THE CLINICAL ADVISOR • FEBRUARY 2017
A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS
■■Hypertension guideline ■■Oral diabetes treatments ■■Herpes screening FEATURE Vulvar Lichen Sclerosus
■■Breaking the silence in a chronic skin condition
TREATING AND PREVENTING
SHINGLES Herpes zoster is contagious after the rash erupts and until the lesions crust.
A clinician must contend with a frivolous lawsuit
n Dermatologic Clinic
A FLUID-FILLED PAPULE PAGE 39
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VOLUME 20, NUMBER 2
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Editor Colby Stong, email@example.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 firstname.lastname@example.org 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 2, 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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EXPERTS If a patient has you stumped, write us and we’ll forward your query to one of our consultants and publish the response in Advisor Forum.You can also use this space to contribute a clinical pearl of your own or comment on another letter.
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.
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.
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.
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.
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
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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
Cohen, MD, is clinical associa te profess of dermat or ology, of Texas MedicaUniversity l Center, Houston.
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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.
SOR • SEPTE
Abimbo la Farinde
is a profess PharmD, or at Columb ia Souther n Univers in Orange ity Beach, Ala.
practices familyCRNP, FNP, with Palmett medicine o Primary Care Physicia ns in Charles ton, S.C.
is a physicia n, PA-C, n at Delawa assistant re Dermatology Valley in Wilmington,Group Del.
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CONTENTS FEBRUARY 2017
NEWS AND COMMENT 9
26 CME Parkinson’s disease: making an evidence-based diagnosis Established diagnostic criteria and testing allow clinicians to make more precise diagnoses.
Newsline ■■Hypertension treatment in older
adults: a new clinical practice guideline ■■USPSTF: folic acid is advised for all pregnant women and women who may become pregnant. ■■NIH releases guidelines to prevent peanut allergies. ■■Oral pharmacologic treatment of type 2 diabetes: a new clinical practice guideline ■■Serologic screening for genital herpes simplex virus ■■Patients with chronic diseases are overly optimistic about their life expectancy. ■■FDA issues warning of anesthesia use in children and pregnant women. ■■The FDA has expanded the approved use of a continuous glucose monitoring system to replace fingerstick blood glucose testing in patients with diabetes.
34 CME Feature posttest
DEPARTMENTS Hypertension in the elderly 9
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Dermatology Clinic horses in the winter n A fluid-filled papule at the corner of the eye
43 Dermatologic Look-Alikes A rash on the chest and back Case study: abnormal Pap test 48
13 Shingles: a complete guide for clinicians An estimated 1 million cases of herpes zoster occur in the US annually.
Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com n A rash on a woman who rides
22 Vulvar lichen sclerosus: breaking the silence Early diagnosis and treatment reduce the risk of malignancy and scarring.
48 Case Study: Women’s Health Abnormal Pap test follow-up in a 30-year-old woman
Continues on page 6
Alt Meds Update: holy basil 61
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1/27/17 11:21 AM
CONTENTS DEPARTMENTS cont’d Evidence-Based Medicine
Legal Advisor The frivolous lawsuit
Alternative Meds Update Holy basil
Commentary Health care under President Trump
“I wish they wouldn’t just leave it there.”
© The New Yorker Collection 2017 from cartoonbank.com. All Rights Reserved.
ADVISOR FORUM 36
Your Comments ■ Oral drugs for diabetes
Clinical Pearls ■ Diabetic peripheral neuropathy
Case Files ■ Blue skin in an elderly woman
“Liverwurst is down an eighth, egg-salad is up two and a half, and peanut-butterand-jelly remains unchanged.”
HOW TO CONTACT US THE CLINIC OR • FEBRU
■ Hyperte nsio ■ Oral diab n guideline etes treatme nts ■ Herpes screening FEATURE
rosus ■ Breaking the silence in a chronic skin conditio n
FEBRUAR Y 2017
| www.Clin icalA
Herpes zost er is cont after the agious rash erup ts until the lesions crus and t.
LEGAL AD VISOR
A clinician must contend with a frivo lous lawsuit
• Send it by e-mail to editor@ClinicalAdvisor.com
■ Dermatolo gic Clini
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EXCLUSIVE TO THE WEB AT
ClinicalAdvisor.com Web Exclusives
Migraine increases stroke risk in surgical patients Surgical patients with a history of migraine have an increased risk of perioperative ischemic stroke and a higher 30-day hospital rate.
ACP releases recommendations for type 2 diabetes treatment The American College of Physicians has updated the 2012 guideline to provide clinical recommendations of oral pharmacologic treatment of type 2 diabetes. Watch the video here: ClinicalAdvisor.com/ACPDiabetesVideo
“Weekend warrior” activity reduces all-cause mortality risk Individuals who perform their physical activity in 1 or 2 sessions during the week can still reduce their risk of all-cause mortality. Monitoring asthma control in children: AAP recommendations for clinicians Recent advances in measuring asthma control tools have enhanced ongoing assessment and monitoring of asthma.
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Sharon M. O’Brien, MPAS, PA-C Improving sleep in socioeconomically disadvantaged children Socioeconomically disadvantaged children have a higher rate of sleep difficulties than children from high-income households.
ClinicalAdvisor.com/cartoons © The New Yorker Collection 2017 from cartoonbank.com. All Rights Reserved.
Guidelines to prevent peanut allergies through early introduction Guidelines published in the Journal of Allergy and Clinical Immunology state that consuming peanut-containing foods during a child’s first year of life may reduce the risk of peanut allergy later in life. Watch the video here:
Jillian Knowles, MPAS, PA-C Is our makeup secretly hurting us? Using powder makeup containing talc may increase the risk of ovarian cancer, but it has been difficult to identify the extent of the risk.
“For want of a better word, I call my idea ‘taxes.’ And here’s the way it works.”
Sean P. L’Huillier, MS, APRN, FNP-C, CEN Celebrating a 1-year anniversary as an FNP A family nurse practitioner reflects on the lessons he has learned in practice throughout the year See more on page 8
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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.
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Journal of Orthopedics for Physician Assistants
Growth disturbances after growth plate fracture A 13-year-old boy presents 1 week after sustaining a right knee injury. He was seen in the ED, and initial radiographs showed a possible distal femur physeal fracture. CT reveals a minimally displaced Salter-Harris type II distal femur fracture at the medial metaphysis. WHICH STATEMENT IS TRUE?
• Growth disturbances can occur in 30% to 60% of young people after a Salter-Harris type II fracture. • Growth arrest most commonly occurs in the physis under the metaphyseal fracture fragment. ● See the full case at ClinicalAdvisor.com/OrthoDx_Feb17
Derm Dx A rash that does not respond to use of steroids A 44-year-old man presents after treatment for an irritated seborrheic keratosis on his back. An incidental finding is an extensive, asymptomatic rash on his chest and abdomen. This was diagnosed elsewhere as eczema, and he was placed on oral prednisone and a topical steroid. CAN YOU DIAGNOSE THIS CONDITION?
• Mycosis fungoides • Pityriasis rubra pilaris • Psoriasis • Tinea versicolor ● See the full case at ClinicalAdvisor.com/DermDx_Feb17
8 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
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Newsline F E B R U A R Y 2 017
NIH guidelines for preventing peanut allergy page 10
Guideline update for treatment of type 2 diabetes page 11
FDA issues warning for use of anesthesia page 12
A NEW CLINICAL practice guideline for the pharmacologic treatment of hypertension in adults aged 60 years and older has been published by the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP). The agencies conducted a systematic review of randomized, controlled trials for primary outcomes and observational studies through January 2015. Evaluated outcomes included all-cause mortality, morbidity and mortality related to stroke, major cardiac events, and harms. The agencies used the GRADE method to evaluate the evidence. “Appropriate management of hypertension reduces the risk for cardiovascular disease, renal disease, cerebrovascular disease, and death,” the authors of the guidelines wrote in the Annals of Internal Medicine. “However, determining the most appropriate BP [blood pressure] targets, particularly for adults aged 60 years or older, has been controversial.” Clinicians are advised to start treatment in adults who are 60 years of age and older with systolic blood pressure persistently greater than 150 mm Hg to reduce the risk of mortality, stroke, and cardiac events (Grade: strong recommendation, high-quality evidence).
“Although this guideline did not specifically address pharmacologic versus nonpharmacologic treatments for hypertension, several nonpharmacologic treatment strategies are available for consideration,” the authors noted. Effective nonpharmacologic treatments include lifestyle modifications such as weight loss, changes in diet, and an increase in physical activity. Pharmacologic treatments include antihypertensive medications such as thiazide-type diuretics, angiotensin-converting enzyme inhibitors, angiotensinreceptor blockers, calcium-channel blockers, and beta-blockers. The ACP and AAFP also recommend that clinicians initiate pharmacologic treatment in adults 60 years of age and older with a history of stroke or transient ischemic attack to achieve a target systolic blood pressure of less than 140 mm Hg to reduce the risk of recurrent stroke (Grade: weak recommendation, moderate-quality evidence). The agencies also state that clinicians should consider initiating or intensifying pharmacologic treatment in adults 60 years of age and older who have a high cardiovascular risk to achieve a target systolic blood pressure of less than 140 mm Hg to reduce the risk of stroke or cardiac events (Grade: weak recommendation, low-quality evidence).
Hypertension treatment in older adults: a new clinical practice guideline Treatment is advised in adults aged 60 and older with systolic BP persistently greater than 150 mm Hg.
Cardiovascular risk should be based on individual assessment, but the agencies state that increased cardiovascular risk generally includes individuals with known vascular disease, most patients with diabetes, older persons with chronic kidney disease with an estimated glomerular filtration rate less than 45 mL/min/per 1.73 m 2 , those with metabolic syndrome, and older individuals. For each recommendation, the ACP and AAFP note that treatment goals should be based on discussions with the patient about the benefits and harms of specific blood pressure targets. The guidelines also state that individual assessment of benefits and harms is particularly important among older individuals with multiple chronic conditions, several medications, or frailty. Although these patients may theoretically benefit from aggressive blood pressure treatment, they are also more susceptible to serious harm from higher rates of syncope and hypotension. This patient population also usually receives multiple medications that are difficult to manage and increase the risk for drug interactions.
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Newsline USPSTF: folic acid advised for all pregnant women THE US PREVENTIVE Services Task Force (USPSTF) recommends that all women who are capable of pregnancy or are planning to become pregnant take a daily supplement of 0.4 to 0.8 mg of folic acid, according to its recommendation statement published in JAMA. The USPSTF gave an A grade to its recommendation, which reaffirms its 2009 recommendation of folic acid supplementation for women of childbearing age for prevention of neural tube defects. The task force examined the benefits and harms of folic acid in this population and determined that the net benefit is substantial. The USPSTF also found substantial evidence that the supplements provide substantial benefit in the periconceptional period in reducing the risk of neural tube defects in the developing fetus.
Folic acid is recommended to prevent neural tube defects such as spina bifida in newborns.
The harms of folic acid to the mother or the infant are small when taken at the usual doses. Clinicians are advised to tell all women who are capable of pregnancy to take daily folic acid supplements. The critical period for folic acid supplementation starts about 1 month before conception and continues through the first 2
to 3 months of pregnancy. In an accompanying editorial, James L. Mills, MD, MS, from the Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, notes that current food fortification may prevent most folate-related neural tube defects. However, the habitual use of folic acid supplements is a more reliable method of ensuring adequate levels than diet. “The USPSTF recommendation that all women of childbearing age take folic acid supplements is a prudent one,” he stated. “Ideally, it will educate all women who are planning or capable of pregnancy to follow this recommendation and thereby reduce the risk of these severe birth defects in their infants.”
AN EXPERT PANEL sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) has released clinical guidelines regarding the early introduction of peanut-containing foods into the diets of infants to prevent the development of peanut allergies. “Living with peanut allergies requires constant vigilance,” stated Anthony S. Fauci, MD, director of the NIAID. “We expect that widespread implementation of these guidelines by healthcare providers will prevent the development of peanut allergy in many susceptible children and ultimately reduce the prevalence
of peanut allergy in the United States.” In the first addendum guideline, the panel recommends that infants with severe eczema, egg allergy, or both be introduced to age-appropriate peanut-containing food at ages 4 to 6 months to reduce the risk of allergy. An evaluation with peanut-specific IgE measurement, skin prick tests, or both should be considered to determine whether peanuts should be introduced and to determine the proper method of introduction. The second guideline suggests that infants with mild-to-moderate eczema should be introduced
Early introduction of peanuts is advised by NIAID panel.
to peanut-containing food around 6 months of age. The panel notes that solid foods should be introduced before introducing peanutcontaining foods, but infants in this category can have dietary peanut introduced at home without an in-office evaluation. Some clinicians may prefer an in-office supervised feeding or evaluation. In the third guideline, the panel recommends that infants without a food energy or eczema should have peanut-containing foods introduced in the diet together with solid foods in accordance with family preferences and cultural practices.
© TOP: SPL / SCIENCE SOURCE, BOTTOM: THINKSTOCK
NIH releases guidelines to prevent peanut allergies
10 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
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THE AMERICAN College of Physicians (ACP) recommends that clinicians prescribe metformin to patients with type 2 diabetes when pharmacologic treatment is required to improve glycemic control, according to the guideline update published in the Annals of Internal Medicine. In addition, the ACP recommends that clinicians consider adding a sulfonylurea, a thiazolidinedione, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or a dipeptidyl peptidase-4 (DPP-4) inhibitor to metformin if a second oral therapy is needed. Researchers conducted a systematic review of randomized, controlled trials and observational studies published through December 2015 that examined the comparative effectiveness of oral medications for type 2 diabetes.
The researchers evaluated metformin, thiazolidinediones, sulfonylureas, DPP-4 inhibitors, and SGLT-2 inhibitors. They examined intermediate outcomes of hemoglobin A1c, weight, systolic blood pressure, and heart rate, as well as outcomes of all-cause mortality, cardiovascular and cerebrovascular morbidity and mortality, retinopathy, nephropathy, and neuropathy. In its first recommendation, the ACP noted that metformin should be prescribed to patients who need pharmacologic therapy to improve glycemic control (Grade: strong recommendation; moderate-quality evidence). They add that metformin is effective for reducing glycemic levels, is associated with weight loss and fewer hypoglycemic episodes, and is cheaper than most pharmacologic agents.
Oral pharmacologic treatment of type 2 diabetes
ACP: metformin improves glycemic control in diabetes.
The ACP stated in its second recommendation that clinicians should consider a sulfonylurea, a thiazolidinedione, a SGLT-2 inhibitor, or a DPP-4 inhibitor if a second oral therapy is needed (Grade: weak recommendation; moderate-quality evidence). Combination therapies with metformin were shown to be more effective than metformin monotherapy in reducing HbA1c levels, weight, and blood pressure.
THE US PREVENTIVE Services Task Force (USPSTF) has released an updated recommendation against routine serologic screening for genital herpes simplex virus (HSV) infection in asymptomatic adolescents and adults, including women who are pregnant. The USPSTF gave a D grade to its recommendation, which updates the 2005 USPSTF recommendation on screening for genital herpes. The task force reviewed the evidence of the accuracy, benefits, and harms of serologic screening for HSV-2 infection in asymptomatic persons. They also reviewed the
USPSTF advises against screening for genital HSV.
evidence of the effectiveness and harms of preventive medications and behavioral counseling interventions to lower symptomatic episodes and transmission to others. Based on the natural history of HSV infection and the available evidence on the accuracy of serologic screening tests, the task force found that the potential benefits of HSV screening in asymptomatic adults and adolescents is small, and concluded that the harms outweigh the benefits of screening for HSV screening in this population. The USPSTF notes that serologic screening in asymptomatic individuals will most likely result
in a large number of false-positive results. Testing to confirm these results is not widely available and is only performed in a single research laboratory. In addition, many areas of research are needed to better understand the detection and management of asymptomatic HSV, including improved epidemiologic data on the prevalence of the virus, the development of screening and diagnostic tests with higher specificity to detect genital HSV-1 and HSV-2 infections, and an increased understanding of the role of HSV in the increasing risk of HIV infection.
Serologic screening for genital herpes simplex virus
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2017 11
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Newsline Chronic disease/ FDA issues warning of anesthesia use life expectancy in children and pregnant women THE FDA HAS released a warning to inform clinicians, parents and caregivers of children younger than 3 years of age, and pregnant women in their third trimester that the repeated or lengthy use of general anesthetic and sedation drugs during surgeries may affect the development of children’s brains. Recent data have shown that a single, relatively short exposure to general anesthetic and sedation drugs in infants is unlikely to have adverse effects on behavior or learning, but further research is needed to determine how early in life anesthetic exposure affects the development of a child’s brain. “To better inform the public of the risks, we are requiring warnings to be added to the labels of these drugs,” stated Janet Woodcock, MD, director of the
Anesthesia may affect development of a child’s brain, per the FDA.
