure 3. Bone marrow aspirate, May-Grunwald-Giemsa stain, 40x. This smear also shows massive infiltration by blasts.

Fine needle aspiration cytology (FNAC) from lymph nodes showed infiltration by immature myeloid cells including early precursors in a background

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Histopathological examination (HPE) of excised soft tissue: On gross examination, it was greenish pink in color measuring 2 Ă&#x2014; 2 Ă&#x2014; 2 cm. On HPE leukemic infiltration was confirmed. The final diagnosis of MS was made (Fig. 5). Immunohistochemistry showed blasts positive for MPO and negative for CD3.

ENT On multicolor flow cytometry blasts were positive for MPO, CD34 and CD45, and negative for CD3 and CD79a.

Park et al, 2003 showed that the most common sites of tumor invasion were the peritoneum, pericardium, bronchus, bladder, mediastinum, kidneys and lung.”6

Discussion

Immunochemical stainings e.g., MPO, lysozyme, CD43 and CD68 are helpful in identifying the tumor as MS. All granulocytic cells, including myeloblasts and myelocytes, stain positive for lysozyme, whereas lymphocytes are negative.7

In this case, the patient was completely unaware of the disease as he had history of bilateral nasal blockade for last two months. As its size enlarged in one month and it started producing difficulty in breathing, then only the patient visited the hospital. He was ultimately diagnosed as MS. It was difficult to predict in this case that which appeared first whether chloroma or AML, as he was diagnosed for both diseases nearly simultaneously by peripheral blood smear, bone marrow examination, FNAC and HPE examination. No history of fever indicates that MS possibly appeared first. MS is also known as granulocytic sarcoma (GC), chloroma or myeloblastoma. The more frequent sites of involvement are the skin, lymph node, gastrointestinal tract, bone, soft tissue and testis. It may be easily confused with primary or secondary carcinoma. Chloroma may progress to AML simultaneously or may remain localized, never progressing to AML. Infiltrates of any site of body by myeloid blast in leukemic patients are not classified as MS unless they present with tumor masses in which the tissue architecture is effaced. Liron et al, 2005 reported that MS could occur in any one of three clinical settings: 1) In patients who have a history of AML, during active disease or a recurrence; 2) in patients with chronic myeloproliferative disorders (MPD), who are at increased risk of blast transformation or 3) in patients with no history of hematologic disease, although it commonly predates the development of leukemia, often within one year.2 Cankaya et al, 2001 reported that MS could very often be misdiagnosed as a malignant lymphoma. Therefore, clinical and histopathological findings should be evaluated before any diagnosis of malignant lymphoma is pronounced.3

When there is no concomitant leukemia, diagnosis of chloroma may be difficult. Routine histological examination of these tumors shows a pleomorphic infiltrate of primitive cells of varying size and nuclear configuration.8 In this case, both were presented simultaneously. Currently, any extramedullary manifestation of AML can be termed as GS. In recent years, the term ‘myeloid sarcoma’ has been favored.9 Soft-tissue masses arising in patients with myelogenous leukemia may have several possible causes, including abscess or hematoma. MS is not a common presentation, but it is important that it is diagnosed early, as it responds more favorably to focal irradiation than to systemic chemotherapy.10 AML may occur simultaneously with the chloroma, later or may not occur at all. It is more common with t (8;21) variant of AML in children, less frequent in adults.11 When it occurs with other MPD, it is considered as blast transformation according to World Health Organization (WHO). The clinical manifestations of a chloroma are nonspecific. The patient may have local pain and a local mass effect. In the case of involvement of paranasal sinuses, patient may present with nasal blockage, complaining of difficulty in breathing. Epistaxis may also be a feature due to ischemic necrosis of the nasal mucosa secondary to leukemic infiltration. Patients may have upper respiratory tract infection, which may show a poor response to standard medical treatment. The prognosis of chloroma is same as with the underlying disease, either AML or MPD. Chloromas are radiosensitive and local radiotherapy can be combined with chemotherapy to get good results.12

Byrd et al, 1995 showed that “chloromas developed most concomitantly with the FAB subtype M5a, M5b M4 and M2 of the AML.”4 But other studies showed that chloroma developed most commonly in undifferentiated or minimally differentiated subtypes.

Conclusion

Byrd et al, 1995 and Uyesugi et al, 2000 observed that “chloromas had an incidence between 3 and 4.7% of the MPD”.4,5

MS should be kept in mind while dealing with MPN, as it can easily be confused with nonhematolymphoid malignancies because of its location.

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ENT References 1. Pui MH, Fletcher BD, Langston JW. Granulocytic sarcoma in childhood leukemia: imaging features. Radiology 1994;190(3):698-702. 2. Pantanowitz L, Thompson L. Myeloid sarcoma. Ear Nose Throat J 2005;84(8):470-1. 3. Cankaya H, Ugras S, Dilek I. Head and neck granulocytic sarcoma with acute myeloid leukemia: three rare cases. Ear Nose Throat J 2001;80(4):224-6, 228-9. 4. Byrd JC, Edenfield WJ, Shields DJ, Dawson NA. Extramedullary myeloid cell tumors in acute nonlymphocytic leukemia: a clinical review. J Clin Oncol 1995;13(7):1800-16. 5. Uyesugi WY, Watabe J, Petermann G. Orbital and facial granulocytic sarcoma (chloroma): a case report. Pediatr Radiol 2000;30(4):276-8. 6. Park HJ, Jeong DH, Song HG, Lee GK, Han GS, Cha SH, et al. Myeloid sarcoma of both kidneys, the brain, and multiple bones in a nonleukemic child. Yonsei Med J 2003;44(4):740-3. 7. Dehner LP. Soft tissue sarcomas of childhood: the differential diagnostic dilemma of the small blue cell. Natl Cancer Inst Monogr 1981;(56):43-59.

8. Neiman RS, Barcos M, Berard C, Bonner H, Mann R, Rydell RE, et al. Granulocytic sarcoma: a clinicopathologic study of 61 biopsied cases. Cancer 1981;48(6):1426-37. 9. Chevallier P, Mohty M, Lioure B, Michel G, Contentin N, Deconinck E, et al. Allogeneic hematopoietic stem-cell transplantation for myeloid sarcoma: a retrospective study from the SFGM-TC. J Clin Oncol 2008;26(30):4940-3. 10. Guermazi A, Feger C, Rousselot P, Merad M, Benchaib N, Bourrier P, et al. Granulocytic sarcoma (chloroma): imaging findings in adults and children. AJR Am J Roentgenol 2002;178(2):319-25. 11. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue. 4th edition, WHO Classification of Tumours, Volume 2. IARC WHO Classification of Tumours, No 2, 2008: Pages 439. 12. Meir W, Byrd JC, Clara DB. Acute and chronic myeloid leukemia. (Chapter 104). In: Harrison’s Principles of Internal Medicine. 17th edition, Fauci AS, et al. (Eds.), McGraw-Hill: United States 2011:p:679.

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Association of Oropharyngeal Cancer with HPV in Young Adults A new study portrays human papillomavirus (HPV) as a causative factor for oropharyngeal cancer among adults. Cancers of tonsils, base of tongue and soft palate have increased in people with <45 years of age in the past 3 decades. Incidence of oropharyngeal cancer has increased due to sexual revolution in the last 3 or 4 decades, which led to an increased transmission of high-risk HPV. The study group consisted of people born during that period and data of incidence of oropharyngeal cancer among these was analyzed. Incidence of cancer of tonsils and base of tongue in young adults was substantial. Oropharyngeal cancers are predominant in men than in women. Apart from tobacco and alcohol use, HPV exposure and infection increases the risk of oropharyngeal squamous cell cancer. This is largely attributed to changes in sexual practices. Almost 50-65% of the study group underwent surgical resection for their tumors. Patients who had both surgery and radiation therapy had the highest 5-year survival rate. Prognosis is favorable and the patients might have to deal with treatment related side effects that may impact their quality-of-life. The 5-year survival for this study group was 54%, which is irrespective of the gender. Incidence in this age-group is more either due to nonsexual transfer of HPV at a younger age or due to reduced latency time period between infection and full-blown cancer. (Source: Medical News Today)

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

HEMATOLOGY

Thrombotic Thrombocytopenia Purpura Refractory to Plasmapheresis Treated Successfully with Rituximab VH Shah*, A Patel†, RK Chavda‡

Abstract Thrombotic thrombocytopenia purpura (TTP) is a rare hematological disease and only 20%-30% of patients present with classic pentad. About 20% of patients with TTP are resistant to plasma exchange. We have described a 28-year-old female patient with TTP who did not have classic pentad of TTP. We ruled out all other differential diagnosis. She was refractory to plasmapheresis and was treated successfully with rituximab. It was thus concluded that on the basis of the literature review, rituximab should be considered in TTP patients who fail to respond after 7-14 days of standard treatment with daily plasmapheresis and glucocorticoids.

Keywords: TTP, plasmapheresis, rituximab, thrombocytopenia

hrombotic thrombocytopenia purpura (TTP) is caused by the development of hyaline thrombi in the microvasculature resulting in thrombocytopenia, microangiopathic hemolytic anemia and organ dysfunction. Classic pentad includes microangiopathic hemolytic anemia, thrombocytopenia, fever, neurological abnormalities and renal failure. However, many patients have neither neurologic nor renal function abnormalities. All such patients are diagnosed via the presence of thrombocytopenia and microangiopathic hemolytic anemia without another clinically apparent cause for the same. About 20% of TTP are resistant to plasma exchange (PE). We describe a patient presenting with a first episode of acute refractory TTP in whom remission was not achieved by plasmapheresis and steroids. He was successfully treated with rituximab. We also review the literature on the role of rituximab in a first episode of acute refractory idiopathic TTP.

Case Report A 28-year-old female patient was diagnosed and treated for TTP in a private hospital and was referred

*Third Year Resident †Second Year Resident ‡Professor and Head Dept. of Medicine Government Medical College, Surat, Gujarat Address for correspondence Dr Vitrag Shah 3-4, Kailash Nagar, Beside Jogani Nagar, Anand Mahal Road, Surat - 395 009, Gujarat E-mail: dr.vitrag@gmail.com

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

to our hospital for plasmapheresis after 2-3 months. The patient had history of cesarean section and healthy twin babies were delivered uneventfully. After 4-5 days of delivery, she complained of low-grade fever and bruises at various sites of venipuncture. Laboratory reports showed anemia and thrombocytopenia and peripheral smear showed schistocytes, suggestive of microangiopathic hemolytic anemia and raised serum lactate dehydrogenase (S-LDH); no other features were suggestive of classic pentad of TTP, no other specific investigations were done and the patient was started with steroids and five cycles of plasmapheresis were given in the private hospital. Platelet count before starting treatment was 28,000/mm3 and S-LDH was 1,180; after five cycles of plasmapheresis, platelet count was 35,000/mm3 and S-LDH was 855. The patient was then referred to our hospital for further cycles of plasmapheresis, but as the patient had no improvement with five cycles of plasmapheresis and steroids, we also investigated for all possible differential diagnosis. The patient had no significant past or family history and no significant drug history. The patient was diagnosed to have hypertension during third trimester of her pregnancy and she complained of pedal edema since last trimester; urine albumin was 1+ to 2+, HELLP syndrome could have presented similarly but liver enzymes were normal; it has been three months since delivery, yet the platelet count did not improve, so we ruled out HELLP syndrome.

HEMATOLOGY Since blood pressure was 140/90 mmHg and fundus was normal, malignant hypertension leading to similar presentation was also ruled out.

Platelet count after 24 hours of first dose of rituximab injection and two doses of vincristine was 1,28,000/mm3, and S-LDH was 628.

Chest X-ray and ultrasonography of the abdomen were normal. Electrocardiography was normal. Reticulocyte count was 4.5%. On admission, Hb was 9.9 g%, TC was 8,800/mm3, platelet count was 32,000/mm3, and MCV 101 Âľm3. S-TSH was normal. RFT and LFT were normal. HIV, HbsAg, and HCV were negative. RA and CRP were negative. WBC count was normal and since there was no sign suggestive of sepsis, it was also ruled out.

After 24 hours of four doses of vincristine and rituximab injections, the patientâ&#x20AC;&#x2122;s platelet count was 2,2,8,000/mm3 and S-LDH was 355. We discharged the patient and on follow-up after one month, the platelet counts were 2,58,000/mm3 and S-LDH was 245.

FBS was 170, PP2BS was 230, and HbA1c was 5.3, therefore patient was having steroid-induced impaired glucose tolerance and impaired fasting hyperglycemia. PT and aPTT was normal, FDP was negative and there was no history of stillbirth and abortion, therefore antiphospholipid antibody syndrome and disseminated intravascular coagulation was also ruled out. ICT and DCT were negative, so Evans syndrome was also ruled out. ANA was negative, so we ruled out systemic lupus erythematosus too. S-Vit B12 was 156 pg/mL and the patient was not on any Vit B12 and folic acid supplements, so we started Vit B12 injection and folic acid tablet as megaloblastic anemia can also be associated with TTP or itself can also present as anemia, thrombocytopenia and raised S-LDH and reticulocyte counts. While ruling out other causes, we continued steroids and plasmapheresis, but again even after further five cycles of daily plasmapheresis and Vit B12 injection and folic acid tablet, platelet count was 30,000/mm3; the patient further developed transfusion-related acute lung injury (TRALI) during fifth cycle of plasmapheresis and recovered from TRALI within 48 hours with noninvasive ventilator support. So, we stopped plasmapheresis and tapered and stopped steroids too. We also went for bone marrow examination to rule out any malignancy or leukemia, but bone marrow aspiration and biopsy was absolutely normal except mild megaloblastic changes. So we considered it as TTP refractory to steroids and plasmapheresis with megaloblastic anemia. We then started giving vincristine injection 1.4 mg/m2 (2 mg) to the patient on days 1, 4, 7, and 10. Platelet count did not improve significantly after first two doses of vincristine injection, so we started giving rituximab injection 375 mg/m2 (500 mg) per dose to the patient once every week for 4 weeks.

Discussion TTP is a rare disease and diagnosis of TTP is clinical. Patients with TTP have unusually large multimers of von Willebrand factor (vWF) in their plasma. Patients with TTP lack a plasma protease (ADAMTS13) that is responsible for the breakdown of these ultralarge vWF multimers or inhibitor (antibody), so steroids and immunosuppressive agents like rituximab are useful in TTP. However, measurement of ADAMTS13 activity is not required for diagnosis or starting treatment. Many patients have neither neurologic nor renal function abnormalities. For example, approximately 50% of patients with TTP-hemolytic uremic syndrome (TTP-HUS) associated with a severe (i.e., <10%) deficiency of ADAMTS13 activity had no or minimal neurologic abnormalities and no evidence for renal failure. However, all such patients are diagnosed via the presence of thrombocytopenia and microangiopathic hemolytic anemia without another clinically apparent cause for the same. TTP usually responds well to PE treatment in the majority of patients. Although there is no generally accepted definition of refractory disease, escalation of therapy should be considered after 7-14 days of adequate treatment with daily PE and corticosteroids if the clinical course deteriorates during that time. In such cases, intensification of PE or the addition of immunosuppressive drugs such as vincristine, cyclophosphamide, or cyclosporine has been recommended. Treatment with rituximab, a chimeric monoclonal antibody directed against the CD 20 antigen present on B lymphocytes, leads to clearance of B lymphocytes responsible for antibody production by complementdependent cytotoxicity, antibody-dependent cellular cytotoxicity, or directly by inducing apoptosis. So, it has a role in the treatment of acute refractory and relapsing autoimmune TTP due to ADAMTS-13 inhibitory antibodies.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

HEMATOLOGY We report on a patient with acute TTP in whom remission was not achieved by initial treatment consisting of PE, plasma infusion and corticosteroids, followed by vincristine and the patient had also complication of plasma infusion in the form of TRALI. So, we started rituximab injection on the patient. Treatment with rituximab appears to be both effective and safe, possibly leading to a significant reduction in plasma requirement and complications of FFP transfusion like TRALI and TACO, or transmission of infection. Conclusion This case emphasized the importance of ruling out other differential diagnosis before treating TTP if classic pentad is not present as it is a rare disease. We also looked for associated diseases – other causes of anemia and thrombocytopenia (S-Vit B12 deficiency in this case). Bone marrow examination should be done in all cases prior to starting secondary treatment of TTP (immunosuppressants) to rule out associated disorders or malignancy or leukemia. We conclude that on the basis of the literature review, rituximab should be considered in TTP patients who fail to respond after 7-14 days of standard treatment with daily plasmapheresis and glucocorticoids. In future, rituximab may be considered as primary treatment of choice too considering hazards of PE with infusion and variable response rate. References 1. Rüfer A, Brodmann D, Gregor M, Kremer Hovinga JA, Lämmle B, Wuillemin WA. Rituximab for acute plasma-

refractory thrombotic thrombocytopenic purpura. Swiss Med Wkly 2007;137:518-24. 2. George JN. How I treat patients with thrombotic thrombocytopenic purpura. Blood 2010;116:4060. 3. Scully M, Hunt BJ, Benjamin S, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol 2012;158:323. 4. Fakhouri F, Vernant JP, Veyradier A, Wolf M, Kaplanski G, Binaut R, et al. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases. Blood 2005;106(6):1932. 5. Ahmad A, Aggarwal A, Sharma D, Dave HP, Kinsella V, Rick ME, et al. Rituximab for treatment of refractory/ relapsing thrombotic thrombocytopenic purpura (TTP). Am J Hematol 2004;77(2):171. 6. Froissart A, Buffet M, Veyradier A, Poullin P, Provôt F, Malot S, et al. Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center. Crit Care Med 2012;40(1):104-11. 7. Jasti S, Coyle T, Gentile T, Rosales L, Poiesz B. Rituximab as an adjunct to plasma exchange in TTP: a report of 12 cases and review of literature. J Clin Apher 2008; 23(5):151. 8. Rock G, Porta C, Bobbio-Pallavicini E. Thrombotic thrombocytopenic purpura treatment in year 2000. Haematologica 2000;85:410-9. 9. Wun T, Besa EC. Thrombotic thrombocytopenic purpura. MedScape. 10. Kaplan AA, George JN. Treatment and prognosis of thrombotic thrombocytopenic purpura: hemolytic uremic syndromes in adults. UpToDate, Wolters Kluwer.

