March 2017 Clinical Advisor by The Clinical Advisor

THE CLINICAL ADVISOR • MARCH 2017

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■ Sepsis and septic shock ■ Earwax guidelines ■ Intervention during birth FEATURE Schizophrenia

■ A clinical overview of a chronic mental disorder

MARCH 2017

| www.ClinicalAdvisor.com

TREATMENT OPTIONS FOR

BIPOLAR DISORDER Managing mood changes in bipolar disorder is a challenge for clinicians.

LEGAL ADVISOR

When a referral to a specialist goes wrong

n Dermatologic Clinic

“BAG-OF-WORMS” FACIAL MASS PAGE 48

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VOLUME 20, NUMBER 3

n Feature

OBESITY: CAUSES AND TREATMENT PAGE 34

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Editor Colby Stong, editor@clinicaladvisor.com Senior editor Sandhya George Associate editor Lauren Grygotis Assistant editor Madeline Morr Contributing editors Mark P. Brady, PA-C; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP; Sharon Dudley-Brown, PhD, FNP; Abimbola Farinde, PharmD; Laura A. Foster, CRNP, FNP; Abby A. Jacobson, PA; Maria Kidner, DNP, FNP; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Mary Newberry, CNM, MSN; Claire Babcock O’Connell, MPH, PA; Kathy Pereira, DNP, FNP; Sherril Sego, DNP, FNP; Ann Walsh, PA-C, SCT(ASCP); Kim Zuber, PA-C Production editor Kim Daigneau Group art director, Haymarket Medical Jennifer Dvoretz Production manager Krassi Varbanov Circulation manager Paul Silver National accounts manager Alison McCauley, 973.224.6414 alison.mccauley @ haymarketmedical.com Publisher Kathleen Hiltz, 201.774.1078 kathleen.hiltz@haymarketmedia.com Editorial director Kathleen Walsh Tulley Senior vice president, digital products and medical magazines Jim Burke, RPh CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 275 7th Avenue, 10th Floor, New York, NY 10001 For advertising sales, call 646.638.6085. For reprints, contact Wright’s Reprints at 877.652.5295. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Clinical Challenge” are not the actual individuals mentioned in the articles.They appear for illustrative purposes only. The Clinical Advisor ® (USPS 017-546, ISSN 1524-7317), Volume 20, Number 3, is published 12 times a year, monthly, for $75.00 per year in the United States; $85.00 in Canada; $110.00 for all other foreign, in U.S. dollars, by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. Single copy: $20 U.S.; $30 foreign. www.ClinicalAdvisor.com. To order or update your paid subscription, call 800.436.9269. Periodicals postage rate paid at New York, NY, and additional mailing offices. POSTMASTER: Send address change to DMD Data Inc., 10255 W. Higgins Rd, Suite 280, Rosemont, IL 60018. Subscription inquiries: call 800.430.5450 to change your address or make other subscription inquiries. Requests for subscriptions from outside the United States must be accompanied by payment. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2017

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Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

CLINICAL PEARLS

It cannot be beat.—TERRI JORDAN, ARNP, Daytona Beach, Fla. (202-2)

NEUTROPHILS AND LYMPHOCYTES In interpreting a complete blood count with differential, anytime the neutrophils and lymphocytes are numerically close, it is a viral cause; when the neutrophils and lymphocytes are numerically distant, it is a bacterial cause. This is very helpful in determining treatment.—DONNA CARTER, FNP-C, Scottsburg, Ind. (202-1) GENERIC “CAINE” IS EFFECTIVE FOR WOUND CARE For pain relief, most pharmacies offer a “caine” at 2-510%, and basically nothing higher, for between $5 and $30 per tube. I work in wound care and use Walmart’s

INTRA-ARTICULAR INJECTIONS FOR SEVERE OSTEOARTHRITIS Patients with severe osteoarthritis in the knees seem to do better with intra-articular injections if you have them sit up and dangle their legs off the examination table and distract the knee slightly when administering the injection.—ROSEMARY LEDBETTER, PhD, PA, Troy, Ill. (202-3)

YOUR COMMENTS SLIPPED CAPITAL FEMORAL EPIPHYSIS IN OBESE ADOLESCENTS I just read the CME/CE article by Marilou Shreve, DNP, APRN, entitled, “Assessing and treating pediatric obesity” [ June 2015]. I was concerned regarding the oversight of a critical issue in obese adolescents: the increased risk of slipped capital femoral epiphysis (SCFE). This was not addressed in the article. The case study (p. 55) gave incomplete advice regarding the evaluation of an obese adolescent male with knee pain. The most common etiology of the insidious onset of knee pain in children is the hip, due to referred pain from the

Equate brand—vagicaine 20% benzocaine. When using this before debriding a wound, give it three minutes to sedate the nerves, then perform the procedure. I get good results, as patients say. It relieves pain and burning for $1.88.

Advisor F

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. You may contact us by e-mail at editor@ clinicaladvisor.com. If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter. No anonymous contributions will be accepted.

orum

These are lette and successe rs from practitioners s, observat around the below. We ions, and country who OUR CONSULTANTS pearls with invite you want to shar to participa their colle e their clinic agues. Resp te. al problems onding cons ultants are identified CON SULTAT IONS

TREATM ENT FOR INFECT URINAR ION SGLT2 REC MALE CHI S IN THE UNC Y TRACT IRCUMCI LD FOR DIA EPTOR BLOCKE If a male SED child conti Deborah L. Cross, MPH, CRNP, Laura A.BET Foster,ES CRNP, FNP, Abby A. Jacobson, PA-C, RS Abimbola Farinde, PhD, PharmD, With the nues toassociate ANP-BC, is practices family medicine is a physician assistant is a professor redevprogram adven t ofPrimary circu SGLT2 recep at Delaware Valley urinaryattract director, Gerontology NP elop Program, mcisi Columbia Southern moda litywith Palmetto on be perfo for type tor infecPhysicians Dermatology University of Pennsylvania School blockersGroup University 2 diabe rmed? regarding inCare as a treatm in Wilmington, Del. in Orange Beach, Ala. useCharleston, S.C. tes, is there ent urology is of Nursing, Philadelphia. any evide NATHAN in patients with to protect the is well advise nce or data type 1 diabe GARDNE d tes mellitus?— R, PA-C, continues to to recommend a circum upper tracts, the kidne CPAAPA, ys. develo cision It p recurr•ent 44 THE ADVISOR AUGUST 2015 •on www.ClinicalAdvisor.com Castleton, severaCLINICAL l consideration urinary tract the male child who As it currently stands N.Y. , SGLT2 s that infections. for glycemic impede the receptor blocke There are control in ability to cleansenter into this decisio rs are FDA adults with n. Poor hygien should the e and quell -approved child have e may appro diet and exercise, but with type 2 diabetes phimosis, simpl infection potential. appropriate the in ved conjun FDA for use in patien Moreover, AdvisorForum_CA0815.indd urine 44 9/29/15ction 2:38 PM e cathet culture can ts with type has stated that they ketoacidosi steroid cream be a challenge. erization to obtain s, or those are not may tempo an FAR with severe 1 diabetes, patients with Having a short tion of the rarily solve renal functi diabetic steroid the trial of informINDE, PhD, Pharm these issues tenden , though after for infection D (See bottom on.—ABIMBOL ation about once again.—C cy redevelops, placin cessaA Dr. Farinde.) of this page Milwaukee g (203-2) for more , Wis. (203- OLEEN ROSEN, the child at risk 1) DNP, FNP -C, CLI Philip R. Cohen, MD,

is clinicaltions associate professor , shou ld of dermatology, University a of Texas Medical Center, The focus of Houston.

NICAL

Send us your letter Advisor Forum, The s with questions New York, and comm Clinical Advisor ents to: , 114 clinicaladvisoNY 10001. You may contacWest 26th Street , please indicatr.com. If you are writing in t us by e-mail at 4th Floor, each item. e so by including response editor@ to a the Letters are policy is edited for number in parent published letter, to heses at length and contribution print the author ’s name with clarity. The Clinicathe end of s will be accepted. l Advisor the letter. No anonym ’s ous

Write us today.

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VAGINA L RESULT DISCHARGE AND ING FRO If a female M TAMPON ODOR patient has USE a ask if she uses tamp history of vaginal disch ons. If she the pelvic arge with says “yes,” exam when cond odor, that you woul , do not enter ucting the rotating of d to take a pap smea vagina in the same the specu way r. Instead, the cervix. lum Most retain from side to side start shallow until reach ed tampons ing are lodge d in the fold

Philip R.

Cohen, MD, is clinical associa te profess of dermat or ology, of Texas MedicaUniversity l Center, Houston.

SEND TO The Clinical Advisor 275 7th Avenue, 10th floor New York, NY 10001

62 THE CLINI

Deborah L. Cross, MPH, ANP-B

CRNP, C, is associa te program director, Geronto logy NP Program University of Pennsyl vania School , of Nursing , Philadelphia.

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practices familyCRNP, FNP, with Palmett medicine o Primary Care Physicia ns in Charles ton, S.C.

Abby A.

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is a physicia n, PA-C, n at Delawa assistant re Dermatology Valley in Wilmington,Group Del.

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CONTENTS MARCH 2017

NEWS AND COMMENT 14

Newsline ■■Sepsis and septic shock: new guidelines for clinical management from the Society of Critical Care Medicine and the European Society of Intensive Care Medicine ■■Earwax: a clinical practice guideline for management and treatment ■■Intervention during labor and birth: new recommendations from the American College of Obstetricians and Gynecologists ■■Accuracy of prediabetes screening tests is low ■■VA lung cancer screening program has low detection rate ■■Radiation exposure and cancer risk from CT screening: a risk–benefit analysis

Pharmacologic options for bipolar disorder Lithium has been the mainstay of treatment for decades, but several other classes of medication have recently been used with varying degrees of success. Schizophrenia: a clinical overview A better understanding of this complicated condition is key to helping patients maximize their quality of life.

MAKING CONTACT

TOC_CA0317.indd 2

CME/CE Updated understandings

CME/CE Feature posttest

of obesity and weight-related health risks Part 1 of a three-part series on issues regarding obesity management.

DEPARTMENTS Guidelines for sepsis and septic shock 14

FEATURES 17

4 3

Schizophrenia: a chronic mental illness 26

Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com

Dermatology Clinic n A facial mass with “bag-of-worms” appearance n Spreading eczema and areas of raw, oozing skin

Dermatologic Look-Alikes A pruritic rash

Legal Advisor A clinician misses a differential diagnosis when she refers a patient to a specialist for rectal bleeding.

Continues on page 8

Alt Meds Update: Frankincense 59

Like us on Facebook facebook.com/TheClinicalAdvisor

www.ClinicalAdvisor.com

Visit us on the web ClinicalAdvisor.com

Download the app ClinicalAdvisor.com/App

2/24/17 2:36 PM

CONTENTS DEPARTMENTS cont’d Alternative Meds Update Frankinsense. Promising studies indicate that frankincense may be useful in fighting the rapid growth of cancer cells and other immune and inflammatory conditions. © The New Yorker Collection 2017 from cartoonbank.com. All Rights Reserved.

ADVISOR FORUM 46

Consultations ■ Transurethral resection of bladder tumor

Your Comments ■ Lifestyle modifications versus pharmacologic treatment for patients with diabetes

Case Files ■ Soft tissue sarcoma of the thigh in an adolescent male

“I think you’ll find this home has real storybook charm.”

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TO SUBMIT AN ARTICLE: • editor@ClinicalAdvisor.com

OR • MARC

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H 2017

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IEW ED FOR UM FOR NUR SE PRA CTIT ION

■ Sepsis and sept ■ Earwax guid ic shock elines ■ Interven tion during birth

FEATURE

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LEGAL AD VISOR

When a refe specialist goe rral to a s wrong

MAR CH

2017

| www.Clin icalA

IONS FO

R BIPOLAR D ISORDER Managing changes in mood bipolar disorder is a challenge for clinician s.

■ Dermatolo gic Clinic

• Send it by e-mail to editor@ClinicalAdvisor.com

“BAG-OF-W FACIAL MA ORMS” SS PAGE 48

✶ FREE CE COURSE!

ER 3

• Mail it to The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001

ENT OPT

COVER TO COME

20, NUMB

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TREATM

VOLU ME

TO CONTACT THE EDITOR: • editor@ClinicalAdvisor.com • Call 646.638.6078

Schizophren

■ A clinical ove chronic men rview of a tal disorder

TO SUBMIT A CLINICAL QUESTION FOR PUBLICATION: • ClinicalAdvisor.com/AdvisorForum

ERS

dvisor.com

NEWSLIN

■ Feature

OBESITY: CA USES AN TREATMEN T PAGE 34 D

2/27/17 1:10 PM

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com Web Exclusives

Multimedia

ClinicalAdvisor.com/News

ClinicalAdvisor.com/Multimedia

Licorice consumption in pregnancy may be harmful for offspring Girls whose mothers consumed high amounts of licorice during pregnancy have more advanced pubertal maturation at age 12 years.

ACP releases recommendations for low back pain treatment The American College of Physicians has released 3 recommendations for treating patients with acute, subacute, and chronic low back pain. Watch the video here:

Prolapse surgery outcomes not improved with transvaginal mesh or biological graft Using transvaginal mesh and biological graft in prolapse surgery did not improve outcomes of effectiveness, quality of life, or adverse events. Mortality rate lower in US patients treated by foreign-educated internists Researchers observed a somewhat lower mortality among patients treated by international graduates. Electronic cigarette use linked to higher CVD risk Electronic cigarettes cause an imbalance of cardiac autonomic tone and increased oxidative stress, which may increase cardiovascular risk.

ClinicalAdvisor.com/ACPBackPainVideo

Clinical officers improve health care in Kenya Clinical officers outnumber physicians working in Kenya and tend to work in rural areas where the need for health care is greatest. Listen to the podcast here: ClinicalAdvisor.com/ClinicalOfficerKenya

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Jillian Knowles, MMS, PA-C Counseling patients about annual Pap smears Counseling patients on the difference between a Pap smear and a pelvic exam will help them realize the importance of following up with a gynecologist for an annual visit. Jim Anderson, MPAS, PA-C, DFAAPA The future of PA practice authority The AAPA is moving forward with its push to eliminate the formal relationship between physicians and physician assistants.

MRI may detect autism before age 1 MRI scans showed that the brain size of infants grew faster between 12 and 24 months, the same time that behavioral signs of autism appeared. 2017 Adult immunization schedule released by the CDC Updates for the influenza, HPV, hepatitis B, and meningococcal vaccines

MAKING CONTACT

Sharon M. O’Brien, MPAS, PA-C The importance of sleep hygiene A handout that lists tips to improve sleep hygiene could help many patients get to sleep and stay asleep throughout the night.

Like us on Facebook facebook.com/TheClinicalAdvisor

Visit us on the web ClinicalAdvisor.com

Go mobile with us mobile.ClinicalAdvisor.com

10 THE CLINICAL ADVISOR •MARCH 2017 • www.ClinicalAdvisor.com

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Advisor Dx

EXCLUSIVE TO THE WEB

INTERACT WITH YOUR PEERS by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/AdvisorDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

Ortho Dx

In partnership with

TheJopa.org

Journal of Orthopedics for Physician Assistants

Chronic lower back pain after a traumatic fall A 42-year-old man presents with chronic lower back pain. He has a history of T12 compression fracture after a traumatic fall that occurred 5 years previously. Anteroposterior and lateral lumbar spine radiographs show fused sacroiliac joints, vertebral body squaring, and interspinous ligament calcification. WHICH DIAGNOSIS IS CORRECT?

• Degenerative disk disease • Reiter syndrome • Scheuermann disease • Ankylosing spondylitis ● See the full case at ClinicalAdvisor.com/OrthoDx_Mar17

Derm Dx A pimple that did not stop growing on a man’s shoulder A 44-year-old man presents for evaluation of a growth on his right shoulder. The lesion was first noted about 3 years previously and began as a “pimple that didn’t stop growing.” Examination reveals a prominent erythematous nodule of the right scapula. CAN YOU DIAGNOSE THIS CONDITION?

• Amelanotic melanoma • Keratoacanthoma • Squamous cell carcinoma • Dermatofibrosarcoma protuberans ● See the full case at ClinicalAdvisor.com/DermDx_Mar17

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2017 11

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Newsline M A R C H 2 017

A clinical practice guideline for managing earwax page 15

How accurate are prediabetes screening tests? page 16

Radiation and cancer risk from low-dose CT page 16

NEW GUIDELINES for sepsis and septic shock emphasize frequent patient re-evaluation and patient-specific tailoring of hemodynamic therapy. The guidelines were presented at the 46th Annual Meeting of the Society of Critical Care Medicine (SCCM) and were published online in Critical Care Medicine and Intensive Care Medicine. The guidelines are an update to the “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012” and provide 93 statements on early management and resuscitation of patients with sepsis or septic shock. The recommendations, according to the panel, include the following: Initial resuscitation

• Sepsis and septic shock are medical emergencies, and we recommend that treatment and resuscitation begin immediately (best practice statement [BPS]). • We recommend that, following initial fluid resuscitation, additional fluids be guided by frequent reassessment of hemodynamic status (BPS). Diagnosis

• We recommend that appropriate routine microbiologic cultures (including blood) be obtained before starting

antimicrobial therapy in patients with suspected sepsis or septic shock if doing so results in no substantial delay in the start of antimicrobials (BPS).

Sepsis and septic shock: new guidelines for clinical management Use of

Fluid therapy

antimicrobials

• We recommend that a f luid challenge technique be applied where fluid administration is continued as long as hemodynamic factors continue to improve (BPS). • We recommend crystalloids as the fluid of choice for initial resuscitation and subsequent intravascular volume replacement in patients with sepsis and septic shock (strong recommendation, moderate quality of evidence).