FDA’s Center for Drug Evaluation and Research. “We recognize that in many cases these exposures may be medically necessary and these new data regarding the potential harms must be carefully weighed against the risk of not performing a specific medical procedure.” The FDA notes that healthcare professionals should balance the benefits and potential risks of appropriate anesthesia in children and pregnant women, especially for procedures that will last more than 3 hours or for multiple procedures that are required in children younger than 3 years of age. In add ition, parents and caregivers should discuss the potential adverse effects of anesthesia with their child’s healthcare professional.
Continuous glucose monitoring in diabetes THE FDA HAS EXPANDED the approved use of the G5 Mobile Continuous Glucose Monitoring System to replace fingerstick blood glucose testing in patients aged 2 years and older who have diabetes. The system (Dexcom, Inc.) uses a small sensor wire inserted below the skin to continuously measure glucose levels. Results are sent wirelessly every 5 minutes to a dedicated receiver and to a mobile app on a compatible device, such as a smartphone or a tablet. In addition, alarms and alerts will indicate glucose levels above or below user-set thresholds. The continuous glucose monitoring system must be calibrated at least 2 times per day using traditional fingerstick blood tests.
However, the FDA notes that additional fingerstick tests throughout the day are no longer necessary, because the results of the device can be used directly by patients to make treatment decisions without confirmation from the fingerstick tests. The FDA used data from 130 adults and children 2 years of age and older with diabetes from 2 studies of the G5 Mobile Continuous Glucose Monitoring System. No serious adverse events were reported. “Although this system requires calibration with 2 daily fingersticks, it eliminates the need for any additional fingerstick blood glucose testing in order to make treatment decisions,” stated Alberto Gutierrez, PhD. n
PATIENTS WITH chronic disease —including chronic obstructive pulmonary disease (COPD), heart failure, end-stage renal failure, and chronic kidney disease—may have perceived life expectancy rates that differ from the predicted survival rate for these diseases, researchers reported in BMJ Open. Researchers included 573 patients with heart failure, 89 with COPD, 62 with end-stage renal failure, and 5 with chronic kidney disease. The mean age of participants ranged from 58 to 75. Overall, self-estimated life expectancy exceeded observed survival. Among patients with heart failure, median self-estimated life expectancy was 40% longer than predicted by a validated model. Outpatients receiving hemodialysis for chronic kidney disease were more optimistic about prognosis than their nephrologists and overestimated their chances of surviving 5 years. Patients with heart failure and COPD were approximately 3 times more likely to die in the next year than they predicted. The only example of self-estimated life expectancy consistent with survival was 1-year mortality in patients with ESRF. The study shows that individuals with chronic disease may have unrealistically optimistic expectations of their prognosis, noted the authors, who added that these expectations may lead some patients to make health decisions and life choices that they would not if their predictions were more realistic.
12 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
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FEATURE: THERESA CAPRIOTTI, DO, MSN, CRNP, AND MEGHAN SCANLON
Shingles: a complete guide for clinicians More than 99% of immunocompetent persons aged 40 years and older have evidence of VZV infection and are susceptible to herpes zoster or shingles.
he varicella-zoster virus (VZV) causes two distinct infections: varicella and herpes zoster. Varicella, commonly known as chickenpox, manifests as the primary infection with VZV, which is a member of the family of herpesviruses. VZV then remains dormant within the sensory neurons, reactivating later in life to cause herpes zoster, commonly known as shingles.1 More than 99% of immunocompetent persons in the United States aged older than 40 years show serologic evidence of past primary VZV infection.2 Therefore, this population of older adults is susceptible to herpes zoster. Herpes zoster develops in approximately 1 of every 3 persons in the United States in their lifetime, with an estimated annual incidence of 1 million cases. The risk for herpes zoster increases with age; about half of all cases occur in adults aged 60 years and older.3-5
© ISM / MEDICAL IMAGES
Risk factors, signs, and symptoms
Typical abdominal shingles rash with vesicular and inflammatory lesions.
The major risk factors for herpes zoster are immunosuppression, particularly a decline of cell-mediated immunity, and increasing age (Table 1).6 The condition commonly begins with prodromal symptoms of malaise, headache, mild fever, and abnormal skin sensations such as itching and burning. A rash begins as pink, maculopapular lesions in a unilateral dermatomal distribution along a sensory nerve tract. The rash is extremely sensitive to touch, and the pain is described as aching, shock-like, stabbing, or burning. The rash may
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SHINGLES: A COMPLETE GUIDE FOR CLINICIANS
TABLE 1. Risk factors for herpes zoster6,7,10 • Cancer (particularly leukemia and lymphoma) • Caucasian ethnicity • Chemotherapy • Diabetes • Female gender • Genetic predisposition • HIV infection • Immunosuppressive agents and steroids
• Intrauterine exposure to VZV • Previous VZV infection (chickenpox) • Psychological stress within previous 6 months • Recent physical trauma • Transplant and transplant-related medications • VZV infection before the age of 18 months
HIV, human immunodeficiency virus; VZV, varicella-zoster virus
cause intense pruritus. The lesions progress to clear vesicles, crust, and heal over the course of 2 to 4 weeks. More than one dermatomal region can be involved. The rash is often distributed over thoracic, cervical, or trigeminal dermatomes.7,8 Pathophysiology of varicella and herpes zoster
Primary VZV infection typically occurs during childhood when wild-type VZV invades the respiratory tract and nasopharyngeal lymphoid tissue. The incubation period is 10 to 21 days, and children typically transmit the virus to one another via nasopharyngeal secretions. During this period, the virus travels to the sensory nerves of the epidermis, causing the typical rash known as chickenpox. Pink, maculopapular lesions usually begin on the trunk and face and spread to the extremities. The lesions are pruritic and evolve from papular to vesicular, crust over, and heal. After
the initial infection subsides, the virus lies dormant in the sensory dorsal root ganglia. Mainly cell-mediated immunity is involved in controlling the virus and keeping it dormant.9,10 Later in life, VZV reactivates to cause herpes zoster, in which intact virions in sensory neurons migrate through axons, spread from cell to cell, and penetrate the epidermis. A painful, vesicular rash develops along the dermatomal distribution of a sensory nerve. Affected ganglia show neuronal destruction and loss, which are usually accompanied by mononuclear inflammatory infiltrates, regional necrosis, and hemorrhage.11 Transmission of herpes zoster
The lesions of persons with herpes zoster contain a high concentration of VZV, which can spread to and cause varicella in susceptible persons who have not had the primary infection (varicella). Herpes zoster is contagious after the rash erupts and until the lesions crust. However, herpes zoster is not as contagious as varicella. Transmission can be decreased by covering the lesions. Herpes zoster is not a reportable condition and is not associated with epidemic spread.7,10 Persons with herpes zoster should avoid contact with susceptible persons in their household or occupational setting until the lesions crust. Susceptible persons include those who have not had chickenpox or received varicella vaccine, pregnant women, premature infants, and immunocompromised individuals.7,10 In recipients of the varicella vaccine, the vaccine strain of VZV can become dormant and clinically reactivate as herpes zoster. The risk for the development of herpes zoster caused specifically by the vaccine strain of VZV is unknown. Clinically, the herpes zoster rash caused by the vaccine strain of
Terminology Breakthrough varicella-zoster virus (VZV) infection: varicella that occurs despite vaccination with varicella vaccine Cell-mediated immunity: immune response involving mainly T cells
Primary VZV infection: varicella (chickenpox) ProQuad ®: combined vaccine for immunization of children against measles, mumps, rubella, and varicella
Herpes zoster: shingles resulting from VZV infection
Vaccine-strain herpes zoster: herpes zoster (shingles) in persons who have received the varicella-zoster vaccine
Herpes zoster ophthalmicus (HZO): herpes zoster that has traveled from the trigeminal ganglion into the eye
Varivax ®: vaccine used to prevent primary VZV infection (varicella)
Herpesviruses: family of DNA viruses that cause a primary infection and then remain dormant until reactivation later in life
VariZIG ®: immunoglobulin preparation available for administration after exposure to VZV
Postherpetic neuralgia (PHN): continual pain over the area of herpes zoster rash after infection subsides
Zostavax ®: vaccination for older adults to prevent herpes zoster
Wild-type VZV infection: naturally occurring VZV infection
14 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
Understanding the epidemiology of chickenpox and shingles and the initiation of vaccines Before 1995, most children had primary varicella-zoster virus (VZV) infection (chickenpox) with wild-type VZV, and the virus remained dormant in their bodies. Because it is a very contagious virus, children commonly transmitted VZV to one another through the airborne route or nasopharyngeal secretions.9 Approximately 4 million cases occurred each year.48 Today, this population is aging, and their dormant VZV is reactivating as herpes zoster (shingles). Studies show that between 1945 and 2007, a fourfold increase occurred in the number of cases of herpes zoster in the United States.49,50 The reasons for this increased incidence are not completely understood, but it is partly due to the increase in the elderly segment of the US population. The epidemiology of varicella has changed dramatically since the introduction of the varicella vaccine in 1995. In the United
States, routine childhood immunization against varicella has reduced the occurrence of chickenpox in children.51 The number of children acquiring natural, wild-type VZV infection is not as high as it was in former years. 52 The incidence of herpes zoster is not as high in children vaccinated against varicella as it is in children who have had wild-type VZVinfection.12 In 2005, the epidemiologic picture of herpes zoster changed. A herpes zoster vaccine was developed and recommended for adults aged older than 60 years. 38 This vaccine has decreased the risk for shingles in older adults; however, a low percentage (approximately 24%) of adults aged older than 60 years have received the vaccine. 53,54 Therefore, a high number of unvaccinated older adults in the population are at risk for herpes zoster.
VZV is indistinguishable from that caused by natural infection. The inception of the varicella vaccine was in 1995, and with time, additional research will be conducted on the development of herpes zoster in children vaccinated for varicella.10,13
of famciclovir and valacyclovir is better than that of acyclovir.8,16 The treatment regimens differ depending on the agent used (Table 2). The outcome is optimal if treatment is initiated within 72 hours of rash onset. Pain management is most important when herpes zoster is being treated. Antiviral medications can decrease pain, but mild-to-moderate pain can be managed with acetaminophen or oral nonsteroidal anti-inflammatory drugs.17 While blistering lesions are present, lotions containing calamine or oatmeal baths may be helpful. The rash should be kept clean, dry, and covered to prevent bacterial superinfection. The patient should avoid scratching the lesions. Once the lesions have crusted, capsaicin cream is effective for relief of pain.17 When pain is severe, opioids are indicated. Initially, begin with an agent such as tramadol (a synthetic opioid analgesic) or codeine. If severe pain continues, consider a stronger
Diagnosis of herpes zoster
Herpes zoster is most commonly diagnosed on the basis of the identification of its clinical manifestations as a vesicular, linear rash in a dermatomal pattern in a patient with a known history of past chickenpox.8 Schmader13 considers polymerase chain reaction (PCR) assay to be the best diagnostic test because it can detect VZV DNA in fluid obtained from vesicular lesions or cell scrapings. Diagnostic testing may be needed to differentiate herpes simplex from herpes zoster in some immunosuppressed patients. For patients with zoster sine herpete, in which symptoms of pain occur but no rash, PCR assay of blood can be used. Visceral herpes zoster can present without a rash, and the diagnosis can be challenging. For persons with central nervous system involvement, PCR assay of the cerebrospinal fluid can be conducted.14 Herpes zoster of the gastrointestinal tract can be diagnosed with a PCR assay of saliva.15 Treatment of acute herpes zoster
The nucleoside analogues acyclovir, famciclovir, and valacyclovir can inhibit viral replication in persons with herpes zoster. These agents decrease the duration of viral shedding, reduce lesion formation, hasten healing, and decrease the risk for progression to postherpetic neuralgia. The bioavailability
TABLE 2.Treatment regimens for herpes zoster8,13 Drug
a Patients with disseminated herpes zoster or herpes zoster ophthalmicus may require intravenous treatment for a number of days followed by oral treatment.
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SHINGLES: A COMPLETE GUIDE FOR CLINICIANS
Postherpetic neuralgia is the most common complication of herpes zoster, occurring in 18% of patients who are aged older than 50 years. opioid, such as hydrocodone, oxycodone, or morphine. Pain medication is best given on a schedule rather than “as needed” and should be used for a short term. According to Schmader,13 a commonly used approach is to start with a short-acting medication at an oxycodone equi-analgesic dose of 5 mg, given 4 times daily. The dose is then titrated until pain is reduced. If the prolonged use of opioids is necessary, referral to a pain specialist is recommended.8,18 Some clinicians add corticosteroids to the treatment regimen, starting with 60 mg of oral prednisone daily and tapering the dose over 10 to 14 days. Some studies show that this regimen decreases pain and hastens healing. However, corticosteroids should be avoided in patients with hypertension, diabetes, gastritis, or osteoporosis.13,16 Herpes zoster ophthalmicus
Herpes zoster ophthalmicus (HZO) can occur when VZV is reactivated in the trigeminal ganglion within the ophthalmic division of the trigeminal nerve. This occurs in 10% to 20% of patients with herpes zoster.19 When the frontal branch of the ophthalmic nerve is affected, ocular involvement can develop. A vesicular rash extending along the side of the nose within the distribution of the nasociliary nerve, called Hutchinson’s sign, portends ocular pathology. The eyelid, conjunctiva, and sclera become erythematous and swollen. The cornea becomes involved in 65% of cases of HZO. Acute retinal necrosis can also occur. Patients have decreased vision, photophobia, loss of corneal sensitivity, and intense pain. The complications of HZO can last for days to months.19 Stroke, TABLE 3. Complications of herpes zoster36,55,56 • Acute retinal necrosis • Bacterial superinfection (staphylococcal or streptococcal) • Cerebellar ataxia • Disseminated herpes zoster • Guillain-Barré syndrome • Hepatitis • Herpes zoster ophthalmicus • Meningoencephalitis VZV, varicella-zoster virus
• Pneumonitis • Postherpetic neuralgia • Ramsay Hunt syndrome (VZV infection of facial nerve) • Reye syndrome (if aspirin is administered) • Stroke caused by VZV vasculopathy along cerebral artery • Temporal arteritis caused by VZV vasculopathy
a life-threatening complication of HZO, is secondary to vasculopathy of a cerebral artery.20 The patient requires a prompt and comprehensive ophthalmologic examination. According to Vrcek et al,20 systemic antiviral treatment is necessary in HZO. According to Cohen,21 early treatment with 500 mg of oral famciclovir 3 times daily or with 1 g of oral valacyclovir 3 times daily for 7 days reduces ocular complications. For keratitis, effective treatment consists of topical ganciclovir applied 5 times a day until healing occurs, then twice a day for 2 to 4 weeks even if oral antiviral agents are ineffective. Oral opiate and nonsteroidal anti-inflammatory medications are frequently indicated for pain. Topical corticosteroids should be used judiciously, and intraocular pressure must be monitored by an ophthalmologist. If the pressure rises significantly above normal values, treatment is required. According to Roat,22 topical corticosteroid treatment consists of 1% prednisolone acetate instilled every hour for uveitis or 4 times daily for keratitis initially, with the interval lengthened as symptoms lessen. The pupil should be dilated with 1 drop of 1% atropine or 1 drop of 0.25% scopolamine 3 times daily. According to Catron and Hern,23 in high-risk cases, admission for the intravenous administration of acyclovir is indicated. Admission is recommended for persons with known immunodeficiency, on immunosuppressive medications, or with involvement of multiple dermatomes, retinal involvement, corneal ulceration, or serious bacterial superinfection. Complications of herpes zoster
Postherpetic neuralgia (PHN) is the most common complication of herpes zoster (Table 3). It occurs in approximately 18% of patients aged older than 50 years and 33% of patients aged older than 80 years.24,25 Replication of the virus in neural ganglia destroys nerve tissue, causing intense pain along corresponding dermatomes. The pain can be stabbing or burning. Sensitivity to touch may develop. The pain may persist for 30 days to more than 6 months, after the lesions heal. The patient can also experience chronic fatigue, anorexia, weight loss, difficulty concentrating, and depression, and they may become inactive. PHN is more common in women and immunocompromised persons.26 Pain management may require the use of acetaminophen, nonsteroidal anti-inflammatory drugs, anticonvulsant agents,
16 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
Breakthrough varicella is common in children who have received only one dose of varicella vaccine, not the recommended two doses. topical medications, tramadol, or oxycodone. According to Mallick-Searle et al,27 first-line treatments include gabapentin or pregabalin; an antidepressant (amitriptyline, nortriptyline, or desipramine); and the lidocaine 5% patch. Tramadol or oxycodone should be a third-line drug and used judiciously because of the potential for dependence. Topical capsaicin 8% may be used but requires frequent reapplication (Table 4).13,27,28 Prevention of varicella
The two different types of vaccine used to prevent varicella (chickenpox) are Varivax® (Varicella Virus Vaccine Live) and ProQuad® (a combination of measles, mumps, rubella, and varicella [MMRV] vaccines). Varivax should be administered subcutaneously to children in two doses: the first dose at age 12 to 15 months and the second dose at age 4 to 6 years. Alternatively, ProQuad can be administered to children aged from 12 months to 12 years. Two doses of MMRV vaccine are recommended and are administered in the same schedule as Varivax.29-31 After age 13 years, children can be vaccinated with the two doses of Varivax, with the doses given at least 28 days apart.10 Varicella vaccine lowers the risk for herpes zoster (shingles) in children and adolescents; however, follow-up study of TABLE 4.Treatment options for postherpetic neuralgia27 Therapy
Start with 100–300 mg at bedtime;a can increase dose up to maximum of 1800–3600 mg/d
• a person who has ever had a life-threatening or severe allergic reaction to gelatin, the antibiotic neomycin, or any other component of shingles vaccine;
Amitriptyline, nortriptyline, desipramine
Start with 25 mg at bedtime; can increase dose by 25 mg/d up to maximum of 150 mg/da
Lidocaine 5% patch
Apply every 4–12 h up to maximum of 3 patches/day
Capsaicin .075% cream
Apply 3–5 times/day
Dosage is 100–400 mg/db
Dosage is variable; because pain is chronic, it is best managed by a pain specialist
Consider lower starting dose and slower titration in geriatric patients. Reduce dose if renal function is impaired.