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Travel More Than Doubles Risk of Blood Clots Long–distance travel can lead to potentially fatal blood clots in some people and the risk grows with the length of the trip. Those at increased risk of blood clots include cancer patients, people who have recently had major surgery such as a joint replacement and women on birth control pills. In general, travel is associated with a nearly 3–fold increase in the risk of venous thromboembolism (blood clots that form in the veins), often in the legs. If such a clot dislodges and travels to the lungs, it can cause a potentially fatal condition, called pulmonary embolism. A combination of factors including dehydration and hours of sitting in cramped conditions explains why some people develop blood clots.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Hematology

Coomb’s Negative Hemolytic Anemia in Wilson’s Disease V Padma*, Halleys Kumar†

Abstract Wilson’s disease is a rare inherited disorder of copper metabolism. Liver and brain are the main organs affected. Hemolytic anemia is a rare clinical manifestation of Wilson’s disease. We present a case of Wilson’s disease who presented with hemolytic anemia.

Keywords: Wilson’s disease, hemolytic anemia

ilson’s disease is an autosomal recessive disorder of copper metabolism characterized by excessive amount of copper in liver, brain, eye and other body tissues. The main clinical symptoms are hepatic (42%) and neurological (34%).1 Hemolytic anemia is rare.2 We present this case for its rarity. CASE REPORT A 37-year-old female patient, a known case of Wilson's disease came to the OPD with complaints of ecchymotic patches over right hand and purpuric spots over both lower limbs for 2 weeks. There was no history of trauma, gum bleeding, fever, weight loss and loss of appetite. Patient did not have any other medical illness. General examination showed anemia. Her blood pressure was 120/80 mmHg, pulse rate was 82/min. There were nonpalpable purpuric spots seen in both upper limbs and lower limbs echymosis, Kayser-Flescher ring was present in both the eyes (Figs. 1 a and b). Patient had dysarthria. There was no cardiac and renal involvement. Abdominal examination showed moderate splenomegaly, mild hepatomegaly. INVESTIGATIONS Hemoglobin was 6.8 g/dL, total leukocytes were 3,550, platelet count was 52,000. The differential *Professor

†Postgraduate

Dept. of Medicine Sree Balaji Medical College, Chrompet, Chennai Address for correspondence Dr V Padma Professor Dept. of Medicine Sree Balaji Medical College, Chrompet, Chennai

Figure 1 (a and b). Kayser-Flescher ring present in boh the eyes.

count was N69%L26%E4%M1%. Peripheral smear showed normocytic normochromic anemia, with pancytopenia. Serum bilirubin was 4 mg/dL, direct bilirubin 0.4 and indirect bilirubin was 3.6 mg/dL, serum albumin 3.8 g/dL, alkaline phosphatase 192 IU/L, reticulocyte count was 9%, urine for hemoglobin was absent. Hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus were negative. Coomb’s test performed twice showed negative results. Ultrasound abdomen showed moderate splenomegaly. Bone marrow aspiration: Out of 500 cells studied 2 were megakaryocytes, 156 myeloid series cells, 14

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HEMATOLOGY erythroid series cells noted, indicating normoerythroid hyperplasia with lesser myeloid megakaryocytic cells. D-pencillamine was stopped to confirm drug-induced hemolytic anemia but there was no improvement. During follow-up patient had one episode of hemolysis and 2 units of blood transfusion was given. DISCUSSION Wilson’s disease is a rare inherited disease presenting between 5-35 years of age.3 The disease does not manifest clinically before 4-5 years of age as it takes time for copper to accumulate in liver. Hepatic manifestations are common early and neurological symptoms are common in adolescents.4 Hemolysis in Wilson’s disease (10-15%) is uncommon. Hemolysis is due to deficiency of ceruloplasmin, a copper transport protein, which results in excessive inorganic copper in blood circulation, much of it which accumulates in red blood cells. The exact mechanism of hemolysis is not known. The diagnosis of Wilson’s disease is based on Kayser-Flescher rings, low serum ceruloplasmin levels and elevated basal urinary copper excretion. Hemolytic anemia often remits and may occasionally recur.

CONCLUSION Hemolytic anemia is rare in Wilson’s disease and can be a cause of anemia. Hemolytic anemia may also be a presenting episode in Wilson’s disease. This is a case of Coomb's negative hemolytic anemia in Wilson’s disease patient not precipitated by D-pencillamine, which is a rare presentation. Hemolytic anemia with liver failure should make a doctor suspect Wilson’s disease as a cause. REFERENCES 1. Grudeva-Popova JG, Spasova MI, Chepileva KG, Zaprianov ZH. Acute haemolytic anemia as an initial clinical manifestation of Wilson’s disease. Folia Med (Plovdiv) 2000;42(2):42-6. 2. McIntyre H, Clink HM, Levi AJ, Cumings JN, Sherlock S. Hemolytic anemia in Wilson’s disease. N Engl J Med 1967;276:439-44. 3. Roberts EA, Schilsky ML; Division of Gastroenterology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada. A practice guidelines on Wilson’s disease. Hepatology 2003;37(6):1475-92. 4. Kalra V, Khurana D, Mittal R. Wilson’s disease - early onset and lessens from a pediatric cohort in India. Indian Pediatr 2000;37(6):595-601.

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Risk for stroke shows a graded association with rising levels of HbA1C in women with type 2 diabetes, new findings from a large prospective study show. Notably, poor control of blood sugar was found to have the strongest effect on stroke in diabetic women over 55 years of age. The Louisiana State University Hospital-Based Longitudinal Study (LSUHLS) aimed to better understand the relationship between glycemic control and stroke and is published online February 24 in Diabetologia. As per FDA, the targeted drug ibrutinib (Imbruvica) can be used as second-line therapy for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Ibrutinib was first approved last November as a treatment for mantle cell lymphoma in patients who failed at least one prior therapy. It inhibits Bruton’s tyrosine kinase, a key component of the intracellular signalling cascade that drives malignant cell proliferation.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Neurology

Communication Between Musculocutaneous and Median Nerve – Different Types and Their Incidence in North Indian Population Priti Chaudhary*, gurdeep Kalsey†, ranjan Singla‡, kamal Arora$

Abstract The variations of the median nerve and the musculocutaneous nerve, like the communication between the two, may prove valuable in the traumatology of the shoulder joint and the upper arm region and in situations when the surgeon has to isolate and trace the median and musculocutaneous nerve distally. The present study was conducted on 60 upper limbs belonging to 30 cadavers (Male: Female = 28:02), (Right: Left = 30:30) obtained from Dept. of Anatomy, Govt. Medical College, Amritsar, Punjab. Brachial plexuses were exposed as per standard guidelines. The observations recorded were as follows: 1). The musculocutaneous nerve was absent in six (10%) limbs; the muscles usually supplied by this being supplied by median nerve in two limbs and by lateral cord (coracobrachialis) and median nerve (biceps and brachialis) in the other four limbs. 2). A single communication between the musculocutaneous and the median nerve was encountered in the six (10%) limbs. It was in the upper third of the upper arm, proximal to the entrance of the musculocutaneous nerve into the coracobrachialis muscle. 3.) A complete fusion of the musculocutaneous nerve and the median nerve after normal formation of the former was seen in four (6.66%) limbs. Out of these four limbs; in 1 limb, coracobrachialis; in 2 limbs, coracobrachialis and biceps and in one limb all three muscles of the anterior compartment were supplied by musculocutaneous nerve before its fusion with the median nerve.

Keywords: Brachial plexus, communication, lateral cord, median nerve, musculocutaneous nerve

rachial plexus is a network of nerves supplying the upper limb with the root value C5-T1. These roots join with each other to form three trunks viz; the upper, middle and lower by union of C5, C6; continuation of C7 and union of the C8 and T1, respectively. The three trunks bifurcate into anterior and posterior divisions. The anterior divisions of the upper and middle trunks unite to form the lateral cord. The anterior division of the lower trunk continues as the medial cord. The posterior divisions of all the three trunks unite to form posterior cord. These cords give rise to different nerves for the upper limb.

*Assistant Professor Dept. of Anatomy, GGS Medical College, Faridkot, Punjab †Professor and Head ‡Associate Professor Dept. of Anatomy, Govt. Medical College, Amritsar, Punjab $Medical Officer, Civil Hospital, Ferozepur, Punjab Address for correspondence Dr Priti Chaudhary, MS Anatomy Assistant Professor, Dept. of Anatomy GGS Medical College, Faridkot, Punjab E-mail: pritiarorafdk@rediffmail.com

ÂÂ

Musculocutaneous nerve is one of the terminal branches of lateral cord and supplies the muscles of anterior compartment of arm i.e., coracobrachialis, biceps brachii and brachialis.

ÂÂ

Median nerve is formed by the union of lateral and medial roots (branches of lateral and medial cords, respectively) and supplies most of the muscles of flexor compartment of forearm. It gives no muscular branch to muscles of the arm.

Variations in the origin of the median and musculocutaneous nerve are quite common. The commonest amongst these is the absence of musculocutaneous nerve with innervation of coracobrachialis, biceps brachii and brachialis by median nerve [Li Minor, (1992); Rao and Chaudhry, (2000); Sud and Sharma, (2000); Rajashree et al, (2003) and Saritha, (2004)]. Another variation is communication between musculocutaneous nerve and median nerve. Venieratos and Anangnostopoulou (1998) believed it to be the most frequent variant of this nerve where some fibers of the lateral root of the median nerve run along with the musculocutaneous nerve and after traveling some distance, leave the latter to join the ultimate destination (the median nerve). We observed all these variations in

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Neurology the different limbs along with the four cases of complete fusion of musculocutaneous nerve and median nerve during a study, performed on 60 upper limbs. Aim of the study was to describe the exact topography of these variations and to discuss their development and clinical significance. MATERIAL AND METHODS The material for the present study comprised of 60 upper limbs belonging to 30 adult human cadavers of known sex (Male: Female = 28:02) obtained from the Dept. of Anatomy, Govt. Medical College, Amritsar, Punjab. These were serialized from 1 to 30 with suffix ‘M’ for male or ‘F’ for female and ‘R’ for right or ‘L’ for left. The brachial plexus was dissected and exposed according to the methods described by Romanes (1995) in Cunningham’s Manual of Practical Anatomy. All its roots, trunks, divisions, cords and branches were cleaned and the pattern of the formation and branching was seen. For measuring the lengths of different parts of brachial plexus, a thread was kept along the length of that part and was marked with Indian ink at designated points. The thread thus marked was lifted off the dissection area and spread along a graduated metric scale to measure the length. All the measurements were taken in centimeters. OBSERVATIONS Out of 60 upper limbs dissected, following variant patterns of musculocutaneous and median nerves were observed:

Absence of the Musculocutaneous Nerve Musculocutaneous nerve was seen coming as one of the terminal branches of the lateral cord in 54 (90.00%) limbs of the present study being absent in rest of the six (10.00%) limbs (i.e., limb no. 4 MR, 4 ML, 9 MR, 9 ML, 11 ML, 13 MR). Out of these six limbs in which it was absent, 4 belonged to two cadavers i.e., it was bilaterally absent in two bodies and unilaterally absent in another two bodies (See below). ÂÂ

In two limbs viz; limb no. 9 MR and 9 ML all the three muscles viz; coracobrachialis, biceps brachii and brachialis, which are usually supplied by musculocutaneous nerve, were supplied by the median nerve.

ÂÂ

In four (6.66%) limbs viz; limb no. 4 MR, 4 ML, 11 ML, 13 MR, there was absence of the musculocutaneous nerve with the innervation of the coracobrachialis from the branches of the lateral cord and of biceps and brachialis by the median nerve. Out of these four limbs, it was seen bilaterally in 4 M (R and L) (Fig. 1).

Communication Between Musculocutaneous and Median Nerve A single communication between the musculocutaneous and the median nerve was encountered in the six (10%) limbs i.e., limb no. 18 MR, 18 ML, 23 ML, 24 MR, 25 ML and 27 MR. In all the limbs, it was in the upper third of the upper arm, proximal to the entrance of the musculocutaneous nerve into the coracobrachialis muscle (Fig. 2). Table 1 shows the length of communicating branch and its distance from point of formation of musculocutaneous and median nerve.

Table 1. Showing Length of the Communicating Branch (CB) and its Distance from the Origin of Musculocutaneous Nerve and Median Nerve

Limb no.

Distance between point of formation of the MCN and of CB (cm)

Distance between point of formation of MN and point of joining of CB with it (cm)

Length of CB (cm)

18 ML

4.5

4.3

3.9

18 MR

3.6

9.3

5.2

23 ML

2.4

2.2

3.2

24 MR

1.9

5.0

4.7

25 ML

2.6

3.0

2.5

27 MR

2.9

7.5

6.3

Mean

2.98

5.21

4.3

CB = Communicating branch; MCN = Musculocutaneous nerve; MN = Median nerve.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Neurology

Figure 1. Showing the absence of musculocutaneous nerve in limb no. 4 MR with lateral cord (LC) giving a branch (BCB) to coracobrachialis (CB) and continuing as lateral root of median nerve (LR). Median nerve (MN) gives a muscular branch (MB) to supply biceps brachii (BB) and brachialis: BBr = Branch to brachialis MR = Medial root; UN = Ulnar nerve.

Figure 3. Showing complete fusion of musculocutaneous nerve (MCN) with the median nerve (MN) in limb no. 1 MR after the former pierces and supply the coracobrachialis muscle (CB). UN = Ulnar nerve; LR and MR = Lateral and medial roots of median nerve.

It is evident from the Table 1, that the communicating branch was given off at an average distance of 2.98 cm (range 1.9-4.5 cm) from the point of origin of the musculocutaneous nerve and joined the median nerve at an average distance of 5.21 cm (range 2.2-9.3 cm) from the latterâ&#x20AC;&#x2122;s formation. Its own average length was 4.3 cm (range 2.5-6.3 cm).

Complete Fusion of the Musculocutaneous and the Median Nerve

Figure 2. Showing the communicating ramus (CR) from the musculocutaneous nerve (MCN) to median nerve (MN) in limb no. 23 ML LC and MC = Lateral and medial cords; LR and MR = Lateral and medial roots of median nerve; UN = Ulnar nerve; CB = Coracobrachialis muscle.