Antimicrobial therapy

is advised to

• We recommend that administration of IV antimicrobials be initiated as soon as possible after recognition and within 1 hour for both sepsis and septic shock (strong recommendation, moderate quality of evidence; grade applies to both conditions). • We recommend use of empiric broad-spectrum therapy with 1 or more antimicrobials for patients presenting with sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage) (strong recommendation, moderate quality of evidence).

cover all likely

Source control

• We recommend that a specific anatomic diagnosis of infection requiring emergent source control be identified or excluded as rapidly as possible in patients with sepsis or septic shock, and that any required source control intervention be implemented as soon as medically and logistically practical after the diagnosis is made (BPS).

pathogens, including bacterial, fungal, and viral infections.

Glucose control

• We recommend the use of a protocolized approach to blood glucose management in ICU patients with sepsis, commencing insulin dosing when 2 consecutive blood glucose levels are >180 mg/dL. This approach should target an upper blood glucose level ≤180 mg/ dL rather than an upper target blood glucose level ≤110 mg/dL (strong recommendation, high quality of evidence). u For more detailed information about these recommendations, please see our expanded coverage at www.ClinicalAdvisor.com

14 THE CLINICAL ADVISOR • MARCH 2017 • www.ClinicalAdvisor.com

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Earwax: a clinical practice guideline for management THE AMERICAN Academy of Otolaryngology–Head and Neck Surgery Foundation (AAOHNSF) has released an updated clinical practice guideline on earwax to help clinicians identify patients who may benefit from intervention. The recommendations include the following: 1. Clinicians should explain proper ear hygiene to prevent cerumen impaction. 2. Clinicians should diagnose cerumen impactions when cerumen accumulation, as seen on otoscopy, is associated with symptoms, prevents needed assessment of the ear, or both. 3. Clinicians should assess the patient with cerumen impaction by history and/or physical examination for factors that modify management, such as: anticoagulant therapy,

An otoscopy should be done to detect the presence of cerumen in patients with hearing aids.

immunocompromised state, diabetes mellitus, prior radiation therapy to the head and neck, ear canal stenosis, exostoses, and nonintact tympanic membrane. 4. Clinicians should not routinely treat cerumen in patients who are asymptomatic and whose ears can be adequately examined.

5. Clinicians should identify patients with obstructing cerumen in the ear canal who may not be able to express symptoms, such as young children and cognitively impaired children and adults. 6. Clinicians should perform otoscopy to detect the presence of cerumen in patients with hearing aids during a healthcare encounter. 7. Clinicians should treat, or refer to a clinician who can treat, the patient with cerumen impaction with an appropriate intervention, which may include: cerumenolytic agents, irrigation, or manual removal requiring instrumentation. 8. Clinicians should recommend against ear candling/coning for treating or preventing cerumen impaction.

WOMEN WITH low-risk pregnancies can benefit from labor techniques that are associated with minimal interventions, according to an updated committee opinion released by the American College of Obstetricians and Gynecologists (ACOG). The committee notes that many obstetric practices have a limited or uncertain benefit for low-risk women in spontaneous labor, and some women may seek to reduce medical interventions during labor and delivery. Therefore, obstetrician-gynecologists should consider using low-interventional approaches when it is appropriate

for intrapartum management of spontaneous labor. A summary of the recommendations from ACOG includes the following: • Labor management may be individualized for a woman who is at term in spontaneous labor with a fetus in vertex presentation. Management techniques may include intermittent auscultation and nonpharmacologic methods of pain relief. • Labor and delivery can be delayed for women in the latent phase of labor when their status and their fetuses’ status are reassuring. Women can be offered

Minimal intervention advised for women with low-risk pregnancies.

contact and support and nonpharmacologic pain management measures. • Women who are admitted for pain or fatigue in latent labor can benefit from techniques such as education and support, oral hydration, positions of comfort, and nonpharmacologic pain management techniques such as massage or water immersion. • Obstetric care providers should inform women with term premature rupture of membrane (PROM) of the potential risks associated with expectant management.

TOP, BOTTOM IMAGES: THINKSTOCK

Intervention in labor and birth: ACOG recommendations

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2017 15

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Newsline Accuracy rate Lung cancer screening program for prediabetes in the VA has low detection rate screening is low IMPLEMENTATION of a comOverall, 2,106 patients had prehensive lung cancer screening program in the Veterans Health Association (VHA) will require significant clinical effort with uncertain patient benefit, according to a study published in JAMA Internal Medicine. Researchers implemented a 3-year Lung Cancer Screening Demonstration Project (LCSDP) in 8 geographically diverse hospitals. Patient criteria included those aged 55 to 80 years without a diagnosis of esophageal, liver, pancreatic, or lung cancer and without a documented estimated life expectancy of fewer than 6 months. Patients were then reviewed for smoking histories to identify current or former (quit less than 15 years ago) cigarette smokers who had smoked a minimum of 30 pack-years.

Researchers found that 1.5% of screened patients had lung cancer.

completed an LDCT scan by June 30, 2015, and were included in the analyses. Of the 2,106 patients, 1,257 (59.7%) screened had a positive test result, including 1,184 patients (56.2%) who had 1 or more nodules needing to be tracked. A total of 73 patients (3.5%) of all patients screened had possible lung cancer findings; of these, 31 patients (1.5%) were confirmed. A total of 857 patients (40.7%) had 1 or more incidental findings reported. The most common were emphysema, other pulmonary abnormalities, and coronary artery calcification. The researchers calculated that 2,780,933 primary care VHA patients potentially met the eligibility criteria for visits, age, and medical history.

Radiation exposure and cancer risk from CT THE LIFETIME ATTRIBUTABLE risk of lung cancer and major cancers from low-dose computed tomography (CT) screening ranges from 5.5 to 1.4, and 8.1 to 2.6, respectively, per 10,000 participants, researchers reported in the BMJ. However, radiation exposure and low-dose CT screening for lung cancer can be acceptable in light of the substantial mortality reduction associated with screening, the authors concluded. During the 10 years of the COSMOS lung cancer screening trial, 5,203 high-risk participants underwent 42,228 low dose CT examinations. A total of 635 PET CT scans were performed in 522 participants with suspicious findings. A total of 259 lung

cancers were diagnosed after 10 years of CT screening. The lifetime attributable risk of lung cancer and major cancers after 10 years of CT screening ranged from 5.5 to 1.4 per 10,000 people screened, and from 8.1 to 2.6 per 10,000 people screened, respectively. In women aged 50 to 54, the lifetime attributable risk of lung cancer and major cancers was about fourfold and threefold higher than for men aged 65 and older, respectively. The rates of lung cancer and major cancer cases were 1.5 and 2.4 per 10,000 people screened, respectively, which corresponded with an additional risk of induced major cancers by 0.05%. n

THE DIAGNOSTIC accuracy of the current tests used to detect prediabetes in screening programs is low, according to a study published in the BMJ. The results showed that the fasting glucose screening test is specific but not sensitive, and the HbA1c test is neither sensitive nor specific. Researchers performed one metaanalysis to summarize the accuracy of screening tests for identification of prediabetes, with the oral glucose tolerance test as the standard, and they conducted an additional metaanalysis that assessed relative risk of progression to type 2 diabetes after lifestyle intervention or treatment with metformin. “A screen and treat policy will be effective only if a test exists that correctly identifies those at high risk (sensitivity) while also excluding those at low risk (specificity); and an intervention exists that is acceptable to, and also efficacious in, those at high risk,” stated the authors. The HbA1c screening test had a mean sensitivity of 0.49 and specificity of 0.79 for the identification of prediabetes, although different studies used different cut-off values. In addition, fasting plasma glucose had a mean sensitivity of 0.25 and a specificity of 0.94. Lifestyle interventions were associated with a 36% reduction in relative risk of type 2 diabetes during the course of 6 months to 6 years, which attenuated to 20% at followup in the period after the trials.

16 THE CLINICAL ADVISOR • MARCH 2017 • www.ClinicalAdvisor.com

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FEATURE: IAN WARD, MMS, PA-C

Pharmacologic options for bipolar disorder Lithium has been the mainstay of treatment for decades, but several other classes of medication have recently been used with varying degrees of success.

Patients with bipolar disorder have high relapse rates.

ipolar disorder is a mood disorder that affects 2% of the population worldwide and is associated with high rates of relapse and suicide.1 Statistics on relapse rates show the difficulty of treating bipolar disorders; patients with stable bipolar disorder relapse into either mania or depression at a rate of 37% after 1 year and 60% after 2 years.1 Patients who have bipolar disorder can present with manic or depressive episodes, and the initial treatment depends on the presentation. For several decades, lithium or other “mood stabilizer” medications have been the mainstay of treatment for bipolar disorder. Patients taking lithium require regular monitoring to keep a safe and effective level of the drug in the bloodstream; excess lithium causes toxicity. Over the last decade, several other medications in different drug classes have been evaluated in clinical trials and approved by the Food and Drug Administration (FDA). In addition, psychiatrists prescribe many medications “off label” to treat bipolar disorder.2 Angst et al3 provide compelling numbers on the importance of treating bipolar disorder and other mental health disorders over the long term. Over the course of 22 to 38 years, their study followed 406 patients with bipolar disorder. The rate of deaths from suicide was significantly lower in those treated with maintenance therapy than in those who did not receive treatment (6 vs 27 deaths). The purpose of this article is to review the current best practices and recommendations

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PHARMACOLOGIC OPTIONS FOR BIPOLAR DISORDER

for the treatment of bipolar disorder, including mania and depression, and for long-term therapy. Characteristics and diagnostic criteria

Bipolar disorder is categorized as bipolar I or bipolar II. Characteristics of bipolar I disorder include manic episodes (Table 1). Patients with bipolar I disorder may also experience hypomania, as described in Table 2, and periods of major depression, as described in Table 3. The diagnostic criteria for bipolar I disorder are presented in Table 4. Bipolar II disorder differs in that patients experience no mania but have at least one episode of hypomania and major depression.4 The diagnostic criteria for bipolar II disorder are presented in Table 5. Methods

This article researches the most recent meta-analyses and recommendations to arrive at conclusions for the best treatment options for patients with bipolar disorder. The author used PubMed, Google Scholar, UpToDate, and the American TABLE 1. Diagnostic criteria for a manic episode15 1. A minimum of one week (or any duration if hospitalized) where, for the most part of most days, an abnormal mood is observed. The mood is continually elevated, expansive, or irritable, and there is a persistently increased level of energy and activity towards specific goals. 2. During this period, three or more of the following symptoms are observed (four when the mood is described as irritable). These symptoms are a marked change from usual behavior and are present significantly during the period of mood elevation. a. Increased self-esteem or appearing grandiose b. Need for lower amounts of sleep (typically 2–3 hours per day). c. Increased talkativeness or a subjective feeling of the need to keep talking d. An experience of racing thoughts or flight of ideas e. Attention is easily distracted f. Increased levels of activity towards specific goals (for example, at work or school, socially, or sexually) or an increased level of activity without purpose, leading to psychomotor agitation g. Excessive risk-taking activities with potentially bad outcomes (eg, promiscuity or misguided financial decisions) 3. The severity of mood disturbance causes impaired social functioning, impaired functioning at work, requires hospitalization, or involves psychotic episodes. 4. The mood change is not due to a medical condition or the effects of a substance. Notes: One manic episode in a lifetime is required to diagnose bipolar I disorder. A manic episode is defined by criteria 1–4 above, or by an episode that occurs during antidepressant treatment and persists beyond the effect of that treatment.

Psychiatric Association website to search for published articles. Search terms included bipolar disorder treatment, mania treatment, bipolar disorder management, and bipolar meta-analysis. Articles based on research directly sponsored by the manufacturer of a medication were eliminated, as were those with a perceived bias or marketing intention. Priority was given to articles completed in the last 5 years. Particular attention was given to articles that focused on medication efficacy and tolerability, and on direct comparisons of treatment regimens. Treatment of mania

Haloperidol, risperidone, and olanzapine are the best options for treating patients presenting with acute manic episodes, according to a meta-analysis by Cipriani et al.5 The metaanalysis included 68 studies of the treatment of acute mania, comparing the acceptability and efficacy of various antimanic medications. All trials included patients with a diagnosis of bipolar I disorder, and the trials were double-blinded. Continues on page 20

TABLE 2. Diagnostic criteria for a hypomanic episode15 1. A minimum of four days where, for the most part of most days, an abnormal mood is observed. The mood is continually elevated, expansive, or irritable, and there is a persistently increased level of energy and activity. 2. During this period, three or more of the following symptoms are observed (four when the mood is described as irritable). These symptoms are a marked change from usual behavior and are present significantly during the period of mood elevation. a. Increased self-esteem or appearing grandiose b. Need for lower amounts of sleep (typically 2–3 hours per day). c. Increased talkativeness or a subjective feeling of the need to keep talking d. An experience of racing thoughts or flight of ideas. e. Attention is easily distracted f. Increased levels of activity towards specific goals (eg, at work or school, socially, or sexually) or an increased level of activity without purpose, leading to psychomotor agitation g. Excessive risk-taking activities with potentially bad outcomes (eg, promiscuity or misguided financial decisions) 3. There is a definite change in the level of functioning of the individual compared to functioning when asymptomatic. 4. The change in mood and level of functioning is noticeable to others. 5. The severity of mood disturbance does not cause markedly impaired social functioning, markedly impaired functioning at work, require hospitalization, or involve psychotic episodes. 6. The mood change is not due to a medical condition or the effects of a substance.

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PHARMACOLOGIC OPTIONS FOR BIPOLAR DISORDER

TABLE 3. Diagnostic criteria for a major depressive episode15 1. Over a continual two-week period, five or more of the symptoms below are present.These symptoms are not due to a medical condition and are different from the individual’s previous level of functioning. One of the five symptoms must be either (a) depressed mood or (b) anhedonia. a. Depressed mood for the most part of most days; the mood can be self-reported or observed by others; for those aged less than 18 years, the mood can be irritable. b. Anhedonia (eg, almost or complete loss of pleasure or interest in daily activities) c. Reduced or increased appetite, or marked unintended weight loss or gain d. Increased or reduced level of sleep most days e. Restlessness or slowing down, which can be noticed by others on most days f. Feeling fatigued or lacking energy most days g. Feeling worthless or guilty; these feelings may be delusional or excessive. h. Reduced concentration levels or ability to think, or being indecisive most days i. Recurring suicidal ideation; this may occur with or without a specific plan or attempted suicide 2. The individual has significant distress or functional impairment in important areas of the daily life. 3. The mood change is not due to a medical condition or the effects of a substance.

TABLE 4. Diagnostic criteria for bipolar I disorder15 A. At least one episode meets the criteria for a manic episode (criteria 1–4 under “Diagnostic criteria for a manic episode” in Table 1). B. The manic episode(s) and any major depressive episode(s) are not better diagnosed as a different psychotic disorder.

TABLE 5. Diagnostic criteria for bipolar II disorder15 A. At least one episode meets the criteria for a hypomanic episode (criteria 1–6 under “Diagnostic criteria for a hypomanic episode” in Table 2), and there has been at least one major depressive episode (criteria 1–3 under “Diagnostic criteria for a major depressive episode” in Table 3). B. There is no history of any manic episodes. C. The hypomanic episode(s) and any major depressive episode(s) are not better diagnosed as a different psychotic disorder. D. The individual has significant distress or functional impairment in important areas of daily life, due to depressive symptoms or unpredictable fluctuations between periods of hypomania and depressive episodes.