Zostavax® (Zoster Vaccine Live) is the only vaccine available for herpes zoster. It is given subcutaneously as one dose and is
Herpes zoster vaccine should not be administered to persons who are immunosuppressed or to any of the following individuals:
Start with 50 mg 3 times/day or 75 mg 2 times/ day;a can increase dose up to 300–600 mg/d
Prevention of herpes zoster
TABLE 5. Contraindications to the administration of varicella vaccine or herpes zoster vaccine8,10,57
varicella. Breakthrough varicella is very rare in persons who have had a wild-type varicella infection in the past. Studies show that breakthrough varicella is common in children who have received only one dose of varicella vaccine, not the recommended two doses.33-35 Breakthrough varicella is usually less severe, with the median number of skin lesions commonly less than 50; the lesions are commonly papules that do not progress to vesicles, so that vesicular lesions are less common. The duration of varicella in vaccinated persons is typically shorter and the incidence of fever lower than in unvaccinated persons.36 Post-exposure prophylaxis. VariZIG® (Varicella Zoster Immune Globulin, Human) is an immunoglobulin preparation available after exposure to VZV. If a person who is susceptible to varicella has close contact with someone who has varicella or herpes zoster, VariZIG can be used for immediate short-term immunity. It has been shown to be 70% to 100% effective if administered 3 to 5 days after exposure. Immunity lasts approximately 3 weeks.10,37
• a person who has a weakened immune system because of any of these reasons: ——HIV/AIDS or another disease that affects the immune system; ——treatment with drugs that affect the immune system, such as steroids; ——cancer treatment, such as radiation or chemotherapy; ——cancer affecting the bone marrow or lymphatic system, such as leukemia or lymphoma; OR ——hematopoietic stem cell transplant (defer vaccination for at least 24 months); • a woman who is or might be pregnant (women should not become pregnant until at least 4 weeks after receiving the herpes zoster vaccine); OR • a patient on an immune modulator, such as an anti-tumor necrosis factor agent (eg, adalimumab, infliximab, etanercept). HIV, human immunodeficiency virus; AIDS, acquired immune deficiency syndrome
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Writers’ Guidelines The Clinical Advisor welcomes submissions from its readers. Writing for us is an opportunity to share your knowledge and experience with your colleagues — and to collect a fee in the bargain! We pay an honorarium for every submission we accept. We’ll be glad to work with you to develop your ideas into compelling articles. As for length, that depends on which kind of article you submit. CLINICAL FEATURES update our readers on the latest information about conditions seen in everyday practice. Running approximately 2,500 to 5,000 words, including the references, features can be written either as regular narratives or as a series of questions and answers. Topics should be selected with the busy primary-care clinician in mind; specialists should review specialty topics from the primary-care point of view. If at all possible, articles should be accompanied by clinical photos. Charts, tables, and algorithms are also encouraged. Please include your title and affiliation. CLINICAL CHALLENGE is our popular department comprising histories of difficult cases. Each case is presented as a step-by-step, chronological account, revealing the author’s thought processes along the way. It is divided into sections in this order: the patient presentation; the patient history; the twists and turns eventually leading to a diagnosis; the treatment and outcome; and a discussion of the lessons learned or of the condition in general. The length should be about 1,500 words, and accompanying images are encouraged. Please include your title and affiliation. DERMATOLOGY CLINIC is a department that presents photos of actual cases and asks readers to identify the condition. Each case opens with one or two color photos and a 75-to-100-word description of the patient presentation, without giving away the diagnosis. This is followed by a 750-to-1,000-word summary that includes a fuller description of the ailment, an explanation of how the correct diagnosis was reached, a general review of the condition along with a differential diagnosis, and a description of the patient’s treatment and outcome. Topics must be approved by the editor prior to submission. Please include your title and affiliation. COMMENTARY is our guest editorial page. It gives you the opportunity to sound off on an issue of importance to your colleagues nationwide. A typical Commentary runs about 600 words in length. Please include your title and affiliation. To discuss your editorial ideas, contact us by phone at 646.638.6078; by e-mail to editor@ClinicalAdvisor.com; or by mail to The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001.
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SHINGLES: A COMPLETE GUIDE FOR CLINICIANS
Which of the following antiviral drugs do you most frequently prescribe for patients with shingles? n=580
■ Acyclovir ■ Famciclovir ■ Valacyclovir
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recommended for adults aged 60 years and older. According to the Shingles Prevention Study,38 Zostavax decreases the incidence of herpes zoster by 70% in persons aged between 50 and 59 years, by 64% in those aged between 60 and 69 years, and by 38% among those aged 70 years or older. The vaccine also reduces the incidence of PHN by 66% among persons aged between 60 and 69 years and by 67% among those aged 70 years or older. The only frequent side effects have been injection-site reactions.38-41 Zostavax is not recommended for persons who have received varicella vaccine. However, because varicella vaccine was first introduced in 1995, few adults aged 40 years or older have received it. Contraindications to the administration of herpes zoster vaccine are listed in Table 5. Persons who have already had herpes zoster can be vaccinated safely with Zostavax.42 According to Hales et al,43 the protection offered by the herpes zoster vaccine wanes within the first 5 years after vaccination. The vaccine’s efficacy for the prevention of PHN also wanes. Currently, the need for revaccination with a booster for continued protection against zoster is unclear. According to Keating,44 in the future, a booster dose may be needed for adults aged 70 years or older who received their first dose of zoster vaccine 10 or more years previously. Administration of adult vaccines at the same visit. According to the Advisory Committee on Immunization Practices,10 zoster vaccine can be administered safely and concurrently with any inactivated vaccine, including influenza vaccine; pneumococcal polysaccharide vaccine (PPSV23); tetanus and diphtheria (Td) vaccine; and tetanus, diphtheria, and acellular pertussis (Tdap) vaccine. The vaccines can be administered at the same visit in separate syringes at separate
anatomical sites.10,45 Zoster vaccine should be administered at least 4 weeks before or after the administration of a live, attenuated vaccine. According to the Food and Drug Administration,46 the immunogenicity of zoster vaccine may be diminished if Pneumovax is administered simultaneously. However, the Advisory Committee on Immunization Practices asserts that because compliance can be an issue and the patient may not return in 4 weeks, it is best to administer Pneumovax and Zostavax at the same visit.10 A new vaccine for herpes zoster, not yet available for clinical use, is being tested. This vaccine contains substances that can boost the immune response to herpes zoster. A study including 8122 participants showed that those administered the new vaccine had fewer episodes of herpes zoster.47 Adverse events. Vaccination can cause temporary localized redness and swelling, which subside. Adverse events after vaccination should be reported to the Vaccine Adverse Event Reporting System (VAERS) at http://www.vaers. hhs.gov or 800-822-7967. Clinicians should be careful to administer the appropriate vaccine: Varivax to children and Zostavax to adults. If a dose of herpes zoster vaccine (Zostavax) is given accidentally in place of varicella vaccine (Varivax), then the dose of herpes zoster vaccine should be considered a single valid dose of varicella vaccine. If varicella vaccine is accidentally administered instead of herpes zoster vaccine to an adult aged 60 years or older, no specific safety concerns exist, but the dose should not be considered valid, and a dose of herpes zoster vaccine should be administered during the same visit.10 ■ Theresa Capriotti, DO, MSN, CRNP, is an associate professor, and Meghan Scanlon is an honors BSN student at Villanova University in Pennsylvania. References 1. Epidemiology and prevention of vaccine-preventable diseases. Varicella-zoster virus. Clinical features. Centers for Disease Control and Prevention website. http://www.cdc.gov/vaccines/pubs/pinkbook/varicella. html#zostervirus. Updated August 11, 2015. Accessed January 4, 2017. 2. Shingles (herpes zoster). Epidemiology. Risk factors. Centers for Disease Control and Prevention website. http://www.cdc.gov/shingles/ hcp/clinical-overview.html#risk-factors. Updated August 19, 2016. Accessed January 4, 2017. 3. Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc. 2007;82:13411349. Erratum in Mayo Clin Proc. 2008;83:255.
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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2017 19
SHINGLES: A COMPLETE GUIDE FOR CLINICIANS
41. Oxman MN. Zoster vaccine: current status and future prospects. Clin Infect Dis. 2010;51:197-213. 42. Morrison VA, Oxman MN, Levin MJ, et al; Shingles Prevention Study Group. Safety of zoster vaccine in elderly adults following documented herpes zoster. J Infect Dis. 2013;208:559-563. 43. Hales CM, Harpaz R, Ortega-Sanchez I, Bialek SR; Centers for Disease Control and Prevention (CDC). Update on recommendations for use of herpes zoster vaccine. MMWR Morb Mortal Wkly Rep. 2014;63:729-731. 44. Keating GM. Shingles (herpes zoster) vaccine (Zostavax ®): a review in the prevention of herpes zoster and postherpetic neuralgia. BioDrugs. 2016;30:243-254. 45. Marin M, Guris D, Chaves SS, Schmid S, Seward JF; Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC). Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recommen Rep. 2007;56(RR-4):1-40. 46. Safety information. Zostavax (zoster vaccine live) suspension for subcutaneous injection. U.S. Food and Drug Administration website. http:// www.fda.gov/Safety/MedWatch/SafetyInformation/ucm200862.htm. Updated March 14, 2016. Accessed January 4, 2017. 47. Cunningham AL, Lal H, Kovac M, et al; ZOE-70 Study Group. Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. N Engl J Med. 2016;375:1019-1032. 48. Galil K, Brown C, Lin F, Seward J. Hospitalizations for varicella in the United States, 1988 to 1999. Pediatr Infect Dis J. 2002;21:931-935. dence among insured persons in the United States, 1993-2006: evaluation of impact of varicella vaccination. Clin Infect Dis. 2011;52:332-340. 50. Kawai K, Yawn BP, Wollan P, Harpaz R. Increasing incidence of herpes zoster over a 60-year period from a population-based study. Clin Infect Dis. 2016;63:221-226. 51. Marin M, Meissner HC, Seward JF. Varicella prevention in the United States: a review of successes and challenges. Pediatrics. 2008;122:e744-e751. 52. Goldman GS, King PG. Review of the United States universal varicella vaccination program: herpes zoster incidence rates, cost-effectiveness, and vaccine efficacy based primarily on the Antelope Valley Varicella Active Surveillance Project data. Vaccine. 2013;31:1680-1694. 53. Joon Lee T, Hayes S, Cummings DM, et al. Herpes zoster knowledge, prevalence, and vaccination rate by race. J Am Board Fam Med. 2013;26:45-51. 54. Williams WW, Lu PJ, O’Halloran A, et al; Centers for Disease Control and Prevention (CDC). Vaccination coverage among adults, excluding influenza vaccination—United States, 2013. MMWR Morb Mortal Wkly Rep. 2015;64:95-102. 55. Shingles (herpes zoster). Complications. Centers for Disease Control and Prevention website. http://www.cdc.gov/shingles/hcp/clinical-overview. html#complications. Updated August 19, 2016. Accessed January 4, 2017. 56. Neuzil KM, Griffin MR. Preventing shingles and its complications in older persons. N Engl J Med. 2016;375;1079-1080. 57. Gelb LD. Reducing the incidence and severity of herpes zoster and PHN with zoster vaccination. J Am Osteopath Assoc. 2009;109(6 suppl 2):S18-S21.
20 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
“Just to be clear, this is just a spaceman and a spacewoman on a spacewalk. This isn’t a spacedate.”
Top, bottom: © Harley Schwadron; middle: © The New Yorker Collection 2017 from cartoonbank.com. All Rights Reserved.
49. Leung J, Harpaz R, Molinari NA, Jumaan A, Zhou F. Herpes zoster inci-
FEATURE: MELISSA MORGAN, MPA, PA-C; LISA DAITCH, MPAS, PA-C
Vulvar lichen sclerosus: breaking the silence Early diagnosis and treatment play a substantial role in a patient’s prognosis and result in a decreased risk of malignancy and scarring.
© DR P. MARAZZI / SCIENCE SOURCE
Lichen sclerosus of the vulva in a 49-year-old woman.
22 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
ichen sclerosus is a chronic inflammatory skin condition that most commonly affects the vulva, groin, and perianal region of postmenopausal women.1,2 This disease is not limited to the anogenital skin of postmenopausal women, as it also less frequently affects men and children, and it develops in extragenital areas as well. The estimated prevalence ranges from 1 in 30 elderly women to 1 in 1,000 patients referred to a dermatologist.3 These numbers are likely underestimated because the disease is often misdiagnosed, never diagnosed due to the patient being asymptomatic, or in some instances, patients are reluctant to seek help due to embarrassment of symptoms.4 Vulvar lichen sclerosus typically presents in a bimodal fashion in prepubertal children and in postmenopausal women. It is more common in women, with a 5:1 female/male ratio.1,4 Because these patients may initially present at the onset of symptoms to a wide variety of practices such as primary care, dermatology, gynecology, urology, pediatrics, or even the emergency department, it is important for practitioners to understand how to properly diagnose and treat those with this disease. Severe cases of vulvar lichen sclerosus can significantly impair the quality of life that patients have, as it often negatively affects women physically, mentally, and emotionally.5 The earlier that the disease is diagnosed and adequately treated, the less likely the disease will progress to irreversible scarring and malignancies such as squamous cell carcinoma.