It was seen in four (06.66%) limbs i.e., limb no. 1 MR, 2 MR, 7 ML and 21 ML. Out of these, in three limbs (1 MR, 7 ML and 21 ML), the other terminal branch of the lateral cord i.e., the lateral root of the median nerve was very thin and the most of the fibers of the lateral cord contributed to the formation of the musculocutaneous nerve, which however joined the median nerve at an average distance of 10.06 cm from the formation of the latter. In the fourth limb (limb no. 2 MR), the lateral root of the median nerve was normal in diameter and musculocutaneous nerve joined with the median nerve at a distance of 7.5 cm from the formation of the median nerve. In the limb no. 1 MR, coracobrachialis muscle was supplied by the musculocutaneous nerve and the biceps brachii and brachialis by the median nerve (Fig. 3).

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Neurology In the limb no. 2 MR and 7 ML, the coracobrachialis and the biceps brachii were supplied by the musculocutaneous nerve and brachialis by the median nerve.

Table 2. Showing the Incidence of Communication between the Musculocutaneous Nerve and the Median Nerve Author

Year

Incidence

In the limb no. 21 ML, the musculocutaneous nerve joined with the median nerve after supplying all the muscles of the anterior compartment of the arm i.e., coracobrachialis, biceps brachii and the brachialis.

Watanabe et al

1985

01.4%

Kosugi et al

1986

21.8%

Yang et al

1995

12.5%

Eglseder and Goldman

1997

36.0%

DISCUSSION

Venieratos and Anagnostopoulou

1998

13.9%

Absence of the Musculocutaneous Nerve

Chiarapattanakom et al

1998

16.0%

Rao and Chaudhary

2000

33.3%

Aktan et al

2000

10.4%

Choi et al

2002

26.4%

Present study

2005

10.0%

In the present study, it was absent in six (10%) limbs. ÂÂ

ÂÂ

In two (3.33%) limbs, all the three muscles viz; coracobrachialis, biceps brachii and brachialis were supplied by the median nerve. Similar situation had been earlier encountered by Broca (1888); Kerr (1918); Li Minor, (1992); Rao and Chaudhry, (2000); Sud and Sharma, (2000); Rajashree et al, (2003) and Saritha, (2004). While Broca (1888) gave its incidence range as 0.3-2.0%, Kerr (1918) could not trace musculocutaneous nerve in 5.14% of his 175 dissections with all muscles being supplied by the median nerve. Rest of the authors have reported only the single cases of this variant. In four (6.66%) limbs, there was absence of the musculocutaneous nerve with the innervation of the coracobrachialis from the branches of the lateral cord and of biceps and brachialis by the median nerve. Earlier Gumusburun and Adiguzel (2000) also came across the same variation, being bilateral, during the dissection of a 72-year-old female cadaver. However, Abhaya et al (2003 b) while reporting a similar case as that of Gumusburun and Adiguzel (2000) named it a dual origin of the musculocutaneous nerve, one from the lateral cord and the other from the median nerve.

Communication Between Musculocutaneous and Median Nerve Another variation noted in the musculocutaneous nerve was its communication with the median nerve encountered in six (10.00%) limbs of the present study. Venieratos and Anangnostopoulou (1998) believed it to be the most frequent variant of this nerve, where some fibers of the lateral root of the median nerve run along with the musculocutaneous nerve and after traveling some distance, leave the latter to join the ultimate destination (the median nerve) thus giving the appearance as if there are two lateral roots of the median nerve.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Its incidence has been variously reported by the earlier workers and compared with the present study in the Table 2. The communication between the musculocutaneous and the median nerve have been classified in different types by Li Minor (1992), Venieratos and Anagnostopoulou (1998) and Choi et al (2002). Li Minor, (1992) categorized these communications into following five type: ÂÂ Type I: There is no communication between the median nerve and the musculocutaneous nerve. ÂÂ Type II: The fibers of the lateral root of the median nerve pass through the musculocutaneous nerve and join the median nerve in the middle of the arm. ÂÂ Type III: The lateral root fibers of the median nerve pass along the musculocutaneous nerve and after some distance, leave it to form the lateral root of the median nerve. ÂÂ Type IV: The musculocutaneous fibers join the lateral root of the median nerve and after some distance the musculocutaneous nerve arises from the median nerve. ÂÂ Type V: The musculocutaneous nerve is absent and the entire fibers of the musculocutaneous nerve pass through the lateral root and fibers to the muscles supplied by the musculocutaneous nerve branch out directly from the median nerve. Similarly based upon its site with relation to the coracobrachialis muscle Venierators and Anagnostopoulou, (2000) classified this communication into three types: ÂÂ Type I: The communication is proximal to the entrance of the musculocutaneous nerve into the coracobrachialis muscle.

Neurology Table 3. Showing the Comparison of Lengths of the Communicating Branch (CB) and Its Distance from the Origin of Musculocutaneous and Median Nerve Author (year)

Total no. of No. of limbs having the Average distance the limbs communication (%) between point of studied formation of the MCN and of CB (cm)

Average distance between point of formation of the MN and point of joining of CB with it (cm)

Mean length of CB (cm)

Rao and Chaudhary (2000)

08 (33.33%)

15.5

Not reported

8.95

Aktan et al (2000)

05 (10.40%)

0.95 ± 0.42

10.25 ± 2.32

5.50

Present study (2005)

06 (10.00%)

2.98

5.21

4.3

CB = Communicating branch; MCN = Musculocutaneous nerve; MN = Median nerve ÂÂ

Type II: The communicating branch arises distal to the coracobrachialis muscle from the musculocutaneous nerve.

ÂÂ

Type III: The musculocutaneous nerve and the communicating branch do not pierce the coracobrachialis muscle.

Later on Choi et al (2002) in a study on 138 cadavers classified these communications into three types: ÂÂ

Pattern 1: Fusion of both nerves (19.2%)

ÂÂ

Pattern 2: Presence of one supplementary branch between both nerves (72.6%).

ÂÂ

Pattern 2a: Single root from musculocutaneous nerve, contributes to the connection (69.9%).

Pattern 2b: There are two roots musculocutaneous nerve (2.7%).

from

Pattern 3: Presence of two branches between both nerves (6.8%).

All our limbs fit into type II of Li Minor (1992), type I of Venieratos and Anagnostopoulou (1998) or into type II (2a) of Choi et al (2002). According to Bergman et al (1988) the communicating branch usually joins the median nerve in the lower third of the upper arm. If it joins the median nerve in the upper third of the upper arm, it is generally considered as the third (double lateral) root of the median nerve. Since in the present study, in all the six limbs it was observed in the upper third of the upper arm, it can be considered as the double lateral root of the median nerve or in other words the median nerve can be said to be formed by three roots: (a) One from the lateral cord; (b) one from the musculocutaneous nerve and (c) the third from the medial cord. Similar variation was observed earlier by different authors - The median nerve, instead of having two roots may have three roots - either one each from

lateral cord, medial cord and musculocutaneous nerve (Chauhan and Roy, 2002; Saritha, 2004) or two from lateral cord and one from the medial cord (Sargon et al, 1995; Mohapatra et al, 2004) or it may have even four roots - three from the lateral cord and one from the medial cord (Uzun and Seelig, 2001). Table 3 compares the lengths of communicating branch and its distance from origin of musculocutaneous and median nerve with the earlier studies. It is evident from Table 3 that there is a lot of difference in the various distances of communicating branch. Whereas, it originated at an average distance of 2.98 cm from the point of formation of the musculocutaneous nerve in the present study. Rao and Chaudhary (2000) found it at a distance of 15.5 cm and Aktan et al (2000) at a distance of 0.95 ± 0.42 cm. Similarly, the other distances are also quite variable in the three studies.

Complete Fusion of the Musculocutaneous and the Median Nerve It was seen in four (6.66%) limbs in the present study. Earlier Lang and Spinner, (1970) reported a complete fusion of the median and the musculocutaneous nerve. Similarly Watanabe et al, (1985) found two cases (1.4%) of fusion of musculocutaneous and median nerves among 140 upper limbs and Yang et al (1995) encountered one such case out of 24 cadaveric specimens (4%).

Ontogeny The presence of the communications may be attributed to the random factors influencing the mechanism of formation of the limb muscles and the peripheral nerves during the embryonic life. Significant variations in the nerve patterns may be a result of the altered signalling between the mesenchymal cells and neuronal growth cones and once formed antenatally persist postnatally

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Neurology (Sannes et al, 2000; Abhay et al, 2003) or these may be due to circulatory factors at the time of fusion of the brachial plexus cords (Kosugi et al, 1986). Iwata (1960) believed that the human brachial plexus appears as a single radicular cone in the upper limb bud, which divides longitudinally into ventral and the dorsal segments. The ventral segments give roots to the median and the ulnar nerves with musculocutaneous nerve arising from the median nerve. He further kept the possibility of failure of the differentiation as a cause for some of the fibers taking an aberrant course as a communicating branch. Chiarapattanakom et al (1998) are of the opinion that the limb muscles develop from the mesenchyme of local origin, while axons of spinal nerves grow distally to reach the muscles and/or skin. They blamed the lack of coordination between the formation of the limb muscles and their innervation for appearance of a communicating branch.

Phylogeny Chauhan and Roy (2002) strongly recommend the consideration of the phylogeny and the development of the nerves of the upper limb for the interpretation of the nerve anomalies of the arm. Considering the communication between the musculocutaneous and the median nerve as a remnant from the phylogenetic or comparative anatomical point of view and that the ontogeny recapitulates the phylogeny, they feel that the variations seen are the result of the developmental anomaly. In the lower vertebrates of the Artiodactyla and Perissodactyla (amphibians, reptiles and birds) there is only one nerve i.e. median nerve supplying the muscles of the upper arm and an independent musculocutaneous nerve is absent (Sisson and Grossman, 1961; Arlamowska â&#x20AC;&#x201C; Palider, 1970). Similar was the situation in both limbs of cadaver no. 9 of our study, which thus represents these vertebrates. Similarly in dogs, the musculocutaneous nerve sends a communicating branch to the median nerve (Sisson and Grossman, 1961; Miller, 1932) as seen in the limb no. 18 ML, 18 MR, 23 ML, 24 MR, 25 ML, 27 MR of the present study.

Clinical Significance Rao and Chaudhary (2000) emphasized upon the value of the knowledge of communicating branch between the musculocutaneous and the median nerve in traumatology of the shoulder and/or the upper arm region and in situations when the surgeon has to isolate

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

and trace the median and/or musculocutaneous nerve distally. They also correlated such communications to the entrapment syndromes of the musculocutaneous nerve in which a part of the median nerve also passes through the coracobrachialis muscle exhibiting the signs and symptoms similar to those encountered in the median nerve neuropathy as in the carpal tunnel syndrome or the pronator syndrome. Knowledge of the communicating branch may be useful for clinicians thereby avoiding unnecessary carpal tunnel release in such cases. Sunderland (1978) is of the opinion that the lesions of the communicating nerve may give rise to the patterns of weakness that may impose difficulty in the diagnosis. Further an injury to the musculocutaneous nerve proximal to the anastomotic branch between the musculocutaneous nerve and the median nerve may lead to the unexpected presentation of weakness of the forearm flexors and the thenar muscles. Choi et al (2002) stressed upon the significance of these communicating branches in diagnostic clinical neurophysiology. Leffert (1985) emphasized to rule out such communications to prevent the unwanted outcomes of operations conducted on the musculocutaneous nerve. SUMMARY and CONCLUSION The musculocutaneous nerve was seen coming as one of the terminal branches of the lateral cord in 54 (90.00%) limbs of the present study, being absent in rest of the six (10.00%) limbs (bilaterally absent in 2 bodies and unilaterally absent in another 2 bodies) and all the three muscles viz; coracobrachialis, biceps brachii and brachialis, which are usually supplied by musculocutaneous nerve, were supplied by the median nerve in two limbs while in the other four limbs, coracobrachialis was supplied by the branches of the lateral cord and biceps and brachialis by the median nerve. Another variation noted in the musculocutaneous nerve was its communication with the median nerve encountered in six (10.00%) limbs in the upper third of the upper arm; thus giving the appearance of the double lateral root of the median nerve or in other words the median nerve being formed by three roots: (a) One from the lateral cord; (b) one from the musculocutaneous nerve and (c) the third from the medial cord. The communicating branch was given off at an average distance of 2.98 cm (range 1.9-4.5 cm) from the point of origin of the musculocutaneous nerve and joined the median nerve at an average distance of 5.21 cm (range 2.2-9.3 cm) from the latterâ&#x20AC;&#x2122;s formation.

Neurology Its own average length was 4.3 cm (range 2.5-6.3 cm). In four (06.66%) limbs, the musculocutaneous nerve after supplying some of the muscles of the anterior compartment of the arm fused with the median nerve. Out of these in one, it supplied the coracobrachialis; in two: Coracobrachialis and biceps and in the fourth coracobrachialis, biceps and brachialis before joining the median nerve. All the variations of the musculocutaneous nerve have been explained ontogenically. The presence of the communications may be attributed to the random factors influencing the mechanism of formation of the limb muscles and the peripheral nerves during the embryonic life - may be as a result of the altered signalling between the mesenchymal cells and neuronal growth cones OR failure of the differentiation as a cause for some of the fibers taking an aberrant course as a communicating branch OR lack of coordination between the formation of limb muscles and their innervation has been held responsible for the development of a communicating branch. Phylogenetically the limbs with no musculocutaneous nerve are equated with amphibians, reptiles and birds and limbs with the communicating branch between the musculocutaneous and the median nerve are equated with dogs thus supporting the dictum, ‘ontogeny recapitulates phylogeny’. Further, the clinical implications of these variations of the musculocutaneous nerve are discussed. Suggested Reading 1. Abhaya A, Bhardwaj R, Prakash R. Dual origin of musculocutaneous nerve. J Anat Soc India 2003a;52(1):94. 2. Abhaya A, Khanna J, Prakash R. Variation of the lateral cord of brachial plexus piercing coracobrachialis muscle. J Anat Soc India 2003b;52(2):168-70. 3. Aktan ZA, Ozturk L, Bilge O, Ozer MA, Pinar YA. A cadaveric study of the anatomic variations of the brachial plexus nerves in the axillary region and arm. Turk J Med Sci 2000;31:147-50. 4. Arlamowska-Palider A. Comparative anatomical studies of nervus musculocutaneous in mammals. Acta Theriol. XV. 1970;22: 343-56. Cited by Prasada Rao PV, Chaudhary SC. Communication of the musculocutaneous nerve with the median nerve. East Afr Med J 2000;77(9):498-503. 5. Bergman RA, Afifi AK, Miyauchi R. Illustrated encyclopedia of human anatomic variation. In: Nervous System – Plexuses. Website: virtualhospital.com.university of iowa care, 1988. 6. Broca (1888). Cited by Gümüsburun E, Adigüzel E. A variation of the brachial plexus characterized by the absence of the musculocutaneous nerve: a case report. Surg Radiol Anat 2000;22(1):63-5.