Researchers used patients’ rating of symptoms to define efficacy and patients’ discontinuation of treatment within 3 weeks after initiation of the treatment to determine acceptability. For the treatment of acute mania, haloperidol, risperidone, and olanzapine showed the best efficacy results, which were superior to those of 5 other drugs studied: valproate, gabapentin, topiramate, lamotrigine, and ziprasidone. For acceptability, olanzapine, quetiapine, risperidone, and haloperidol scored highest. Other drugs compared and found to have inferior acceptability were lithium, placebo, topiramate, gabapentin, and lamotrigine. A second meta-analysis of antimanic treatments, conducted by Yildiz et al,6 focused on direct comparisons of individual medications and on effects of classes of medication. Second-generation antipsychotic medications in general and haloperidol (a first-generation antipsychotic) proved more effective than mood stabilizers (lithium, valproate, and carbamazepine) for the treatment of acute mania. The differences in efficacy among the antipsychotics were inconclusive for recommending specific medications. Persons with acute mania can present in either inpatient and outpatient settings. Patients with a previous diagnosis of bipolar disorder may present with severe manic episodes, defined by suicidal ideation, homicidal ideation, psychosis, or aggression. For these patients, continuance of their mood stabilizer (typically lithium or valproate) plus the addition of an antipsychotic leads to a 20% higher rate of response.7 For patients whose symptoms are resistant to treatment, different combinations of medications are recommended. For example, a patient can switch from lithium to valproate (or vice versa) and/or can change from one antipsychotic medication to another among the choice of haloperidol, olanzapine, quetiapine, and risperidone.7 Electroconvulsive therapy (ECT) can be reserved as a treatment of last resort for patients with refractory symptoms who have failed a minimum of 4 to 6 combinations of medications.7 Treatment of depression in patients with bipolar disorder

Patients who have bipolar disorder and present with major depressive symptoms face a difficult situation because treatment with regular antidepressants can precipitate a swing into a state of mania or rapid cycling between manic and depressive symptoms. Bobo and Shelton8 present clinical trial evidence against the use of antidepressants as monotherapy in patients with bipolar disorder. However, these authors also present evidence for the limited use of antidepressants in conjunction with a mood stabilizer or antipsychotic. The

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TABLE 6. Main polarity benefit of maintenance treatments for bipolar disorder10 Medication

Mania

Depression

Lithium

Yes

Some

Aripiprazole

Yes

Olanzapine

Yes

Adjunctive quetiapine

Yes

Risperidone long-acting injectable

Yes

Adjunctive ziprasidone

Yes

Lamotrigine

Yes

best-studied therapy with effective results for the treatment of depression in patients with bipolar disorder is fluoxetine plus olanzapine, now available as a combination drug. In the United Kingdom, the National Institute for Health and Care Excellence (NICE)9 made recommendations for the treatment of bipolar disorder after consulting with experts and agreed with the recommendation of the fluoxetine and olanzapine combination. NICE also recommends quetiapine as a good adjunct to the antidepressant prescribed. Transitioning from acute to maintenance treatment

Transitioning patients from the acute treatment of bipolar disorder to long-term maintenance therapy requires careful management. The rates of relapse and suicide are higher among patients with bipolar disorder than among those with many other diseases and disorders. Manning10 provides a methodology to monitor adverse effects, symptom reduction,

and signs of relapse. The author proposes the use of common rating scales to judge patient outcomes. These include the Patient Health Questionnaire 9 (PHQ-9) for symptoms of depression and the National Institute of Mental Health Life-Chart Method (NIMH-LCM) to track the long-term efficacy of bipolar disorder maintenance therapy. Manning10 proposes continuation of the medication(s) used for acute remission, with thorough monitoring of response levels. Maintenance treatment of bipolar disorder

The FDA has approved 7 medications for the maintenance treatment of bipolar disorder: lithium, lamotrigine, aripiprazole, olanzapine, quetiapine (as an adjunct), ziprasidone (as an adjunct), and long-acting injectable (LAI) risperidone.11 Most patients with bipolar disorder demonstrate polarity, relapsing more frequently into either mania or depression. Patient polarity influences the choice of maintenance treatment (Table 6). Lamotrigine or quetiapine reduces depressive relapses in patients who have a depressive polarity. For patients with a mania polarity, the recommended therapies are lithium, aripiprazole, olanzapine, LAI risperidone, and either ziprasidone or quetiapine with mood stabilizers.10 Miura et al 2 conducted research into the longer-term efficacy and tolerability of the medications used for the maintenance treatment of bipolar disorder. The authors analyzed 33 randomized, controlled trials to determine recommendations. The trials did not distinguish between subtypes of bipolar disorder. The authors concluded that lithium remains a good first-line option for maintenance treatment, but that olanzapine should be considered for Continues on page 24

TABLE 7. Long-acting injectable antipsychotic medications13 Dose, mg

Time between injections, d

Overlap with oral medication, wk

Loading dose

Bipolar disorder, schizophrenia

12.5–50

None

Abilify Maintena

Schizophrenia

160–400

None

Paliperidone palmitate

Invega Sustenna

Schizophrenia, schizoaffective disorder

39–234

Variable

Required

Haloperidol decanoate

Haldol Decanoate

Psychosis

20–450

May be required

Olanzapine

Zyprexa Relprevv

Schizophrenia

150–405

14–28

Variable

Required

Fluphenazine decanoate

Prolixin Decanoate

Psychosis

12.5–100

7–21

May be required

Generic

Brand name

Indication

Risperidone

Risperdal Consta

Aripiprazole

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PHARMACOLOGIC OPTIONS FOR BIPOLAR DISORDER

POLL POSITION

Which of the following issues is the most difficult that you encounter in patients with bipolar disorder? n = 510

■ Distinguishing bipolar disorder from depression ■ Determining the best medication to prescribe

21.37% 50%

■ Patient noncompliance with treatment

28.63%

For more polls, visit ClinicalAdvisor.com/Polls.

patients with mania-dominant polarity and quetiapine for patients with depression-dominant polarity. Hayes et al12 conducted one of the most recent large studies to compare lithium with newer second-generation antipsychotics as maintenance monotherapy for bipolar disorder. The authors concluded that for monotherapy, lithium remains the best option. The time to failure (defined as the need to add a second drug to treat symptoms or the need to stop treatment) was approximately twice as long with lithium. This study adds to evidence for the use of lithium as a first-line drug, with antipsychotics as second-line or adjunct therapies. Post4 reviewed the recommendations in recent clinical trials for first-, second-, and third-line options in treating bipolar disorder. The recommended first-choice therapy is continuation of the medication(s) used to treat the acute episode. For second-line options, data show that lithium once again is the superior initial monotherapy. Data also support valproate, quetiapine, and lamotrigine as secondline options for monotherapy, especially for patients who fail or have contraindications to lithium therapy. Third-line options include drug combinations of lithium or valproate with an antipsychotic. Long-acting injectable medications

A major problem in the treatment of bipolar disorder is patient noncompliance with treatment. Patients may be given short-term intramuscular antipsychotic treatment for acute mania, but the use of LAI antipsychotics in psychiatry has been increasing during the last decade. Presently, several LAI antipsychotics are available (Table 7). Although several LAI antipsychotics are used for psychosis and schizophrenia, their use for bipolar disorder is off label. Presently, only Risperdal®

Consta®, the LAI form of risperidone, has an FDA-approved indication for the treatment of bipolar disorder.13 Future research considerations

In their review, Severus et al14 do not make additional treatment recommendations but argue for the necessity of further clinical trials. The authors state that trials should enroll broader populations of patients with bipolar disorder (including patients distinguished by subtype and polarity). Ideally, these patients would be naïve to the treatments used in comparisons. The trials should also more frequently involve direct comparisons between medications. The high relapse rates among patients with bipolar disorder suggest that all current medications are less than ideal. Conducting further clinical trials of current medications, as described, would be beneficial, as well as continuing the development of newer treatments. Conclusions

The treatment of patients with bipolar disorder requires careful monitoring, conducted best with continuation of care by a primary provider skilled in treatment or by referral to a specialist. For the treatment of acute mania, haloperidol, risperidone, and olanzapine show the best efficacy. If the manic patient has a previous diagnosis of bipolar disorder, his or her prior medication should be continued or restarted if needed. For patients who have bipolar disorder presenting with a depressive episode, antidepressant monotherapy should be avoided. Mixed therapy with fluoxetine and olanzapine or another selective serotonin reuptake inhibitor with quetiapine is recommended. For the maintenance treatment of bipolar disorder, the first-line treatment should be continuation of the medications used during the manic or depressive episode. In case of treatment failure, lithium is the best first-line monotherapy, with valproate, quetiapine (for patients with depression-dominant polarity), and olanzapine (for patients with mania-dominant polarity) as viable alternatives. Second-line dual therapy for patients with resistant symptoms should consist of either lithium or valproate with a second-generation antipsychotic. LAI risperidone is available as an option for noncompliant patients. Patients with bipolar disorder continue to have high relapse rates, indicating that further clinical trials are needed to identify the best options for specific subtypes of patients, and that research into new treatment solutions should be continued. ■ Ian Ward, PA-C, is an assistant professor of clinical medicine in the Methodist University Physician Assistant Program in Fayetteville, N.C.

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References 1. Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381:1672-1682. 2. Miura T, Noma H, Furukawa TA, et al. Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic review and network meta-analysis. Lancet Psychiatry. 2014;1:351-359. 3. Angst F, Stassen HH, Clayton PJ, Angst J. Mortality of patients with mood disorders: follow-up over 34-38 years. J Affect Disord. 2002;68:167-181. 4. Post RM. Bipolar disorder in adults: choosing maintenance treatment. UpToDate. http://www.uptodate.com/contents/bipolar-disorder-in-adultschoosing-maintenance-treatment. Updated August 29, 2016. Accessed February 6, 2017. 5. Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments metaanalysis. Lancet. 2011;378:1306-1315.

“Where do you see yourself when the hot weather hits?”

6. Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology. 2011;36:375-389. 7. Stovall J. Bipolar disorder in adults: pharmacotherapy for acute mania and hypomania. UpToDate. http://www.uptodate.com/contents/bipolardisorder-in-adults-pharmacotherapy-for-acute-mania-and-hypomania. Updated May 17, 2016. Accessed February 6, 2017. sion with antidepressants. UpToDate. http://www.uptodate.com/contents/ bipolar-disorder-in-adults-treating-major-depression-with-antidepressants. Updated July 13, 2016. Accessed February 6, 2017. 9. National Institute for Health and Care Excellence (NICE). Bipolar disorder: assessment and management. Clinical guideline (CG185). http://www.nice.org. uk/guidance/cg185. Updated February 2016. Accessed February 6, 2017. 10. Manning JS. Measuring patient outcomes and making the transi-

“You’ll see it when it’s done.”

tion from acute to maintenance treatment for bipolar depression. J Clin Psychiatry. 2015;76:e1603. 11. Frye MA, Prieto ML, Bobo WV, et al. Current landscape, unmet needs, and future directions for treatment of bipolar depression. J Affect Disord. 2014;169(suppl 1):S17-S23. 12. Hayes JF, Marston L, Walters K, Geddes JR, King M,Osborn, DP. Lithium vs valproate vs olanzapine vs quetiapine as maintenance monotherapy for bipolar disorder: a population-based UK cohort study using electronic health records. World Psychiatry. 2016;15:53-58. 13. Chou Y H, Chu P-C, Wu S-W, et al. A systemic review and experts’ consensus for long-acting injectable antipsychotics in bipolar disorder. Clin Psychopharmacol Neurosci. 2015;13:121-128. 14. Severus E, Schaaff N, Möller H-J. State of the art: treatment of bipolar disorders. CNS Neurosci Ther. 2012;18:214-218. 15. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Publishing; 2013.

“Remember, Joey, life is a good preparation for stocks — lots of ups and downs.”

8. Bobo WV, Shelton RC. Bipolar disorder in adults: treating major depres-

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FEATURE: ABIMBOLA FARINDE, PhD, PHARMD

Schizophrenia: a clinical overview A better understanding of this complicated condition is key to helping patients reduce their symptoms and maximize their quality of life.

chizophrenia is recognized as a chronic and disabling mental illness that has affected and continues to affect the lives of millions of people all over the world.1 Nonetheless, significant strides have been made to date in understanding and treating patients with this chronic disease.

Pathophysiology

PET scans of a healthy patient (top) and a patient with schizophrenia (bottom).

A proposed explanation for the development of schizophrenia is that it is a neurochemical disorder in which low dopamine levels (hypodopaminergic activity) in the mesocortical pathway, particularly the frontal lobes, cause the negative symptoms. High dopamine levels (hyperdopaminergic activity) in the mesolimbic pathway are thought to be responsible for the positive symptoms.1 In addition, serotonergic, nicotinic, and N-methyl-d-aspartate (NMDA) receptors are involved and are the focus of the mechanism of action of newer antipsychotic medications. NMDA receptor dysfunction is thought to contribute to the condition, with NMDA receptor antagonists causing positive symptoms by increasing dopamine release in the limbic area and reducing dopamine release from the ventral tegmental area. Genetic and environmental components are also involved in schizophrenia. The risk for schizophrenia is increased among the biological relatives of affected persons—10 times in first-degree relatives; the risk among children who have two parents with schizophrenia is

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35%, and concordance rates of 23% to 78% and 8% to 28% have been observed in monozygotic and dizygotic twins, respectively.1,2 Symptoms

Schizophrenia is defined as a psychotic thought disorder characterized by a mixture of symptoms. These may involve alterations in perception, cognition, emotions, behavior, attention, concentration, motivation, and judgment (Table 1).1,2 Affected persons may experience difficulty relating to people in their environment as a result of a breakdown in thought processes and a deficit in the ability to display normal emotional responses to others.3 The clinical features that many patients with schizophrenia may exhibit include hallucinations, delusions, loosening of associations, misinterpretations of reality, “negative” symptoms, mannerisms, and catatonia.2 The most commonly identified positive symptoms of schizophrenia are hallucinations and delusions, with auditory hallucinations being the most commonly identified (in 74% of patients with schizophrenia).3 Negative symptoms can be associated with the absence of normal capabilities and may include emotional withdrawal, blunted affect, avolition, anhedonia, and alogia; these are fundamental to understanding the functional limitations caused by the disorder.4-6 The symptoms of schizophrenia are significant enough to cause a decline in the social and/or occupational functioning of affected persons.7 Although the etiology of schizophrenia remains unclear, it is certain that the combination of an unfavorable hereditary predisposition and unfavorable life experiences is a factor.8 The development of schizophrenia is not the result of a single inherited predisposition; rather, multiple physical, mental, inherited, and acquired traits can lead to the disorder.8 The combination of persistent negative symptoms and episodic displays of the positive symptoms of schizophrenia can have a profound effect on an individual’s activities of daily living, social functionality, and quality of life.9 Diagnosis

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, the diagnosis of schizophrenia is based on the presence of two or more symptoms (eg, delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms) for a significant portion of time during a 1-month period.10 Since the onset of

the disturbance, there should have been a significant portion of time when major areas of functioning have been impaired. The signs of the disturbance should have lasted for at least 6 months, with the 6 months including at least 1 month of symptoms.11,12 Also, during the prodromal period (before the full development of symptoms) or the residual periods (when prominent symptoms are absent), the disturbance may be manifested only by negative symptoms or by two or more negative symptoms.11 For a patient to receive a diagnosis of schizophrenia, other disorders must be ruled out, such as schizoaffective disorder and mood disorders with psychotic features.12 Symptoms of a major depressive episode, manic episode, or mixed episode should not have occurred with the active-phase symptoms, and the disturbance is not the result of the direct physiologic effect of a substance.13,14 When schizophrenia is diagnosed, the illness can be categorized as paranoid, disorganized, or catatonic—the three main subtypes.15 Paranoid schizophrenia is characterized by a preoccupation with one or more delusions or the presence of frequent auditory hallucinations. Disorganized schizophrenia is characterized by disorganized speech, disorganized behavior, and a flat or inappropriate affect.15,16 Catatonic schizophrenia is characterized by prominent motor symptoms and nonreactivity to the environment.17 Undifferentiated schizophrenia is considered to be a type of schizophrenia in which symptoms of the disease are present but the criteria for the paranoid, disorganized, or catatonic type are not met.17 Course

Schizophrenia has been known to have an age of onset in the early twenties in men and the late twenties to early thirties in women. The incidence is generally equal in the TABLE 1. Symptoms of schizophrenia Positive psychotic symptoms

Positive disorganization symptoms

Negative symptoms

• Hallucinations • Delusions

• Disorganized speech, thought, language • Thought disorder characterization: thought blocking, loosening of associations, tangentiality • Disorganized behavior

• Alogia (poverty of speech) • Flat affect • Poor attention • Avolition (loss of motivation) • Anhedonia (lack of pleasure) • Loss of social interest • Attentional deficits

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SCHIZOPHRENIA: A CLINICAL OVERVIEW

Antipsychotic medications for schizophrenia TABLE 2.Typical (first-generation) antipsychotic medications2 Generic name (brand name)

Dosage forms

Average dose titration, mg

Dopaminergic (D2) effect

Serotonergic (5-HT2) effect

Muscarinic effect

Alpha1- adrenergic effect

Antihistamine effect

Chlorpromazine (Thorazine)

T, I

600–800

++++

Fluphenazine (Prolixin)

T, L, I, I (LA)

10–20

++++

Haloperidol (Haldol)

T, L, I, I (LA)

10–20

++++

Loxapine (Loxitane)

75–100

+++

++++

+++

++++

Perphenazine (Trilafon)

60–80

++++

+++

Thioridazine (Mellaril)

600–800

++++

Thiothixene (Navane)

30–40

++++

+++

Trifluoperazine (Stelazine)

30–40

++++

+++

Key: C, capsule; I, injection; LA, long-acting; L, lozenge; T, tablet

Level/degree of effect: + = low; ++ = moderate; +++ = high; ++++ = very high

TABLE 3. Atypical (second-generation) antipsychotic medications2,22 Generic name (brand name[s])

Dosage forms

Average dose, mg

Chlorpromazine equivalent, mg

Dopaminergic (D1) effecta

Serotonergic (5-HT2) effecta

Muscarinic (M1) effecta

Alpha1adrenergic effecta

Antihistamine (H1) effecta

Aripiprazole (Abilify)

T, ODT, L, I

15–30

2–4

265

3.4

>10,000

Asenapine (Saphris)

T (sublingual)

5–10

N/A

1.4

0.06

8128

1.2

6.2

T, ODT

300–600

126

1.9

160

Iloperidone (Fanapt)

12–24

N/A

216

5.6

>1000

—

473

Lurasidone (Latuda)

40–160

N/A

Olanzapine (Zyprexa)

T, ODT, I

5–20

1.9

Paliperidone (Invega)

T (ER), I (LA)

6–12

—

1.2

3.4

Quetiapine (Seroquel)

T, T (ER)

400–600

455

295

120

Risperidone (Risperdal)

T, ODT, L, I (LA)

2–8

1–2

430

0.5

>10,000

Ziprasidone (Geodon)

C, I

80–160

5–10

525

0.4

>1000

Clozapine (Clozaril; FazaClo)

Key: C, capsule; ER, extended release; I, injection; LA, long-acting; L, lozenge; N/A, not applicable; ODT, orally disintegrating tablet; T, tablet. a Receptor binding affinity (Ki data).

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TABLE 4. Doses of typical and atypical antipsychotic drugs2,22 Antipsychotic generation

First generation

Second generation

TABLE 6. Additional side effects of typical antipsychotic medicationsa Sedation: This is usually worse initially, then tolerated better with time.