right-hand column like this one does at the top
Etiology of the disease
The exact etiology of lichen sclerosus has not been ascertained; however, evidence points to an increased likelihood of an autoimmune and genetic component.4 In a study of 350 women with lichen sclerosus, researchers found that 21.5% had 1 or more autoimmune-related diseases, 21% had a family history of autoimmune disease, and 42% had autoimmune antibodies.4 The most common autoimmune diseases associated with lichen sclerosus are autoimmune thyroiditis, alopecia areata, vitiligo, and pernicious anemia.4 In addition to an autoimmune factor, it appears that genetics has a pathogenetic role as well. A study of 1,052 women with vulvar lichen sclerosus found that 12% of participants had a positive family history of lichen sclerosus.4 Trauma and chronic irritation have also been linked to being contributory factors of vulvar lichen sclerosus.4 Cases of the skin condition have been reported in patients with genital jewelry, postsurgical procedures, and genital trauma.4 Furthermore, chronic irritation caused by urine exposure and reduced estrogen levels have also been associated with anogenital lichen sclerosus.4
to: localized scleroderma, cutaneous discoid lupus erythematous, atrophic lichen planus, lichen simplex chronicus, vitiligo, mucous membrane pemphigoid, anal fissures and hemorrhoids, candidiasis, estrogen deficiency, and vulvar intraepithelial neoplasia. Biopsy of suspected vulvar lichen sclerosus in adults is preferred during the initial visit rather than after empiric therapy because of: 1) the risk for atypia or malignancy; 2) the expansive list of possible differentials associated with vulvar pruritus and whitening can lead to misdiagnosis and/or delay in diagnosis; 3) steroid treatment within 2 weeks prior to biopsy may affect pathological accuracy; and 4) classic signs and symptoms may not be present, further complicating diagnosis.3 TABLE 1. Clinical checklist for vulvar lichen sclerosus Symptoms
• Vulvar pruritus, worse at night • Vulvar pain and soreness • Burning of skin lesions • Dysuria, difficulty urinating • Pruritus ani, rectal bleeding, dyschezia • Sexual dysfunction, dyspareunia, apareunia, anorgasmia, diminished sexual sensation • Dysesthesia of affected area • Asymptomatic
• Hour-glass configuration of whitening surrounding vulvar and anal areas • Macular, whitened/ivory appearing atrophic lesions, with classic “parchment-like” paper appearance • Bleeding, telangectasia • Purpura • Excoriation and lichenification secondary to scratching • Skin fissures; including anal fissures • White to brown follicular plugs on the surface and hyperkeratosis • Architectural changes: labial flattening, clitoral scarring, introital stenosis, scarring of vulvar and anal tissue • Well-demarcated, slightly elevated non-specific erythema located around periclitoral hood
• Varies; may involve only a small isolated area or may involve the entire anogenital region Possible extension to the genitocrural folds, buttocks, thighs
Areas not involved
• Genital mucosal involvement; vagina very rarely involved and cervix never involved
• Localized scleroderma • Cutaneous discoid lupus erythematous • Atrophic lichen planus • Lichen simplex chronicus • Vitiligo • Mucous membrane pemphigoid • Anal fissures and hemorrhoids • Candidiasis • Estrogen deficiency • Vulvar intraepithelial neoplasia
Physical findings and clinical presentation
Physical examination findings can vary widely in presentation and severity among patients (see Table 1).1 Typical vulvar lichen sclerosus characteristics may include hypopigmentation, atrophy, erythema, fissures, and purpura of the skin.6 These skin characteristics are often described as “parchment-like” or “cigarette paper” and present in an hourglass configuration surrounding the intraoital and perianal area.1,3 As the disease progresses, atrophy of the epidermis can cause development of scar tissue, resulting in the loss of vulvar architecture, labial fusion, phimosis of the clitoral hood, and intraoital constriction.7 All of these dermal skin changes are usually associated with symptoms of intense pruritus and pain, although it is possible for patients to be entirely asymptomatic. In mild cases, erythema may be the only sign present; however, in more severe cases, inflammation, subepithelial hemorrhages, and chronic ulceration may be evident.1 Diagnosis
Diagnosis is typically based on the characteristic clinical presentation and is preferably confirmed with histologic features of a 3-mm punch biopsy.3 Several other disorders that present with vulvar pruritus and/or similar presentations need to be considered when diagnosing this condition. A differential diagnosis should include, but is not limited
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2017 23
VULVAR LICHEN SCLEROSUS: BREAKING THE SILENCE
Although there is no cure for vulvar lichen sclerosus, treatment can provide significant relief of symptoms and prevent disease progression. Management
Psychological. In addition to the adverse physical effects of vulvar lichen sclerosus, patients often experience psychological consequences. Frustration and despair are commonly reported.8 Quality of life tends to decline due to the difficulties associated with vulvar lichen sclerosus.8 Patients may have trouble sleeping, interacting socially with others, or even being productive in their everyday life.2 The various symptoms may be so severe that they may necessitate the need for psychosomatic or psychological therapy and counseling.2 Sexual dysfunction. The atrophy, strictures, and scarring of the affected genitalia secondary to vulvar lichen sclerosus often result in sexual dysfunction, specifically dyspareunia.7 These anatomical changes may also lead to decreased lubrication and decreased sensation, resulting in a decreased ability to achieve orgasm.7 A study conducted by Dalziel established the adverse effect of vulvar lichen sclerosus on sexual function with a high rate of dyspareunia and reduced frequency of intercourse.7 When these patients were treated appropriately, sexual dysfunction improved but did not completely resolve.6,7 Malignancy. The lesions associated with vulvar lichen sclerosus are not considered to be premalignant, but patients have an increased risk of developing squamous cell carcinoma (SCC).3 SCC tends to develop within long-standing lesions with irreversible changes in 3% to 10% of patients.1,9 Early detection, biopsy/excision, and treatment of vulvar lichen sclerosus may lead to a reduced risk of these patients developing SCC.3 Associated comorbidities. Patients with vulvar lichen sclerosus may also have bladder, pain, and bowel comorbidities.5 Bladder comorbidities that were self-reported more frequently among patients with vulvar lichen sclerosus than in the general population include urinary incontinence and stress urinary incontinence.5 Pain disorders such as vulvar pain, interstitial cystitis, fibromyalgia, and temporomandibular joint pain syndrome were also self-reported significantly more frequently among patients with vulvar lichen sclerosus than in the general population.5 This trend was equivalent for gastrointestinal disorders such as inflammatory bowel diseases, chronic constipation, and irritable bowel syndrome.5 Practitioners should be aware of these associated comorbidities and appropriately screen for them among their patients with vulvar lichen sclerosus.
Although there is no cure for vulvar lichen sclerosus, treatment can provide significant relief of symptoms and prevent progression of the condition. Early diagnosis is imperative because the disease can lead to irreversible scarring and anatomical changes if left untreated. Topical ultrapotent corticosteroids are considered the gold standard of treatment for patients with vulvar lichen sclerosus. In one study, ultrapotent corticosteroids resulted in the improvement of symptoms in nearly all participants, complete relief of symptoms in about 70%, and complete remission of skin changes in about 20%.4 The use of topical clobetasol propionate 0.05% has been examined in several studies and appears to provide therapeutic benefit and improve the quality of life in patients with vulvar lichen sclerosus.2 Initial course of treatment is usually 6 to 12 weeks, with ointment being applied nightly to the affected skin. If patients do not respond to this treatment after an adequate amount of time, dosage is appropriate, and patient compliance is confirmed, practitioners should investigate other likely diagnoses. Possible contact allergy, secondary infection, and malignancy should also be considered.4 Once these have been ruled out, patients can use topical calcineurin inhibitors as a 2nd-line therapy. Maintenance therapy is recommended for patients with vulvar lichen sclerosus even when they report complete relief of symptoms after initial treatment.10 Maintenance therapy should consist of mometasone furoate, 0.1%, ointment applied 2 to 3 times weekly.10 This is a less potent corticosteroid that provides greater anti-inflammatory benefits and has a longer
© SPL / SCIENCE SOURCE
Adverse effects and associated comorbidities
FIGURE 1. Lichen sclerosus on the labia of an adult female patient. Topical corticosteroids are considered the gold standard of treatment.
24 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
It is estimated that 96% of patients will respond to topical corticosteroids initially, but relapse is likely without long-term maintenance therapy. duration of action compared with those corticosteroids of similar potency.3 Topical corticosteroids are less effective on thickened hypertrophic plaques. Practitioners should consider intralesional injections of triamcinolone hexacetonide or triamcinolone acetonide for patients with lesions of this type.3 Various other therapies have also been studied in the treatment of vulvar lichen sclerosus; however, when compared with topical clobetasol propionate 0.5%, they are less efficacious, less convenient for patients, or have increased side effects associated with their use. These therapies, which include UV-A1 phototherapy, photodynamic therapy, oral acitretin, and topical progesterone/testosterone, should only be used as 3rd-line therapy.3 Surgical intervention should only be used in a limited number of circumstances, such as in patients with malignancy or to correct irreversible scarring and adhesions. Intraoital surgical widening can be used to correct micturition difficulties or sexual dysfunction caused by the subsequent anatomical changes.4
by the disease, but mentally and emotionally as well. It is important for practitioners to be aware of the adverse effects and associated comorbidities when diagnosing and treating patients with vulvar lichen sclerosus. Earlier detection and subsequent adequate management can lead to a reduction of these adverse outcomes. Topical ultrapotent corticosteroids remain the gold standard of treatment; however, various 2ndline therapies can be used among patients whose condition is refractory to the topical ultrapotent corticosteroids. The disease is highly treatable, but long-term maintenance therapy and lifetime follow-up are imperative among all patients with this chronic and debilitating condition. n Melissa Morgan, MPA, PA-C, is a physician assistant with North Atlanta Primary Care, and Lisa Daitch, MPAS, PA-C, is clinical medicine II course coordinator at Augusta University in Georgia. References 1. Ferri F. Ferri’s Clinical Advisor 2016. Philadelphia, PA: Elsevier; 2016. 2. Schwegler J, Schwarz J, Eulenburg C, Blome C, Ihnen M, Mahner S, et al. Health-related quality of life and patient defined benefit of clobetasol
0.05% in women with chronic lichen sclerosus of the vulva. Dermatology.
Although vulvar lichen sclerosus cannot be cured, it is highly treatable. Early diagnosis, early treatment, and patient compliance play a substantial role in the patient’s prognosis and result in a decreased risk of malignancy and scarring.9 It is estimated that 96% of patients will respond to topical corticosteroids initially, but relapse is likely without long-term maintenance therapy.9 Patients often see an increase in quality of life and decrease in sexual dysfunction with adequate treatment of this condition. Long-term follow-up is strongly encouraged and recommended due to the chronic nature of this condition and associated risk for malignancy. Patients should be advised that they need to follow up for evaluation at least once annually after their condition is well-managed and under control.3
2011;223(2):152-160. 3. Cooper SM, Arnold SJ. Vulvar lichen sclerosus. http://www.uptodate. com/contents/vulvar-lichen-sclerosus?source=search_result&search=vulva r+lichen+sclerosus&selectedTitle=1~13 4. Fistarol SK, Itin PH. Diagnosis and treatment of lichen sclerosus: an update. Am J Clin Dermatol. 2013;14(1):27-47. 5. Berger MB, Damico NJ, Menees SB, Fenner DE, Haefner HK. Rates of self-reported urinary, gastrointestinal, and pain comorbidities in women with vulvar lichen sclerosus. J Low Genit Tract Dis. 2012;16(3):285-289. 6. Burrows LJ, Creasey A, Goldstein AT. The treatment of vulvar lichen sclerosus and female sexual dysfunction. J Sex Med. 2011;8(1):219-222. 7. Pinelli S, D’Erme AM, Lotti T. Management of sexual dysfunction due to vulvar lichen sclerosus in postmenopausal women. Dermatol Ther. 2013;26(1):79-82.
8. Ventolini G, Patel R, Vasquez R. Lichen sclerosus: a potpourri of misdiag-
Vulvar lichen sclerosus is a chronic inflammatory skin condition that often leads to a decreased quality of life if left undiagnosed and subsequently untreated. The etiology of the disease is still undetermined, but it is thought that genetic and autoimmune factors may predispose patients to the condition. Generally, the disease is diagnosed based on characteristic clinical presentation; however, biopsy is recommended to confirm the diagnosis. Women are not only affected physically
nosed cases based on atypical clinical presentations. Int J Womens Health. 2015;7:511-515. 9. Brodrick B, Belkin ZR, Goldstein AT. Influence of treatments on prognosis of vulvar lichen sclerosus: facts and controversies. Clin Dermatol 2013;31(6):780-786. 10. Cooper SM, Madnani N, Margesson L. Reduced risk of squamous cell carcinoma with adequate treatment of vulvar lichen sclerosus. JAMA Dermatol. 2015;151(10):1059-1060.
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2017 25
n EDUCATIONAL OBJECTIVES After participating in this activity, clinicians should be better able to: • Utilize evidence-based protocols to arrive at an accurate and timely diagnosis of Parkinson’s disease (PD) • Interpret recent clinical data and recommendations for incorporation of neuroimaging in order to improve diagnostic accuracy in patients with suspected parkinsonian syndrome
n COMPLETE THE POSTTEST: Page 34
Release Date: February 29, 2016 Expiration Date: August 31, 2017 Estimated time to complete: 30 minutes Accredited Provider: This program is provided by Albert Einstein College of Medicine. Commercial Supporter: This activity is supported by an educational grant from GE Healthcare. Program Description: Parkinson’s disease (PD) remains as a condition with no clear diagnostic test. Diagnosis is based on the clinical, observational presence of 2 or more of the cardinal signs: tremor, bradykinesia, and rigidity. Therefore, the diagnosis of PD is challenging, particularly during its early stages when the first signs and symptoms are subtle and nonspecific. Moreover, there is an overlap of PD symptoms with those of similar movement disorders, such as essential tremor, dystonic tremor, and other parkinsonian syndromes. Nonmotor symptoms (eg, dysarthria, dysphagia, and sialorrhea) and inadequate response to dopaminergic medication further cloud the diagnostic picture in PD. Timely and proper diagnosis creates a need for clinicians to recognize PD diagnostic criteria and appropriate testing, particularly in atypical cases where further evaluation is warranted. This activity is intended to provide clinicians with information to make more precise diagnoses, especially in the early stages of the disease, and on the role of imaging modalities. Intended Audience: Neurologists, primary care clinicians, movement disorder specialists, and other healthcare professionals who diagnose patients with Parkinson’s disease Conflict of Interest Disclosure Policy: It is the policy of Albert Einstein College of Medicine to ensure balance, independence, objectivity, and scientific rigor in all its educational activities. In accordance with ACCME policies and standards, all faculty participating in any sponsored activity are expected to disclose to the audience any real or apparent conflict(s) of interest that may have a direct bearing on the subject matter of the continuing educational activities in which they participate. This pertains to relationships with pharmaceutical companies, biomedical device manufacturers, or other entities. The intent of this policy is not to prevent a speaker with a potential conflict of interest from making a presentation. It is merely intended that any potential conflict should be identified openly so that the participants may form their own judgments about the presentation with the full disclosure of the facts. It is required by the ACCME that each speaker disclose to the audience any discussion of unlabeled use of a commercial product or device or an investigational use not yet approved for any purpose. Faculty David M. Kaufman, MD Professor, The Saul R. Korey Department of Neurology Professor, Department of Psychiatry and Behavioral Sciences Montefiore Medical Center New York, NY Daniel Truong, MD Neurologist and Medical Director The Parkinson and Movement Disorder Institute Orange Coast Memorial Fountain Valley, CA
STEADY PD3, Cynapsus Therapeutics Inc., Biorasi, Acorda Therapeutics Inc., Merz Pharmaceuticals, Impax Laboratories, GE Healthcare, and Pfizer. Accredited Provider Disclosure: The staff of the Center for Continuing Medical Education of Albert Einstein College of Medicine have nothing to disclose with regard to commercial support. Publishing Staff Disclosures: Priya Wanchoo, MD, and Mary Ellen Journick of Haymarket Medical Education have nothing to disclose with regard to commercial support. Accreditation Statement: Albert Einstein College of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation Statement: Albert Einstein College of Medicine designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit(s)TM. Physicians should claim only credit commensurate with the extent of their participation in the activity. Disclosure of Unlabeled Use: This educational activity may contain discussion of approved and/or investigational uses of agents that are not indicated by the FDA. GE Healthcare, Albert Einstein College of Medicine, and Haymarket Medical Education do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of GE Healthcare, Albert Einstein College of Medicine, and Haymarket Medical Education. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. If you have any questions relating to the accreditation of this activity, please contact Mildred Adighiuzor at 718-920-6674. Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period February 29, 2016 through August 31, 2017, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the pre-assessment test; 3) study the educational activity; 4) complete the poll questions; and 5) complete the post-test and submit it online. A statement of credit will be issued only upon receipt of the above elements and a post-test score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/Feb17feature.
Faculty Disclosures: Dr. Kaufman has nothing to disclose. Dr. Truong has disclosed that he receives grants/research support from AbbVie Inc., Adamas Pharmaceuticals, Inc., Kyowa Hakko Kirin Pharma, Inc.,
1/26/17 12:20 PM
FEATURED COURSE: DAVID M. KAUFMAN, MD; DANIEL TRUONG, MD
Parkinson’s disease: Making an evidence-based diagnosis Utilizing established diagnostic criteria and testing allows clinicians to make more precise diagnoses, especially in the early stages of the disease.