7. Chauhan R, Roy TS. Communication between the median and musculocutaneous nerve: a case report. J Anat Soc India 2002;51(1):72-5. 8. Chiarapattanakom P, Leechavengvongs S, Witoonchart K, Uerpairojkit C, Thuvasethakul P. Anatomy and internal topography of the musculocutaneous nerve: the nerves to the biceps and brachialis muscle. J Hand Surg Am 1998;23(2):250-5. 9. Choi D, Rodríguez-Niedenführ M, Vázquez T, Parkin I, Sañudo JR. Patterns of connections between the musculocutaneous and median nerves in the axilla and arm. Clin Anat 2002;15(1):11-7. 10. Eglseder WA Jr, Goldman M. Anatomic variations of the musculocutaneous nerve in the arm. Am J Orthop (Belle Mead NJ) 1997;26(11):777-80. 11. Gumusburun E, Adiguzel E. A variation of the brachial plexus characterized by the absence of musculocutaneous nerve: a case report. Surg Radiol Anat 2000;22(1)63-5. 12. Iwata H. Studies on the development of the brachial plexus in Japanese embryo. Rep Dept Anat Mie Prefect Univ Sch Med 1960;13:129-144. Cited by Prasada Rao PV, Chaudhary SC. Communication of the musculocutaneous nerve with the median nerve. East Afr Med J 2000;77(9):498-503. 13. Kerr AT. The brachial plexus of nerves in man, the variations in its formation and branches. Am J Anat 1918; 23(2):285-395. 14. Kosugi K, Mortia T, Yamashita H. Branching pattern of musculocutaneous nerve. 1. Cases possessing normal biceps brachii. Jikeakai Med J 1986;33:63-71. 15. Lang J, Spinner M. An important variation of the brachial plexus--complete fusion of the median and musculocutaneous nerves. Bull Hosp Joint Dis 1970;31(1): 7-13. 16. Leffert RD. Brachial plexus injuries. In: Anatomy of the Brachial Plexus. Churchill Livingstone: New York 1985:p.384. 17. Le Minor JM. A rare variation of the median and musculocutaneous nerves in man. Arch Anat Histol Embryol 1990;73:33-42. 18. Miller RA. Comparative studies upon the morphology and distribution of the brachial plexus. Am J Anat 1932; 54(1):143-66. 19. Mohapatra BB, Chinara PK, Dutta BK, Nayak AK. Variation in the formation and branching pattern of median nerve. J Anat Soc Ind 2004;53(1):31-66. 20. Rajashree B, Arati D, Mamata S, Chinmayi M, Charulata S. Absence of musculocutaneous nerve - a case report. J Anat Soc India 2003;52(1):94. 21. Prasada Rao PV, Chaudhary SC. Communication of the musculocutaneous nerve with the median nerve. East Afr Med J 2000;77(9):498-503. 22. Romanes GJ. The pectoral region & axilla and side of the neck. In: Cunningham’s Manual of Practical Anatomy. 15th edition, Vol. 1 & 3. The English Language Book Society and Oxford University Press: Edinburgh, London 1995p.26-8, 28-34 resp.

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Neurology 23. Sannes HD, Reh TA, Harris WA. Axon growth and guidance. In: Development of Nervous System. Academic Press: New York 2000:p.189-97. 24. Sargon MF, Uslu SS, Celik HH, Akşit D. A variation of the median nerve at the level of brachial plexus. Bull Assoc Anat (Nancy) 1995;79(246):25-6. 25. Saritha S. Variations in the median and musculocutaneous nerves-A surgical prospective. J Anat Soc Ind 2004; 53(1):31-66. 26. Sisson S and Grossman JD. The anatomy of the domestic animals. 4th Edition. London: Charles e. Tuttle 1961:835-75. Cited by Prasada Rao PV, Chaudhary SC. Communication of the musculocutaneous nerve with the median nerve. East Afr Med J 2000;77(9):498-503. 27. Sud M, Sharma A. Absence of musculocutaneous nerve and the innervation of coracobrachialis, biceps brachii and brachialis from the median nerve. J Anat Soc India 2000;49(2):176-7. 28. Sunderland S. The Median Nerve: Anatomical and Physiological features. In: Nerves and Nerve Injury.

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2nd edition, Churchill Livingstone: Edinburgh 1978;6727, 691-727. Cited by Chauhan R, Roy TS. Communication between the median and musculocutaneous nerve: a case report. J Anat Soc India 2002;51(1):72-5. Uzun A, Seelig LL Jr. A variation in the formation of the median nerve: communicating branch between the musculocutaneous and median nerves in man. Folia Morphol (Warsz) 2001;60(2):99-101. Venieratos D, Anagnostopoulou S. Classification of communications between the musculocutaneous and median nerves. Clin Anat 1998;11(5):327-31. Watanabe M, Takatsuji K, Sakamoto N, Morit Y, Ito H. Two cases of fusion of the musculocutaneous and median nerves. Kalbo gaki Zasshi 1985; 60:1-7. Cited by A variation of the brachial plexus characterized by the absence of the musculocutaneous nerve: a case report. Surg Radiol Anat 2000;22(1):63-5. Yang ZX, Pho RW, Kour AK, Pereira BP. The musculocutaneous nerve and its branches to the biceps and brachialis muscles. J Hand Surg Am 1995;20(4):671-5.

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The Neurology of Insulin Secretion The autonomic nervous system, which is the part of the nervous system beyond conscious control, plays an important role in the release of insulin from b-cells in the endocrine part of the pancreas. The process by which this occurs has been a mystery, since it is difficult to give detailed study to such an inaccessible organ. However, researchers at Karolinska Institutet in Sweden have now managed to graft b-cells into the eyes of mice in order to study them in a living organism over a prolonged period of time. As a result, the group and a team of colleagues from the University of Miami have gained detailed knowledge of how the autonomic nervous system regulates b-cell insulin secretion. For this study, a technique of transplanting b-cells to the anterior chamber of the mouse eye was used. This technique was previously developed by Professor Per-Olof Berggren’s group at Karolinska Institutet. In the anterior chamber of the eye the b-cells receive a supply not only of blood vessels, but also of nerves from the sympathetic and parasympathetic system, which constitute the autonomic nervous system. Put simply, the sympathetic nervous system can be said to prepare us for flight; one way it does this is to boost our energy by reducing insulin release and increasing glycogen, and consequently blood glucose. The parasympathetic nervous system operates in the reverse direction when we are at rest. _____________________________________________________________________________ A person with Alzheimer’s disease may live anywhere from 2 to 20 years after diagnosis. To lower your Alzheimer’s risk: i) Maintain a healthy weight, ii) check your waist line, iii) eat mindfully (reducing intake of junk food and refined carbohydrates, iv) exercise regularly and v) keep your important health numbers under control such as blood pressure, sugar and cholesterol. As per Harvard News Letter, a recent international survey has shown that Alzheimer’s is the second most feared disease after cancer. It is characterized by progressive damage to nerve cells and their reactions. The result is devastating and includes memory loss, having difficulties with verbal communication and even personality changes.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Obstetrics and Gynecology

A Comparative Study Between Cleavage Stage Embryo Transfer at Day 3 and Blastocyst Stage Transfer at Day 5 in IVF/ICSI on Clinical Pregnancy Rates P Kaur*, ML Swarankar†, M Maheshwari†, V Acharya†

Abstract Objective: To evaluate the efficacy of blastocyst transfer in comparison with cleavage stage transfer. Study design: A randomized, prospective study was conducted in Infertility Clinic, Dept. of Obstetrics and Gynecology, Mahatma Gandhi Hospital, Jaipur on 300 patients aged 25-40 years undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ ICSI) cycle from May 2010 to April 2011. When three or more Grade I embryos were observed on Day 2 of culture, patients were divided randomly into two study groups, cleavage stage transfer and blastocyst transfer group having 150 patients each. Primary outcomes evaluated were, clinical pregnancy rate and implantation rate. The results were analyzed using proportions, standard deviation and Chi-square test. Results: Both the groups were similar for age, indication and number of embryos transferred. Clinical pregnancies after blastocyst transfer were significantly higher 66 (44.0%) compared to cleavage stage embryo transfer 44 (29.33%) (p < 0.01). Implantation rate for blastocyst transfer group was also significantly higher (p < 0.001). Conclusion: Blastocyst transfer having higher implantation rate and clinical pregnancy rate leads to reduction in multiple pregnancies.

Keywords: Blastocyst transfer, embryo transfer, in vitro fertilization, clinical pregnancy rates, intracystoplasmic sperm injection

dvances in the dynamics of embryo culture allow us to culture embryos to the blastocyst stage. Prolonging the duration of culture to Day 5 allows chromosomally competent embryos to develop to the blastocyst stage and permits selection of embryos that have the potential for continued development under embryonic genomic control.1 In addition, selection of Day 5 embryos has the advantage of physiological synchronization with the uterine endometrium, thereby resulting in better pregnancy rates.2 The introduction of sequential media that takes into account the changing metabolic requirement of the embryo, as it develops from the zygote to the blastocyst stage, allows extended culture.3,4

Blastocyst transfer should enable transfer of fewer but higher quality embryos resulting in increased implantation rates. This would maintain a high pregnancy rate while controlling the multiple pregnancy rate.5 Reasons for higher success rates with blastocysts are mainly related to embryo selection process. Embryos selected for transfer on Day 5 are healthier and carry a lower risk of being aneuploid, thereby increasing patient’s chance of achieving an ongoing pregnancy.6 Although blastocyst transfer has been shown to be beneficial in good prognosis patients, similar benefits were not seen in an unselected group. The aim of our study was to evaluate the efficacy of blastocyst transfer in comparison with Day 3 embryo transfer. Material and Methods

*Resident †Professor Dept. of Obstetrics and Gynecology Mahatma Gandhi Medical College and Hospital, Jaipur Address for correspondence Dr Prabhleen Kaur A-2/93 Janak Puri, New Delhi - 110 058 E-mail: dr.prabhleenahuja@gmail.com

Three hundred patients aged 25-40 years undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycle between May 2010 and April 2011 were included in our study, meeting the inclusion criteria set namely, 2-20 years of infertility, having minimum five

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Obstetrics and Gynecology oocytes at oocyte pick up and endometrial thickness of 7 mm and more indicating good ovarian response, having normal uterine cavity and basal folliclestimulating hormone (FSH) (<10 mIU/mL). Complete patient work-up, baseline routine investigations and hormonal analysis was done and postmenstrual diagnostic hysteroscopy was done. Patients were put on long protocol, gonadotropin-releasing hormone (GnRH)-agonists started on cycle Day 21 daily doses given subcutaneously till Day 3 of next cycle. Hormonal evaluation: Serum FSH, luteinizing hormone (LH), estradiol (E2) and transvaginal sonography was done on Day 3 to confirm down regulation. Induction with recombinant FSH (rFSH) was started once pituitary down regulation was confirmed. The dose schedule was modified according to parameters like body mass index (BMI), previous response and ovarian reserve estimates and was given for 5 days (Day 3-7). Follicular monitoring was initiated on Day 8 of cycle and further doses of rFSH were given according to follicle size and continued till Day 11. Women were scheduled for oocyte retrieval when at least three follicles reached 18 mm size and injection human chorionic gonadotropin (hCG) 10,000 IU was given. Transvaginal sonography guided oocyte retrieval was then planned 36 hours after hCG, which was performed under short general anesthesia. The retrieved oocytes were then incubated for 3-4 hours in IVF-30 media and then, depending on maturity of oocytes and previous IVF performance, IVF or ICSI was performed. Short incubation insemination for 2 hours and group culture was followed for IVF. Denudation of oocytes was carried out mechanically before ICSI was performed. Oocytes were incubated overnight in IVF-30 media in a carbon dioxide (CO2) incubator and observed after 16-18 hours postinsemination for fertilization. The fertilized oocytes were then transferred into a cleavage medium and incubated. Embryos were observed on Day 2 and transfer was scheduled according to random allocation of patients into two groups based on availability of minimum three good quality embryos: Group 1: Included patients undergoing embryo transfer on Day 3. Group 2: Included patient in which extended culture till Day 5 was done in G2 plus media and blastocysts were transferred on Day 5. Random allocation of patients was done equally so that study population in both groups was comparable.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

The number of blastocysts/embryos transferred was determined by the availability of embryos, patients age and previous clinical history. Not more than three embryos/blastocysts were transferred on any occasion. All transfers were performed using Edward-Wallace catheter. Luteal support was given in form of micronized vaginal progesterone in a dose of 200 mg thrice-daily for 18 days post retrieval. In addition, injection hCG 2,000 IU was given intramuscular on Days 5, 8 and 11 after retrieval. Serum b-hCG was performed on Day 15 following embryo transfer and if positive then transvaginal sonography was performed 15 days later to detect and confirm intrauterine pregnancy. Positive cases were followed till 6 weeks to check for fetal cardiac activity.

Outcome Measures Primary outcome ÂÂ

Implantation rate

ÂÂ

Clinical pregnancy rate

Secondary outcome ÂÂ

Fertilization rate

ÂÂ

Cleavage rate

ÂÂ

Multiple pregnancy rate

ÂÂ

Mean number of embryos/blastocysts transferred.

Implantation rate: Defined as the number of gestational sacs determined by ultrasound by number of embryos transferred. Clinical pregnancy rate: Defined as presence of gestational sac with a fetal pole with cardiac activity on transvaginal ultrasound at 6 weeks. Fertilization rate: Defined as total number of fertilized oocytes by total number of mature oocytes retrieved. Cleavage rate: Total number of Day 3 embryos by total number of fertilized oocytes.

Study Analysis The results were analyzed by using proportions, standard deviation (SD) and Chi-square test. Results Total 300 patients were randomized for the study and allocated into two groups of 150 patients each. As shown in Table 1 no significant difference were found for age, duration of infertility, type of infertility, ratio of ICSI:IVF cases and mean E2 level at hCG injection. Table 2 shows that no significant difference between both the study groups in term of indication for IVF.

Obstetrics and Gynecology Table 1. Demographic Profile Variable

Day 3 transfer (n = 150)

Day 5 transfer (n = 150)

32.46 ± 4.3

32.04 ± 4.4

25-40

8.9 ± 5.2

7.7 ± 4.7

Primary

101

100

Secondary

No. of cases with ICSI

No. of cases with IVF

104

1158.3 ± 890.2

1327.52 ± 917.62

Age (years, mean ± SD) Range Duration of infertility (years) Type of infertility

Estradiol at hCG injection (pg/mL, mean ± SD)

No statistically significant difference was demonstrated between the two groups.

Table 2. Clinical Profile of Patients Infertility indication (n)

Day 3 transfer (n = 150)

Day 5 transfer (n = 150)

Tubal

Endometriosis

Anovulation

Male

Mixed

Unexplained

No statistically significant difference was demonstrated between the two groups.

Table 3. Results after Oocyte Aspiration with Respect to Number of Oocytes and Embryos Variable

Day 3 transfer (n = 150)

Day 5 transfer (n = 150)

Oocytes at OR (n)

1,094

1,141

Mature oocytes (n)

922

1,007

Fertilized oocytes (n)

599

658

Total Day 3 embryos (n)

447

549

Embryos transferred (n)

309

290

No. of oocytes at OR (mean ± SD)

7.3 ± 2.1

7.6 ± 2.3

No. of mature oocytes (mean ± SD)

6.1 ± 1.6

6.6 ± 2.1

No. of two-pronucleate embryos (mean ± SD)

3.9 ± 1.7

4.3 ± 1.5

2.04 ± 0.74

1.93 ± 0.48

Fertilization rate (%)

64.96

65.34 (p > 0.05) NS

Cleavage rate (%)*

74.62

83.43 (p < 0.001) HS

No of embryos per transfer (mean ± SD)

No statistically significant difference was demonstrated between the two groups. NS = Not significant; HS = Highly significant. *Cleavage rate was significantly higher in blastocyst transfer.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Obstetrics and Gynecology Table 4. Results After Oocyte Aspiration with Respect to Outcome Variable

Day 3 transfer (n = 150)

Day 5 transfer (n = 150)

Positive b-hCG

Percentage per OR

45.33

Clinical pregnancies (n)

29.33

Embryos transferred (n)

309

290

Total gestational sacs on USG (n)

102

21.35

35.17

Clinical pregnancy rate (%)

Implantation rate Total multiple pregnancies Multiple pregnancy rate

31.81

48.48

p value

5.6

<0.01 (S)

6.3

<0.01 (S)

14.12

<0.001 (HS)

2.36

>0.05 (NS)

S: Significant; HS: Highly significant; NS: Not significant.

Table 5. Pregnancy Outcome Variable

Day 3 transfer (n = 150)

Day 5 transfer (n = 150)

44 (29.33%)

66 (44%)

Missed

3 (2%)

2 (1.33%)

Ectopic

1 (0.66%)

Single

Twin

Triplets

Positive b-hCG Clinical pregnancies

c2 =

5.20; df = 1; p < 0.01 (significant).

Hence, women in blastocyst transfer group had significantly higher clinical pregnancy rates, implantation rate and cleavage rates. Discussion Blastocyst transfer is gaining popularity nowadays due to its higher clinical pregnancy rates and implantation rates. In this study, no significant difference was found between both the study groups in terms of age, duration of infertility, indication of infertility and type of infertility. This was in agreement with the study conducted by Van der Auwera et al.7 The mean number of embryos transferred in both groups showed no significant difference (2.04 and 1.93, p > 0.05).

Table 4 shows higher clinical pregnancies per oocyte retrieval was observed in blastocyst transfer group than in Day 3 embryo transfer group (44% and 29.33%) (p < 0.01) and higher implantation rate per embryo transfer in blastocyst transfer group (35.17%) than in Day 3 embryo transfer group (21.35%) (p < 0.01).