Agent (chemical class)

• Chlorpromazine (aliphatic phenothiazine): average dose, 600–800 mg • Fluphenazine (piperazine phenothiazine): average dose, 10–20 mg • Haloperidol (butyrophenone): average dose, 10–20 mg • Perphenazine (piperazine phenothiazine): average dose, 60–80 mg • Piperacetazine (Quide; piperadine phenothiazine): dose range, 2–16 mg • Thioridazine (piperidine phenothiazine): average dose, 600–800 mg • Thiothixene (thioxanthene): average dose, 30–40 mg • Trifluoperazine (piperazine phenothiazine): dose range, 20–200 mg • Aripiprazole (quinolone): average dose,15–30 mg • Asenapine (dibenzo-oxepino pyrrole): average dose, 10–20 mg (twice-daily dosing) • Clozapine (dibenzodiazepine): average dose, 300–600 mg; range, 25–600 mg • Iloperidone (piperidinyl-benzisoxazole): average dose, 6–12 mg twice daily • Olanzapine (thienobenzodiazepine): average dose, 5–20 mg; can increase up to 40 mg • Paliperidone (benzisoxazole): average dose, 6–12 mg • Quetiapine (dibenzothiazepine): average dose, 400–600 mg • Risperidone (benzisoxazole): average dose, 2–8 mg • Ziprasidone (benzisothiazole): average dose, 80–160 mg

TABLE 5. Level of adverse effects of typical antipsychotic medications22 Typical antipsychotic

Sedating effects

Anticholinergic effects

Extrapyramidal effects

Chlorpromazine

High

Low

Fluphenazine

Low

Very high

Haloperidol

Very low

Very high

Loxapine

Moderate

Low

Moderate

Molindone

Very low

Low

Moderate

Perphenazine

Low

High

Pimozide

Low

High

Thioridazine

High

Low

Thiothixene

Low

High

Trifluoperazine

Low

High

Anticholinergic effects: Patients for whom these may be a problem should probably receive a high-potency agent. Anti-adrenergic effects: Patients predisposed to the alpha-adrenergic blocking effect (eg, elderly, dehydrated) should receive a high-potency agent. Neurologic effects: • Parkinsonism: Bradykinesia, rigidity, tremor, or akinesia; usually responsive to anticholinergic agents (benztropine, diphenhydramine) • Acute dystonia: Sustained muscle contractions; earliest onset of all extrapyramidal symptoms (EPS; group of side effects associated with antipsychotic medications that includes parkinsonism, akathisia, dystonia, and tardive dyskinesia); also treated with anticholinergic agents • Akathisia: Somatic restlessness; this may respond to anticholinergic agents but may be more responsive to a lipophilic beta blocker (ie, propranolol) • Tardive dyskinesia: This is a result of long-term therapy, and the risk increases with continued exposure to the drug; usually involves the jaw or oral musculature and is difficult to treat; decreasing or increasing the dose may help; clozapine has not been associated with tardive dyskinesia, and switching to this drug is the intervention of choice; other atypical antipsychotics also are unlikely to cause tardive dyskinesia; supplementation with vitamin E is helpful if this problem develops • Neuroleptic malignant syndrome: More common in patients taking high-potency drugs; manifested by agitation, confusion, changing levels of consciousness, fever, tachycardia, labile blood pressure, and sweating; has a high mortality rate; treatment: discontinue agent, provide supportive care (fluids and cooling); bromocriptine and dantrolene have been used with varying success. Weight gain: Occurs in up to 40% of patients and may be a result of actions at histamine and/or serotonin receptors; keep dose as low as possible Sexual dysfunction: Erectile problems occur in 23% to 54% of men; loss of libido and anorgasmia may occur in men and women Miscellaneous: Low-potency agents (thioridazine and chlorpromazine) can cause pigmentary deposits on the retina; low-potency antipsychotic drugs are relatively cardiotoxic, and high-potency antipsychotics are also cardiotoxic; prolongation of QT interval, PR interval, and T wave; depression of ST segment; low-potency D2 receptor antagonists decrease seizure threshold more than high-potency D2 receptor antagonists a See Table 5 for information on sedating effects, anticholinergic effects, and extrapyramidal effects.

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SCHIZOPHRENIA: A CLINICAL OVERVIEW

Antipsychotic medications for schizophrenia TABLE 7. Adverse effects of atypical antipsychotic medications22 Dose-related extrapyramidal side effects

Risperidone=paliperidone>olanzapine=ziprasidone=aripiprazole=iloperidone>quetiapine=clozapine

Sedation

Clozapine>quetiapine>paliperidone=clozapine=risperidone=ziprasidone=aripiprazole=iloperidone=asenapine

Anticholinergic effects

Clozapine>olanzapine>quetiapine>paliperidone=risperidone=ziprasidone=aripiprazole=iloperidone=asenapine

Weight gain

Clozapine=olanzapine>quetiapine=risperidone=paliperidone>iloperidone>aspenapine>ziprasidone>aripiprazole

Lipid abnormalities

Clozapine=olanzapine>quetiapine>iloperidone>asenapine>risperidone>paliperidone>ziprasidone>aripiprazole

Lowering of seizure threshold (dose-related)

Clozapine>olanzapine=risperidone=paliperidone=quetiapine; ziprasidone=aripiprazole=iloperidone=asenapine

Glucose intolerance

Clozapine=olanzapine>quetiapine=risperidone=paliperidone>ziprasidone=aripiprazole-iloperidone=asenapine

Increased prolactin level

Paliperidone>risperidone>olanzapine=ziprasidone=quetiapine=clozapine=iloperidone=asenapine>aripiprazole

TABLE 8. Monitoring parameters for patients on atypical antipsychotic medicationsa,2 Monitoring parameter

Baseline

Every 4 weeks

Every 8 weeks

Every 12 weeks

Personal/family history

Weight (BMI)

Blood pressure

Fasting plasma glucose

Fasting lipid profile

Quarterly

Annually

Every 5 years

X X

Key: BMI, body mass index a More frequent assessment may be necessary depending on patient characteristics.

two genders. In most patients, the illness fluctuates between acute episodes and periods of remission. Schizophrenia evolves in four phases. In the prodromal phase, a gradual development of symptoms may go unnoticed until a major symptom (eg, isolation, deterioration of hygiene, loss of interest in work or school, dysphoria) occurs. The acute phase consists of a full-blown episode of psychotic behavior. Patients may be unable to care for themselves.16,17 In the stabilization phase, the acute symptoms decrease; this phase may last several months. Lastly, in the stable phase, the symptoms markedly decline and may resolve. However, a complete remission without symptoms is uncommon in individuals with schizophrenia. Pharmacotherapy

The pharmacotherapy of schizophrenia generally consists of the use of antipsychotic medications. Chlorpromazine was

the first antipsychotic medication. Synthesized in the 1950s, the drug served as the prototype for many other antipsychotic agents, and numerous antipsychotic medication options have become available since then.18 The development of chlorpromazine led to the creation of additional first-generation (typical) antipsychotics. Subsequently, clozapine, the first second-generation (atypical) antipsychotic, was discovered in the 1950s and introduced into the market in the 1970s; it is used in a subset of individuals with psychotic disorder who have not benefited from conventional antipsychotic medications.19,20 Both typical and atypical antipsychotic medications have been shown to be helpful in the treatment of the positive symptoms (eg, hallucinations, delusions), negative symptoms (eg, social withdrawal, poverty of speech), and cognitive symptoms (eg, reduction in working memory and attention) of schizophrenia.19 Antipsychotics are considered by

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many to be the drugs of choice in the management and treatment of schizophrenia, with efficacy demonstrated through dopamine (D2) receptor antagonism for the typical antipsychotics and the combination of D2 and serotonin (5-hydroxytryptamine [5-HT2]) receptor antagonism for the atypical antipsychotics.20 Many of the antipsychotic medications block post-synaptic D2 receptors in the central nervous system, particularly in the mesolimbic-frontal system.20 It has been reported that for an antipsychotic to be considered effective, it must exhibit a level of dopamine antagonism of at least 60 to 80% because lower levels of dopamine antagonism generally do not produce observable antipsychotic effects, and in about 60% to 70% of patients, schizophrenia may not be adequately controlled.19 Patients with schizophrenia require long-term maintenance antipsychotic treatment, so the effectiveness of antipsychotic medication is vital if they are to perform the activities of daily living and sustain an adequate quality of life.21 Individuals with a new diagnosis of schizophrenia may appear to be more sensitive to antipsychotic medication therapies than those with a long-standing diagnosis; however, regardless of the selection, antipsychotic medications have demonstrated comparable efficacy and achievement of symptom control.21 Clinicians must be familiar with the available typical and atypical antipsychotics and their dose ranges, relative potencies, side effect profiles, and monitoring parameters (Tables 2–8).21,22 The selection of the appropriate antipsychotic medication is at the discretion of the prescribing provider, but patient preference, tolerance, and efficacy should also be considered to increase the probability of achieving optimal therapeutic results.22

off drugs may be attempted. Patients with a prior history should be symptom-free for 5 years before drug discontinuation is considered.24 Treatment goals

There is generally no gold standard in the selection of antipsychotic medications for schizophrenia; the choice can be based on patient preference, tolerability, and side effect profile. The goal in treating schizophrenia is to reduce or eliminate the frequency/occurrence of symptoms, attempt to maximize quality of life and improve adaptive functioning skills, and enable recovery by assisting patients in attaining personal life goals (eg, in work, housing, and interpersonal relationships). During the treatment process, the pharmacist can serve as a drug information specialist, informing patients about expected side effects, potential drug interactions, and other facts relevant to antipsychotic therapy. When the pharmacist provides this valuable information, patients can acquire a better idea of what to expect from their antipsychotic medication. n Abimbola Farinde, PhD, PharmD, is a professor at Columbia Southern University in Orange Beach, Alabama. References 1. Gupta S, Kulhara P. What is schizophrenia: a neurodevelopmental or neurodegenerative disorder or a combination of both? A critical analysis. Indian J Psychiatry. 2010;52:21-27. 2. Hahn RK, Albers LJ, Reist C. Psychiatry. Blue Jay, CA: Current Clinical Strategies Publishing; 2008. 3. Kandil F, Pedersen A, Wehnes J, Ohrmann P. High-level, but not lowlevel, motion perception is impaired in patients with schizophrenia. Neuropsychology. 2013;27:60-68. 4. Rollins A, Bond G, Lysaker P, McGrew J, Salyers M. Coping with

Initiation and outcome of patients who have had antipsychotic therapy

positive and negative symptoms of schizophrenia. Am J Psychiatr Rehabil.

Patients undergoing antipsychotic treatment for schizophrenia commonly exhibit poor adherence, characterized by high rates of discontinuation and frequent changes in treatment. For these reasons, effective treatment interventions are of utmost importance.23 The administration of very high doses initially, causing “neurolepsis,” is no longer recommended because of increased side effects and lack of benefit. Continuous maintenance of an antipsychotic medication at the minimal effective dose may be the best approach in most cases. Typical agents are associated with greater long-term risks than atypical agents. For some patients who have had a first episode and have been symptom-free for 2 years, a trial

5. Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR. The NIMH-

2010;13:208-223. MATRICS consensus statement on negative symptoms. Schizophr Bull. 2006;32:214-219. 6. Flanagan E, Solomon L, Johnson A, Ridgway P, Strauss J, Davidson L. Considering DSM-5: the personal experience of schizophrenia in relation to the DSM-IV-TR criteria. Psychiatry. 2012;75:375-386. 7. Schaub D, Brüne M, Jaspen E, Pajonk F, Bierhoff H, Juckel G. The illness and everyday living: close interplay of psychopathological syndromes and psychosocial functioning in chronic schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2011;261:85-93. 8. Strauss J, Bowers M, Keith S, Bleuler M. What is schizophrenia? Schizophr Bull. 1984;10:8-10.

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SCHIZOPHRENIA: A CLINICAL OVERVIEW

9. Hoffmann H, Kupper Z, Kunz B. Hopelessness and its impact on reha-

17. Dickson RA, Dalby JT, Williams R, Warden SJ. Hospital days in

bilitation outcome in schizophrenia—an exploratory study. Schizophr Res.

clozapine-treated patients. Can J Psychiatry. 1998;43:945-948.

2000;43:147-158.

18. Jafari S, Fernandez-Enright F, Huang X. Structural contributions of

10. American Psychiatric Association. Diagnostic and Statistical Manual of

antipsychotic drugs to their therapeutic profiles and metabolic side effects.

Mental Disorders, Fifth Edition (DSM-5). Arlington, VA: American Psychiatric

J Neurochem. 2012;120:371-384.

Publishing; 2013.

19. Gardner K, Bostwick J. Antipsychotic treatment response in

11. Keller W, Fischer B, Carpenter J. Revisiting the diagnosis of schizophre-

schizophrenia. Am J Health Syst Pharm. 2012;69:1872-1879.

nia: where have we been and where are we going? CNS Neurosci Ther.

20. Conley RR, Kelly DL. Current status of antipsychotic treatment.

2011;17:83-88.

Curr Drug Targets CNS Neurol Disord. 2002;1:123-128.

12. Idrees M, Khan I, Irfan M, Sarwar R. First rank symptoms in the diagnosis

21. Guo X, Fang M, Zhai J, et al. Effectiveness of maintenance treat-

of schizophrenia. J Postgrad Med Inst. 2010;24:323-328.

ments with atypical and typical antipsychotics in stable schizophrenia

13. Suvisaari J, Perälä J, Saarni S, Juvonen H, Tuulio-Henriksson A,

with early stage: 1-year naturalistic study. Psychopharmacology (Berl).

Lönnqvist J. The epidemiology and descriptive and predictive validity of

2011;216:475-484.

DSM-IV delusional disorder and subtypes of schizophrenia. Clin Schizophr

22. College of Psychiatric and Neurologic Pharmacists. 2010-2011 BCPP

Relat Psychoses. 2009;2:289-297.

examination review and recertification course. New Brunswick, NJ:

14. Fenton WS, McGlashan TH. Natural history of schizophrenia subtypes.

Ortho-McNeil Janssen Scientific Affairs, LLC; 2010.

I. Longitudinal study of paranoid, hebephrenic, and undifferentiated

23. Roussidis A, Kalkavoura C, Dimelis D, et al. Reasons and clinical

schizophrenia. Arch Gen Psychiatry. 1991;48:969-977.

outcomes of antipsychotic treatment switch in outpatients with

15. Schatzberg AF, Cole JO, DeBattista C. Manual of Clinical

schizophrenia in real-life clinical settings: the ETOS observational study.

Psychopharmacology. 7th ed. Washington, DC: American Psychiatric

Ann Gen Psychiatry. 2013;12:42.

Association; 2010.

24. Mayo Clinic Staff. Schizophrenia. Treatment. http://www.mayoclinic.

16. Nisbet B, Dulmus C, Greyber L, Langa M. The spectrum clozaril clinic:

org/diseases-conditions/schizophrenia/basics/treatment/con-20021077.

a successful model for treatment of psychotic disorders. Best Pract Ment Accessed January 25, 2017.

“It would be nice if she left me her money, but mostly I want her overstuffed chair.”

Health. 2010;6:69-84.

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CME CE FEATURED COURSE

n LEARNING OBJECTIVES After completing the activity, the participant should be better able to: • Review and apply updated information on the roles of hormonal/neural mechanisms in regulation of appetite, food intake, and weight • Describe the components of a multimodal obesity treatment plan that not only reduces body weight but also improves health outcomes • Utilize pharmacologic therapy in appropriate patients with overweight and obesity • Implement shared decision-making and motivational interviewing strategies when treating patients with obesity n COMPLETE THE POSTTEST: Page 44

This activity is supported by an educational grant from Novo Nordisk and is a result of a collaborative effort between Haymarket Medical Education, Global Education Group, and the American Society of Endocrinology Physician Assistants (ASEPA). Release Date: March 31, 2017 Expiration Date: March 31, 2018 Estimated time to complete the educational activity: 1 hour Target Audience: This activity has been designed to meet the educational needs of Physician Assistants, Nurse Practitioners, and Dieticians. Faculty Lee M. Kaplan, MD Director, Obesity, Metabolism, & Nutrition Institute Massachusetts General Hospital Associate Professor of Medicine Harvard Medical School Boston, MA Accreditation Statements Physician Credit: Haymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Credit Designation: HME designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. For Registered Dietitians/Registered Dietetic Technicians The following activity has been approved by the ACCME, whose approval is recognized by the Commission on Dietetic Registration and, as such, RDs/DTRs will be able to receive 1.00 CPEU. Nursing Credit: Global Education Group is accredited with distinction as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. Credit Designation: This educational activity for 1.00 contact hours is provided by Global Education Group. Nurses should claim only the credit commensurate with the extent of their participation in the activity. This activity is jointly provided by Global Education Group and Haymarket for ANCC credit.

with any commercial interest. HME and Global Education resolve all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational activities. The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME/CE activity. Faculty Disclosures Lee M. Kaplan, MD, is a consultant for Ethicon, Fractyl, Gelesis, GI Dynamics, Janssen, Merck, Novo Nordisk, Rhythm, Pfizer and Zafgen. He is also a share stockholder in Gelesis, GI Dynamics and Rhythm. Staff/Planners’ Disclosures Haymarket Medical Education staff involved in the planning and content review of this activity have no relevant financial relationships to disclose. CME Reviewer, Priya Wanchoo, MD, has no relevant financial relationships to disclose. Global Education Group staff, Ashley Marostica, RN, MS, Andrea Funk, and Lindsay Borvansky, have no relevant financial relationships to disclose. Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. HME and Global Education Group do not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Method of Participation: To obtain credit, a score of 70% or better on the post-test is required. This activity is offered at no cost to participants. Please proceed with the activity until you have successfully completed this program, answered all test questions, completed the post-test and evaluation, and have received a digital copy of your credit certificate. Your online certificate will be saved on myCME within your Profile/Exam History, which you can access at any time. Disclaimer: The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Novo Nordisk, Global Education Group, and Haymarket Medical Education. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. If you have any questions relating to the accreditation of this activity, please contact cmequestions@haymarketmedical.com.