© MEDICALIMAGES.COM / BSIP / JAMES CAVALLINI
Brain MRI from a patient with Parkinson’s disease
arkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the clinical presentation of particular motor and nonmotor symptoms (Table 1).1,2 Though some symptoms are more common than others, each patient with PD experiences symptoms differently.2 The presentation of symptoms typically occurs in one side of the body and spreads to the other same-side extremities before progressing to the other side of the body.1 Within the PD patient population, there is significant disability and decreased quality of life,1 as patients with PD experience progressive decline in both motor and cognitive function as well as increased mortality. Risk factors at diagnosis for a more rapid motor function decline include advanced age, prominent bradykinesia, and prominent rigidity.3 PD is a common neurological disorder, affecting 7 to 10 million people worldwide—of whom 1 million are in the United States.1,2 The prevalence of PD increases with age and is believed to affect approximately 1% of all individuals 60 years of age and older.1 Men are 1.5 times more likely to be afflicted with PD compared with women. Prevalence of the disease also varies geographically, with higher rates in Europe, North America, and Australia as compared with Asia.1 Parkinson’s disease inflicts an economic burden on individuals and society as well. For example, in the United States alone, the annual cost incurred due to PD is estimated at $11 billion, more than half of which is direct costs.4 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2017 27
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TABLE 1. Symptoms of Parkinson’s disease1,2 Primary motor symptoms • Resting tremor • Bradykinesia
• Rigidity • Postural instability
Secondary motor symptomsa • Freezing of gait • Micrographia (ie, shrinkage of handwriting)
• Mask-like expression • Unwanted accelerations
Early, nonmotor symptoms • Loss of sense of smell • Constipation • Orthostatic hypotension
• REM sleep behavior disorder • Mood disorders
Other nonmotor symptoms • Sleep disturbances • Bladder problems • Sexual problems • Excessive saliva • Weight loss or gain • Vision and dental problems
• Cognitive issues (ie, memory impairment, slowing thinking, confusion, dementia) • Fatigue or loss of energy • Depression • Skin problems • Fear/anxiety
REM, rapid eye movement. a These are the cardinal secondary motor symptoms; additional secondary motor symptoms may be observed, including stooped posture, dystonia, impaired fine motor dexterity and motor coordination, impaired gross motor coordination, poverty of movement (eg, decreased arm swing), speech problems, difficulty swallowing, sexual dysfunction, cramping, and drooling.
William is a 60-year-old recently retired carpenter. He is currently receiving a statin for hypercholesterolemia and metoclopramide for heartburn. His father had diabetes, but no family member had a tremor or other neurological illness. In his retirement, William has taken up whittling wooden figurines that he sells at local craft fairs. He relates that in the past, he was able to whittle quickly and nimbly, but says that his fingers in both hands “don’t seem to work as well as they used to.” He attributed his symptoms to age. William has also been concerned about bladder control problems. On neurologic examination, William is alert and oriented, exhibiting good memory and judgment. His gait is shuffling, but he has no tremor or other neurologic abnormality. ■ Which of the following should be given the greatest consideration when assessing William’s potential for a PD diagnosis?
a. Gait impairment b. Lack of tremor c. Bilateral onset of mild bradykinesia in upper extremities d. Former career in the construction industry
The diagnosis of PD is primarily a clinical exercise, requiring the physician to identify the cardinal features of the disease as no standard diagnostic test is available.3,5 Diagnosis is particularly difficult in the early stages of the disease.3 While several clinical diagnostic criteria have been proposed, the most widely used clinical criteria are those proposed by the United Kingdom Parkinson’s Disease (UK PD) Society Brain Bank (Table 2). They consist of a 3-step method, detailing signs that must be present, those that must not be present, and other supportive criteria.6,7 Misdiagnosis of PD is very common, particularly in the primary care setting. Additionally, the earlier in the disease continuum the patient lies, the greater the likelihood for misdiagnosis.5 This was the case for William. He initially consulted his primary care physician (PCP) regarding his lack of agility in his fingers while woodworking and was diagnosed with mild rheumatoid arthritis. After several weeks of non-steroidal anti-inflammatory (NSAID) therapy with no resolution of the issue, William went back to his PCP. It was at this time that his PCP noted a slight tremor in William’s left leg in addition to his previously noted symptoms, and he referred William to a neurologist for further evaluation. Because PCPs rarely encounter patients with parkinsonian syndrome, it is difficult for them to maintain a high level of knowledge around it and provide optimal patient care. As such, it is recommended that PCPs refer patients with suspected parkinsonian syndrome to movement disorder specialists.5 The heaviest cost and quality-of-life burdens associated with PD occur in the later stages of the disease, and management strategies employed after a definitive diagnosis earlier in the disease course have the best potential to both limit expenditures and improve the experience of those living with PD.4 However, most people with PD currently receive a diagnosis only after motor symptoms have appeared, at which point 40% to 60% of dopamine neuronal markers have already been lost.5 ■ Which of the following is required for a diagnosis of PD per the 1992 UK PD Society Brain Bank criteria?
a. Dementia b. More than 1 affected relative c. Bradykinesia d. 3-5 Hz tremor Differential diagnosis
Even within the specialty setting, misdiagnosis is frequently a problem. In this patient population, movement disorder
28 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
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specialists fail to reach an accurate diagnosis nearly half of the time, while general neurologists may misdiagnose patients up to 75% of the time.5 The differential diagnosis of PD includes other causes of parkinsonism, which are listed in Table 3 along with their distinguishing features.1 Patients with conditions listed in Table 3 often are initially misdiagnosed with PD. Conversely, many patients with PD are misdiagnosed as having a condition listed in Table 3. Patients with PD who were initially misdiagnosed are most commonly initially diagnosed with essential tremor, vascular parkinsonism, dementia, or drug-induced parkinsonism.8 Misdiagnosis leads to incorrect disease prognosis and patient management, including prescription of unwarranted medications, exposure to drug-related adverse events, and unnecessary costs.9 William’s neurologist confirmed that he is showing parkinsonism symptoms but is unsure if PD is the correct diagnosis. He explained to William that the bradykinesia he is experiencing in his fingers and the slight tremor are characteristic of PD, but the bilateral onset is not a classic presentation and the tremor is under the 4 Hz to 6 Hz threshold. Moreover, he is not demonstrating signs of muscular rigidity or postural instability.7 The bladder control issues may be due to PD, several other conditions commonly misdiagnosed as PD, or simply an enlarged prostate.5 Importantly, the metoclopramide treatment that William recently began to control his heartburn is associated with drug-induced parkinsonism.10 He instructed William to stop taking the metoclopramide and advised him on diet, lifestyle changes, and over-thecounter heartburn medications. William’s neurologist suggested pursuing William’s response to levodopa as a diagnostic criterion. However, use of the so-called “levodopa challenge test” as a means of confirming a PD diagnosis is controversial.5 Continuous levodopa response may occur in atypical parkinsonism disorders as well, and false-positive and false-negative responses may occur in as many as 40% of cases.5,6 The UK PD Society Brain Bank diagnostic criteria, published in 1992, lists “excellent response” (ie, 70%-100%) to levodopa as a diagnostic criterion for PD.7 The American Academy of Neurology (AAN) practice parameter for the diagnosis of PD, published originally in 2006 and reaffirmed in 2013, lists levodopa response as “probably useful” in distinguishing PD from other parkinsonism syndromes.11,12 However, the 2013 European Federation of Neurological Societies and the European Section of the Movement Disorder Society (EFNS/MDS-ES) diagnostic guidelines do not recommend use of the levodopa challenge for the diagnosis of PD.6
TABLE 2. UK PD Society Brain Bank Clinical Diagnostic Criteria7 STEP 1. Diagnosis of parkinsonian syndrome • Bradykinesia (slowness of initiation of voluntary movement with progressive reduction in speed and amplitude of repetitive actions) and at least 1 of the following: – Muscular rigidity – 4-6 Hz tremor – Postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction STEP 2. Exclusion criteria for Parkinson’s disease • History of repeated strokes, with stepwise progression of parkinsonian features • History of repeated head injury • History of definite encephalitis • Oculogyric crises • Neuroleptic treatment at onset of symptoms • More than 1 affected relative • Sustained remission • Strictly unilateral features after 3 years • Supranuclear gaze palsy • Cerebellar signs • Early severe autonomic involvement • Early severe dementia with disturbances of memory, language, and praxis • Babinski reflex • Presence of cerebral tumor or communicating hydrocephalus on CT scan • Negative response to large doses of levodopa (if malabsorption excluded) • MPTP exposure STEP 3. Supportive prospective positive criteria for Parkinson’s disease • 3 or more of the following are required for definitive Parkinson’s disease diagnosis: – Unilateral onset – Rest tremor present – Progressive disorder – Persistent asymmetry affecting the side of onset most – Excellent response (70%-100%) to levodopa – Severe levodopa-induced chorea – Levodopa response for 5 years or more – Clinical course of 10 years or more CT, computed tomography; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; UK PD, United Kingdom Parkinson’s Disease.
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TABLE 3. Conditions commonly misdiagnosed as Parkinson’s disease1,5 Condition
• Tremor (action/postural) is main feature • Other family members have tremor • Alcohol responsiveness • No response to PD medications
Progressive supranuclear palsy (PSP) or Steele-RichardsonOlszewski disease
• Supranuclear gaze palsy • Early gait instability • Falls
Imaging in differential diagnosis
• Pseudobulbar affect
At his next visit, William’s neurologist suggested pursuing both the levodopa response and imaging. Typically, imaging plays a limited role in diagnosis and is not recommended for use in routine diagnosis. However, imaging may have utility in assisting physicians with a differential diagnosis in challenging patients.3 Current recommendations regarding the use of imaging in PD diagnosis are listed in Table 4. Pathologically, PD is characterized by depigmentation and neuronal loss in the pars compacta of the substantia nigra and the presence of Lewy bodies (eg, neuronal cells with pigmented inclusion bodies) and pale bodies (ie, Lewy body precursors).1,14,15 The hallmark of PD is a deficit of dopamine in the striatum, the site of axonal projection from the substantia nigra.1 Imaging techniques aim to visualize this loss to aid in PD differential diagnosis. Conventional magnetic resonance imaging (MRI) at 1.5 T is principally helpful to exclude symptomatic parkinsonism due to other pathologies as well as in the differentiation of PD from atypical parkinsonism syndromes.6 Additionally, “neuromelanin-sensitive” MRI techniques (ie, highresolution, T1-weighted MRI sequence at 3 T) can be used to detect neuromelanin, a pigment that is a byproduct of dopamine and noradrenaline metabolism that has paramagnetic properties.16 This latter technique, however, has several limitations, including long acquisition time and relatively low spatial resolution, and it requires the implementation of post-processing software that is not widely available.16 William had stopped using the metoclopramide for 2 weeks, but had no resolution of any of his symptoms. However, some patients with drug-induced parkinsonism continue to display symptoms for several months after drug withdrawal.17 William’s neurologist suggested using a molecular imaging technique that would definitively rule out drug-induced parkinsonism.17
• Autonomic disturbances • Cerebellar signs • Relative absence of tremor • Early gait instability • Dysphagia • Poor or atypical response to levodopa
Corticobasal ganglionic degeneration (CBGD)
• Limb apraxia • Corticol sensory abnormalities • Limb rigidity and dystonia • Focal reflex myoclonus • Nonfluent aphasia
Dementia with Lewy bodies (DLB)
a. Have William drink alcohol to see if the tremor is relieved b. Ask William to recall if he was exposed to any toxins (eg, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP], manganese) c. Order a bone density scan to look for osteoporosis d. Utilize an imaging technique
• Upright posture • Dysphagia
Multiple system atrophy (MSA)
■ William presents a challenge where it is proving difficult to differentiate PD from similar disorders. Which of the following is the most reasonable approach for a differential diagnosis?
• Early dementia • Visual hallucination • Fluctuating cognition • REM sleep behavior disorder
• Dementia (primary symptom)
• Exposure to dopamine-blocking drugs • Symmetrical signs
• History of chronic hypertension • Stepwise progression (if any) • Imaging • Unilateral • Lower-body parkinsonism in multi-infarct states
PD, Parkinson’s disease; REM, rapid eye movement.
30 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
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TABLE 4. Recommendations for imaging use in Parkinson’s disease diagnosis11,13 Imaging technique
American Academy of Neurology (AAN)
National Institute for Health and Clinical Excellence (NICE)
Fludeoxyglucose positron emission tomography (PET)
Evidence insufficient to make recommendation
In research settings only
Magnetic resonance imaging (MRI)
Possibly useful to distinguish PD from multisystem atrophy
• Not recommended for PD diagnosis • Consider for diagnosis of parkinsonian syndromes
Single-photon emission computed tomography (SPECT)
Possibly useful to distinguish PD from essential tremor
Distinguishes PD from essential tremor
Insufficient evidence to make recommendation
PD, Parkinson’s disease.
Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) measure the biodistribution of minute concentrations (<10 -10 molar) of in vivo radio-labeled biomolecules. These techniques are capable of submillimeter resolution and can quantify the molecular kinetic processes in which biomolecules participate. A radiotracer, labeled with a radioisotope, is used that has a high affinity and specificity for a receptor site. The radioligands allow for in vivo evaluation of receptor density and affinity measured with binding potential.17 There are several SPECT and PET radiotracers available for use; those with the most relevance to PD are listed in Table 5. William’s neurologist chose to perform a DaTscan™ ([123I] Ioflupane injection; known as DaTSCAN in the European Union), a US Food and Drug Administration (FDA)approved SPECT imaging technique.18 DaTscan is capable of detecting abnormalities in striatal dopamine transporters in cases of early, suspected parkinsonian syndrome (Figure 1).19 Scan A. Normal DaTscan demonstrates normal uptake bilaterally: “comma shape” on both sides representing the caudate head and putamen. The image was largely symmetrical with approximately equal level of uptake. Scan B. Unilateral abnormal DaTscan has normal, comma-shaped uptake on the right side and decreased uptake on the left side. Scan C. Abnormal DaTscan shows a diffuse decrease in uptake bilaterally, particularly in the putamen, and less so involving the caudate heads. Increased background activity is also present because of decreased radiotracer uptake resulting in significant reduction in contrast. DaTscan alone is not capable of diagnosing PD, but it does aid clinicians in optimizing diagnostic accuracy and planning
clinical management in many cases.19 In a single-dose, prospective, randomized clinical trial, DaTscan had a significant impact on clinical management, diagnosis, and confidence of diagnosis in patients with clinically uncertain parkinsonian syndrome.19 Additional phase 3 trials in both the United States and the European Union have demonstrated the utility of DaTscan in achieving an accurate differential diagnosis.5 Table 6 lists in detail the appropriate and inappropriate uses of DaTscan in PD per a multidisciplinary expert panel.5 TABLE 5. Recommendations for imaging use in Parkinson’s disease diagnosis17 System and measurement target
[123I]-PE2I or RTI-32
DOPAMINERGIC SYSTEM Dopamine transporter (DAT) Dopa-decarboxylase activity
NONDOPAMINGERGIC SYSTEM D2 receptor Vesicular monoamine transporter (VMAT-2)
DTBZ, dihydrotetrabenazine; IBZM, iodobenzamide; PE2I, N-(3-iodoprop-(2E)-enyl)-2betacarboxymethoxy-3beta-(4’-methylphenyl)nortropane; PET, positron emission tomography; RTI-32, 3 beta-(4-methylphenyl) tropane-2 beta-carboxylic acid methyl ester; SPECT, singlephoton emission computed tomography.
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TABLE 6. Expert panel recommendations regarding use of DaTscan in Parkinson’s disease5
Uncertain diagnosis • Nonclassic presentation • Monosymptomatic • Atypical/unusual parkinsonism • Incomplete parkinsonism
Certain diagnosis of PD • Not appropriate for routine confirmation of PD diagnosis
Tremor of uncertain etiology
Monitoring disease course (will become appropriate after introduction of diseasemodifying therapy)
Suspected dementia with Lewy bodies
Known PD mutation
PD patients as candidates for deep brain stimulation
Certain non-PD/non-ET diagnosis
Nonmotor complex or supportive features in patients without established clinical diagnosis of PD • Constipation • Depression • Cognitive changes • Anosmia • Autonomic symptoms ET, essential tremor; PD, Parkinson’s disease.
The DaTscan technique has several limitations. The injected substance is radioactive and is considered a scheduled, controlled substance in the United States. As such, a US Drug Enforcement Administration (DEA) license is required for its handling and administration.5,18 Additionally, patient positioning, motion, use of different color scales, and lack of reader experience may lead to erroneous interpretations.20 Scan C
■ Which of the following situations would merit an appropriate use of DaTscan imaging?
a. Routine confirmation of PD diagnosis b. Known PD mutation c. Monitoring PD course d. Tremor of uncertain etiology Images courtesy of Dr. Benjamin Lee, Orange Coast Memorial Medical Center, Fountain Valley, CA.
FIGURE 1. Normal and abnormal DaTscan SPECT images
Weeks after stopping the metoclopramide, DaTscan imaging revealed nigrostriatal degeneration, leading William’s neurologist to feel conf ident in a diagnosis of PD.
32 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
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He recommended initiating treatment based on William’s symptoms and functional impairment in alignment with the AAN recommendations, which direct the use of treatments once patients develop functional disability.21 Combination carbidopa-levodopa (Sinemet) was chosen as the initial treatment course as it is the most effective agent available for the treatment of motor symptoms.3 Additionally, if William responded to levodopa therapy, it would bolster support for the PD diagnosis.7
8. Schrag A, Ben-Shlomo Y, Quinn N. How valid is the clinical diagnosis of Parkinson’s disease in the community? J Neurol Neurosurg Psychiatry. 2002;73(5):529-534. 9. Gayed I, Joseph U, Fanous M, et al. The impact of DaTscan in the diagnosis of Parkinson disease. Clin Nucl Med. 2015;40(5):390-393. 10. Shin H-W, Chung SJ. Drug-induced parkinsonism. J Clin Neurol. 2012;8(1):15-21. 11. Suchowersky O, Reich S, Perlmutter J, et al. Practice parameter: diagnosis and prognosis of new onset Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American
Academy of Neurology. Neurology. 2006;66(7):968-975.