In our study, the proportion of clinical pregnancies occurring as the result of blastocyst transfer was higher 66 (44%) as compared to embryo transfer, which was 45 (30%), the association was statistically significant and similar results were seen in the study by Van der Auwera et al7 and Mangalraj et al.8 Although, the fertilization rate was higher with blastocyst transfer (65.34%) compared to Day 3 embryo transfer (64.96%) in our study, but association was not significant (p < 0.05) and same association was observed in study of Mangalraj et al.8

Table 5 shows that although multiple pregnancy rate in blastocyst transfer group were higher than Day 3 embryo transfer group, association was not significant (48.48% and 31.81%) (p > 0.05). Pregnancy rate in blastocyst transfer group was significantly higher than Day 3 embryo transfer group (44% and 29.33%). Day 3 embryo transfer group reported 2% of pregnancies as missed abortions and 1% as ectopic, while Day 5 blastocyst transfer group had no ectopic pregnancy and 1.33% pregnancies ended up as missed abortions.

Amongst both the study groups, cleavage rates (74.62% and 83.43%) and implantation rates (21.35% and 35.17%) were significantly higher in blastocyst transfer/Group 2 over Day 3 embryo transfer/ Group 1. The results of our study were similar to the study by Van der Auwera et al7 and Mangalraj et al.8 Although, the proportion of multiple pregnancy in our study was higher with blastocyst transfer (48.48%) than with embryo transfer (31.81%), but the association was not significant (p > 0.05).

As shown in Table 3, both the groups had a comparable mean number of oocytes at retrieval, same proportion of mature oocytes and fertilized oocytes and a comparable mean number of embryos per transfer.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Obstetrics and Gynecology Thus in younger women with good ovarian response and with three or more Grade I embryos on Day 3, extended culture can be offered. The good clinical pregnancy and implantation rates observed will confidently allow transfer of not more than two good quality blastocysts and allow women to enjoy benefits of limiting numbers for transfer. Hence, by transferring fewer embryos at blastocyst stage in selected group of good prognostic patients, physicians are practicing preventive medicine, as there are fewer multiple gestations and ultimately greater pregnancy success is achieved. Conclusion In conclusion, this study has shown that in younger patients with good ovarian response, extended culture to Day 5 can be offered, as blastocyst transfer is found to have good clinical pregnancy rates. The good clinical pregnancy and implantation rates observed will confidently allow transfer of not more than two good quality blastocysts and allow women to enjoy the benefits of limiting numbers for transfer. References 1. Racowsky C, Jackson KV, Cekleniak NA, Fox JH, Hornstein MD, Ginsburg ES. The number of eight-cell embryos is a key determinant for selecting day 3 or day 5 transfer. Fertil Steril 2000;73(3):558-64.

2. Alper MM, Brinsden P, Fischer R, Wikland M. To blastocyst or not to blastocyst? That is the question. Hum Reprod 2001;16(4):617-9. 3. de los Santos MJ, Mercader A, Galán A, Albert C, Romero JL, Pellicer A. Implantation rates after two, three, or five days of embryo culture. Placenta 2003;24 Suppl B:S13-9. 4. Gardner DK, Surrey E, Minjarez D, Leitz A, Stevens J, Schoolcraft WB. Single blastocyst transfer: a prospective randomized trial. Fertil Steril 2004;81(3):551-5. 5. Kolibianakis EM, Zikopoulos K, Verpoest W, Camus M, Joris H, Van Steirteghem AC, et al. Should we advise patients undergoing IVF to start a cycle leading to a day 3 or a day 5 transfer? Hum Reprod 2004;19(11): 2550-4. 6. Papanikolaou EG, Camus M, Kolibianakis EM, Van Landuyt L, Van Steirteghem A, Devroey P. In vitro fertilization with single blastocyst-stage versus single cleavage-stage embryos. N Engl J Med 2006;354(11): 1139-46. 7. Van der Auwera I, Debrock S, Spiessens C, Afschrift H, Bakelants E, Meuleman C, et al. A prospective randomized study: day 2 versus day 5 embryo transfer. Hum Reprod 2002;17(6):1507-12. 8. Mangalraj AM, Muthukumar K, Aleyamma T, Kamath MS, George K. Blastocyst stage transfer vs cleavage stage embryo transfer. J Hum Reprod Sci 2009;2(1):23-6.

■■■■

What Precautions Should be Carried While Carrying a Multiple Pregnancy? Monitoring a multiple pregnancy: Prenatal diagnosis by chorionic villus sampling can be done near the end of the first trimester to screen for Down syndrome and other genetic abnormalities. Amniocentesis is performed between 16 and 20 weeks. Many physicians perform cervical examinations every week or two beginning early in pregnancy to determine if the cervix is thinning or opening prematurely. If an exam or ultrasound shows that the cervix is thinning or beginning to dilate prematurely, a cerclage, or suture placed in the cervix, may prevent or delay premature dilatation. Tocolytic agents are medications that may slow or stop premature labor. These medications are given in hospital “emergency” settings in an attempt to stop premature labor. Cesarean section: Vaginal delivery of twins may be safe in some circumstances. Many twins can be delivered vaginally if the presenting infant is in the head first position. Most triplets are delivered by Cesarean section. Appropriate anesthesia and neonatal support are essential, whether delivery is performed vaginally or requires cesarean section.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Oncology

Prognostic Impact of CD3 Tumor Infiltrating Lymphocytes in Triple-negative Breast Cancer Ankita Singh Rathore*, Madhu Mati Goel*, Annu Makker*, Sandeep Kumar†, AN Srivastava‡

Abstract Background: Aim of the present study was to evaluate the prognostic significance of CD3+ tumor infiltrating lymphocyte (TILs) in triple-negative breast cancer (TNBC). Methods: Immunohistochemistry was done with antibodies to CD3 TIL, estrogen receptors (ERs), progesterone receptor (PR) and C-erbB2 in tissue sections of 49 TNBC patients. CD3+ intratumoral and stromal TILs were counted in relation to known clinicopathological factors. Results: Intratumoral CD3+ TILs were significantly associated with stage (p = 0.05) with insignificant association with age, menopausal status, family history, grade and lymph node status. Higher counts of stromal CD3+ TILs were significantly associated with stage (p = 0.05), whereas grade, lymph node status, age, menopausal status and family history were insignificant with CD3+ count. The higher CD3 intratumoral and stromal counts both showed significant association with good prognosis (p 0.05). Conclusion: CD3+ TILs may serve as good prognostic marker in TNBC. The results of present study need further validation on larger sample size.

Keywords: Tumor infiltrating lymphocytes, triple-negative breast cancer

reast cancer is one of the most frequent causes of cancer death in women worldwide1 and is second most common cancer in females in India.2 The predictable prognostic factors in breast cancer include histological grade, clinical stage, lymph node and hormone receptor status. Higher clinical staging and grading are known bad prognostic markers. Lymph node positivity also indicates bad prognosis. However, each kind of tumor has different biological behavior. Triple-negative breast cancer (TNBC) is clearly a distinct subtype of breast cancer.3 TNBC lacks the expression of estrogen receptor (ER), progesterone receptor (PR) and C-erbB2. TNBC are known to be more aggressive with worse prognosis. Tumor infiltrating lymphocytes (TILs) have been thought to play an important role in inhibiting tumor proliferation, metastasis in tumors and may be an

independent prognostic marker.4-7 The infiltrating lymphocytes counts within the tumor cell have been reported to associate with good prognosis in different kind of tumors.8-11 CD3 antigen is a receptor glycoprotein present on all T lymphocytes. Controversy still surrounds the prognostic role of TILs within a tumor microenvironment. While higher concentration of CD3 TIL has been shown to link with favorable outcome in oropharyngeal cancer,12 a low CD3 count has been reported to predict a shorter disease free survival in colon and cervical cancer.13,14 Role of TIL in TNBC is not well-understood. The present study was done to evaluate the density, localization and distribution of CD3 TIL in TNBC patients. The findings were correlated with known clinicopathological factors and survival. Material and Methods

Patients *Dept. of Pathology, King George’s Medical University Lucknow, Uttar Pradesh †All India Institute of Medical Sciences, Bhopal, Madhya Pradesh ‡Dept. of Pathology, Era’s Lucknow Medical College and Hospital, Lucknow Uttar Pradesh Address for correspondence Dr Ankita Singh Rathore SRF, Dept. of Pathology King George’s Medical University Lucknow - 226 003, Uttar Pradesh E-mail: ankita.rathorekg@gmail.com

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

A total of 25 histologically proven cases of TNBC recruited from the Dept. of General Surgery, King George’s Medical University, Lucknow, Uttar Pradesh, India after informed written consent and institutional ethical clearance were included in this study. Demographic details, clinical history, complete general/ local examination and epidemiological risk factors including family history, clinical stage, tumor grade,

Oncology lymph node status, ER, PR and Cerb B2 were recorded on a detailed proforma specially designed for the study. All patients had preoperative tissue diagnosis of breast cancer either by fine-needle aspiration cytology (FNAC) and/or core biopsy of the breast. All the patients underwent surgery with axillary lymph node dissection, and none of these patients had received preoperative antitumor therapy. Detailed histopathological examination was done in the Dept. of Pathology, King George Medical University Lucknow, Uttar Pradesh.

Immunohistochemistry Immunohistochemistry (IHC) was performed using primary antibodies to CD3+ (Novacastra, UK), ER, PR and CerbB-2 (Biogenex Laboratories, Inc, CA, US). Sections were deparaffinized in xylene followed by hydration in graded ethanols. Secondary antibody kit used was polymer detection kit (Novacastra, UK). Formalin-fixed, paraffin-embedded tissues sections (3-4 μm thick) were taken on 3-aminopropyl triethoxysilane (APTS)-coated glass slides. Sections were immersed in antigen-retrieval solution (Citrate buffer pH 6.0) and antigen retrieval was done in the antigen-retrieval system (Biogenex Laboratories, Inc, CA, US) at 100°C for 20 minutes. The sections were then brought to room temperature. Endogenous peroxidase activity was blocked in 3% hydrogen peroxide for 5 minutes and nonspecific binding sites were blocked with protein block for 5 minutes. Sections were covered with 50 μl of individual primary antibody, kept in moist chamber and slides were incubated over night at 40°C. Slides were then washed with tris buffer saline (TBS), followed by a 30 minutes incubation with post-primary block at room temperature (RT). Sections were then washed again in TBS and incubated with secondary antibody for 30 minutes at RT. 3,3-diamino-benzidine was used as chromogen for visuation of antigen antibody complex. Sections were counterstained with hematoxylin and mounted with DPX. Section from tonsillar tissue was taken as positive control for CD3+ cells.

Microscopic Evaluation of CD3 TIL CD3 positive TILs were counted in five randomly selected high power fields at 40X magnification and the counts were averaged. Initially, CD3 positive TILs count was recorded as: + (1-25 cells), ++ (≥25 cells) in the tumor and in the stroma separately. CD3 positive TIL upto 25 cells were considered as low CD3 TIL count and above 25 cells i.e. ++ were considered as high count.

The mean follow-up period was 32 months. Followup data were available for all patients. Details of clinical progress and survival were obtained from the hospital records. During the follow-up period, eight patients were not well (recurrence/death). The histomorphology and immunostaining patterns of intratumoral and stromal CD3 TILs are shown in Figures 1 a and b.

Statistical Analysis Statistical software Stata 11.2 version was used for statistical analysis. The data were described as number and percentages or mean ± SD, as applicable. Chi-square test (χ2) was used to test the association between categorical variables. The age was compared by Mann-Whitney test because of non-normal nature of our data. Results The clinicopathological characteristics of the patients included in this study are summarized in Table 1. The median age of study sample was 50 years (range 25-86 mean 49.16 years). Out of 25 TNBC patients, majority of the cases were postmenopausal (64%). All patients were recruited in the study were TNBC showing higher clinical stage (T3,T4) with 66%, higher histological grade (III, IV) with 52% and lymph node positivity with 60%. The scoring of intratumoral and CD3+ TILs in relation to clinicopathological variables is shown in Table 2. CD3 positive TILs were detected in intratumoral and stromal areas of immunostained histological sections of all the TNBC. Intratumoral CD3+ TILs were significantly associated with clinical stage (p = 0.05). The association of intratumoral CD3 TIL was insignificant in relation to age, menopausal status, family history, histological grade and lymph node status (Table 2). Similarly, the stromal CD3 TIL was also significantly associated with clinical stage (p = 0.05), whereas age, menopausal status, family history, grade and lymph node status did not show significant association with CD3+ stromal TIL count (Table 2). Immunostaining of intratumoral and stromal CD3 TIL are shown in (Figs. 1 a and b). Follow-up for disease-free survival was available for 17 patients. In our analysis, patient with higher intratumoral and stromal CD3+ T-cell infiltration showed a longer disease-free survival (p = 0.004) and (p = 0.01), respectively. Higher number of CD3+ TILs were observed to be associated with better outcome.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Oncology Stromal CD3 TILs Intratumoral CD3 TILs

(b)

(a)

Figure 1 a and b. Show intratumoral and stromal TILs in TNBC; section showing intratumoral and stromal area of TNBC (H&E x100) (a); immunostain section showing CD3 + in intratumoral and stromal area of TNBC (H&x 100) (b).

Table 1. Clinicopathological Characteristics of the Breast Cancer Patients Characteristics Age (years) Mean Âą SD (range)

n = 25 (100%) 49.16 Âą 12.62 (25-86)

Menopausal status Premenopause

9 (36%)

Postmenopause

16 (64%)

Family history Yes

2 (8%)

23 (92%)

Grade I, II

12 (48%)

III, IV

13 (52%)

Tumor stage T1,T2

11 (44%)

T3,T4

14 (66%)

Lymph node status Positive

15 (60%)

Negative

10 (40%)

Survival status Well

17 (68%)

Not well

8 (32%)

Discussion Patients with TNBC have significantly bad prognosis, compared to women with other sybtypes of breast cancer. The fundamental difference between relapse

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

and mortality rate of patients may be elucidated in part by different steps of metastatic spread.15 The current assumption is that TNBC metastasize to axillary lymph nodes and bone less frequently than the non TNBC subset of breast cancer, favoring a hematogenous spread.16,17 In the present study, we observed significantly high intratumoral CD3+ counts in relation to tumor stage. Association of CD3+ TILs with other factors like age, menstrual status, family history, histological grade and lymph node status were not significant. High grade, stage and lymph node positivity are known poor prognostic factors in breast cancer. Similar findings have been reported for medullary carcinoma of breast by other workers.18 The presence of CD3+ TILs has been attributed to the positive outcome in several studies.19,20 The high counts of CD3+ TILs compared to low counts have been reported to be associated with better survival in Stage IB cervical cancer.21 In a recent study, the presence of intratumoral CD3+ TILs was associated with better survival in epithelial ovarian cancer.22 It is well-known that women with TNBC had significantly shorter disease free and overall survival time than other subtypes.23 The high intratumoral and stromal TILs in our study predicted longer survival (p = 0.004 and p = 0.01), respectively), implying that higher CD3+ TILs may act as good prognostic marker in TNBC. We used IHC for CD3+ TILs semi-quantification, which had the distinct advantage of morphologically observing the TILs in intratumoral and stromal areas. Further, the size of the histological sections taken for

Oncology Table 2. Association of Intratumoral and Stromal CD3+ Count with Clinicopathological Characteristics Variables

Intratumoral CD3+ count

Stromal CD3+ count

Low (n = 8)

High (n = 17)

p value

Low (n = 9)

High (n = 16)

p value

52.3 ± 11.7

48.5 ± 13.4

0.49

49.8 ± 14.4

49.5 ± 12.2

0.96

(30-80)

(25-86)

(26-87)

(26-85)

Premenopause

4 (50%)

5 (29.41%)

3 (33.33%)

6 (37.5%)

Postmenopause

4 (50%)

12 (70.59%)

6 (66.67%)

10 (62.5%)

8 (100%)

15 (88.24%)

8 (88.89%)

15 (93.75%)

Yes

2 (11.76%)

1 (11.11%)

1 (6.25%)

I-II

2 (25%)

10 (58.82%)

2 (22.22%)

10 (62.5%)

III-IV

6 (75%)

7 (41.18%)

7 (77.78%)

6 (37.5%)

T1-T2

1 (12.5%)

10 (58.82%)

1 (11.11%)

10 (62.5%)

T3-T4

7 (87.5%)

7 (41.18%)

8 (88.89%)

6 (37.5%)

Negative

2 (25%)

8 (47.06%)

3 (33.33%)

7 (43.75%)

Positive

6 (75%)

9 (52.94%)

6 (66.67%)

9 (56.25%)

Well

2 (25%)

15 (88.24%)

3 (33.33%)

14 (87.5%)

Not well

6 (75%)

2 (11.76%)

6 (66.67%)

2 (12.5%)

Age (years) Mean ± SD (range) Menstrual status 0.40

1.00

Family history 1.00

1.00

Grade 0.20

0.09

Stage 0.04

0.03

Lymph node 0.40

0.69

Treatment response

IHC is also significant if morphological observations are to be made separately within the tumor areas and the stromal component. We performed IHCs on larger tissue sections obtained from resected specimens, not on core biopsies. The idea in our study was to locate whether IHC with infiltrating CD3+ TILs could be used as an adjunct to all cases of TNBC. This could be useful in stratifying the patients into high-risk or low-risk category at the time of tissue diagnosis on resected specimen. Conclusion The present study proposes that detection of the density and location of CD3+ TILs in TNBC could be a good prognostic factor. A larger number of sample size need to be studied and linked with their survival. References 1. Key TJ, Verkasalo PK, Banks E. Epidemiology of breast cancer. Lancet Oncol 2001;2(3):133-40.