Disclosure Policy In accordance with the ACCME Standards for Commercial Support, HME and Global Education require that individuals in a position to control the content of an educational activity disclose all relevant financial relationships

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CME CE FEATURED COURSE: LEE M. KAPLAN, MD

PART 1 OF A 3-PART SERIES

Updated understandings of obesity and weight-related health risks New understandings of the hormonal and neural mechanisms that underlie the regulation of appetite, food intake, and weight have led to the development of novel targets for obesity therapy.

espite the high prevalence of obesity and its strong contribution to the leading causes of preventable death, and the documented, beneficial effects of weight loss, obesity is generally unaddressed and untreated in the healthcare setting. Many healthcare providers cite their lack of familiarization with available tools to treat obesity as a major contributor to this deficit. In this article—the first in a series of 3 interrelated CME/CE activities—the causes and consequences of obesity will be reviewed, and an overview of the options currently available for the long-term treatment of obesity will be discussed.

IMAGES: ©THINKSTOCK; PHOTO ILLUSTRATION: J. DVORETZ

■ Case Study

A key component of the successful management of any chronic condition, including obesity, is patient engagement.

Jennifer P. is a 32-year-old woman who recently joined your practice. This is her second visit since the birth of her first child 1 year ago. She works part-time managing a small nonprofit organization and spends most of her day working in an office or at home caring for her 1-year-old child. She says that with the additional time required to care for her baby, she has been eating more irregularly, consuming more “fast” food, and exercising substantially less often than before she became pregnant. Her lifestyle has become more hectic generally and her stress level has increased as she tries to balance her professional and family life, stress that is only exacerbated by increased pressure for productivity at work. Caring for her daughter has been an unpredictable, 24/7 job. She says that she rarely gets enough sleep, and is “always tired.” www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2017 35

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CME CE

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Obesity is associated with numerous “comorbid” disorders and has been demonstrated to be the cause or a major contributor to many of them. As a result of these changes, she’s gained an additional 25 lb over the past year, on top of the 15 lb she had gained during pregnancy and has since been unable to lose. Obesity: definition and prevalence

Obesity is defined as excess body fat that presents a risk to health. With recent studies demonstrating that the body has powerful and accurate physiologic mechanisms to maintain body fat in a healthy range, it is now recognized that obesity results from a disruption of these mechanisms. The current obesity epidemic appears to result from powerful, widespread changes in the modern environment interfering with the normal regulation of body fat mass in biologically susceptible individuals. Obesity is associated with nearly 200 “comorbid” disorders in all body systems and has been demonstrated to be the cause or a major contributor to many of them.1 As a result, obesity is associated with substantially increased healthcare costs and reduced lifespan.2 In addition, it often disrupts social well-being and economic success, and can have a strongly negative effect on psychological health and overall quality of life.3-5 Although obesity is defined by total fat mass, its presence, progression, and response to treatment can be easily and rapidly assessed through the marker of body mass index (BMI), which is a representation of body weight corrected for height. In routine practice, people with a BMI >25 kg/m 2 are generally considered to be overweight, the mildest form of the disease, with those whose BMI is >30 kg/m 2 meeting the diagnostic criterion for obesity. Since BMI is not a direct measure of body fat, its relationship to obesity can vary somewhat among individuals and patient populations. For example, because of their greater predilection for metabolic sequelae such as type 2 diabetes mellitus (T2DM), the BMI diagnostic criterion for south and east Asians is generally 27.5 kg/m 2. The adverse effects of obesity are so pleiotropic that it is useful to consider them in different pathophysiologic categories, including metabolic (eg, dyslipidemia, diabetes, fatty liver disease, hypertension, gallstones, infertility), structural or anatomic (eg, gastroesophageal reflux, obstructive sleep apnea, reduced mobility, chronic back pain, urinary incontinence), inflammatory (eg, disease, autoimmune skin and joint disorders), degenerative (eg, heart failure, cirrhosis, complications of diabetes), neoplastic (endometrial, breast, ovarian, prostate, liver, gallbladder,

kidney, and colon cancer, among others), and psychological (eg, depression, anxiety, and eating disorders).6-8 Loss of 5% to 10% of body weight can prevent or ameliorate many of these disorders, leading to dramatic improvement in overall morbidity and mortality. Even more modest weight loss (<5%) has been shown to improve clinical outcomes in people with T2DM and reduce the progression from prediabetes to diabetes.9-15 The prevalence of obesity dramatically increased in the second half of the 20th century; today in the United States, more one-third of adults and more than one in 6 children have this disease.6,9 Although rare monogenetic forms of obesity exist,10 in most people with obesity the role of genetics is to increase their susceptibility to environmental “obesogenic” influences. Indeed, the recent dramatic increase in rates of obesity in the US and worldwide reflect both the potency of these environmental influences and the fact that most of us are genetically susceptible to them to one degree or another. These powerful environmental factors, all increasingly prevalent in our modern, industrialized society, include changes in the chemical composition of our diets, labor-saving machinery and devices, diminished sleep, disruption of normal circadian rhythms, stressinducing changes in societal structure, and the increasing use of obesogenic medications.4 Despite increased recognition of the adverse effects of obesity, greater understanding of its pathophysiology and the role of environmental factors, and numerous public health campaigns aimed at more effective prevention, the worldwide prevalence of obesity continues to climb rapidly, with several countries now surpassing the US in overall prevalence. In the US, despite slowing growth of obesity prevalence, the severity of obesity continues to rise, with increasing rates of more severe forms and complications of this disease (Figure 1).9 These observations suggest the need for new approaches to complement the efforts in place today. First, obesity is a heterogeneous disorder; people with obesity are differentially susceptible to different obesogenic environmental influences. More effective prevention strategies may come from better understanding of these susceptibilities and a more targeted approach. Second, with more than one-third of the population already having obesity, most with 1 or more of its medical comorbidities, there is an urgent need for more widespread use and effective application of available anti-obesity therapies. Doing so will require greater

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Long-term weight loss by simple calorie restriction is rarely successful without addressing the underlying cause of obesity. identification of–and attention to–the presence and severity of obesity in routine clinical practice, and learning how to use the currently available therapies most effectively. Many clinicians perceive that available treatments for obesity are not adequately effective, too risky, or too cumbersome or time consuming to provide. Others report having inadequate familiarity with and understanding of obesity itself or the treatment options, and some are unaware of recent advances in the understanding of obesity as a disease, amenable to classical medical interventions.16-20 Practitioners with specialized training in obesity medicine have demonstrated effective and efficient use of anti-obesity therapies, but despite their growing numbers, these specialists alone will never adequately address the huge clinical need. It thus falls on the primary care community, the army of clinicians who are the mainstay of healthcare, to address this problem. With greater awareness of the available tools, and better training in how to use them safely, effectively, and efficiently, primary care providers (PCPs) in all disciplines will be most able to help control this epidemic. Physiologic consequences of obesity

Body fat mass, and hence body weight, are regulated by a complex interaction among the brain, the gastrointestinal tract, and other regulatory organs (eg, muscle, liver, pancreas and fat itself ).4,21-23 Neurons that detect nutrients and

hormonal signals of energy availability are located in multiple brain regions that regulate hunger, satiety, the reward value of food, nutrient utilization, and energy expenditure—including the hypothalamus, the limbic areas, and the brain stem.21,22 Neuroendocrine signals from the gastrointestinal tract and peripheral tissues communicate nutrient availability, energy needs and utilization, and adequacy of energy stores, which together enables the brain to regulate appetite, energy expenditure, and behavior. Nutrient intake and energy expenditure are highly regulated over both the short and long term.22,24,25 Short-term responses to changes in energy intake and utilization include regulation of appetite, nutrient availability (glucose and fatty acids), and metabolic rate. Long-term adaptations include changes in nutrient utilization, intestinal absorptive function, adipocyte number and size, and relevant neuronal circuitry. Obesity results from the changes in the body’s perceived energy needs, causing it to seek and defend an elevated total fat mass. The physiologic mechanisms by which the body defends its so-called fat mass set point are both powerful and accurate, even when that set point has been elevated to an abnormal level by the internal and external forces that promote obesity in the first place. As a result, long-term weight loss by simple calorie restriction is rarely successful without addressing the underlying cause of the abnormally high defended fat mass. 24,26 While

Percent

30 20 10 0 1999-2000

2001-2002 2003-2004

2005-2006

2007-2008

2009-2010 20011-2012 20013-2014

Survey Years FIGURE 1. Trends in obesity prevalence among adults aged 20 years and older9 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2017 37

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CME CE

FEATURED COURSE

Some food ingredients are now shown to contribute to obesity via mechanisms that are independent of calorie content. short-term weight loss is relatively easy, the body’s perceived need to defend the higher fat mass induces compensatory mechanisms (eg, increased appetite and reduced metabolic rate) that almost invariably lead to regain of most or all of the lost weight. The only approaches likely to achieve long-term success are those that reduce the defended set point, either by reducing the obesogenic environmental influences or by enhancing the body’s ability to compensate for those influences.27 Key to the brain’s ability to regulate and defend its energy stores (fat mass) is its ability to monitor those stores and to detect and respond appropriately to signals of current energy needs. One of the signals of the level of energy stores is the hormone leptin, a protein secreted by adipocytes (fat cells) whose circulating levels closely reflect the body’s total mass of fat tissue.28,29 Leptin plays an important role in the regulation of body weight, influencing both food intake and energy expenditure through direct and indirect mechanisms.30 In people with obesity, leptin levels are elevated; however, leptin levels decrease with weight loss.29,31 In the weight-reduced state, leptin administration partially normalizes the increased appetite and reduced energy expenditure.30 These findings suggest that the threshold for leptin sensitivity is altered as a result of obesity and that this reduced leptin threshold persists even after weight loss.24,30

Food Composition Weight-gain Promoting

Stress

Obesity Disruption of Circadian Rhythms

Decreased Need for Exercise Sleep Deprivation

FIGURE 2. Environmental contributors to obesity

Long-term changes in leptin and other gastrointestinal hormones, including ghrelin, glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), and amylin have been documented to occur after calorie restriction-induced weight loss, which persist for at least 1 year despite substantial (but incomplete) weight regain, and which are likely to persist indefinitely until either the lost weight is fully regained or the body is induced to reduce its defended fat mass.31 These changes likely contribute to the increased hunger reported by these individuals immediately and after weight loss, and reinforce the need for long-term, physiologically relevant treatment. In addition to disruption of neuroendocrine signaling, prolonged excess adiposity can alter lipid and glucose metabolism and metabolic regulation more broadly, causing or exacerbating diabetes, dyslipidemia, hypertension, fatty liver, gallstones, and sleep apnea. Excess adiposity often stimulates the production of inflammatory mediators (adipokines and other cytokines), promoting the development of inflammatory and autoimmune disorders including asthma, arthritis, skin disorders, steatohepatitis, and hypothyroidism. Despite the obviously greater fat storage, obesity is also associated with greater fat synthesis and transport, resulting in elevated triglycerides and free fatty acids,32,33 and excess lipid accumulation in muscle and liver; these changes further stimulate macrophage activity and inflammatory responses.32 Among the effects of these inflammatory changes is the exacerbation of insulin resistance, diabetes, and disordered nutrient metabolism, supporting a vicious cycle of progressive metabolic and inflammatory dysfunction.34 Thus the goal of effective anti-obesity therapy is to induce durable weight loss, both for its own benefit and to break this cycle and thereby reduce the risk and health burden of these complicating, comorbid disorders. To be effective, each of these therapies must help overcome the forces that caused the body to seek and defend inappropriately elevated energy (fat) storage and the powerful physiologic forces working to maintain that elevated fat mass. Environmental drivers of obesity

The modern environment contributes to obesity in many ways (Figure 2). Some of these contributors are well recognized. The abundance of high-calorie food is often cited as a cause of obesity.35-37 Perhaps more importantly, some food ingredients are now shown to contribute to obesity

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Circadian misalignment is associated with obesity and risk of developing cardiometabolic disease. via mechanisms that are independent of calorie content. For example, fructose stimulates uric acid generation, which causes mitochondrial oxidative stress that stimulates fat accumulation and increases the risk for developing diabetes.38 Exposure to other nonfood items such as endocrine disruptors also increases the risk of obesity and diabetes.39 Obesity is also associated with elevated stress and an altered stress response. For example, obesity is associated with elevated activation of the hypothalamic-pituitaryadrenal (HPA) axis, increased sympathetic tone, and elevated cortisol, which contributes to hypertension, inflammation, insulin resistance, and increased visceral adiposity.40-43 Common psychosocial stressors include low socioeconomic status, personal conflict, stressful work environment, lack of social support, challenges to work/life balance, and caring for a family member.44 Changes in sleep patterns and lack of sleep are both independently associated with obesity. Circadian misalignment is associated with obesity and risk of developing cardiometabolic disease.45 An example of the cardiometabolic perturbations in circadian misalignment is illustrated by shift workers. Dyslipidemia (eg, high triglycerides, low high density lipoprotein [HDL] cholesterol), elevated postprandial glucose and insulin, increased inf lammatory markers, and increased incidence of diabetes and obesity have all been documented in night workers. Sleep deprivation increases food intake46 and some studies have shown a correlation between sleep deprivation and increased insulin, inflammatory markers, leptin, BMI, and decreased blood glucose and ghrelin.47-49 Exercise has many protective effects against obesity and obesity-related disorders. In addition to increasing energy expenditure, exercise restores insulin and glucose metabolism, improves dyslipidemia, and attenuates sympathetic tone.50-52 There is a dose-dependent beneficial effect of exercise on metabolic and cardiovascular risk factors and mortality.53 Because of the low exercise requirements of modern society, the lack of exercise contributes to obesity, and, more importantly, dysfunctional adiposity or “sick fat,” such that even individuals with a BMI <30 kg/m2 may have many of the cardiovascular and metabolic disorders associated with obesity.54 In addition, some medications for obesity comorbidities are associated with weight gain. This includes many antidepressants

and antipsychotics, as well as some diabetes medications, antihistamines, steroids, and adrenergic blockers.55 Assessment and follow-up

Recent guidelines for Managing Overweight and Obesity in Adults56 recommend calculating BMI yearly or more frequently depending on the patient’s risk factors. The US Centers for Medicare & Medicaid Services also mandates that electronic medical records calculate BMI as part of Core Measures on Vital Signs.57 It is recommended that patients with BMI >25 kg/m2 be evaluated for compromised cardiometabolic, mechanical, and/or psychological function to assess the type, severity, and complications of obesity and to guide appropriate treatment. Patients with insulin resistance and/or cardiovascular consequences (eg, hypertension) should undergo additional evaluation including waist circumference, fasting, and 2-hour glucose tolerance testing and lipids, blood pressure, and liver function tests. Those with mechanical problems should be assessed for osteoarthritis, stress incontinence, orthopedic complications, and chronic pulmonary disease. Assessment of psychological health and psychiatric history should also be conducted.56 To assess identifiable causes and contributors to their excess adiposity, weight-related environmental factors should be included in the history of all patients with obesity (see Figure 2). It may be helpful to include a timeline of the patient’s weight, and assessment of any developmental (eg, puberty, pregnancy, or menopause) or environmental changes (eg, smoking cessation, changes in personal or work life, alterations in physical activity, or initiation of a potential weight-gain-promoting medication that correlate with periods of significant weight gain). This information should then be used to guide therapy, with recommended changes in lifestyle designed to address the specific contributors identified in the patient’s history. ■ Case Study, continued

The patient’s current BMI is 36 kg/m 2. She has a history of hypertension (treated with an angiotensin-receptor blocker) and polycystic ovarian syndrome. She developed diabetes during her pregnancy that has since resolved. Recent laboratory testing, however, has shown a mildly elevated plasma glucose (120) and HbA1c (5.8%) consistent with continued prediabetes.

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CME CE

FEATURED COURSE

Obesity interventions should be directed at changing the patient’s body weight “set point,” ie, changing the biology of appetite, energy balance, and metabolic function.

BMI

Classification

18.5 to 24.99

Normal

25.00 to 29.99

Overweight

modifications alone, illustrating the difficulty of overcoming physiology with behavior. 26 Anti-obesity medications (AOMs) are a useful addition for such patients.5,64-66 These medications are indicated for individuals with BMI ≥30 kg/m 2 or 27 kg/m 2 and one or more comorbidity. Most AOMs reduce appetite and may assist with adherence to a hypocaloric diet.67 Because the efficacy and tolerability of these medications vary widely across individuals, it is important to discuss the efficacy and adverse event profile of AOMs with your patient before initiating treatment. Additionally, a 3-month follow-up appointment should be scheduled to review efficacy and tolerability, consider dose adjustments, or to switch AOMs. Bariatric surgery is a frontline, durable treatment for severe (BMI ≥40 kg/m2) obesity and is currently the most effective weight-loss intervention because it produces immediate and long-term changes in the body weight “set point.”55 Bariatric surgery is limited to patients with a BMI of at least 40 kg/ m2, or at least 35 kg/m2 and an associated serious medical condition such as T2DM, and is associated with dramatic and sustained weight loss, reduced overall mortality, and significant improvements in comorbidities, including diabetes, sleep apnea, cardiovascular risk, along with improvement in quality of life.68-73 While bariatric surgery is currently the most effective treatment option for obesity, it is also associated with the highest degree of risk. Mortality for modern laparoscopic surgery is generally low, however, re-operation rates for surgical complications are high.74 Furthermore, surgery requires dramatic and lifelong changes in diet as well as vitamin supplementation, and postsurgical complications, as well as weight regain, may require additional follow-up and treatment.55 Patients who have undergone bariatric surgery may benefit from continued lifestyle change or the addition of an AOM to manage diet, increase exercise, and maintain weight loss and health benefits.