Diagnosis of PD, particularly in its early stages, remains challenging as it is primarily based on clinical observations.3,5 Misdiagnosis of PD is very common, particularly in the primary care setting.5 The symptoms of many movement disorders overlap with those of PD. As such, patients with non-PD disorders are misdiagnosed with PD and, conversely, those with PD are misdiagnosed with other movement disorders. Patients with PD are most commonly misdiagnosed with essential tremor, vascular parkinsonism, dementia, and drug-induced parkinsonism.8 While imaging techniques are not capable of diagnosing PD, they do aid clinicians in optimizing diagnostic accuracy and in planning clinical management in many cases.19 Timely and proper diagnosis requires a thorough understanding of PD diagnostic criteria and appropriate testing, particularly in atypical cases. An accurate diagnosis is the starting point for optimal disease management. n
12. American Academy of Neurology. AAN Summary of EvidenceBased Guideline for Clinicians: Diagnosis and Prognosis of New Onset Parkinson Disease. http://tools.aan.com/professionals/practice/ guidelines/PD_Clinicians_Sum.pdf. Updated July 13, 2013. Accessed January 20, 2016. 13. National Institute for Health and Care Excellence (NICE). Parkinson’s Disease in Over 20s: Diagnosis and Management. Clinical Guideline (CG35). https://www.nice.org.uk/guidance/cg35/resources/parkinsons-disease-inover-20s-diagnosis-and-management-975388237765. Published June 28, 2006. Accessed January 21, 2016. 14. The Free Dictionary by Farlex. Medical Dictionary. Lewy body. http://medical-dictionary.thefreedictionary.com/Lewy+body. Accessed February 18, 2016. 15. Wakabayashi K, Tanji K, Odagiri S, et al. The Lewy body in Parkinson’s disease and related neurodegenerative disorders. Mol Neurobiol. 2013;47(2):495-508. 16. Reimão S, Pita Lobo P, Neutel D, et al. Substantia nigra neuromelanin magnetic resonance imaging in de novo Parkinson’s disease patients. Eur J
1. Truong D, Bhidayasiri R. Parkinson’s disease. In: Lisak RP, Truong D,
17. Felicio AC, Shih MC, Godeiro-Junior C, et al. Molecular imaging stud-
Carroll WM, Bhidayasiri R, eds. International Neurology. 2nd ed. Chichester,
ies in Parkinson disease: reducing diagnostic uncertainty. Neurologist.
West Sussex; Hoboken, NJ: John Wiley & Sons Inc; 2016;chap 50.
2. Parkinson’s Disease Foundation. What is Parkinson’s disease? http://
18. DaTscan [package insert]. Arlington Heights, IL: GE Healthcare;
www.pdf.org/en/about_pd. Accessed January 19, 2016.
3. Gazewood JD, Richards DR, Clebak K. Parkinson disease: an update. Am
19. Kupsch AR, Bajaj N, Weiland F, et al. Impact of DaTscan SPECT
Fam Physician. 2013;87(4):267-273.
imaging on clinical management, diagnosis, confidence of diagnosis,
4. Pagan FL. Improving outcomes through early diagnosis of Parkinson’s
quality of life, health resource use and safety in patients with clini-
disease. Am J Manag Care. 2012;18(7 suppl):S176-S182.
cally uncertain parkinsonian syndromes: a prospective 1-year follow-
5. Cummings JL, Fine MJ, Grachev ID, et al. Effective and efficient diag-
up of an open-label controlled study. J Neurol Neurosurg Psychiatry.
nosis of parkinsonism: the role of dopamine transporter SPECT imaging
with ioflupane I-123 injection (DaTscan™). Am J Manag Care. 2014;20(5
20. Bajaj N, Hauser RA, Grachev ID. Clinical utility of dopamine trans-
porter single photon emission CT (DaT-SPECT) with (123I) ioflupane
6. Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES/ENS recommen-
in diagnosis of parkinsonian syndromes. J Neurol Neurosurg Psychiatry.
dations for the diagnosis of Parkinson’s disease. Eur J Neurol. 2013;20(1):16-34.
7. UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic
21. Miyasaki JM, Martin W, Suchowersky O, et al. Practice parameter:
initiation of treatment for Parkinson’s disease: an evidence-based review.
cgi?id=phd000042. Accessed May 12, 2015.
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POST-TEST Expiration date: August 31, 2017
Credit Designation: Albert Einstein College of Medicine designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit(s)TM. Physicians should claim only credit commensurate with the extent of their participation in the activity. A statement of credit will be issued only upon receipt of a completed pre-assessment test, polling questions, activity evaluation form, and post-test with a score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/Feb17feature. CREDITS: 0.50 | Parkinson’s disease: Making an evidence-based diagnosis
1. FJ, a 55-year-old African American male, presents to your clinic for an initial evaluation regarding his Parkinson’s disease (PD). Upon examination, you observe a significant resting tremor, postural instability, and noticeable rigidity. FJ is experiencing _______________. a. b. c. d.
Primary motor symptoms Secondary motor symptoms Early, nonmotor symptoms Other nonmotor symptoms
2. The “levodopa challenge test” is endorsed by the United Kingdom Parkinson’s Disease (UK PD) Society Brain Bank, which states that there are “excellent response” rates when using the challenge as a diagnostic technique. Which of the following guidelines do not endorse the use of the levodopa challenge test? a. 2006 American Academy of Neurology (AAN) recommendations b. 2013 AAN recommendations c. 2013 European Federation of Neurological Societies and European Section of the Movement Disorder Society (EFNS/MDS-ES) d. 2006 EFNS/MDS-ES 3. Which of the following statements is true regarding diagnostic imaging for PD? a. Magnetic resonance imaging (MRI) is superior to DaTscan for diagnosing PD. b. DaTscan imaging can assist in diagnosing PD by detecting abnormalities in dopamine transporters.
c. Positron emission tomography (PET) scans are the preferred imaging technique when diagnosing PD. d. Ultrasonography is equivalent in efficacy to DaTscan imaging technique when diagnosing PD. 4. Parkinson’s disease is often considered difficult to diagnose. However, the most widely used clinical criteria are those from the UK PD Society Brain Bank. Which of the following statements is true regarding these criteria? a. The UK PD’s guidelines address only inclusion criteria, not exclusion criteria. b. The UK PD’s guidelines address only exclusion criteria, not inclusion criteria. c. The UK PD’s clinical criteria comprise 3 steps: diagnosis of parkinsonian syndrome, exclusion criteria for PD, and supportive prospective positive criteria for PD. d. The UK PD’s clinical criteria comprise 2 steps: diagnosis of parkinsonian syndrome and supportive prospective positive criteria for PD. 5. An injection of _______________ is required prior to performing DaTscan imaging. a. Ioflupane, which is considered a controlled substance in the United States. b. Ioflupane, which is not considered a controlled substance in the United States. c. Dihydrotetrabenazine, which is considered a controlled substance in the United States. d. Dihydrotetrabenazine, which is not considered a controlled substance in the United States.
TO TAKE THE POST-TEST please go to: ClinicalAdvisor.com/Feb17feature
34 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
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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.
YOUR COMMENTS A DIFFERING OPINION ON THE ACP’S NEW DIABETES TREATMENT GUIDELINES I was terribly disappointed to read “ACP releases updated guidelines for oral pharmacologic treatment of type 2 diabetes” [page 10; with full version appearing on ClinicalAdvisor. com]. As a Fellow of the American College of Physicians, I am dismayed to see the recommendations given by the ACP. The recommendation to provide metformin in patients with type 2 diabetes “who need pharmacological therapy to improve glycemic control”—graded as strong recommendation; moderate-quality evidence—is incorrect, and it causes a disservice in treating the epidemic we have with type 2 diabetes where “clinical inertia” is so common. We know from the UK Prospective Diabetes Study and other studies that therapeutic lifestyle changes alone fail in the great majority of patients. As a result of these older studies and the NIH-sponsored Diabetes Prevention Program, the 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 firstname.lastname@example.org. 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.
American Diabetes Association recommends therapeutic lifestyle changes even in prediabetes. The recommendation of giving it only after therapeutic lifestyle changes fail is archaic and does not help improve care. The opposite is true. The second recommendation is not much better. As a second oral agent (combination therapy with metformin), the ACP recommends prescribing equally either sulfonylureas, thiazolidinediones, sodium-glucose cotransporter 2 inhibitors, or dipeptidyl peptidase 4 inhibitors. This recommendation is given even when it is well known that sulfonylureas can cause weight gain and hypoglycemia, particularly in the elderly with an increased number of hospitalizations. Also, the literature supports that sulfonylureas not only cause hypoglycemia and weight gain but also have a high rate of cardiovascular mortality when compared with other agents. Finally, the FDA’s approval of Jardiance (empagliflozin) as an agent—the only agent thus far to improve cardiovascular mortality—was not mentioned in the guidelines, and all oral agents were lumped together at the same level. I am very familiar with the article by Qaseem et al in the Annals of Internal Medicine [“Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline update from the American College of Physicians; January 3, 2017], which published these recommendations. I can criticize the studies chosen and the methodology, but this is not the place. I am also perfectly aware, as are all
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.
36 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
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.
healthcare providers and patients, of the high cost of branded medications, all insulins, and all paraphernalia necessary to treat diabetes. I want to stress the need to change the way we treat diabetes. Instead of waiting for the A1c to be high or stay high causing organ damage, “chasing” A1cs, we need to be more proactive and use pharmacotherapy and combination therapy early in the disease. Continuing a slow step-up approach, can only result in mismanagement of patients, with half of our US patient population not treated at an A1c goal of < 7%. Continuing to undertreat diabetes can only perpetuate the tremendous economic and social burden of the disease. I have published an article precisely proposing to change this paradigm [“Strategies for diabetes management: using newer oral combination therapies early in the disease. Diabetes Ther. October 31, 2016]. The ACP’s recommendations propose archaic and inappropriate approaches for management of diabetes.—JOEL ZONSZEIN, MD, CDE, FACP, FACE, Bronx, N.Y. (220-1)
KRATOM AND OXYCODONE I think that kratom is much safer than some of the FDA- and US Drug Enforcement Administration–approved medications, such as oxycodone [Alt Meds Update. “Kratom.” January 2017, page 79]. I treat patients for opioid addiction, and I have a few who have stopped using opioids and are now on a stable, individualized dose that the patient decides. I know that this takes the control away from physicians and other governmental agencies, and there is also the loss of money for some drug companies. But so far, there have been no deaths or patients who needed to go to rehabilitation from using kratom. In my opinion, kratom is safer than oxycodone and other narcotics.—ANACE SAID, MD, Wallingford, Conn. (220-2)
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.
CLINICAL PEARLS TREATING PATIENTS WITH DIABETIC PERIPHERAL NEUROPATHY I have had significant success using alpha-lipoic acid 600 mg daily in some patients with diabetic peripheral neuropathy [“Diabetic peripheral neuropathy.” December 2016, page 12].—GEORGE KRONER, PA-C, Durham, N.C. (220-3)
CASE FILES BLUE SKIN IN AN ELDERLY WOMAN Contributed by Sherril Sego, FNP-C, DNP (See photo at bottom of this page for more information about Dr. Sego.) A 70-year-old white woman presents with having a bluetinged skin discoloration for several years, which is worse in her feet and ankles. She denies any pain or pruritus, is a heavy smoker, and has multiple comorbidities and a lengthy medication list. One of her conditions is rheumatoid arthritis, for which her previous provider had been prescribing minocycline. On exam, she is obese, with a strong tobacco odor. Her skin is very dry, with +3 nonpitting edema of her feet and ankles. Pulses are intact, and there is a dark gray-blue pigmentation scattered in an irregular distribution, mostly on her feet and lower legs. Long-term use of minocycline has been associated with patchy hyperpigmentation as a result of iron deposition in the dermal cells. After consultation with a rheumatologist, the patient opted to continue this treatment since it controlled her symptoms. She was relieved to know the pigmentation changes were harmless. Pigmentation changes will fade if the drug is discontinued, but it may take months. (220-4) 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 rash on a woman who rides horses in the winter KATIE FRISBEE, PA, AND ALICIA ELAM, PHARMD
A 32-year-old white woman who has never smoked presents with pruritic, tender, erythematous, violaceous patches with eczema-like blisters on her upper, lateral thighs. In 2012, she began traveling annually from Pennsylvania to South Carolina, from January through April, where she works with and rides horses daily from morning to evening. Her symptoms began in her first year in South Carolina and appear consistently from January through March. Her lesions appear initially in mid-January as a red dot and progress by mid-February. They resolve spontaneously in March. What is your diagnosis? Turn to page 40.
A fluid-filled papule at the corner of the eye MELINDA LIU, BA, AND MAURA HOLCOMB, MD
A healthy 45-year-old woman presents with a several-month history of a small papule at the corner of her right eye. The lesion is asymptomatic and is not enlarging, but she has cosmetic concerns. She denies diplopia, vision loss, or any other lesions on her face and body. Examination reveals a domeshaped, smooth, translucent papule filled with watery fluid located below the lateral canthus of her right eye. What is your diagnosis? Turn to page 41. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • FEBRUARY 2017 39
1/26/17 11:14 AM
Dermatology Clinic CASE #1
Deep punch biopsies were performed and histologic analyses were consistent with a diagnosis of equestrian cold panniculitis, also known as equestrian perniosis (EP). EP involves inflammation of cutaneous and fatty tissue in response to exposure to cold temperatures.1,2 Although the pathogenesis and etiology of the disease is uncertain, EP can present as an idiopathic dermatosis or with an underlying autoimmune disease.1 It has been described as a cold injury that particularly affects the fatty region of the lateral thighs and hips.3 The condition was first described in 1980 by Beacham et al,4 observing young, overweight women wearing poorly insulated and tight-fitting pants during the winter while riding horses for more than 2 consecutive hours. Men do not appear to be affected by EP.5 It is a rare phenomenon observed primarily in young women who ride horses. Patients who do not ride horses and have similar symptoms are diagnosed with a localized form of vasculitis called chilblains, which usually occur on acral skin.1,3,6 Cases of chilblains have been reported in children wearing wet boots, hikers wading through rivers, cyclists, people who deliver milk, and golf cart drivers.3,6 According to Yang et al1 and Boada et al,2 all reported cases of EP found in the literature originate in regions with a cold, humid climate. Cold agglutinins were detected in two patients with EP and persisted with repeat testing over 6 months.5 High titers of cold agglutinins could attribute to the persistence of EP skin lesions.5 Cold agglutinins are immunoglobulins that are circulating in the blood and cause clumping of erythrocytes. They are thought to play a role in an underlying autoimmune hemolytic anemia that could manifest as EP. Cold agglutinins can develop from tight-fitting pants and cold temperatures (not below 0Â°C) and are attributed to declining circulation through subcutaneous fat in peripheral areas.6 Heavy smoking has also been associated with EP skin symptoms.6 Wearing tight clothing may be a contributing factor for the development of equestrian perniosis. A Finnish study found that riders who wore tight-fitting pants all day, instead of only when riding, were at risk of developing skin symptoms.6 The epidemiologic survey was performed to determine the prevalence of EP among Finnish horseback riders.6 Of the 234 questionnaires sent to members of the
Equestrian Federation of Finland, 107 were included in the analysis. There were no other known comorbidities or underlying medical conditions noted, other than the skin lesions. The coldest months of the year in Finland are October through February; one-third of the riders reported symptoms in October, with worsening presentations in January. Demographics, type of work, and skin symptoms were similar to those in the patient presented in our vignette. Results of a punch biopsy that includes subcutaneous fat can aid in confirmation of the diagnosis of EP, although clinical presentation, riding history, and location of the lesions can
Wearing tight clothing could be a contributing factor for the development of equestrian perniosis in this patient. provide a clinical diagnosis of the condition.6 Differential diagnoses should include cutaneous lupus erythematosus, cutaneous sarcoidosis, and chilblains.2 When differentiating chilblains, cutaneous lupus erythematosus, and EP, pathology results will not always confirm the diagnosis. Chilblains and EP have histologic features similar to those of cutaneous lupus erythematosus. Thus, clinical history and distribution of the skin lesions are more conclusive for diagnosis than pathology alone.1 According to Boada et al,2 histopathologic detection of perieccrine distribution in lymphocytic infiltrate is the major identification differentiating between an underlying autoimmune disorder and idiopathic etiology. Routine or expensive blood tests are often not necessary; however, an antinuclear antibody test can aid in distinguishing an underlying autoimmune disorder. Investigating cold agglutinins can contribute to ruling out vasculitis, erythema nodosum, or erythema multiforme.5,6 Treatment options include wearing warmer clothing, insulating the affected areas more efficiently, and smoking cessation.5,6 A dihydropyridine calcium channel blocker, nifedipine, is recommended for treatment but has poor evidence supporting therapeutic efficacy. Corticosteroids have been found to help alleviate symptoms; however, there is no one, simple therapy that will prevent or cure EP.6 For the patient in our case, deep punch biopsies were performed and sent to two different dermatopathologists for analysis. One biopsy report found superficial and deep perivascular and interstitial lymphocytic infiltrate, whereas the other found perivascular infiltrate composed primarily of small mononuclear cells with infiltration of vessel walls. Both
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histology explanations are consistent with the diagnosis of EP. After follow-up, the patient stated that topical corticosteroid treatment improved her pruritic symptoms; however, the outside temperature increased in the days following her appointment and she has not yet tried any insulating techniques. Katie Frisbee, PA, is a physician assistant practicing in family medicine/urgent care, and Alicia Elam, PharmD, is an associate professor in the Physician Assistant Department of Augusta University in Georgia.