0.004

0.01

2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127(12):2893-917. 3. Dent R, Hanna WM, Trudeau M, Rawlinson E, Sun P, Narod SA. Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat 2009;115(2):423-8. 4. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313(5795):1960-4. 5. Chiba T, Ohtani H, Mizoi T, Naito Y, Sato E, Nagura H, et al. Intraepithelial CD8+ T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: possible association with suppression of micrometastasis. Br J Cancer 2004;91(9):1711-7. 6. Schumacher K, Haensch W, Röefzaad C, Schlag PM. Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res 2001;61(10):3932-6. 7. Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, et al. Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell

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19. Rabinowich H, Cohen R, Bruderman I, Steiner Z, Klajman A. Functional analysis of mononuclear cells infiltrating into tumors: lysis of autologous human tumor cells by cultured infiltrating lymphocytes. Cancer Res 1987;47(1):173-7.

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20. Topalian SL, Solomon D, Rosenberg SA. Tumor-specific cytolysis by lymphocytes infiltrating human melanomas. J Immunol 1989;142(10):3714-25.

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21. Baxevanis CN, Dedoussis GV, Papadopoulos NG, Missitzis I, Stathopoulos GP, Papamichail M. Tumor specific cytolysis by tumor infiltrating lymphocytes in breast cancer. Cancer 1994;74(4):1275-82.

14. Ancuta E, Ancuţa C, Zugun-Eloae F, Iordache C, Chirieac R, Carasevici E. Predictive value of cellular immune response in cervical cancer. Rom J Morphol Embryol 2009;50(4):651-5.

22. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003;348(3):203-13.

15. Dent R, Hanna WM, Trudeau M, Rawlinson E, Sun P, Narod SA. Time to disease recurrence in basal-type breast cancers: effects of tumor size and lymph node status. Cancer 2009;115(21):4917-23.

23. Banerjee S, Reis-Filho JS, Ashley S, Steele D, Ashworth A, Lakhani SR, et al. Basal-like breast carcinomas: clinical outcome and response to chemotherapy. J Clin Pathol 2006;59(7):729-35.

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It Even Happens in US: Doctor Gave Chemo to Patients without Cancer Hematologist-oncologist Farid Fata, MD, in suburban Detroit, Michigan, was arrested August 6 and charged with Medicare fraud. In a criminal complaint filed in a federal district court in Detroit, prosecutors said that the 48-year-old Dr Fata ordered toxic chemotherapy for patients who did not have cancer or whose cancer was in remission. Rather than keeping their heads down, some employees at Dr. Fata’s high-profile practice challenged his actions before he was arrested, according to the government. One employed oncologist, for example, told agents from the FBI and the Dept. of Health and Human Services that he discovered that Dr Fata had ordered chemotherapy for a patient whose cancer was in remission. This oncologist and other employees also reported that Dr Fata ordered intravenous immunoglobulin (IVIG) for patients whose antibody levels did not warrant the therapy. One nurse practitioner (NP) told federal agents that she pulled the charts for 40 patients scheduled for IVIG therapy and saw that 38 had neither low antibody levels nor a recurrent infection, which is another indication for the treatment. The NP consulted 2 other employees about the issue, and the 3 of them canceled the IVIG therapy for the 38 patients. Dr Fata’s employees had internally challenged other practices they considered unethical, such as fabricating cancer diagnoses in patient records to justify insurance claims for chemotherapy and positron emission tomography (PET) scans. Dr Fata vehemently denies all the allegations.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Psychiatry

A Clinical Study in Management of Primary Insomnia: Hypnotic versus Anxiolytic Sreekumar D*, Santhosh Kumar M†

Abstract Background: Hypnotic benzodiazepines remain the proven treatment of primary insomnia although newer nonbenzodiazepine agents may also be used. Additionally, anxiolytic benzodiazepine like alprazolam is commonly prescribed off-label for managing primary insomnia. When anxiety is not the cause of primary insomnia, why use an anxiolytic in the first place? Hence, the objective of this study was to evaluate the safety and efficacy of hypnotic drug nitrazepam in comparison with anxiolytic alprazolam in treatment of primary insomnia. Study design: An open label, active control, parallel study carried throughout India in 40 clinics on 160 patients. A subjective sleep diary card was used to evaluate sleep parameters and tolerability to both drugs. Results: A statistically significant increase in total sleep duration and improvement in sleep quality was noted in nitrazepam group compared to alprazolam group as early as Day 7. There was a significant reduction in sleep latency with number of night time awakenings in the nitrazepam group compared to the alprazolam group. Treatment-related adverse drug reactions and post-treatment rebound insomnia were significantly higher in the alprazolam group. Conclusion: Significantly more patients in the nitrazepam group had a superior hypnotic effect with lesser adverse reactions and fewer rebound insomnia compared to the alprazolam group.

Keywords: Primary insomnia, nitrazepam, alprazolam, rebound insomnia

leep accounts for one-third of human life, is vital for maintaining good health and survival. The general consensus based on many population studies is that approximately 30% of variety of adult samples drawn from different countries report one or more of the following symptoms: Difficulty in initiating or maintaining sleep, waking-up too early or in some case poor quality of sleep.1 Insomnia is not defined by total sleep time but by the inability to obtain sleep of sufficient length or quality to produce refreshment the following morning.2 Given the fact that sleep disorders for the most part still remain under-diagnosed, the actual prevalence of sleep

*Professor and HOD, Dept. of Psychiatry Amala Institute of Medical Sciences Amala Nagar, Thrissur, Kerala †Medical Advisor Anglo-French Drugs & Industries Ltd. Rajajinagar, Bangalore, Karnataka Address for correspondence Dr Sreekumar D Professor and HOD, Dept. of Psychiatry Amala Institute of Medical Sciences Amala Nagar, Thrissur - 680 555, Kerala E-mail: sreekumar.amala@gmail.com

disorders is not known.3 There are not many studies published from India regarding the prevalence of sleep disorders as it is unrecognized as a major public issue. A study published by the National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore reported 18.6% of insomnia. A higher prevalence of sleep disorders related to initiation and maintenance of sleep (28%) was reported in an urban population of north India.4 Despite the wide availability of pharmacological treatments and increased knowledge of behavioral interventions, the vast majority of individuals with primary insomnia do not appear to be receiving the right and adequate treatment. Inadequate treatment leads to several important and under-recognized consequences including subsequent development of psychiatric disease and increased substance use.5 The American Psychiatric Association defines two types of insomnia: Primary and secondary. The term ’Primary insomnia’ used to distinguish insomnia that is considered to be a distinct diagnostic entity from insomnia that is a secondary symptom of an underlying medical and/or psychiatric condition. Psychotherapy, behavioral approaches and pharmacotherapy, alone

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Psychiatry or in combination should be considered in the formulation of a comprehensive treatment plan. When pharmacotherapy is indicated, benzodiazepine receptor agonist is preferable.6 The currently used hypnotics for treatment of primary insomnia are benzodiazepine receptor agonists that include both benzodiazepine and newer nonbenzodiazepine drugs (Z group of drugs). Other classes of drugs frequently used in the treatment of primary insomnia are anxiolytics, antidepressants, anti-psychotics, antihistamines and anticonvulsants.7 Over-prescribing and/or inappropriate prescribing of anxiolytic benzodiazepines especially alprazolam in primary insomnia is a common problem that leads to increased risks of patient dependence.8 In addition to the risk of misuse and overdose, there is growing anecdotal evidence of a link between these drugs and aggressive behavior, particularly in relation to alprazolam.9 Withdrawal from alprazolam has been described a tedious process and unresponsive to standard medical withdrawal regimens.10 In India, alprazolam is the most commonly prescribed as offlabel or obtained over-the-counter for this purpose. The present study was undertaken to evaluate the safety and efficacy of hypnotic drug nitrazepam in comparison with anxiolytic alprazolam in treatment of primary insomnia.

Exclusion Criteria ÂÂ

Recent history of (<2 years) alcohol or drug abuse or current evidence of substance dependence.

ÂÂ

Transient or situational insomnia, e.g., insomnia due to time-zone shifts, shift-work schedules, acute stress and drugs.

ÂÂ

Subjects with a known hypersensitivity to nitrazepam, alprazolam or any of the excipients in the formulation.

ÂÂ

History or current manifestations of sleep apnea, restless leg syndrome or a history of routine day time napping.

ÂÂ

Current or past history of seizure disorder, clinically significant head injury or a major psychiatric disorder that would likely affect the study.

ÂÂ

Subjects who had used any other investigational drug within the last 30 days.

ÂÂ

Subjects receiving hypnotics, tricyclic antidepressants, monoamine oxidase inhibitors, serotonin reuptake inhibitors, lithium, β-blockers, alprazolam, triazolam, neuroleptics or barbiturates. Subjects receiving any of these compounds were eligible for entry provided the medication was stopped 2 weeks prior to study entry.

ÂÂ

Patients with serious cardiac disorders, serious hepatic impairment and serious renal diseases.

MATERIAL AND METHODS

Study Design

Patients of either sex aged between 21-65 years, diagnosed to have primary insomnia as per Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) and who had the following symptoms present at least 1 week prior to randomization: Typical or modal time to sleep onset of 30 minutes or more in four out of seven nights, insomnia-associated day time complaints (fatigue, irritability, difficulty concentrating), a mean total sleep duration of not ≥6.5 hours per night or frequent (three or more per night) nocturnal awakenings with difficulty falling back to sleep were enrolled in the study.11

This was an open label, active control, multi-clinic parallel group study carried throughout India from February 2014 to April 2014. The study period was 21 days for all enrolled patients, treatment period of 14 days and follow-up period of 7 days. After patients fulfilled the study inclusion and exclusion criteria, they were enrolled randomly at a ratio of 1:1 in either of nitrazepam 5 mg group or alprazolam 0.25 mg group. The patients were asked to take one tablet at bedtime for 14 consecutive days. All patients in both groups were given a sleep diary card and told how to record daily sleep-related events like the duration of period awake before falling asleep (sleep latency), quality of sleep, duration of sleep, number of time awakenings during the night and any adverse reactions daily upon awakenings. Patients in both groups (n = 80 in each group), were advised to attend the outpatient clinic on morning of Days 8, 15 and 21 for clinical evaluation. At the follow-up visit, the patient’s responses to the study drug and compliance were evaluated along with any drug-related adverse reactions. The patients were advised not to use any other medication for sleep during the study period.

Inclusion Criteria ÂÂ

Not taken any insomnia medication for 7 days before study entry (washout period).

ÂÂ

Women should not be pregnant/breastfeeding and had to be using adequate contraception.

ÂÂ

In the investigator’s judgment, subject is mentally competent to participate in the study and complete study-related activities like willing to come to follow-up and record the sleep-related responses.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Psychiatry Outcome Variables Primary efficacy variable was the mean sleep duration (total sleep time) during 2 weeks treatment period compared to baseline. Secondary efficacy variables were assessment of the change in mean sleep latency (time required to fall asleep), mean number of night time awakenings and quality of sleep (patients impression during study period rated according to the following scale: 1 = excellent, 2 = very good, 3 = good, 4 = poor and 5 = very poor) from baseline to Week 2. Incidence of rebound insomnia in 7 days follow-up (worsening of insomnia symptoms beyond baseline levels) and safety and tolerability assessment throughout the treatment period were also evaluated.

Statistical Analysis Parametric methods (student ‘t’ test) were used to test difference between groups, for outcome variables like duration of sleep, time to fall asleep and number of night time awakenings. While nonparametric methods (Mann-Whitney ‘U’ test) were applied for the sleep quality score. In order to find out whether any significant difference in adverse effects and rebound insomnia between both groups existed, chi-squared test was used. The treatment difference were considered significant at p < 0.05. Statistical Package for Social Sciences (SPSS) version 20.0 was used for analysis. RESULTS AND OBSERVATION A total of 160 patients were enrolled in the study, 80 in each group. One patient in alprazolam group was lost to follow-up. Hence, 159 patients completed the study without major deviations and were evaluated.

The baseline characteristics of patients with regard to sex (M:F 1.4:1 in alprazolam group and 1.5:1 in nitrazepam group), age in years (average 45.5 years) and baseline sleep parameters were comparable in both groups with no significant difference. A statistically significant increase in total sleep duration was noted in nitrazepam group compared to alprazolam group as early as 7th day and 14th day of treatment (p < 0.001). There was a significant reduction in sleep latency with number of night time awakenings and a significant increase in proportion of patients who reported improvement of sleep quality in nitrazepam group compared to alprazolam group both on Day 7 and Day 14 (Table 1 and Figs. 1-4).

Safety and Withdrawal Symptoms Common expected adverse drug reactions like dizziness, headache, day time somnolence and memory impairment occurred in the study groups. The incidence of treatment-related adverse drug reactions were significantly higher in alprazolam group (74.69%) compared to 41.25% in nitrazepam group (p < 0.05). Treatment with alprazolam was associated more with occurrence of adverse events than that with nitrazepam (χ2 = 18.2, p < 0.001). There were other drug reactions that occurred with lesser frequency in nitrazepam drug group compared to alprazolam drug group, though the difference was not significant (Table 2). The odds ratio (unadjusted) of reporting an adverse reaction with nitrazepam treatment was 0.25 (95% confidence interval [CI] 0.12-0.47) to one with alprazolam treatment. The incidence of rebound insomnia during posttreatment period was seen in only three patients (3.75%) in nitrazepam group compared to 49 patients (62.02%) in

Table 1. Mean Changes in Sleep Measurement from Baseline Day 1 (Baseline)

Total sleep duration (in hours) Sleep latency (in minutes) Number of night time awakenings Sleep quality score

Nitrazepam (n = 80)

Alprazolam (n = 79)

4.19 (1.23)

4.17 (1.04)

145.06 (79.3) 154.24 (68.8)

Day 7

Day 14

Nitrazepam Alprazolam P value (n = 80) (n = 79)

Nitrazepam (n = 80)

Alprazolam (n = 79)

P value

6.8 (1.2)

5.72 (1.3)

<0.001*

7.1 (0.94)

6.06 (1.3)

<0.001*

54.2 (53.3)

81.37 (63.5)

0.005*

41.64 (41.62)

71.104 (61.7)

0.001*

4.65 (1.53)

4.70 (1.46)

1.4 (1.35)

2.38 (1.55)

<0.001*

1.09 (0.95)

2.3 (1.39)

<0.001*

4.43

4.41

2.52

3.35

<0.001#

2.21

3.18

<0.001#

Data presented as mean (SD), * = ‘t’ test, # = Mann-Whitney ‘U’ test.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

6.00

5.00

Error bars: 95% CI

150

100

4.00 Baseline Day 7 Day 14

Baseline Day 7 Day 14

Nitrazepam

Alprazolam

Figure 1. Comparison of mean total sleep duration in hours.