≥30.0

Obese

■ Case Study, continued

27.0

Criteria for considering treatment with an anti-obesity medication: BMI 27 kg/m2 + obesity-related complication (eg, diabetes, hypertension)

35.0

Criteria for considering bariatric surgery: BMI 35 kg/m2 + obesity-related complication (eg, diabetes, hypertension, obstructive sleep apnea)

The principles of obesity treatment: changing the body weight “set point”

The US Preventive Services Task Force (USPSTF) recommends that clinicians screen all adults for obesity and offer intensive behavioral interventions to affected indivdiuals. BMI is the most common indicator of the degree of excess adiposity; there is a clear association between BMI, obesityrelated complications, and mortality (Table 1).59-61 However, BMI alone is insufficient to assess the degree of risk in every individual. Obesity treatment should facilitate behavior modification to reduce obesogenic environmental factors (discussed above and shown in Figure 2). The approach to anti-obesity treatment is outlined in Figure 3. These interventions are directed at changing the patient’s body weight “set point,” ie, changing the biology of appetite, energy balance, and metabolic function that drive obesity. Healthcare providers can assist patients with developing a weight-loss plan and provide these individuals with either internal or external resources for lifestyle modification directed at achieving weight loss. Data from The Look AHEAD and Diabetes Prevention Program clearly demonstrate that lifestyle intervention composed of behavioral sessions, meal replacements, and physical activity increase the likelihood of achieving weight loss and clinically significant improvements in blood pressure, triglycerides, HDL cholesterol, and glycemic control.13,14,56 Many patients are unsuccessful in achieving and maintaining clinically significant weight loss with lifestyle TABLE 1. Common BMI cutoffs for adults59

Sustained lifestyle change is difficult under the best of circumstances, and factors unrelated to the obesity itself may facilitate, or compromise, a patient’s ability to make and maintain the beneficial changes. Thus, care in the prioritization, number, timing, and presentation of recommended changes is essential. Clinicians should discuss weight-loss goals with the patient and stress that many of

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Clinicians who treat patients with obesity should initiate conversations on the impact of excess body weight on various health parameters. the lifestyle changes used to treat obesity, even when unsuccessful at inducing weight loss, can have a beneficial effect on obesity-related comorbidities and overall health. As the first step in managing the patient’s obesity, Jennifer P.’s clinician first seeks to determine her readiness and ability to make the lifestyle changes that would be necessary for weight loss. Since she is the mother of a very young child and is the primary caregiver, she is understandably concerned about having enough time and energy to prepare healthier meals and to increase her level of physical activity. As a starting point, Jennifer’s clinician encourages her to utilize the wide of array of free, electronic resources that are available; the clinician provides her with a list of several online patient resources that have helped a number of her patients to implement behavioral interventions for weight loss. The healthcare provider and patient set a realistic goal for weight loss (5% within 2 months) and set up a series of bimonthly appointments to monitor the attainment of this goal. Summary

Now defined by experts as a chronic disease, obesity is associated with serious complications including T2DM, hypertension, dyslipidemia, cardiovascular disease, stroke, depression, osteoarthritis, obstructive sleep apnea, increased risk of some cancers, and nonalcoholic fatty liver disease. It is imperative that clinicians who treat patients with

overweight or obesity are able to initiate conversations with these individuals on the impact of excess body weight on various health parameters, the potential benefits of even a relatively minimal degree of weight loss, and strategies by which to set and attain weight-related health goals. At the present time, weight-loss interventions are underutilized, leaving affected patients at risk for the development of numerous weight-related health issues. PCPs are integral in the treatment of obesity. Because obesity is a chronic disease, regular follow-up is important, even in patients who lose weight, to ensure weight maintenance and management of comorbidities. To help patients achieve and maintain weight-loss goals over the long term, clinicians should first evaluate the causes and contributors to obesity and match the patient with the most appropriate treatment option(s) for him or her. It is important to completely assess comorbidities, take a complete weight-related patient history, and identify behaviors or lifestyle factors that may contribute to weight gain. Healthcare providers should initiate appropriate lifestyle modification and introduce AOMs or discuss surgical options as appropriate. n References 1. Yuen MM, Lui DT, Kaplan LM, et al. A systematic review and evaluation of current evidence reveals 195 obesity-associated disorders. T-P-3166. Poster presented at: the Obesity Society 2016 Annual Meeting. October 31, 2016-November 5, 2016; New Orleans, LA.

Self-directed Lifestyle Change

Professionally Directed Lifestyle Change

Anti-obesity Medication (AOM)

Surgery

Postsurgical Combinations

FIGURE 3. Anti-obesity treatment model www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2017 41

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CME CE

POST-TEST Expiration date: March 31, 2018

Credit Designation: HME is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. HME designates this educational activity for a maximum of 1.0 AMA PRA Category l Credit™. The following activity has been approved by the AACME, whose approval is recognized by the Commission on Dietetic Registration and, as such, RDs/ DTRs will be able to receive 1.0 CPEU. Global Education Group is accredited with distinction as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. This educational activity for 1.0 contact hours is provided by Global Education Group. Participants should only claim credit commensurate with the extent of their participation in the activity. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better. Posttest must be completed and submitted online. Please go to myCME.com/Mar17CAFeature.

CREDITS: 1.00 | Change to Updated Understandings of Obesity and Weight-Related Health Risks 1. Which of the following statements is true? a. At the present time, approximately one-quarter of US adults are obese. b. Obesity is now believed to result from predominately genetic causes. c. The American Medical Association (AMA) recently redefined obesity as a disease. d. All of the above. 2. Most individuals with obesity are unable to maintain weight loss over the long term. This is most likely because: a. There are no effective pharmacologic weight loss interventions at the present time. b. A continuous state of obesity results in physiologic changes that defend excess adiposity. c. Obesity is genetically predetermined in most cases. d. Most patients fail to make appropriate changes to their physical activity levels along with dietary changes. 3. Changes in leptin and other gastrointestinal hormones, including ghrelin, glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), and amylin: a. Do not influence body weight as much as was previously believed. b. May dictate how much body weight an individual with obesity can actually lose. c. Usually reverse quickly after weight loss. d. Have been documented to persist for at least 1 year after weight loss 4. Which of the following statements is true? a. Some food ingredients are now shown to contribute to obesity via mechanisms that are independent of calorie content. b. Exposure to other nonfood items such as so-called “endocrine disruptors” actually has no impact on obesity or weight-related health conditions. c. Fructose inhibits uric acid generation, which reduces mitochondrial oxidative stress and may thus decrease the risk for developing diabetes. d. All of the above. 5. Which of the following statements is true? a. Stress has less of an effect on the development of obesity than was previously believed. b. Sleep deprivation actually decreases overall food intake. c. Exercise has the potential to restore insulin and glucose metabolism. d. Increased physical activity has little effect on weight-related health parameters. 6. Data from The Look AHEAD and Diabetes Prevention Program clearly demonstrate that: a. Lifestyle intervention may help reduce body weight in individuals with obesity but has no significant effects on other health parameters.

b. Moderate physical activity actually has a greater impact on weight loss than dietary changes for patients with obesity. c. A very-low-fat diet is most likely to lead to significant reductions in weight over the long term. d. Lifestyle interventions consisting of behavioral sessions, meal replacements, and physical activity increase the likelihood of achieving weight loss and clinically significant improvements in blood pressure, triglycerides, HDL cholesterol, and glycemic control. 7. The criteria for consideration use of AOMs is: a. BMI of 25 or higher, regardless of the presences of obesity-related complications. b. BMI of 27 or higher, with at least 1 obesity-related complication (eg, diabetes, hypertension). c. BMI of 30 or higher, with at least 1 obesity-related complication. d. None of the above. 8. Bariatric surgery: a. Is currently the most effective treatment option for obesity. b. Is associated with low re-operation rates for surgical complications. c. Precludes the use of AOMs in most cases. d. Should only be considered in patients with a BMI of at least 40 kg/m2, regardless of comorbidities. 9. Julia L. is a 43-year-old patient with a BMI of 30 kg/m2; she also exhibits early signs of hypertension and dyslipidemia (family history of both). Two years ago, she was able to lose 25 lb by following a low-carbohydrate diet; however, she has since regained the weight plus an additional 5 lb. According to the evidence, which of the following is the most appropriate course of action for this patient? a. Refer the patient to a bariatric surgery consultation. b. Recommend the patient implement a very-low-calorie (VLC) diet. c. Advise the patient to begin a vigorous exercise program to be done for at least 1 hour per day, 5 days per week. d. Utilize an anti-obesity medication along with lifestyle interventions. 10. Robert M. is a 53-year-old patient with a BMI of 42 kg/m2 . He also has obstructive sleep apnea and diabetes, which is poorly controlled despite lifestyle interventions and metformin. Which of the following would be an appropriate approach to this patient? a. Recommend a commercial weight-loss program and defer discussion of AOMs or weight-loss surgery until the patient brings it up. b. Recommend an AOM. c. Refer the patient to a bariatric surgery consult. d. All of the above. e. Both b and c.

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CONSULTATIONS TRANSURETHRAL RESECTION OF BLADDER TUMOR I recently had a patient diagnosed with a T1a high-grade urothelial carcinoma with focal invasion of the lamina propria sized at 3 × 2 × 1 cm. The patient recently underwent a TUR but is unaware if the clinicians performed a chemotherapy instillation following the procedure. I am interested in knowing the gold standard of care with bladder tumor removal, follow-up, recurrence, and instillation guidelines for chemotherapy.—ELIZABETH FITZPATRICK, MS, APRN, GNP-BC, Port Jervis, N.Y. A TURBT (transurethral resection of bladder tumor) allows examination and determination of histology, depth of invasion, and involvement beyond the bladder. A patient with a primary tumor without muscle invasion should undergo TURBT; if there is significant risk of recurrence and/or progression, intravesical therapy is recommended. Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001.You may contact us by e-mail at editor@clinicaladvisor.com. If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter. No anonymous contributions will be accepted.

A patient with a tumor without invasion should undergo radical cystectomy with urinary diversion. Neoadjuvant cisplatin-based chemotherapy should be considered with a goal to increase survival. Adjuvant chemotherapy may have a role in high-risk invasive carcinoma in patients who are otherwise candidates for chemotherapy; however, results of randomized controlled trials are controversial. If the patient is unable or unwilling to undergo radical cystectomy with urinary diversion, TURBT followed by radiation and chemotherapy can be offered (“bladder sparing” approach). All tumors are at risk for recurrence; long-term surveillance is required. After cystectomy, lab studies (urine cytology, liver enzymes, renal function, and electrolytes) should be done every 3 months for the first year, every 6 months for the second and third year, and annually thereafter for up to 5 years. Imaging (CT scan of chest, abdomen, and pelvis) should be done every 6 months for 3 years. After bladder preservation therapy, more frequent surveillance is required to look for local recurrence and detect new cancers.—CLAIRE O’CONNELL, MPH, PA-C (221-1)

YOUR COMMENTS LIFESTYLE MODIFICATIONS VERSUS PHARMACOLOGIC TREATMENT FOR PATIENTS WITH DIABETES I could hardly contain my anger and frustration while reading the comment by Joel Zonszein, MD, CDE, in “A

OUR CONSULTANTS

Philip R. Cohen, MD,

is clinical associate professor of dermatology, University of Texas Medical Center, Houston.

Deborah L. Cross, MPH, CRNP, ANP-BC, is associate program

director, Gerontology NP Program, University of Pennsylvania School of Nursing, Philadelphia.

Abimbola Farinde, PhD, PharmD,

is a professor at Columbia Southern University in Orange Beach, Ala.

Laura A. Foster, CRNP, FNP,

Abby A. Jacobson, MS, PA-C,

practices family medicine with Palmetto Primary Care Physicians in Charleston, S.C.

is an assistant professor at Thomas Jefferson University and a dermatology PA at Family Dermatology of Reading, Pa.

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differing opinion on the ACP’s New Diabetes Treatment Guidelines” [Advisor Forum, February 2017, page 36]. Dr. Zonszein takes issue with the UK Prospective Diabetes Study recommendations for patients with type 2 diabetes and prediabetes to be taught therapeutic lifestyle modifications first. He also reports that the similar recommendations that were made by the American Diabetes Association and the NIH’s Diabetes Prevention Program are inadequate and miss the mark. Is he kidding? He is way too entrenched in our mainstream conventional medicine approach, which simply uses pharmaceuticals to help patients gain glycemic control. I have been in the field of diabetes for 30 years and am a Doctor of Nurse Practitioner and also a certified diabetes educator. I did my doctorate on using the Paleo diet (a low carbohydrate diet) to prevent the progression of prediabetes to type 2 diabetes. My results reveal that lifestyle modifications DO NOT fail. It is the patients who fail to carry them out. Every one of my study participants who followed my carefully laid out instructions for the study period had improved fructosamine, HDL cholesterol, triglycerides, weight, and BMI, and, of course, gained amazing glycemic control. Many went on to prevent type 2 diabetes. It can be done and should absolutely not be discounted when dealing with our huge population of patients with prediabetes and type 2 diabetes. We just can’t give up! I certainly understand that there is a place in medicine for using pharmaceuticals. But nothing is more disheartening than to hear “when diet and exercise fail … use this drug.” You cannot solve a lifestyle disease with drugs. You can only solve it with lifestyle. I teach RNs to become nurse practitioners in the graduate program of a local university, and I teach them all to never give up on people. The problem is not that we are not using

Debra August King, PhD, PA,

is senior physician assistant at New York-Presbyterian Hospital, New York City.

Mary Newberry, CNM, MSN,

provides well-woman gynecologic care as a midwife with Prima Medical Group, Greenbrae, Calif.

the drugs right. It is that our society does not value living a healthy lifestyle … hence all the “lifestyle diseases” based on our modern culture such as type 2 diabetes, cardiovascular disease, and cancer. Until that changes, physicians such as Dr. Zonszein will continue to attempt to treat lifestyle diseases exclusively with pharmaceuticals, and his patients will not get better.—CHRYSTYNE OLIVIERI, DNP, FNP-BC, CDE, Brookville, N.Y. (221-2)

CASE FILES SOFT TISSUE SARCOMA OF THE THIGH IN AN ADOLESCENT MALE Contributed by Sherril Sego, FNP-C, DNP A mother and father brought in their 12-year-old son with a complaint of a tender mass on his left thigh. They denied trauma and said that he just noticed it when it started hurting. Imaging and biopsy confirmed an osteosarcoma. Osteosarcoma, the 8th-most common pediatric cancer, is a malignant process that occurs most commonly in children and tends to focus in areas of active bone growth, especially near the knee. Treatment is aggressive due to the high potential for metastasis. This young man underwent initial chemotherapy, followed by resection of the femur with prosthetic rod implantation. He then underwent another round of chemotherapy. At his 1-year follow-up, scans showed a lesion in the apex of his left lung, which was resected, and followed by experimental oral chemotherapy. At the time of this writing, a second lung lesion has been detected, and his family and treatment team are considering their diminishing options. (221-3) n

Claire O’Connell, MPH, PA-C,

an associate professor at the Rutgers University Physician Assistant Program, Piscataway, N.J.

Katherine Pereira, DNP, FNP,

is assistant professor, Duke University School of Nursing, Durham, N.C.

Sherril Sego, FNP-C, DNP,

is an independent consultant in Kansas City, Mo.

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Dermatology Clinic CASE #1

A facial mass with “bag-of-worms” appearance MELINDA LIU, BA, AND MAURA HOLCOMB, MD

A 30-year-old healthy Hispanic woman presents with a slowly progressive facial deformity present since early childhood. She denies any new lesions during this time, any history of trauma to the area, and any family history of similar skin lesions. Examination reveals a bulging, deformed dermal mass with a “bag-of-worms” appearance involving the upper right quadrant of her face, with hypertrophy of the overlying skin and soft tissues. Neurofibromas and café-au-lait macules are not observed. What is your diagnosis? Turn to page 49

CASE #2

Spreading eczema and areas of raw, oozing skin ESTHER STERN, NP

A 13-month-old toddler with spreading eczema on his trunk and arms is brought in by his mother. She is applying moisturizer and a cortisone cream. However, 2 days earlier, a wound appeared on his left hand that appears to be infected. Since then, more areas of raw, oozing skin have developed. Examination reveals lichenified scaling plaques scattered on the trunk and posterior knees and arms, and his left arm has monomorphic crusted vesicles and ulcerations on an erythematous base. What is your diagnosis? Turn to page 50 48 THE CLINICAL ADVISOR • MARCH 2017 • www.ClinicalAdvisor.com

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Dermatology Clinic CASE #1

Plexiform neurofibroma

Plexiform neurof ibromas (PNFs) are rare, benign, per iphera l ner ve sheath tumors composed of a variable mixture of Schwann cells, perineural elements, fibroblasts, and hematopoietic cells in a collagenous or myxoid stroma.1-3 These lesions typically present at birth or during the first years of life; however, a few cases of late-onset PNFs have also been described.1,3 Depending on their location and size, they may be cosmetically unacceptable.4 In addition, PNFs have the potential to transform into malignant peripheral nerve sheath tumors, which is the most common cause of mortality.4 The exact pathogenesis of PNFs is unclear. Trauma is thought to be an inciting factor, although no clear associations have been made.5 Another theory involves the secretion of high concentrations of stem cell activators by tumorigenic Schwann cells, which activates mast cells to release inflammatory cytokines, further stimulating these Schwann cells and the surrounding fibroblasts and blood vessels.2 Although PNFs are commonly associated with neurofibromatosis type 1 (NF1), they are not pathognomonic.2,6 Regardless, their presence should prompt search for other stigmata of NF1, including >5 café-au-lait macules, >1 neurofibroma or ≥1 PNF, intertriginous freckling, optic gliomas, >1 Lisch nodule, a distinctive osseous lesion (including dysplasia of the sphenoid bone or thinning of the long bone cortex), and a first-degree relative with NF1.5 Presence of ≥2 of these criteria described by the National Institutes of Health is diagnostic of NF1.5 Clinically, PNFs appear as ill-defined, subcutaneous, or dermal masses commonly located in the head and neck region.2,4,7 Because they arise from multiple nerves as bulging and deforming masses involving the connective tissue and skin folds, PNFs are often described as having a “bag of worms” appearance.4,7 Although all peripheral nerves are susceptible to PNF formation, there is a predilection for the larger peripheral nerves of the face, neck, and extremities.5 Some lesions may be only a few centimeters in diameter, whereas others may affect an entire limb, resulting in a phenomenon called elephantiasis neuromatosa.5 Lesions exhibit increased growth rates during childhood and periods of hormonal change.5