Take-away points for hidrocystomas Clinical presentation
• Characterized by small, solitary, dome-shaped papules containing watery fluid • May be transparent, translucent, or bluish-black • Most commonly located on the head and neck, especially along the inner eyelid margin
• Cystic pleomorphic adenomas, Warthin tumors, cystadenomas, mucoepidermoid carcinoma, mucous retention cysts, basal cell carcinomas, melanomas, sclerosing polycystic adenosis
• Diagnosed clinically, but confirmed histologically • Histologic features of apocrine hidrocystomas include a cyst lined by a double layer of epithelial cells: an outer layer of myoepithelial cells and an inner layer demonstrating decapitation secretion • Histologic features of eccrine hidrocystomas include a unilocular cyst composed of one or two layers of cuboidal cells lacking papillary projections
• Simple needle puncture for singular hidrocystomas • Electrodessication and carbon dioxide laser vaporization for multiple hidrocystomas • Lesions do not spontaneously resolve
References 1. Yang AY, Schwartz L, Divers AK, Sternberg L, Lee JB. Equestrian chilblain: another outdoor recreational hazard. J Cutan Pathol. 2013;40:485-490. 2. Boada A, Bielsa I, Fernández-Figueras MT, Ferrándiz C. Perniosis: clinical and histopathological analysis. Am J Dermatopathol. 2010;32:19-23. 3. Weismann K, Larsen FG. Pernio of the hips in young girls wearing tightfitting jeans with a low waistband. Acta Derm Venereol. 2006;86:558-559. 4. Beacham BE, Cooper PH, Buchanan CS, Weary PE. Equestrian cold panniculitis in women. Arch Dermatol. 1980;116:1025-1027. 5. De Silva BD, McLaren K, Doherty VR. Equestrian perniosis associated with cold agglutinins: a novel finding. Clin Exp Dermatol. 2000;25:285-288. 6. Pekki A, Sauni R, Vaalasti A, Toivio P, Huotari-Orava R, Hasan T. Cold panniculitis in Finnish horse riders. Acta Derm Venereol. 2011;91:463-464.
Hidrocystomas (HCs) are benign, cystic, tumor-like lesions presenting as translucent nodules.1,2 HCs are classified into two major subtypes depending on their origin: eccrine or apocrine sweat gland ducts. These lesions occur predominantly in adults aged between 30 and 75 years, and they affect both sexes equally.1-4 They grow slowly, persist indefinitely, and do not exhibit familial inheritance patterns.4 Although the exact pathogenesis of adult-onset HC is unclear, it is hypothesized that occlusion of the sweat duct apparatus results in sweat retention and a dilated cystic structure.1,2,4 Clinically, eccrine and apocrine HCs present similarly as solitary dome-shaped papules containing watery fluid.4-6 These nodules may be translucent, transparent, or
bluish-black, due to the Tyndall phenomenon.6 Lesions most commonly occur along the inner canthus of the eyelid margin, as well as other locations on the head and neck containing sweat glands.1,4-6 In rare cases, HCs may also occur on the chest, shoulder, axillae, groin, and nipple.4,6 Although HCs are usually solitary, they may also occur in groups and are occasionally associated with inherited syndromes.4,6 Multiple apocrine HCs of the eyelids are associated with Schöpf-Schulz-Passarge syndrome, an autosomal recessive condition causing palmoplantar hyperkeratosis, hypodontia, and hypotrichosis.4,6 Multiple periocular apocrine HCs are also associated with the X-linked dominant condition Goltz-Gorlin syndrome (also known as focal dermal hypoplasia), which causes microcephaly, midfacial hypoplasia, malformed ears, papillomas of the lips, tongue, axilla, and anus, skeletal abnormalities, and mental retardation.4,6 Diagnosis of HC is clinical; however, biopsy results aid confirmation and are required to distinguish between the apocrine and eccrine subtypes.4 Decapitation secretion is the hallmark of apocrine HCs.1,6 Histologically, apocrine HCs appear as large unilocular or multilocular cystic spaces in the dermis with a double lining of epithelium.2,3,6 The lining consists of a double layer of epithelial cells.2,3,6 The outer layer consists of flattened myoepithelial cells and the inner layer consists of tall columnar to cuboidal cells with eosinophilic cytoplasm and round or oval vesicular nuclei at
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“You and your ‘Let’s send a comic valentine to the I.R.S. and sign our names’!”
Melinda Liu, BA, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston. References 1. Mukherjee B, Desai A, Krishnakumar S, Biswas J. A giant apocrine hidrocystoma presenting as lacrimal gland mass. Orbit. 2015;34:342-344. 2. Kikuchi K, Fukunaga S, Inoue H, Miyazaki Y, Ide F, Kusama K. Apocrine hidrocystoma of the lower lip: a case report and literature review. Head Neck Pathol. 2014;8:117-121. 3. Sarabi K, Khachemoune A. Hidrocystomas—a brief review. MedGenMed. 2006;8(3):57. 4. Ovhal AG, Deshkulakarani SV, Abhange RS, Birare SD. Rare benign cystic lesions on face: apocrine hidrocystoma. Indian J Dermatol. 2016;61:237. 5. Behshad S, Weil NC, Ho ST, Mayhall GK, Valenzuela AA. A cyst you can’t miss: a rare presentation of an orbital apocrine hidrocystoma. Orbit. 2015;34(4):229-231. 6. Verma SB. Multiple apocrine hidrocystomas: a confusing clinical diagnosis. An Bras Dermatol. 2010;85:260-263.
“I can see why they made February the shortest month of the year.”
Top, middle: © Harley Schwadron; Bottom: © The New Yorker Collection 2017 from cartoonbank.com. All Rights Reserved.
the base.2,3,6 Periodic acid–Schiff-positive granules may be seen in the cytoplasm of the inner lining.3,6 Approximately 50% of apocrine HCs have small papillary projections growing into the central cavity.3,6 In contrast, eccrine HCs appear as unilocular cysts composed of one to two layers of cuboidal cells and lack papillary projections.5 The differential diagnosis includes lesions that may appear similar clinically but lack the apocrine-like secretory epithelium.2 These include cystic pleomorphic adenomas, Warthin tumors, cystadenomas and cystadenocarcinomas, mucoepidermoid carcinoma, and mucous retention cysts.2 HCs may also be difficult to distinguish from basal cell carcinomas and melanomas and may require biopsy.2,3 Sclerosing polycystic adenosis may appear histomorphologically similar to apocrine HCs, but lesions of sclerosing polycystic adenosis are differentiated by their classic histologic features of nodular sclerosis and xanthomatous infiltrate.2 The most common approach to treatment of HCs consists of a simple needle puncture.4,6 However, patients with multiple lesions do not respond well to this treatment and lesions often recur after several weeks.3,6 In these cases, electrodessication is an effective treatment.6 Providers may also prescribe topical 1% atropine; however, the anticholinergic side effects may be unacceptable.4,6 Other potentially successful therapies include carbon dioxide laser vaporization and trichloroacetic acid application.4 In our case, the patient had a single HC and desired quick resolution. She was successfully treated with a simple needle puncture. n
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Dermatologic Look-Alikes A rash on the chest and back EMILY GUO, BA, AND RANA MAYS, MD
A 52-year-old white man with a history of hypertension and diabetes presents with an intermittent, ongoing blistering rash on his chest and back that has persisted for more than 3 years. The patient reports that the rash was sometimes irritated and painful, and he denies pruritus. He had tried over-the-counter antifungal creams for several months with no improvement. On examination, he has no oral ulcers or lesions. He denies history of any skin cancer.
An otherwise healthy 54-year-old white man presents with a 2-year history of an intermittent plaques on his chest and back that worsened with sun exposure. He denies any pruritus, pain, or irritation, but he says that the rash is worsening. The patient has no history of medical problems or allergies, takes no medications, and reports tobacco use at 1 pack per day. He has tried applying over-the-counter topical steroids for 2 weeks without improvement.
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Dermatologic Look-Alikes CASE #1
Pemphigus vulgaris (PV) is an autoimmune blistering disease involving the skin and mucous membranes. A high incidence of PV has been observed in Ashkenazi Jewish patients and those of Mediterranean ancestry, an observation that has been strongly related to the human leukocyte antigen (HLA) classes HLA-DRB1*04 and HLA-A*10.1 PV occurs more commonly in women, and the average age of onset of the disease in the United States is between 50 and 70 years.2 The incidence of PV increases with age, especially in women, likely due to altered immune regulation with aging.1 In the majority of patients with PV, oral lesions are present when the disease initially manifests.3,4 Skin lesions typically occur either at the same time as oral lesions or within several months.4 The primary skin lesion of PV is a flaccid blister that is fragile and breaks easily, leaving denuded areas of varying size. The erosions can be large and crusted, and they tend to spread at their periphery.2 Nikolsky sign, which occurs when lateral pressure is applied to the edge of a blister, resulting in separation of the epidermis, is characteristic of PV.2,3 Nikolsky sign can also be elicited in staphylococcal scalded skin syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Asboe-Hansen sign is also common and is produced when pressure is applied directly over an intact blister, resulting in lateral spread.3 Symptoms of the lesions include pruritus and pain. PV lesions typically heal without scarring; however, transient postinflammatory hyperpigmentation is common and usually resolves with time.3 Common sites of involvement include the scalp, face, axilla, and oral cavity.3 PV is characterized by immunoglobulin G (IgG) antibodies that target desmogleins, cell-to-cell adhesion glycoproteins found in desmosomes. Patients with mucosal-dominant PV typically only have autoantibodies to desmoglein 3, whereas patients with mucocutaneous PV have autoantibodies to both desmoglein 1 and 3.5 Enzyme-linked immunosorbent assay can be performed to detect these autoantibodies to desmoglein. In PV, cleavage occurs in the stratum spinosum of the epithelium, and the basement membrane remains intact.4 The histopathologic hallmark of the disease is acantholysis, or loss of epidermal cell cohesion, resulting in formation of suprabasal intraepidermal bullae.2,3 The basal epidermal
cells may split from each other but remain attached to the basement membrane, appearing as a “row of tombstones.”3 Direct immunofluorescence (DIF) for PV shows IgG bound to the cell surface of keratinocytes in a net-like pattern. The biopsy for DIF when suspecting PV should be performed on normal-appearing perilesional skin.2 Other clinical variations of pemphigus include pemphigus foliaceus, pemphigus erythematosus, and drug-induced pemphigus. Pemphigus foliaceus manifests as superficial scaly and crusted shallow erosions on the skin without oral involvement.2,3 Pemphigus foliaceus is characterized by autoantibodies to desmoglein 1, resulting in subcorneal acantholytic blisters with intercellular deposits of IgG located predominantly in the superficial epidermal layers.3,5 Brazilian pemphigus foliaceus is a variant that is endemic in rural areas of South America, most commonly Brazil. This disease is most common in children, adolescents, and young adults. It is histologically and immunopathologically indistinguishable from pemphigus foliaceus but is theorized to be the result of an insect-vectored virus.3 Pemphigus erythematosus (or Senear-Usher syndrome) is characterized by erythematous hyperkeratotic lesions over the nose, malar area, upper back, chest, and intertriginous areas without oral involvement.2,3 Its histology is identical to pemphigus foliaceus but has immunopathologic features of both pemphigus and lupus erythematosus.3 Drug-induced pemphigus has been reported to occur most significantly with penicillamine use, but it has also been reported with penicillin, captopril, rifampin, and phenobarbital use.2,3 The primary treatment of PV is immunosuppression. Systemic corticosteroids have historically been the mainstay of treatment, resulting in a dramatic reduction in mortality.3,6,7 However, due to the significant side effects of long-term corticosteroid use, adjunctive nonsteroidal immunosuppressive therapies such as azathioprine, cyclophosphamide, methotrexate, cyclosporine, mycophenolate mofetil, and dapsone are used, as well as intravenous immunoglobulin, plasmapheresis, immunoadsorption, and rituximab.6,7 Most PV deaths now result from side effects of immunosuppressive agents rather than the disease or its sequelae.6,7 Topical steroids may also be used for local effects on PV lesions. For the patient in our case, a 4-mm punch biopsy was performed and sent for hematoxylin and eosin staining, as well as DIF. The biopsy and DIF results were consistent with PV. Oral prednisone was initiated at 20 mg/d, as was topical steroids. The rash resolved in 1 month. The patient was subsequently tapered off of the oral steroids, and ultimately, his condition was well-controlled on topical steroid therapy.
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Tumid lupus erythematosus
Tumid lupus e rythematosus (TLE) is a rare subset of chronic cutaneous lupus erythematosus. TLE was first reported by Hoffman in 1909 at a meeting of the Berlin Dermatological Society during which he reported on two patients with edematous, indurated, facial lesions, with minimal to absent surface changes, which he called “lupus erythematosus tumidus.”8 Similar lesions were again described in two patients in 1930 by Gougerot and Burnier9 using the term “lupus érythémateux tumidus.” Since then, there has been an increase in reports and recognition of TLE; however, there is still confusion in the literature regarding differentiation of TLE from other cutaneous disorders that manifest in a similar clinical and histologic manner.10-12
TLE occurs with less frequency than the other forms of cutaneous lupus; as such, the precise epidemiologic data for the disease is difficult to determine.13 Several small case series have reported that TLE occurs primarily in young women.14,15 A larger study of 40 patients by Kuhn et al12 showed that TLE occurs slightly more often in men than women (55% vs 45%, respectively), with a mean age of onset of 36 years. The mean time from onset of disease to diagnosis is approximately 5 years, and the mean duration of the disease is approximately 8 years.12 Inappropriate activation of the innate immune mechanisms is thought to play an important role in lupus erythematosus, especially type I interferons.11 TLE appears clinically as smooth, shiny erythematous and edematous nonscarring plaques. Typically, the lesions are without surface changes such as follicular plugging, atrophy, or scale.10,12,13 Like other forms of cutaneous lupus erythematosus, photosensitivity is a prominent exacerbating factor. The lesions of TLE involve sun-exposed areas of skin, characteristically the face and neck.12 Onset typically occurs in the summer due to sun exposure.12 In some cases, the skin
A comparison of pemphigus vulgaris and tumid lupus erythematosus Pemphigus vulgaris
Tumid lupus erythematosus
• Fragile flaccid blisters resulting in erosions of varying size • Positive Nikolsky sign, positive Asboe-Hansen sign
• Smooth, shiny erythematous and edematous plaques • Nonscarring • No surface changes
• High incidence in Ashkenazi Jewish patients and those of Mediterranean ancestry • More common in women with average age of onset between 50 and 70 years
• Imprecisely defined in the literature due to confusion in differentiating TLE from other cutaneous disorders
• Autoimmune due to IgG antibodies targeting desmogleins 1 and 3
• Inappropriate activation of innate immune mechanisms • No clear characteristic autoantibodies
• Oral cavity, scalp, face, and axillae
• Sun-exposed areas of skin, such as the face and neck
• Acantholysis resulting in suprabasal intraepidermal blisters • “Row of tombstones” appearance of basal epidermal cells • Diffuse immunofluorescence shows IgG bound to cell surface of keratinocytes in a net-like pattern
• Superficial and deep perivascular and periadnexal lymphocytic infiltration • Abundant mucin deposition in the reticular dermis • Minimal to no epidermal or dermoepidermal involvement
• Biopsy for H&E and diffuse immunofluorescence • ELISA for desmoglein 1 and 3 autoantibodies
• Clinical features with confirmation by histopathology
• Systemic corticosteroids • Topical corticosteroids • Non-steroidal adjuvant therapies • IVIG • Plasmapheresis • Immunoadsorption • Rituximab
• Antimalarial agents such as hydroxychloroquine • Topical corticosteroids • Lesions may disappear spontaneously but can reoccur in the original distribution
ELISA, enzyme-linked immunosorbent assay; H&E, hematoxylin and eosin; IgG, immunoglobulin G; IVIG, intravenous immunoglobulin; TLE, tumid lupus erythematosus
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Dermatologic Look-Alikes lesions of TLE may coalesce in the periphery, resulting in a gyrate or annular configuration.12,14,15 Lesions can disappear spontaneously, even if the disease is chronic, with recurrence occurring in the original distribution.12,13,15 In a study by Alexiades-Armenakas et al,10 antinuclear antibodies were detected in a speckled pattern in five of 11 cases (46%) of TLE that were evaluated serologically, in titers ranging from 1:40 to 1:160. Anti–double-stranded DNA, anticentromere, anti-Sm, anti-Ro/SSA, anti-La/SSB, and anti-RNP antibodies have all been reported in the literature to be negative for TLE.10,14 Histologic features of TLE include superficial and deep perivascular and periadnexal lymphocytic infiltration, and abundant mucin deposition in the reticular dermis.10,12,13,15 Unlike classic lupus erythematosus, there is minimal to no epidermal or dermoepidermal involvement in TLE.14 The constellation of clinical findings with histopathologic presentation permits a specific diagnosis of TLE.12,15
Treatment of TLE includes systemic therapy with antimalarial agents such as hydroxychloroquine.10,12 Topical corticosteroids can also be used on TLE lesions for local effects.12 A biopsy was performed in our patient and results were consistent with TLE. Our patient was started on oral hydroxychloroquine, 200 mg twice daily. He was counseled on the importance of tobacco cessation and sun avoidance. At our patient’s 1-month follow-up appointment, his TLE lesions were significantly improved. n Emily Guo, BA, is a medical student and Rana Mays, MD, is a dermatology resident at Baylor College of Medicine in Houston. References 1. Kridin K, Zelber-Sagi S, Khamaisi M, Cohen AD, Bergman R. Remarkable differences in the epidemiology of pemphigus among two ethnic populations in the same geographic region. J Am Acad Dermatol. 2016;75:925-930. 2. Payne AS, Stanley JR. Pemphigus. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, eds. Fitzpatrick's Dermatology in General
Treatment of tumid lupus erythematosus includes systemic therapy with antimalarial agents such as hydroxychloroquine.