Alprazolam

Figure 2. Comparison of mean sleep latency in minutes.

Mean sleep quality score

Error bars: 95% CI

4 3 2 1 0

Baseline Day 7 Day 14

Nitrazepam

Mean no. of night time awakenings

200

Error bars: 95% CI

7.00

Mean sleep latency (in minutes)

Mean total sleep duration (in hours)

Psychiatry

Baseline Day 7 Day 14

Error bars: ±2 SE

(Very poor) 5 (Poor) 4 (Good) 3 (Very good) 2 (Excellent) 1 0

Baseline Day 7 Day 14

Nitrazepam

Baseline Day 7 Day 14

Nitrazepam

Baseline Day 7 Day 14

Alprazolam

Figure 3. Comparison of mean number of night time awakenings.

Figure 4. Comparison of mean sleep quality score.

Table 2. Treatment-related Adverse Drug Reactions in Both Groups Drug nitrazepam (n = 80)

Drug alprazolam (n = 79)

χ2

P value

Dizziness

16 (20%)

38 (48.101%)

13.9

<0.001

Headache

11 (13.75%)

26 (32.91%)

8.17

0.004

4 (5%)

13 (16.45%)

5.4

0.02

4 (5.06%)

4.1

0.04

Anxiety

4 (5%)

8 (10.12%)

1.4

Body ache and stiffness

4 (5%)

4 (5.06%)

Null

Adverse event

Day time somnolence Memory impairment

Nausea and vomiting

1 (1.25%)

4 (5.06%)

1.8

Double vision

1 (1.25%)

3 (3.79%)

1.05

Muscle weakness

1 (1.25%)

3 (3.79%)

1.05

1 (1.26%)

1.01

Mild confusion Sleep disturbance

1 (1.26%)

1.01

Chest pain

1 (1.26%)

1.01

Breathlessness

1 (1.26%)

1.01

χ2 = Chi-square test, NS = Not significant.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Psychiatry alprazolam group. Rebound insomnia was significantly lesser in patients treated with nitrazepam compared to patients treated with alprazolam (Ď&#x2021;2 = 61.33, p < 0.001). The odds ratio (unadjusted) of reporting a rebound insomnia with nitrazepam treatment was 0.023 (95% CI 0.006-0.082) to one with alprazolam treatment. All adverse reactions noted in this study were minor in nature; there was no reported serious adverse drug reaction in either of the patients groups. None of the patients pulled out of the study due to adverse drug reactions. DISCUSSION Several studies have been carried out and published to establish the safety and efficacy of hypnotics like flurazepam, triazolam, nitrazepam, temazepam and nonbenzodiazepines (Z group of drugs) in the treatment of primary insomnia. Benzodiazepine receptor agonists have been the drugs of choice for the treatment of insomnia since their introduction in the early 1960s. They are relatively safe when used under medical supervision. In contrast off-label use of anxiolytic benzodiazepine receptor agonist like alprazolam in treatment of primary insomnia is not approved or no studies published to establish their dose and safety. In a similar study by Kales et al, it was concluded that the clinical utility of alprazolam when wrongly administered in insomnia patients appears to be limited because of a relative rapid development of tolerance and possible disinhibitory reactions during drug use.12 Alprazolam is not generally recommended for simple hypnotic use, in view of a rapidly appearing tolerance and notable rebound insomnia.13 Although, the clinical benefits of nitrazepam have been established and published in the treatment of primary insomnia, this is the first study in India providing a direct comparison between a commonly used off-label drug alprazolam with a known hypnotic nitrazepam. It can be seen from the present study, there was a statistically significant increase in total sleep duration noted in nitrazepam group compared to alprazolam group as early as 7th day. A significant reduction in sleep latency and number of night time awakenings compared to baseline was noted in nitrazepam group compared to alprazolam group. In a comparative study by Anderson et al, it was observed that nitrazepam improved all sleep measures of efficacy from the first night and effectiveness was maintained all throughout the 2 weeks of treatment period.14

There was a significant increase in proportion of patients who reported improvement of sleep quality in nitrazepam group versus alprazolam group in the present study. In a study by Gotestam et al, nitrazepam was evaluated both in regard to alleviating insomnia and to withdrawal symptoms. The results show that the drug was effective in inducing sleep and increasing sleep quality in insomnia.15 The incidence of treatment-related adverse drug reactions were significantly higher in alprazolam drug group (74.69%) compared to nitrazepam drug group (41.25%). Forty-nine patients (62.02%) in alprazolam group showed rebound insomnia during post-treatment (Days 15-21), whereas only three of the patients in nitrazepam group showed rebound insomnia. A study by Anderson et al reported no rebound insomnia was evident during the 7-day post-treatment withdrawal period and tolerance was good for nitrazepam.14 In a study by Priest et al, patients on nitrazepam were a little more clear-headed in the morning, though they tended to wake later, sleep longer and take more sleep over the 24-hour period. No toxicity was found with the drug over the 434 patient days of administration.16 A study by Kales et al reported occurrence of rebound insomnia following withdrawal from alprazolam when evaluated in chronic insomniacs.12 Although, these drugs share the same mechanism of action as hypnotics, their hypnotic doses are not known, have no safety and efficacy studies published, hence their use as hypnotics in treatment of primary insomnia is not advised. CONCLUSION In summary, the results of this study are consistent with other published studies regarding safety and efficacy of hypnotic nitrazepam in treatment of primary insomnia. In general, clinicians should use regularly approved hypnotics for treatment of primary insomnia. They should apply extreme caution in off-label use of anxiolytic drugs like alprazolam not approved for treatment of primary insomnia as they can lead to drug dependence and rebound insomnia.

List of Study Doctors Dr AK Sharma (Lucknow); Dr AK Singh (Sambalpur); Dr Anil Kumar Bansal (Ghaziabad); Dr Anjali Jain (Jaipur); Dr Arvind A Kunde (Ghatkopar, West Mumbai); Dr Avinash Swaroop (Jaipur); Dr Avula Ramachander Rao (Hyderabad); Dr GC Pradhan (Mishra Pada, Angul); Dr Gouranga Choudhury (Berhampur); Dr HD Santdasani (Siddhpur); Dr HK Panchal

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Psychiatry (Palanpur); Dr Herdeep Singh (Sambalpur); Dr Himanshu G Chauhan (Baroda); Dr JP Singh Nimi (Muzaffarnagar); Dr J Venkatesan (Thanjavur); Dr Jayaprakesh KK (Kakkanad); Dr K Ramesh (Bangalore); Dr Kalaichelvan (Chennai); Dr Krutagnasinh (Baroda); Dr M Murugappan (Madurai); Dr M Srinivasa Raju (Vijayawada); Dr Minaketan Kar (Sambalpur); Dr Muthusamy (Salem); Dr Naren U Rewar (Kalachoky, Mumbai); Dr NP Sinha (Jharkhand); Dr Nazifizziadi (Hyderabad); Dr Om Prakash Saha (Purnea); Dr P Prasad Babu (Visakhapatnam); Dr Rajesh Kewalramani (Dahisar, Mumbai); Dr Rajesh U Motwani (Rajkot); Dr Rakesh Ghildiyal (Badlapur, New Mumbai); Dr Sreekumar D (Thrissur); Dr Surendra Kumar (Muzaffarpur); Dr Suresh G (Trivandrum); Dr T Muralidhar Rao (Karimnagar); Dr T Jayaramakrishnan (Tirunelveli); Dr Uma Jyothi (Guntur); Dr VD Meel (Jaipur); Dr Vimal Kumar Razdan (Jodhpur) and Dr Yadhava Kumar SD (Mysore).

Acknowledgment We thank all the study investigators for their support, the patients who took part in the study with their valuable feedback, and Mr. Abhijit Sonowal (AFDIL) for helping in preparation of this manuscript.

References 1. Roth T. Insomnia: definition, prevalence, etiology, and consequences. J Clin Sleep Med 2007;3(5 Suppl):S7-10. 2. Attarian HP. Pharmacological Treatment of Insomnia. Clinical Handbook of Insomnia, Totowa, NJ 2004:p. 173-86. 3. Sharma PK, Shukla G, Gupta A, Goyal V, Srivastava A, Behari M. Primary sleep disorders seen at a Neurology service-based sleep clinic in India: Patterns over an 8-year period. Ann Indian Acad Neurol 2013;16(2):146-50. 4. Panda S, Taly AB, Sinha S, Gururaj G, Girish N, Nagaraja D. Sleep-related disorders among a healthy population in South India. Neurol India 2012;60(1):68-74.

5. Drake CL, Roehrs T, Roth T. Insomnia causes, consequences, and therapeutics: an overview. Depress Anxiety 2003;18(4):163-76. 6. Drugs and insomnia: the use of medications to promote sleep. NIH Consens Statement Online 1983;4(10):1-19. 7. Bhatia M, Sharma M. Insomnia and its management. Indian J Sleep Med 2009;4(4):125-31. 8. Drug use review. Missouri DuReport. News letter, June/ July 2004;9(1). 9. Jones KA, Nielsen S, Bruno R, Frei M, Lubman DI. Benzodiazepines - Their role in aggression and why GPs should prescribe with caution. Aust Fam Physician 2011;40(11):862-5. 10. Dickinson B, Rush PA, Radcliffe AB. Alprazolam use and dependence. A retrospective analysis of 30 cases of withdrawal. West J Med 1990;152(5):604-8. 11. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. The American Psychiatric Association: Washington, DC, 2000. 12. KalesA, Bixler EO, Vela-BuenoA, Soldatos CR, Manfredi RL. Alprazolam: effects on sleep and withdrawal phenomena. J Clin Pharmacol 1987;27(7):508-15. 13. Mohns EB. Discontinuation and withdrawal problems of alprazolam. West J Med1989;151(3):312. 14. Anderson AA. Zopiclone and nitrazepam: a multicenter placebo controlled comparative study of efficacy and tolerance in insomniac patients in general practice. Sleep 1987;10 Suppl 1:54-62. 15. Götestam KG, Oppöyen F, Berntzen D. Treatment of insomnia with two benzodiazepines: a double-blind crossover study. Eur J Clin Pharmacol 1991;41(2):137-40. 16. Priest RG, Rizvi ZA. Nitrazepam and temazepam: a comparative trial of two hypnotics. J Int Med Res 1976;4(3):145-51.

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Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

UROLOGY

Nephrotic Syndrome: A Rare Presentation of AIDS Prabhat Agrawal*, Ashish Gautam*, Manish Kumar Bansal†, Ayush Agrawal‡

Abstract The clinical presentation of HIV-associated nephropathy (HIVAN) include proteinuria, typically in nephrotic range (often massive) and renal insufficiency. HIVAN can be an early manifestation of HIV infection. The term HIVAN is reserved for focal segmental glomerulosclerosis (FSGS) but other glomerular lesions may be there. We are reporting a case of nephrotic syndrome (MPGN) in an otherwise asymptomatic HIV-infected patient.

Keywords: HIVAN, nephrotic syndrome, MPGN

uman immunodeficiency virus (HIV) disease usually presents with the classical features of acquired immunodeficiency syndrome (AIDS) and opportunistic infections. According to available literature, presentation of anasarca is rare. HIV-associated nephropathy (HIVAN) is one of the leading causes of end-stage renal disease (ESRD) among HIV-infected patients. HIVAN is characterized by heavy proteinuria and impairment of renal function. HIVAN could be an early manifestation of HIV infection. The term HIVAN is reserved for the characteristic light microscopic pattern of focal segmental glomerulosclerosis (FSGS) with collapsing feature and related mesangiopathies.1 Here, we are reporting a case who presented with anasarca, an uncommon feature of HIV-associated nephropathy.

CASE REPORT A 24-year-old male came to the outdoor department (OPD) with complaints of progressive generalized swelling for 20-25 days. There was no history of fever, decreased urinary output, jaundice, rash, oral ulcers, sore throat, arthralgia, hematuria, blood transfusion or recent vaccination.

*Assistant Professor †Associate Professor ‡Junior Resident PG Dept. of Medicine Sarojini Naidu Medical College, Agra, Uttar Pradesh Address for correspondence Dr Prabhat Agrawal Assistant Professor PG Dept. of Medicine Sarojini Naidu Medical College, Agra, Uttar Pradesh E-mail: prabhatagrawal123@rediffmail.com

On examination, the blood pressure reported was 170/100 mmHg and pulse rate was 88 per minute. The patient was having pallor and generalized swelling (pitting type), without lymphadenopathy or icterus. Chest, cardiovascular and neurological examination was normal. On abdominal examination, distended abdomen and mild hepatosplenomegaly was present. His investigations revealed hemoglobin (Hb) was 8.8 g/dL, total leukocyte count was 6,900/mm3 (P-40, L-46, E-12, M-2), platelet count was 1.78 lakh/mm3, blood urea was 75 mg/dL and serum creatinine was 2.2 mg/dL. On urine examination, albumin was 4+, RBCs: 20-30 per high power field, 2-3 pus cells/HPF and granular and hyaline casts were present. Total serum proteins reported were 4.2 g/dL with both albumin and globulin being 2.1 mg/dL each. Serum cholesterol was 310 mg/dL. Antistreptolysin O (ASO) titer was negative at the time of admission and after 1 week. Liver function tests (LFTs), thyroid function tests and serum electrolytes and blood sugar levels were found to be normal. Chest X-ray was normal. Ultrasonography (USG) abdomen showed bilaterally enlarged kidneys with the right kidney being 151 × 67 mm and left kidney being 155 × 75 mm, hepatosplenomegaly and mild ascites. On further investigations, C3 complement levels were low (< 0.30 g/dL) and C4 was normal. Twentyfour hours urinary protein was found to be 17.8 g. The patient was found to be HIV-1 positive by enzyme-linked immunosorbent assay (ELISA) and his absolute CD4 count was 301. Hepatitis B surface antigen (HBsAg) and anti-HCV (hepatitis C virus) were negative. Renal biopsy was done with universal precautions and on light microscopy membranoproliferative glomerulonephritis (MPGN) was diagnosed.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

UROLOGY The working diagnosis was kept as an immunocompromised state that presented with anasarca, the cause being nephrotic syndrome (MPGN).

renal disease with heavier proteinuria and higher incidence of nephrotic syndrome and associated renal insufficiency.

The patient was treated conservatively with salt and fluid restriction along with antihypertensives, diuretics and angiotensin-converting enzyme (ACE) inhibitors. The patient was put on corticosteroids (prednisolone 1 mg/kg daily) and antiretroviral therapy (ART) after the biopsy report. On follow-up after 1 month, his anasarca had subsided and the patient was asymptomatic. His 24-hour urine protein had decreased to 7.5 g/dL. Now the patient is on ART and tapering dose of steroids over 2-3 months, and is in regular follow-up after every 15 days.

Racial factors are also important as they are involved in the mutation of HIV receptors, which may in part, explain some differences in the racial predisposition of HIV infection to HIVAN. Although intravenous drug use has been the most common risk factor for HIVAN, the disease has been seen in all groups at risk for AIDS including homosexuals, those with perinatally acquired disease, heterosexual transmission and exposure to contaminated blood products. HIVAN usually occurs in patients with a low CD4 count, but full blown AIDS is not a pre-requisite for the disease. In one New York study, the onset of HIVAN was most common in otherwise asymptomatic HIV-infected patients (12 out of the 26 were asymptomatic patients). There is no relationship between the development of HIVAN and the patient age, duration of HIV infection or the presence or absence of other opportunistic infections.