Some patients may also have pain, aesthetic problems, and neurologic involvement, depending on the location.7 PNFs may also induce hypertrophy and pigmentary changes of overlying skin and soft tissue, and, in some cases, may change the surrounding osseous architecture.5 Diagnosis of PNF is based on clinical features, although histopathology can be useful to exclude malignant transformation.4 On histology, neurofibromas consist of small, bland, elongated spindle cells with characteristic wavy or comma-shaped nuclei in a myxomatous stroma.5 Unlike schwannomas and other forms of neurofibromas, PNFs

Clinically, PNFs appear as ill-defined, subcutaneous, or dermal masses commonly located in the head and neck region. are unencapsulated and involve several nerve fascicles.5 Positive immunohistochemical staining for S100 protein can differentiate this neurogenic sarcoma from other sarcomas.5 Radiologically, PNFs appear as large, round masses consisting of numerous neurofibromas, referred to as the Take-away points for plexiform neurofibromas Clinical presentation

• Characterized by a “bag-of-worms” appearance because they arise from multiple nerves as bulging, ill-defined, subcutaneous or dermal masses • Most commonly located on the head, neck, and extremities • Increased growth rates in childhood and during hormonal changes

Differential diagnosis

Schwannomas, neurofibromas, synovial sarcomas, other soft tissue sarcomas

Diagnosis

• Definitive diagnosis requires histopathologic examination, which reveals small, bland, elongated spindle cells with characteristic comma-shaped nuclei in a myxomatous stroma; the lesion is not encapsulated and involves several nerve fascicles • Stains for S100 on immunohistochemistry

Management

• Complete surgical resection is the only definitive treatment • Imatinib may be useful in reducing tumor volume, especially in cases of unresectable and progressive lesions

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Dermatology Clinic “central dot sign,” and diffuse thickening of the involved nerve, often with extension into nerve branches.6 The differential for PNFs includes schwannomas and other forms of neurofibromas, which may be distinguished via histology as described, synovial sarcomas, other types of soft tissue sarcomas; these, in turn, may be distinguished via immunohistochemistry, and synovial sarcomas, which often demonstrate mineralization with calcification—a histologic finding not present in PNF.5 Definitive treatment requires complete surgical resection. Unfortunately, PNFs tend to recur despite an appropriate resection, especially in younger patients and when they involve the head and neck region.4,5,7 Their tendency to bleed profusely with surgical removal often makes complete resection difficult.7 Imatinib treatment may be useful in reducing tumor volume, especially in cases of unresectable, progressive, and symptomatic lesions.3 Finally, all patients with PNFs require serial follow-ups to monitor for the development of malignant peripheral nerve sheath tumor, which may be asymptomatic until distant metastases occur.1 In our case, the patient declined surgery and chose to undergo clinical follow-up every 6 months. Melinda Liu, BA, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston. References 1. Chieng GH, Bhatnagar A, Mirza M. Solitary plexiform neurofibroma, a pitfall in diagnosis of lipoma. BMJ Case Rep. 2010 Sep 20. doi: 10.1136/ bcr.01.2010.2696 2. Huang W, Chong WS. Facial plexiform neurofibroma: is it truly just skin deep? BMJ Case Rep. 2013 Oct 7. doi: 10.1136/bcr-2013-200716 3. Jungmann J, Heydt C, Bohle R, Pföhler C, Vogt T, Müller CS. Genetic basis of a solitary familial plexiform neurofibroma without verified associated neurofibromatosis. J Dtsch Dermatol Ges. 2016;14:525-527. 4. Tchernev G, Chokoeva AA, Patterson JW, Bakardzhiev I, Wollina U, Tana C. Plexiform neurofibroma: a case report. Medicine (Baltimore). 2016;95:e2663. 5. Blitz NM, Hutchinson B, Grabowski MV. Pedal plexiform neurofibroma: review of the literature and case report. J Foot Ankle Surg. 2002;41:117-124. 6. Cebesoy O, Tutar E, Isik M, Arpacioglu O. A case of isolated giant plexiform neurofibroma involving all branches of the common peroneal nerve. Arch Orthop Trauma Surg. 2007;127:709-712. 7. Mishra PK, Dwivedi R, Shrivastava DC, Gaur SC. Isolated plexiform neurofibroma of arm with unusual presentation — a rare case report. J Clin Diagn Res. 2015;9:RD03-RD04. doi: 10.7860/JCDR/2015/ 10530.5407

CASE #2

Eczema herpeticum

Eczema herpeticum (EH), also known as varicelliform eruption, pustulosis varioliformis acuta, and KaposiJuliusberg dermatitis, is a herpetic superinfection of inflamed skin. Although mild disease may be self-limited in healthy individuals,1 early diagnosis and treatment is critical to prevent systemic spread of the infection, particularly in higher-risk patients, such as infants, the elderly, and immunocompromised individuals. Classic EH appears as clusters of monomorphic, domeshaped, or umbilicated vesicles on an area of inflamed skin; it is often accompanied by abrupt onset of fever, malaise, and lymphadenopathy. As the disease progresses, vesicles may coalesce and transform to punched-out ulcerations, erosive pits, and crusts. Frequently affected areas are the head, neck, upper trunk,2 and extremities. EH commonly occurs in the setting of eczematous skin disease, but can also occur with Darier disease, allergic or irritant contact dermatitis,3 Hailey-Hailey disease, cutaneous T-cell lymphoma, and other dermatoses. Wolf et al4 described EH in the setting of sunburn. The underlying pathology among these conditions is an impaired stratum corneum and compromised skin integrity, which allows for viral invasion. Most cases of eczema herpeticum are caused by herpes simplex virus I or II. It can result from either primary infection of the virus or from reactivation or reinfection.2 Occasionally, it can be caused by coxsackievirus A16, or vaccinia virus. In addition, EH may become secondarily infected with Staphylococcus aureus, β-hemolytic streptococci, and Pseudomonas aeruginosa.5 Wollenberg et al2 found that early onset of atopic disease, severe untreated lesions, and high levels of total serum immunoglobulin E were risk factors for EH. Conversely, secondary diagnoses, family history of atopy, and corticosteroid treatment were not found to be risk factors. Although EH is typically a clinical diagnosis, laboratory testing can help confirm the diagnosis. Polymerase chain reaction, immunofluorescence, and electron microscopy are useful in detecting the herpes virus. The Tzanck test reveals multinucleated giant cells confirming viral infection, whereas viral culture and serologic testing are less useful. The differential diagnosis of EH includes various disseminated

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infections, including impetigo, varicella zoster virus infection, and animal pox infection. In addition, bullous contact dermatitis and autoimmune bullous diseases should be considered. Antiviral therapy with acyclovir for 5 to 10 days is the treatment of choice. More severe cases may require intravenous administration in the hospital setting. In addition, oral antibiotics may be considered if there is a concern of bacterial superinfection. Pain should be assessed and adequately managed. Patients should remain adequately hydrated while on acyclovir; patients should also be instructed to apply bland emollients to the skin, reserving topical corticosteroids for when the EH resolves.6

Because the risk of virus reactivation is high, patients with severely compromised immune systems should be considered for prophylactic systemic antiviral agents.1 For the patient in our case, the mother was educated regarding the serious nature of the infection and the need to be aware of signs of worsening infection. Treatment was initiated with acyclovir suspension, 250 mg, 4 times daily, for 5 days. At a follow-up appointment 3 days later, the patient was noted to have marked improvement of the eczema overall, as well as minimal remaining ulcerations. n Esther Stern, NP, is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J.

“If a sixth borough opens up, I’ll let you know.”

References 1. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, PA: Saunders-Elsevier; 2011. 2. Wollenberg A, Zoch C, Wetzel S, Plewig G, Przybilla B. Predisposing factors and clinical features of eczema herpeticum: a retrospective analysis of 100 cases. J Am Acad Dermatol. 2003;49:198-205. 3. Vanchinathan V, Christopher B, Sklar L. A case of vulvar eczema herpeticum. J Am Acad Dermatol. 2013;68(4 suppl 1):AB132. 4. Wolf R, Tamir A, Weinberg M, Mitrani-Rosenbaum S, Brenner S. Eczema herpeticum induced by sun exposure. Int J Dermatol. 1992;31:298-299. 5. Brook I, Frazier EH, Yeager JK. Microbiology of infected eczema herpeticum. J Am Acad Dermatol. 1998;38:627-629. 6. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence. 5th ed. Toronto, Canada: Elsevier; 2016.

“I’m Juliet. Who the heck is Rapunzel?”

Antiviral therapy with acyclovir for 5 to 10 days is the treatment of choice for patients with eczema herpeticum.

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Dermatologic Look-Alikes A pruritic rash BRIGETTE MARY LEE, BS, AND CHRISTOPHER RIZK, MD

CASE #1

CASE #2

A 54-year-old woman presents with a 1-day history of a painful pruritic rash on the lower extremity. There are several intact and excoriated bullae on the lower extremity overlying large areas of erythema. The patient states that the rash developed 1 to 2 days after she returned home from her annual family camping trip. She does not have any recollection of being bitten, falling, or injuring herself on her trip. The patient feels fine and is afebrile. She is stable and has no symptoms that would indicate a systemic infection.

A 42-year-old man who is a car mechanic presents with an 8-month history of a waxing and waning rash on his right upper extremity. The patient says that the area is mildly pruritic but is not painful. After questioning from the clinician, he states that he has significant pain in his right elbow secondary to multiple traumas he sustained while playing college football. He mentions that the area is usually covered by a large elbow brace that helps alleviate the pain. The patient has no other dermatologic or medical problems.

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Dermatologic Look-Alikes CASE #1

Allergic contact dermatitis

There are two types of dermatitides resulting from substances coming into contact with the skin: allergic contact dermatitis (ACD), which accounts for 20% of contact dermatitis cases, and irritant contact dermatitis (ICD), which accounts for the remaining 80%.1,2 ACD is an acquired delayed-type hypersensitivity reaction, with a response only occurring in people who have already been sensitized to the allergen.1,2 ACD affects a wide range of individuals, including the old and young, all races, and both sexes. There may be some sex-based differences, but this is due more to exposure patterns. For example, nickel allergies occur more frequently in women, likely because women wear more jewelry and are therefore exposed to more nickel.2 In ACD, initial sensitization occurs when an individual first comes into contact with the causative substance.2-5 This initial exposure does not necessarily lead to apparent changes to the skin.1 The allergen enters the skin where it is processed by antigen-presenting cells and is transported to lymph nodes.4 There, the antigen is presented to T cells, causing proliferation of allergen-specific T cells.4 Individuals may be exposed to these allergens for years before they develop hypersensitivity.1 The second phase in the development of ACD is the elicitation phase, in which additional exposure to the allergen leads to the presentation of the substance to primed T cells, resulting in the release of multiple cytokines and chemotactic factors, including interferon-Îł, interleukin (IL)-2, and IL-17.2,3,5 The activated T cells cause apoptosis in keratinocytes, leading to a clinical presentation of erythema, edema, vesicles, oozing, and pruritus.2,3 Sensitization is affected by genetic variability, as well as other factors, such as the concentration of the allergen, its vehicle, timing and exposure site, occlusion, age, sex, and race of the patient, and the presence of other skin or systemic disorders.1 After an individual becomes sensitized, only a low concentration of the allergen is necessary to elicit a reaction.2 ACD presents as a well-demarcated pruritic eczematous eruption that can be acute or chronic. Acute stages are characterized by blistering, weeping, and/or edema associated with intense itch, burning, and sometimes pain. Chronic stages demonstrate lichenified, hyperkeratotic, scaly, or

fissured plaques.2,3 The reaction is typically localized to the region of skin that contacted the allergen, but wide-spread reactions known as autoeczematization can occur.2 Common areas of involvement include hands, neck, and eyelids.1,5 Histologically, the acute stage of ACD can show a variable degree of spongiosis with a mixed dermal inflammatory infiltrate that contains lymphocytes, histiocytes, and some eosinophils.2 In more moderate and severe reactions, spongiosis leads to intraepidermal vesiculation.2 In the chronic stage, epidermal hyperplasia, often psoriasiform, develops.2 However, it should be noted that the use of topical corticosteroids may alter the histologic findings.2

Allergic contact dermatitis presents as a well-demarcated pruritic eczematous eruption that can be acute or chronic. Some common causes of ACD in the United States include toxicodendrons (poison ivy, oak, or sumac), nickel sulfate, balsam of Peru (Myroxylon pereirae), neomycin, formaldehyde and formaldehyde-releasing preservatives, bacitracin, rubber compounds, and cobalt chloride; currently nickel sulfate is the most common cause.1,2,6 ACD must be differentiated from other types of dermatitides, including ICD, atopic dermatitis, stasis dermatitis, and seborrheic dermatitis, as well as the erythematous form of rosacea.2 Chronic ACD, particularly on the extremities, can be difficult to differentiate from psoriasis. The distribution of the rash, as well as a comprehensive history including time course and exposures, can be useful.2 Atopic dermatitis begins in childhood, displays a chronic course, and frequently occurs in conjunction with allergic rhinitis and asthma. Stasis dermatitis occurs in patients with venous insufficiency and is localized to the lower extremities. Seborrheic dermatitis almost invariably occurs in a seborrheic distribution, involving the scalp, eyebrows, nasolabial folds, and ears, and often is not associated with significant pruritus. Rosacea flares with heat, consumption of spicy foods and alcohol, and exercise, and it can be differentiated from facial ACD by history. Psoriasis classically affects the scalp, knees, elbows, gluteal cleft, and nails; thus, involvement of these areas can help differentiate psoriasis from ACD. ACD is most commonly diagnosed clinically, but patch testing is sometimes necessary for diagnosis or to elucidate

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Dermatologic Look-Alikes causative agents.1,2 Suspected allergens are applied to uninflamed skin, commonly the back, using individually prepared patches or by a set of commercially available premade patches called the thin-layer rapid-use epicutaneous (TRUE) test.1 The TRUE test is more convenient to use but is limited in that it only screens for 35 allergens.2-4 Patches are removed after 48 hours, and results are read in 72 hours.1 A positive reaction is usually indicated by erythematous papules and vesicles with edema and are graded based on severity.1 Other diagnostic tools for ACD include the provocative use test and the photopatch test.1 Treatment for ACD includes educating the patient to read labels and avoid exposure to the allergen to prevent future reactions.2 The dermatitis is treated with topical corticosteroids or systemic corticosteroids, if necessary.1,2 It may take 6 or more weeks for complete clearing, even if the patient practices avoidance.2 Narrow-band ultraviolet (UV) B phototherapy or psoralen plus UVA (PUVA) treatments may help some patients with chronic ACD.3 The patient in our case had likely been exposed to poison ivy, a common plant in the area in which she was camping. Due to the extensive nature of the rash, the patient was treated with a 15-day prednisone taper, which quickly led the resolution of her rash.