DISCUSSION Renal involvement in a patient infected with HIV may include glomerulonephritis, tubule interstitial disease, acute tubular necrosis, drug-related interstitial nephritis, pyelonephritis, nephrocalcinosis, electrolyte abnormalities, neoplasms (Kaposiâ&#x20AC;&#x2122;s sarcoma and lymphoma) and opportunistic infections (such as aspergillosis, mucormycosis and adenovirus infections).2 The classic and the most common HIV-associated glomerulopathy is an aggressive form of FSGS, an entity that is termed as HIVAN. This disease may be the first manifestation of infection in an otherwise asymptomatic patient.3 Renal biopsy typically reveals visceral epithelial cell swelling, collapse of the glomerular capillary tuft, severe tubule-interstitial inflammation and microcystic dilatation of renal tubules. The presence of tubuloreticular inclusions and the aggressive clinical course distinguish HIVAN from idiopathic FSGS. The mechanisms of renal cell injury are still being defined. Viral DNA has been demonstrated in the renal epithelia of HIV-infected patients with or without nephropathy, suggesting that pathogenic factors, other than the infection of cells, are required for the induction of disease. In HIV-infection, about 73% are FSGS (HIVAN), about 10% are MPGN, 6% are minimal change disease and 5% are membranous nephropathy. Immunoglobulin A nephropathy and mesangioproliferative nephropathy make up the remaining fraction.1 There is strong predilection for HIVAN among black HIV-infected patients. The black:white ratio among patients with HIVAN is 12:1.4 Blacks are also more likely to have more severe clinical

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

The clinical features of HIVAN include the presenting features of proteinuria (typically in the nephrotic range) and renal insufficiency. Other manifestations of the nephrotic syndrome including edema, hypoalbuminemia and hypercholesterolemia have been common. The sonographic evaluation may reveal enlarged kidneys. The clinical course in most patients is marked by progression to ESRD within weeks to months. MPGN may be the most common pattern of immune complex-mediated glomerulonephritis seen in HIVinfected patients.5 MPGN is a pathologic term characterized by thickening of the glomerular basement membrane, proliferation of mesangial cells and influx of mononuclear inflammatory cells. This disease is often the result of immune complexes. Immune complex disease associated with HCV coinfection is the most common cause of MPGN in HIV-1 infection. Renal function in some patients has been reported to improve dramatically in response to treatment with corticosteroids, but this is not predictable and carries significant risk.6 At present, the therapy of HIVAN should include the same ART as the patients without nephropathy. ACE inhibitors have been shown to decrease the proteinura in HIVAN and to slow the progression to renal failure. Renal transplantation is a viable option in selected patients.7 Our patient of nephrotic syndrome was diagnosed to be a case of MPGN, which can be the initial manifestation

UROLOGY of HIV infection. Therefore, we suggest that in an unexplained case of nephrotic syndrome in an adult, the HIV status should be checked.

4. Bourgoigine JJ, Ortiz-Interian C, Green DF. The human immunodeficiency virus epidemic and HIV associated nephropathy. In: Nephrology. Hatano M (Ed.), SpringerVerlag: Tokyo 1990:p.484-92.

REFERENCES

5. Appel, Radha Krishnan, D’Agati. Secondary glomerular disease. In: Brenner and Rector’s: The Kidney. 7th edition, Brenner BM (Ed.), Saunders 2004:p.1381-447.

1. D’Agati V, Appel GB. Renal pathology of human immunodeficiency virus infection. Semin Nephrol 1998; 18(4):406-21. 2. Rao TK, Freidman EA, Nicastri AD. The types of renal disease in acquired immunodeficiency syndrome. N Engl J Med 1987;316(17):1062-8.

6. Smith MC, Pawar R, Carey JT, Graham RC Jr, Jacobs GH, Menon A, et al. Effect of corticosteroid therapy on human immunodeficiency virus associated nephropathy. Am J Med 1994;97(2):145-51.

3. Brady HR, Yvonne M, Meara O’, Barry M, Brenner. Glomerular disease. In: Harrison’s Principles of Internal Medicine. 18th edition. Kasper DL (Ed.),

7. Winston JA, Klotman PE. Renal disease. In: AIDS Therapy. 2nd edition, Dolin R, Masur H, Sarg MS (Eds.), Churchill Livingstone 1999:p.853-9.

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A patient’s immune response may provide better and more rapid insights into the cause, severity and prognosis of certain bacterial infections than conventional tests, according to a study appearing in an upcoming issue of the Journal of the American Society of Nephrology (JASN). Such an “immune fingerprint” could lead to more accurate diagnoses and more appropriate antibiotic treatment. Approximately 11% of kidney failure patients on dialysis receive peritoneal dialysis, which is home-based. Peritoneal dialysis is generally perceived as less burdensome and as effective as clinic-based hemodialysis, but infections can cause treatment failure and even patient death if not detected early. Unfortunately, current tests for infections - which use microbiological culture methods - are slow and inefficient. Fear of infection is the major reason for patients and their doctors to opt against peritoneal dialysis despite its otherwise potential clinical benefit. “To our knowledge, this is the first study in acutely infected patients exploiting the notion that microorganisms display distinct sets of pathogen-associated patterns and interact with the immune system in a unique and specific manner for diagnostic purposes,” said Professor Topley. In addition to potentially improving the diagnosis and treatment of peritonitis in peritoneal dialysis patients, the findings may also be applicable to other local and systemic infections. Dr. Eberl added that “the data suggest that it may be possible to develop a simple fingerprintbased point-of-care test that can be used by a general practitioner - at the bed-side or at home - to ensure that the right treatment is given to each patient.” In an accompanying editorial, Marien Fieren, PhD (Erasmus Medical Center, in The Netherlands) noted that the study “deepens our understanding of the complex, local pathogen-host interactions. Such patient-based studies are important not only from a theoretical perspective but also for the prospect of future developments that could improve diagnosis and management of the various forms of peritonitis.” Customizing Treatments for Deadly Prostate Cancer with Tumor Genomics. A new study at Mayo Clinic is using genomic sequencing to develop customized treatments for men with castration-resistant prostate cancer, a progressive and incurable stage of prostate cancer, which no longer responds to hormone therapies that stop or slow testosterone production. Several new therapies have recently been approved by the FDA for use in treating castration-resistant prostate cancer, offering new hope for men with this disease. However, many questions remain over which medications to use in individual cases. In the PROMOTE study, researchers and doctors are using exome sequencing and RNA profiling to identify molecular fingerprints within prostate cancers that can be used to identify the optimal drug for the individual patient. Prostate cancer is the most commonly diagnosed solid organ malignancy in the US with more than 2,38,000 new diagnoses annually and an estimated 29,720 deaths. It is the second leading cause of cancer deaths among American men, according to the Surveillance Epidemiology and End Results Program of the National Cancer Institute.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Around the Globe

News and Views ÂÂ

A retrospective study has recently revealed that worse outcomes for women with bladder cancer than for men could be in part, due to the underrecognition by general practice clinicians that hematuria is a likely sign of cancer. The findings of the study were presented at the American Urological Association (AUA) 2014 Annual Scientific Meeting.

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A study presented at the American Association of Clinical Endocrinologists (AACE) 23rd Annual Scientific and Clinical Congress has put forward data stating that testosterone therapy in men is not associated with an increased risk for myocardial infarction (MI) or stroke and may even be cardioprotective. This novel data is contrary to recent findings regarding risks of testosterone therapy.

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The American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) have proposed a new definition of obesity that takes complications into account, along with body mass index (BMI). The 2014 advanced framework for a new diagnosis of obesity as a chronic disease was presented at the American Association of Clinical Endocrinologists (AACE) 23rd Annual Scientific and Clinical Congress.

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A novel study presented at the American Urological Association (AUA) 2014 Annual Scientific Meeting has pointed that ultrasound may be comparable to CT in its ability to discriminate between renal calculi and other causes of flank pain.

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Another study presented at the AUA 2014 Annual Scientific Meeting has revealed that better control of glycemia in type 2 diabetes could possibly reduce the risk of developing kidney stones. Insulin therapy was significantly protective against low urine pH, whereas HbA1C levels were associated with more acidic urine.

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A study presented at the Heart Failure Congress 2014 has revealed that hospitalization for heart failure increases more than two-fold during inflammatory bowel disease (IBD) flares. Study authors noted that patients with new-onset IBD had a 37% increased risk of hospitalization for heart failure during a mean follow-up of 6.4 years compared to the healthy population. A recent review has suggested that taking sleeping pills increases the risk of cardiovascular events in

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

patients with diastolic heart failure. In the study, heart failure patients with a preserved ejection fraction (HFpEF) who were prescribed sleeping pills were eight times more likely to experience hospital readmission for heart failure or suffer cardiovascular–related death, compared with HFpEF patients who were not prescribed these medications. ÂÂ

A study published online May 19 in Pediatrics has shown that administering the RotaTeq rotavirus vaccine to infants in the neonatal intensive care unit (NICU) appears to be safe, with no evidence of infection transmission to neighboring infants.

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An article published online May 19 in Pediatrics reports that delaying the first measles-mumpsrubella vaccine (MMR) or the first measles-mumpsrubella-varicella vaccine (MMRV) beyond the age of 15 months may increase a 2-year-old’s risk for postvaccination seizures more than two-fold.

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Ultrasound is equal to CT for emergency department evaluation of suspected kidney stones as shown in a randomized trial said Marshall Stoller, MD, of the University of California San Francisco. Ultrasound performed by a radiologist or emergency physician led to serious adverse events in about 11% of cases, as did CT. Severe and attributable serious adverse events occurred in fewer than 1% of 2,800 patients and rates did not differ between patients evaluated by ultrasound or CT, Stoller and colleagues reported here at the American Urological Association meeting.

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A crossover trial, published online May 15 in Diabetologia, has pointed that eating just two large meals a day, consisting of breakfast and lunch, could be the best way to control weight and blood sugar for people with type 2 diabetes. Patients following this regime lost more weight and had less hepatic fat and lower blood glucose, fasting insulin and fasting glucagon than those consuming six smaller meals.

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A novel research from the UK has revealed that in patients with type 1 diabetes who exercise in the evening, a low-glycemic meal and bedtime snack prevent hyperglycemia and early hypoglycemia; however they do not prevent late nocturnal hypoglycemia. The study was published online in Diabetes Care.

Around the Globe ÂÂ

A study presented at the Digestive Disease Week (DDW) annual meeting has reported that MUSE™ System (less invasive surgical anterior fundoplication with standard surgical staples) is safe and effective for patients with PPI-responsive, moderate-to-severe GERD. Researchers noted that the majority of patients (74%) treated with the MUSE™ System remained off daily PPI at three years post-procedure.

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The European Commission (EC) has cleared for marketing the protease inhibitor simeprevir for treatment of adults with hepatitis C (HCV) genotypes 1 and 4 infection in combination with other drugs. The approval is based on three phase III studies involving more than 1000 patients.

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A study published online in Hypertension has shown that visit-to-visit variability in blood pressure (BP) is not associated with mortality in elderly primary care patients; however, long-term changes in BP are. Study authors noted that both large and small BP changes during follow-up were linked with higher mortality than moderate BP changes over time.

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A study presented at the American Society of Hypertension 2014 Annual Scientific Meeting has revealed that BP measured in the clinic has no association with the risk of cardiovascular outcomes, including stroke. On the contrary, nighttime BP may be associated with a risk of adverse clinical outcomes. Researchers noted a 25% increase in the risk of CV outcomes for every 10-mm-Hg increase in nighttime systolic BP. An analysis published in the June issue of Pediatrics states that children with complex chronic conditions have increased likelihood to visit emergency departments (EDs) for drug reactions than other children. The highest rates of adverse events for these children are associated with drugs like psychotropic agents, antimicrobial agents, anticonvulsants, hormones and analgesics. Two separate articles being published in Annals of Internal Medicine have pointed that less frequent echocardiographic screening of childhood cancer survivors is effective for detecting asymptomatic left ventricular dysfunction (ALVD) and appears to be more cost-effective than following the widely accepted Children’s Oncology Group (COG) screening guidelines. The US Food and Drug Administration (FDA) has approved vedolizumab (VDZ) injection for the treatment of adults with moderate to severe ulcerative colitis and moderate to severe Crohn’s disease.

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A new study has revealed that adults with migraine have 2-fold increased odds of subclinical brain infarction as compared to their migraine–free peers. The new findings, published online May 15 in Stroke, have been obtained from the ongoing Northern Manhattan Study (NOMAS).

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Vitamin D supplementation does not have any significant impact on the rate of first treatment failure or exacerbation in patients with asthma and low vitamin D levels, reports a study presented at the American Thoracic Society 2014 International Conference. Significant reductions in exacerbations and the rate of first treatment failure were noted in those with normal vitamin D levels.

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Two novel studies presented at the American Urological Association (AUA) 2014 Annual Scientific Meeting have revealed that botulinum toxin type A, besides its wrinkle-erasing properties, can also ease the strains of overactive or neurogenic bladder disorders.

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Findings from a new study presented at the American Geriatrics Society 2014 Annual Scientific Meeting have revealed that in patients with fecal incontinence, psyllium fiber may be as effective as loperamide for reducing bowel leakage, without intolerable adverse effects.

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Results of the Optical Coherence Tomography Assessment of Gender Diversity in Primary Angioplasty (OCTAVIA) study have shown that the pathophysiology of STEMI is nearly identical in men and women and that women respond just as well as men to primary PCI and stenting, despite their smaller vessels and higher risk profile. The study was presented recently at the EuroPCR 2014.

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A study presented at the American Society of Hypertension (ASH) 2014 Annual Scientific Meeting has pointed that hyperkalemia occurs frequently in patients with resistant hypertension treated with spironolactone. The study reported the incidence of hyperkalemia to be 8.2% in these patients.

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A study published online in Otolaryngology – Head & Neck Surgery has stated that children with cochlear nerve deficiency (CND) who receive auditory brainstem implants (ABI) are more likely to learn how to communicate verbally than those fitted with cochlear implants (CI).

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The risk of experiencing birth asphyxia increases for babies born to women who are overweight or obese, reports a recent study published in PLOS Medicine. Study authors noted that the rates of low Apgar scores increased with maternal BMI.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

lighter reading

Lighter Side of Medicine Quote

Make Sure

During Medical Practice

“Never look back…if Cinderella had gone back to pick up her shoe, she wouldn’t have become a princess”

A patient on amlodipine developed severe gum hypertrophy.

Mind Trivia

Oh my God! Why was amlodipine not stopped?

1. Four friends are sitting around a square table. Meena is to the right of Padma and Beena is to the left of Krishna. Who is sitting in front of each other if Krishna is sitting at the left of Padma? a. Padma and Krishna, b. Krishna and Beena, c. Beena and Meena d. Meena and Krishna

©IJCP Academy

2. How can you add eight 8’s to get the number 1,000? (only use addition)

Make sure that all patients on amlodipine are watched for gum hypertrophy as its side effect. KK Aggarwal

Situation: A 13-year-old diabetic child needed to

increase his metformin dose.

an oral dose of 500 mg, administered oncedaily. The dose can be increased by 500 mg increments, initially as 500 mg twice-daily, to a maximum daily dose of 2000 mg given as 1000 mg twice-daily. Diabetes Care 2002;25:89. Dr KK Aggarwal

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

©IJCP Academy

You can increase up to 2 gms per day

Lesson: In pediatric patients, metformin is started as

4. You build a house facing south in all four directions. A bear walks up to your door. What color is the bear? Ans. (1) d. (2) 888 +88 +8 +8 +8 =1,000. (3) Neither. They both weigh a pound. (4) White. He’s a polar bear. You’re at the North Pole, the only place on Earth where south is in every direction.

ILLUSION

Dr. Good & Dr. Bad

Metformin is not given to children

3. “Which weighs more, a pound of lead, or a pound of feathers?”

Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767). Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so. The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript. Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper. Covering letter –

– –

The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper. Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors. Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

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Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors. Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the departments and institutions where the work was performed,

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Confidence intervals for the measurements should be provided wherever appropriate.

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Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Discussion –

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses). At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution. Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes. Q. J. Expt. Physiol. 1955;40:89-111.

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Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________

Books

5. Special requests _____________________________

Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

6. Suggestions for reviewers (name and postal address)

Articles in Books

2.____________ 2.________________

Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

3.____________ 3.________________

4.____________ 4.________________

Tables –

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends – These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text. –

The legend must include enough information to permit interpretation of the figure without reference to the text.

Indian Journal of Clinical Practice, Vol. 25, No. 1, June 2014

Indian 1.____________Foreign 1.________________

7. All authors’ signatures________________________ 8. Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

Online Submission Also e- Issue @ www.ijcpgroup.com For Editorial Correspondence

Dr KK Aggarwal

Group Editor-in-Chief Indian Journal of Clinical Practice E-219, Greater Kailash, Part-1 New Delhi - 110 048. Tel: 40587513 E-mail: editorial@ijcp.com Website: www.ijcpgroup.com

R.N.I. No. 50798/90 Date of Publication 13th of Same Month Date of Posting 13-14 Same Month

POSTAL REGISTRATION NO. DL (S)-01/3200/2012-2014 Posted in N.D. PSO New Delhi