CASE #2

Irritant contact dermatitis

Irritant contact dermatitis (ICD) is a localized, nonimmunologically initiated inflammatory reaction that occurs in most individuals who contact a substance.1,2 Clinical presentation includes erythema, scaling, edema, vesiculation, and erosions; chronic cases lead to lichenification, hyperkeratosis, and fissures.2 In ICD, a reaction occurs in any individual if the concentration of the irritant substance is sufficiently high or repetitive.1 The severity and timing of the reaction depends on many factors, including the concentration and type of toxic substance, duration of exposure, and condition of the skin at exposure.1 Furthermore, a reaction can occur on the first exposure and usually occurs within minutes, or a few hours at most.1

ICD is the most common form of occupational skin disease and is estimated to represent 70% to 80% of all occupational skin disorders.2 Infants and the elderly often are more affected by ICD and develop more severe symptoms due to a weakened epidermal barrier.2 The hands and the face are the most commonly affected areas in ICD.2 A history of atopic dermatitis correlates with a 13.5-times greater risk of developing occupational dermatitis.2

Irritant contact dermatitis can be caused by alkalis, which are found in soaps, detergents, and bleaches, and by acids. Although the exact cellular mechanisms leading to ICD are unknown, there is evidence that activated keratinocytes may act as signal transducers and may be key immunoregulators in the process.2 Cytokines such as IL-1α, IL-1β, and tumor necrosis factor-α upregulate intercellular adhesion molecule-1 expression, promoting the inflammatory response.2,7 There are several other effects that have been associated with ICD and may play a role in its mechanism. These include denaturation of epidermal keratins, disturbance of the permeability barrier, cell membrane injury, and direct cytotoxic effects, which vary with different irritants. 2 Additionally, the mechanisms appear to differ between acute ICD and chronic ICD. In the acute phase, there is direct cytotoxic damage to keratinocytes; in the chronic phase, the stratum corneum’s role as a barrier is altered, leading to loss of cohesion of corneocytes, desquamation, and increased transepidermal water loss.2 Histologically, the pathology of ICD includes mild spongiosis, necrosis of epidermal keratinocytes, and inflammatory infiltrate.2 Over time, acanthosis with mild hypergranulosis and hyperkeratosis develops.2 There are many substances that can cause ICD. Alkalis, found in soaps, detergents, and bleaches, are common culprits, as are acids.1,2 Hydrofluoric acid and sulfuric acid tend to cause the most severe burns, whereas organic acids tend to be less irritating.2 However, there are many other acids that can cause a reaction, including nitric acid, hydrofluoric acid, oxalic acid, phenol (carbolic acid), and chromic acid.1 ICD from alkalis and acids are colloquially referred to as “burns.” Detergents, present in skin cleansers, cosmetics, and household cleaning products, frequently cause chronic ICD.2

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Allergic contact dermatitis and irritant contact dermatitis: clinical presentation and treatment Allergic contact dermatitis

Irritant contact dermatitis

Clinical presentation

• Acute: blistering, erythema, weeping, and edema • Chronic: eczema, hyperkeratosis, erythema, desquamation, fissures, lichenified or scaly plaques

• Acute: erythema, scaling, edema, vesiculation, erosions, and in rare cases, full thickness necrosis • Chronic: erythema, lichenification, hyperkeratosis, and fissures

Symptoms

Pruritus

Burning and stinging

Pathogenesis

• Sensitization: initial contact with the allergen will lead to allergen-specific T-cell proliferation • Elicitation: additional exposure to the allergen results in the release of cytokines and other factors, which lead to a reaction

• Cytokines IL-1α, IL-1β, and TNF-α upregulate ICAM-1 expression, promoting the inflammatory response • Acute phase: cytotoxic damage to keratinocytes • Chronic phase: stratum corneum is disrupted, leading to loss of cohesion of corneocytes, desquamation, and increased transepidermal water loss

Onset

Delayed onset

Fast onset, minutes to hours

Histology

• Acute: spongiosis, with a mixed dermal inflammatory infiltrate that contains lymphocytes, histiocytes, and some eosinophils • Chronic: epidermal hyperplasia, often psoriasiform

• Acute: mild spongiosis, necrosis of epidermal keratinocytes, and inflammatory infiltrate • Chronic: acanthosis with mild hypergranulosis and hyperkeratosis

Diagnosis

• History • Distribution • Patch testing

• History • Distribution • Exclusion of a suspected allergen from a negative patch test

Treatment

• Avoiding allergens • Topical corticosteroids • Systemic corticosteroids • PUVA • Narrow-band UVB phototherapy

• Avoiding irritants • Topical corticosteroids • Systemic corticosteroids • Barrier creams • PUVA • Narrow-band UVB phototherapy • Systemic immunomodulators

ICAM, intercellular adhesion molecule; IL, interleukin; PUVA, psoralen plus ultraviolet A; TNF, tumor necrosis factor; UV, ultraviolet

Solvents are another common cause of ICD, responsible for approximately 10% of occupational dermatitis.1 Many different solvents are used in chemical reactions, hydraulic systems, metal refining, dry cleaning, and metal degreasing.2 They function primarily by disrupting the intercellular lipid barrier of the epidermis, which allows for more percutaneous penetration.2 After repeated exposure to solvents, the clinical presentation consists of erythema, scaling and dryness, and eventually eczema on the hands or the hands and face.2 Alcohols and glycols are commonly used as solvents, disinfectants, and in cosmetics, and may cause a reaction.1,2 Other causes of ICD include plastics, food and food additives, water, bodily fluids, airbag dermatitis, metal salts, fiberglass, dusts, capsaicin, tear gas, and chlorinated compounds.1,2 ICD and allergic contact dermatitis (ACD) can appear similar clinically and histologically, especially the chronic types.1,2 A thorough history is extremely important to determine exposure to possible irritants at home or in the

workplace.1,2,7 Symptoms of ICD include pain, burning, and stinging.1,2 This is in contrast to the itch that is more frequently observed in allergic reactions, and it can be helpful in distinguishing between ICD and ACD.1 Additionally, diagnosis of ICD is a diagnosis of exclusion when the reaction is unexplained by patch test to an allergen.2 For many, ICD will spontaneously resolve despite continuous exposure due to the hardening effect in which repeated exposure to milder substances leads to the skin becoming more resistant to irritation caused by this substance.1,2,8 Other causes of spontaneous resolution may include increased skin permeability to irritants and changes to remove irritants more quickly, as well as immunologic changes that promote anti-inflammatory reactions to irritants.2 A history of atopy, female sex, and the presence of ACD are indicators of a poor prognosis.2 The main method of treatment is to avoid the irritants at home or in the workplace.1,2 This can include substitution of

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Dermatologic Look-Alikes substances that are nonirritating when possible, or protecting the skin, with the use of gloves or special clothing.1,2 Barrier creams offer an additional method of protection.2,9 Topical corticosteroids are frequently used.1,2,10 Systemic corticosteroids are not useful in treating chronic ICD, unless methods are also taken to avoid the irritants.2 For patients who are nonresponsive to these therapies, other sources of treatment include photochemotherapy (psoralen plus ultraviolet [UV] A [PUVA]) or narrow-band UVB irradiation, as well as systemic retinoids or systemic immunomodulators.2,10 The patient in our case had started using a new large elbow brace to help with his elbow pain, and the ICD was confined to the area under the new elbow brace he had been using. The patient was advised to stop using (or exchange) his elbow brace, which led to the resolution of his rash. n Brigette Mary Lee, BS, is a medical student and Christopher Rizk, MD, is a dermatology resident at Baylor College of Medicine in Houston. References 1. James W, Berger T, Elston D, Neuhaus I. Andrews’ Diseases of the Skin. 2. Bolognia J, Jorizzo J, Schaffer J. Dermatology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012. 3. Kostner L, Anzengruber F, Guillod C, Recher M, Schmid-Grendelmeier P, Navarini AA. Allergic contact dermatitis. Immunol Allergy Clin North Am. 2017;37:141-152. 4. Fonacier LS, Sher JM. Allergic contact dermatitis. Ann Allergy Asthma Immunol. 2014;113:9-12. 5. Ho KK, Campbell KL, Lavergne SN. Contact dermatitis: a

“If only the aftertaste came first.”

comparative and translational review of the literature. Vet Dermatol. 2015;26(5):314-327. 6. DeKoven JG, Warshaw EM, Belsito DV, et al. North American Contact Dermatitis Group Patch Test Results: 2013-2014. Dermatitis. 2017;28:33-46. 7. Ale IS, Maibach HI. Irritant contact dermatitis. Rev Environ Health. 2014;29:195-206. 8. Watkins SA, Maibach HI. The hardening phenomenon in irritant contact dermatitis: an interpretative update. Contact Dermatitis. 2009;60:123-130. 9. Hines J, Wilkinson SM, John SM, et al. The three moments of skin cream application: an evidence-based proposal for use of skin creams in the prevention of irritant contact dermatitis in the workplace. J Eur Acad Dermatol Venereol. 2017;31:53-64. 10. Cohen DE, Heidary N. Treatment of irritant and allergic contact dermatitis. Dermatol Ther. 2004;17(4):334-340.

“We’re decluttering.”

12th ed. Philadelphia, PA: Elsevier; 2016.

56 THE CLINICAL ADVISOR • MARCH 2017 • www.ClinicalAdvisor.com

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LEGAL ADVISOR CASE

When a referral goes wrong

ANN W. LATNER, JD

Ms N, aged 36 years, was a nurse practitioner who had worked out of a general practitioner’s office. She saw her own patients, and she sometimes covered patient appointments for the physician, Dr M, as well. She had been working at the practice for almost a decade, and she and Dr M had a close relationship. He had been something of a mentor to her, and she respected his advice. One piece of advice that he had given her early on was that “if you don’t think you can diagnose a specific problem, you should refer the patient to someone who can” — meaning a specialist. She understood this to be good advice, and regularly referred patients to cardiologists, gastroenterologists, endocrinologists, and other specialists. She knew that she could not be the expert at everything, and she wanted to make sure that her patients had the best outcomes possible. One of Ms N’s patients was Mrs V, aged 60 years. Mrs V came in regularly for annual check-ups, and she occasionally made

A clinician misses a differential diagnosis when she refers a patient to a specialist for rectal bleeding.

Knowing when to make a referral and when to look more carefully into a patient’s condition is frequently a difficult decision for clinicians.

appointments for minor illnesses. The patient, a postmenopausal woman, was in good overall health, did not smoke, and was the appropriate weight for her height. Her blood pressure was borderline high, but no medication had been prescribed yet as the patient was trying to control it with dietary changes. Her only other issue was hypothyroidism, which was being successfully treated with replacement levothyroxine. One afternoon, Mrs V came in for an appointment after complaining about abdominal pain. “I’m quite uncomfortable most of the time these days,” she told Ms N. “I thought maybe it was something I ate, but it hasn’t gone away and it doesn’t really feel like my stomach.…” After further discussion, Mrs V confided that she had also been experiencing rectal bleeding. Ms N questioned her about this, but the Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

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LEGAL ADVISOR patient’s description was not consistent with what Ms N had found was the most common cause of rectal bleeding in her patients — hemorrhoids. A physical examination did not reveal anything out of the ordinary. Ms N decided the best option was to refer the patient to a gynecologist. She explained this to the patient, and Mrs V agreed to see the specialist. A few weeks later, Ms N was notified that the gynecologist had diagnosed a likely uterine fibroid after an ultrasound but that an endometrial biopsy was benign. The gynecologist diagnosed benign pelvic disease. However, Mrs V began calling the nurse practitioner, complaining of continued symptoms. The patient even came into the office on two occasions to tell Ms N that she was still experiencing discomfort. Ms N initially reassured the patient that her issues were benign, as per the gynecologist. But, after several months of Mrs V’s continued complaints, Ms N ordered an abdominal computed tomography (CT) scan. The scan revealed a malignant rectal mass displacing the uterus. Mrs V required several surgeries and was told that had the cancer been discovered earlier, she would have had a better chance of successful treatment. The patient eventually consulted with a plaintiff’s attorney who advised her to sue Ms N and the gynecologist.

The clinician did not attempt to make a differential diagnosis or immediately order a CT scan for the patient. After hearing that she was being sued, Ms N was upset but believed that she did not have to worry. After all, she had referred the patient to a specialist, so she believed her obligation to the patient was satisfied. The defense attorney provided by her insurance company told her that was not the case. He hired a medical expert to go over the records. After reviewing the medical records and speaking to Ms N, the expert told the attorney that Ms N appeared to have been reassured by the gynecologist’s finding of benign pelvic disease. “This is an example of what we call ‘premature closure,’ ” the expert said. “It seems that once the referral was made, the thinking stopped. Ms N should have focused on a differential diagnosis, focusing on the common causes of rectal

bleeding, and this would have likely led to a timelier cancer diagnosis and a better outcome for the patient.” After considering the expert’s opinion and the costs of trial, the defense attorney recommended settling the case out of court for an amount within Ms N’s insurance. Legal background

Medical experts are essential in malpractice cases in several ways. First, attorneys use them to help decide whether a case exists, in particular whether or not a clinician has strayed from the accepted standard of care. Second, medical experts are used during a trial to educate the jury members as to what the appropriate standard of care should have been for the patient and to explain the medical terminology to the jurors. Often, both defense attorneys and plaintiff’s attorneys will use medical experts to help them decide whether to pursue a trial, or whether to settle the case out of court. Medical experts are generally physicians or clinicians in the same field as the defendant (such as nurse practitioners). Protecting yourself

Making a referral to a specialist is common in primary care medicine — after all, no one can be an expert in everything. It makes perfect sense that when a patient has an unidentifiable skin problem, he or she would be referred to a dermatologist. Similarly, a patient who has unremitting stomach problems might be referred to a gastroenterologist. Making a referral is a good way to look out for the health of your patient and as well as your practice, because it allows you to focus on the things that are your specialty, and it allows your patient to get the help that he or she needs. In this month’s case, however, we see what happens when a referral was not the best option. Ms N intended to do the best for her patient by referring her to a specialist. Often, that is the right thing to do. But in this case, the patient was actually harmed by the fact that Ms N did not attempt to make a differential diagnosis for the rectal bleeding and abdominal pain and order a CT scan immediately. Knowing when to make a referral and when to look more carefully into a patient’s problems on your own is difficult. However, it is important to consider all options when diagnosing a patient. n Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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ALTERNATIVE MEDS UPDATE

What you should know about the herbs and supplements patients use By Sherril Sego, FNP-C, DNP Ms. Sego is an independent consultant in Kansas City, Mo.

Frankincense

Yes, the holidays are past and the topic of frankincense will probably not be on most of our minds for another year. However, with the increasing popularity of essential oils, frankincense is now the topic of intense research. Many of those raised with Christian traditions grew up hearing the story of the three Magi and their gifts of gold, frankincense, and myrrh. Although gold may be familiar to most, the value of frankincense (and myrrh) is not well-known. Promising studies indicate that frankincense may be useful in fighting the rapid growth of cancer cells and many other immune and inflammatory conditions.

Background Frankincense comes from the resin found in the tree Boswellia.1 While there are four main types of Boswellia, the more common species from which most commercial resin is harvested is Boswellia serrata. Frankincense is a term derived from the French language meaning ‘high-quality incense.’ These trees grow in the harsh terrains of the Middle East, North Africa, and Somalia, and they have been documented in folk literature and as valued trading goods for more than 5,000 years.2 The prized resin is harvested by slashing the bark of the tree and allowing the resin to ‘weep’ and gradually harden. The oils are distilled from these nuggets.

Science One of the more exciting potential uses of frankincense is in the treatment of cancer. Early studies indicate that the mechanism of action may be two-pronged. Frankincense

exerts an anti-inflammatory effect that is not cell-specific, so any localized tumor swelling and irritation is reduced. Frankincense also interferes specifically with the development of the cancer cell at several points in the cell cycle, ultimately both reducing the growth of new cells and enhancing cell death of malignant cells. One laboratory trial examined the effect of frankincense oil on a line of cultured human bladder cancer cells.3 These cell cultures were divided into a control group that was maintained to simply continue its current growth pattern and the other group was sub-divided into several sets that were subjected to increasing dilutions of frankincense oil. The experimental groups were monitored for increase in cell number and attachment to the tissue medium over time and compared with the control group. Cells exposed to frankincense oil showed dramatic decreases in cell number as well as detachment, or ‘shrinking’ from the tissue culture. Further analysis indicated that cell death and inhibition of new cell growth was due to genetic stimulation of factors inducing cell death.3

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ALTERNATIVE MEDS UPDATE In another study, researchers recruited 44 patients who were receiving radiation therapy for brain tumors.4 The primary endpoint of the study was to monitor the effect of oral frankincense on cerebral edema, a problematic effect of this type of therapy. Results of the trial showed that 60% of patients receiving frankincense had a decrease from baseline in brain tissue swelling in a range of no edema at all to <25%. Interestingly, the researchers also found something that was not listed as an endpoint but could be even more significant. Patients in the study who received the extract were found to have a superior response to the radiotherapy compared to the control patients. As with the study of bladder cancer cells,3 a similar study using cultured human breast cancer cells was conducted to evaluate cell death and cell cycle progression in cells treated with frankincense oil.5 Outcomes achieved were nearly identical to the bladder cancer study, giving further evidence of frankincense oil’s ability to selectively target cancer cells and both destroy current cells and inhibit new cell formation. These actions closely interact with the immunomodulatory and inflammatory activities of the body. In a study of 75 patients with diagnosed osteoarthritis, participants were randomly assigned to receive daily doses of 100 mg or 250 mg of a standardized Boswellia serrata extract or placebo.6,7 Patients were assessed at baseline and 90 days using validated scales for pain and physical function. Both active treatment groups showed significant improvement in these outcomes.

How supplied, dose, cost Frankincense may be purchased in a variety of forms. Most products are either oral or topical. Essential oil of frankincense can be costly, as much as $50 or more per 0.5 ounces. Oral capsules of the resin are less expensive due to the lower concentration of the essential oil. Frankincense essential oil is typically applied directly to the skin up to 4 times daily. Oral frankincense capsule doses can range from 900 mg to as high as 3 gm daily. Most frankincense products are either oral or topical.

Frankincense is one of a multitude of rediscovered botanical products being studied for use in a variety of diseases and conditions.

Safety, interactions, side effects

Summary Frankincense is one of a multitude of rediscovered botanical products that is now being studied for its potential use in treating a variety of diseases and conditions. Since there is not yet a large body of evidence-based literature for this product, recommendation for use should be carefully evaluated for both safety and efficacy. n References 1. Dharmananda S. Myrrh and frankincense. Institute for Traditional Medicine website. http://www.itmonline.org/arts/ myrrh.htm. Published May 2003. Accessed February 15, 2017. 2. Ammon HP. Bowellic acids in chronic inflammatory diseases. Planta Med. 2006;72:1100-1116. 3. Frank MB, Yang Q, Osban J, et al. Frankincense oil derived from Boswellia carteri induces tumor cell-specific cytotoxicity. BMC Complement Altern Med. 2009; 9:6. 4. Kirste S, Treier M, Wehrle SJ, et al. Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors. Cancer. 2011;117:3788-3795. 5. Suhail MM, Wu W, Cao A, et al. Boswellia sacra essential oil induces tumor-cell-specific apoptosis and suppresses tumor aggressiveness in cultured human breast cancer cells. BMC Complement Altern Med. 2011;11:129. 6. Sengupta K, Alluri KV, Satish AR, et al. A double-blind, randomized, placebo-controlled study of the efficacy and safety of 5-Loxin for treatment of osteoarthritis of the knee. Arthritis Res Ther. 2008;10:R85. 7. Khajuria A, Gupta A, Suden P, et al. Immunomodulatory activity of biopolymeric fraction BOS 2000 from Boswellia serrata. Phytother Res. 2008;22:340-348. 8. Burfield T. Safety of essential oils. International Journal of Aromatherapy. 2000;10:16-29.

Any initial use of a frankincense product should be approached with caution until individual tolerance is determined. For oils, a simple small ‘patch’ test on the inner arm is a good test for allergic response.8 The use of any frankincense product is not recommended for children, pregnant women, or nursing mothers. Potential drug interactions have been reported when using frankincense in conjunction with a selective serotonin reuptake inhibitor. People interested in daily frankincense use should consult with their healthcare provider. 60 THE CLINICAL ADVISOR • MARCH 2017 • www.ClinicalAdvisor.com

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