Medicine. 8th ed. New York, NY: McGraw-Hill; 2012:586-599. 3. Korman N. Pemphigus. J Am Acad Dermatol. 1988;18:1219-1238. 4. Eversole LR, Kenney EB, Sabes WR. Oral lesions as the initial sign in pemphigus vulgaris. Oral Surg Oral Med Oral Pathol. 1972;33:354-361. 5. Amagai M, Tsunoda K, Zillikens D, Nagai T, Nishikawa T. The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. J Am Acad Dermatol. 1999;40:167-170.
Immunohistochemical findings for TLE show predominantly T lymphocytes, typically with a CD4:CD8 ratio greater than 2:1.10 Results of direct immunofluorescence in TLE are typically negative at the dermoepidermal junction or around the papillary and reticular dermal blood vessels.12 The differential diagnosis for TLE includes Jessner lymphocytic infiltrate, discoid lupus erythematosus, systemic lupus erythematosus, reticular erythematous mucinosis, polymorphous light eruption, deep gyrate erythema, granuloma annulare, and pseudolymphoma.12-14 In particular, Jessner lymphocytic infiltrate may be indistinguishable from TLE and has been theorized by Dekle et al13 to possibly represent a spectrum of the same disease. TLE can be distinguished from DLE by its lack of follicular plugging and clearance without scarring.13 REM has also been considered by some authors to be a variant of TLE or DLE, given the photosensitive nature of lesions and the efficacy of antimalarial agents in treatment; however, the lesions of REM typically occur on the central chest or back.12 PMLE can be differentiated from TLE based on its lack of mucin deposition and predominance of CD8 over CD4 lymphocytes, as opposed to TLE, which demonstrates interstitial mucin deposition and CD4 predominance.10
6. Sinha AA, Hoffman MB, Janicke EC. Pemphigus vulgaris: approach to treatment. Eur J Dermatol. 2015;25:103-113. 7. Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med. 2006;355:1772-1779. 8. Hoffman E. [Isolierter Lupus erythematosus tumidus der Gesichtshaut]. Derm Zeitschr. 1909;16:159-160. 9. Gougerot H, Burnier M. [Lupus érythémateux tumidus]. Bull Soc Fr Dermatol Syphiligr. 1930;37:1291-1292. 10. Alexiades-Armenakas MR, Baldassano M, Bince B, et al. Tumid lupus erythematosus: criteria for classification with immunohistochemical analysis. Arthritis Rheum. 2003;49:494-500. 11. Maize JC Jr, Costner M. Tumid lupus erythematosus: a form of lupus erythematosus. Arch Dermatol. 2010;146:451. 12. Kuhn A, Richter-Hintz D, Oslislo C, et al. Lupus erythematosus tumidus—a neglected subset of cutaneous Lupus erythematosus: report of 40 cases. Arch Dermatol. 2000;136:1033-1041. 13. Dekle CL, Mannes KD, Davis LS, Sangueza OP. Lupus tumidus. J Am Acad Dermatol. 1999;41:250-253. 14. Hsu S, Hwang LY, Ruiz H.Tumid lupus erythematosus. Cutis. 2002;69:227-230. 15. Ruiz H, Sánchez JL. Tumid lupus erythematosus. Am J Dermatopathol. 1999;21:356-360.
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Case Study | WOMEN’S HEALTH HISTORY
Abnormal Pap test follow-up in a 30-year-old woman The patient had her first abnormal Pap test at the age of 23. DENISE LINTON, DNS, FNP-BC; RACHEL ELLISON, PhD
THE CASE Ms Y, a 30-year-old Caucasian, is self-referred for an annual examination. She reports a history of abnormal Pap test results and wants to establish care with a provider in the city to which she has relocated. She has no other complaints.
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Ms Y started undergoing annual Pap tests prior to her 18th birthday. She reports that her mother also came to her appointments because of her history of dysmenorrhea. Ms Y’s first menses (menarche) was at age 12; menses was every 28 days, 5- to 7-day duration, with moderate cramping, and heavy, light, or normal bleeding. Ms Y’s first sexual experience was at age 21, she has had 8 lifetime partners, and she has never been pregnant. Her first abnormal Pap test was performed by her previous provider in 2007 when she was 23 years old. The result was atypical squamous cells of undetermined significance (ASCUS) and positive for human papillomavirus (HPV). A colposcopy was performed, and her provider at that time recommended against the cervical cancer vaccine because she was already HPV-positive. Socially, Ms Y has never smoked, does not use drugs, drinks 5 cups of caffeinated beverages per day, and has 1 or 2 alcoholic drinks per month. Ms Y reports a surgical history related to abnormal Pap test results that include multiple colposcopies with biopsy, cryocautery of the cervix, and loop electrical excision procedure (LEEP). She has a history of migraine and herpes simplex virus, has no known allergies, and takes the following medications: Excedrin Migraine as needed for migraine headache, Lutera (28) once per day for contraception, and valacyclovir 500 mg for herpes. There is no family history of gynecologic cancer, but her father and paternal grandmother have type 2 diabetes.
PHYSICAL EXAMINATION Ms Y’s initial vital signs are: blood pressure 112/79 mm Hg, heart rate 76 beats per minute, and body mass index (BMI) 27.76. Physical examination of the neck, chest, breasts, and skin, as well as the cardiovascular, gastrointestinal, genitourinary, neurologic, and psychiatric areas and systems, is negative.
EVALUATION AND TESTS
Based on Ms Y’s history of abnormal Pap test results, a repeat Pap test with HPV testing was performed. In addition, she was screened for sexually transmitted infections. The Pap test result was high-grade squamous intraepithelial lesion (HSIL), whereas HPV high-risk, chlamydia, and gonorrhea tests were negative. A colposcopy with biopsy and endocervical curettage were performed within 3 weeks. Ms Y’s evaluation and results are shown in Table 1. The specimen type for her Pap tests was Thin Prep, and the statement of adequacy for her Pap tests was “satisfactory for interpretation. Endocervical cells/transformation zone component present.” Because her result was low-grade SIL and high-grade SIL could not be ruled out, the pathologist recommended “repeat cytology testing in 6 months.” A decision was made by her current provider to repeat cytology in 3 months instead of 6 months due to the result of “high-grade SIL could not be ruled out.” The cytology result was high-risk HPV-positive.
OUTCOME Ms Y’s most recent Pap test result, performed 7 months after the LEEP, was normal and negative for HPV. Her next follow-up for cervical cancer screening with the Pap test was scheduled for November 2016, a year after her last Pap test. TABLE 1. Evaluation and results with current provider Date
Atypical squamous cells of undetermined significance
Positive high-risk HPV
Loop electrical excision procedure
Negative high-risk HPV
Practitioners who provide healthcare services to women should be knowledgeable about the Pap test and follow-up of abnormal results. Unfortunately, there are misconceptions and a lack of knowledge among patients about the follow-up of abnormal Pap test results. Ms Y kept all of her appointments, yet she reported, “I felt uneasy about the whole thing … I felt as though I did not know enough about what was going on.” Ms Y thought the Pap test was used “to check for diseases” and “I did not know that there were guidelines to follow.” The following sections will discuss current evidencebased guidelines regarding cervical cancer screening, cervical cancer vaccines, and the follow-up of abnormal Pap test results. Cervical cancer screening. Cervical cancer screening with the Pap test is only effective if precancerous lesions are treated before they progress to cervical cancer.1 Prior to 2012, the consensus was that providers should perform an initial Pap test in women who are 18 years old or at least 3 years after their first sexual experience.2,3 The guidelines were subsequently changed, and the current recommendation is that cervical cancer screening with the Pap test alone should begin at 21 years of age and continue to 29 years of age.1,4,5 Women who are aged 30 and older (up to 65 years of age) should obtain a Pap test along with HPV testing.1,4,5 Generally, HPV testing should not occur in women who are younger since HPV is prevalent among them and they tend to clear the virus before it causes changes to the cervix and cervical cancer. Aggressive treatment of HPV-positive results in women younger than age 30 is avoided, as is subsequent cervical insufficiency and the delivery of preterm babies.5 Cervical cancer vaccine. Gardasil 9 is the most recent HPV vaccine that prevents disease associated with HPV.6 It is a 9-valent vaccine that prevents genital warts due to HPV types 6 and 11 and cervical, vulvar, vaginal, and anal cancers due to HPV types 16, 18, 31, 33, 45, 52, and 58. Gardasil 9 was approved by the FDA for females aged 9 to 26 years and males aged 9 to 15 years.6 The recommended age for routine vaccination is 11 and 12, and providers can make the decision if the vaccine is appropriate at the ages of 9 and 10.6,7 Gardasil 9 is given in 3 intramuscular doses; the first dose is administered during the recommended age.6 The second dose is given 1 to 2 months after the first dose, and the third and final dose is given 6 months after the first dose.6 Recently, after reviewing numerous studies, the CDC approved a 2-dose vaccine regimen for preteens who are 11 to 12 years of age.8 It was found that a 2-dose vaccine regimen produced the Continues on page 56
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Case Study TABLE 2. Organizational resources Organizations
References 1. American Cancer Society. Cancer facts & figures 2016. Available at: http://www.cancer.org/acs/groups/content/@research/documents/ document/acspc-047079.pdf 2. American Cancer Society. Cancer facts & figures 2009. Available at: www.cancer.org/acs/groups/content/@nho/documents/document/
3. US Preventive Services Task Force. 2014. The guide to clinical preven-
tive services: Screening for cervical cancer. Publication No. 06-0588. Available at: https://www.ahrq.gov/professionals/clinicians-providers/ guidelines-recommendations/guide/section2a.html#Cervical
same or higher immune response as a 3-dose vaccine.8 The most common adverse effects are pain, swelling, and redness at the injection site, as well as headaches.6 Abnormal Pap test results. The American Society for Colposcopy and Cervical Pathology (ASCCP) (2014) provides evidence-based guidelines for the management of abnormal Pap test results.7 Recommendation for the follow-up of abnormal Pap test (cytology) results differs according to the results of HPV and cytology testing. For example, HPV and cytology (co-testing) screening for women aged 30 and older is recommended every 5 years.4,7 Additional information can be obtained from the organizational resources that are shown in Table 2.
4. Cervical cancer screening. The American Congress of Obstetricians and Gynecologists. Available at: http://www.acog.org/Patients/FAQs/ Cervical-Cancer-Screening 5. US Preventive Services Task Force. Final recommendation statement: cervical cancer: screening. Available at: http://www. uspreventiveservicestaskforce.org/Page/Document/ RecommendationStatementFinal/cervical-cancer-screening 6. FDA. FDA approves Gardasil 9 for prevention of certain cancers caused by five additional types of HPV. Available at: http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm426485.htm 7. American Society for Colposcopy and Cervical Pathology. Algorithms: Updated consensus guidelines for managing abnormal cervical cancer screening tests and cancer precursors. Available at: http://www.asccp.org/ asccp-guidelines 8. CDC Newsroom. CDC recommends only two HPV shots for younger adolescents. Available at: https://www.cdc.gov/media/releases/2016/ p1020-hpv-shots.html
Denise Linton, DNS, FNP-BC, is an associate professor and nurse practitioner coordinator, and Rachel Ellison, PhD, is an assistant professor at the University of Louisiana at Lafayette, College of Nursing and Allied Health Professions. 56 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
“He’s out jogging.”
© Harley Schwadron
Ms. Y’s most recent treatment plan was accurate according to the ASCCP guidelines, but one important step was missed in her previous treatment. She could have received the HPV vaccination at age 23, regardless of her diagnosis of HPV. Advancements in technology and medicine have made it easier for practitioners to stay current with the most upto-date guidelines and recommendations for abnormal Pap tests and HPV diagnosis. The ASCCP developed a mobile app for providers to have the most current guidelines at their fingertips. The app is user friendly and has the updated consensus guidelines for managing abnormal Pap test results and cancer precursors. Recommendations and algorithms can be viewed following client data entry with a few simple keystrokes. The newest HPV vaccination, Gardasil 9, is on the market and helps prevent cervical cancer. Guidelines, technology, and advanced medicine make it possible for practitioners to provide quality care to clients such as Ms Y. ■
Evidence-Based Medicine This department uses the best available scientific findings to offer practice guidance on a wide range of conditions seen in primary care.The author, Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Mass., and assistant clinical professor in Family Medicine, University of Massachusetts Medical School in Worcester. DynaMed (www.ebscohost.com/dynamed/) is a database that provides evidence-based infor- mation on more than 3,000 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.The most important evidence identified is summarized here.
REGULAR PROTON PUMP INHIBITOR USE ASSOCIATED WITH AN INCREASED RISK OF DEMENTIA IN THE ELDERLY Level 2 [mid-level] evidence Proton pump inhibitors (PPIs) are commonly used to treat gastroesophageal reflux disease (GERD) and peptic ulcer disease. PPIs are widely available as both prescription and over-the-counter medications, and their use has been steadily increasing in certain populations, especially the elderly. However, a growing body of evidence has found an increased risk of adverse effects associated with use of PPIs, including bone fractures, cardiovascular events, acute nephritis and infection, and mortality. Recently, a large observational study from Germany examined whether long-term prescription PPI use was associated with an increased risk of dementia in the elderly (Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016;73:410-416). Medical records of 73,679 persons aged 75 years or older without dementia were reviewed. Of these, 2,950 persons (4%) were taking regular PPI medication, defined as at least 1 PPI prescription in each quarter of an 18-month interval. The data was adjusted for confounding factors including age, sex, polypharmacy (≥5 prescription medications besides PPI), stroke, depression, ischemic heart disease, and diabetes. Overall, 40% of the study population developed dementia. Compared to no PPI use, regular PPI use was associated with an increased risk of incident dementia (adjusted hazard ratio, 1.44; 95% confidence interval [CI], 1.36-1.52). These results were consistent in subgroup analyses of women and men, and subgroup analyses by
Regular proton pump inhibitor use in the elderly was associated with an increased risk of incident dementia (adjusted hazard ratio, 1.44), compared with no proton pump inhibitor use, according to researchers.
age found the risk of dementia with PPI use decreased with increasing age. The findings of this study suggest that regular PPI use by the elderly may be associated with an increased risk of dementia. This study agrees with previous findings from another German longitudinal study in elderly patients that found an increased risk of dementia with PPI use (Haenisch B, von Holt K, Wiese B, et al. Risk of dementia in elderly patients with the use of proton pump inhibitors. Eur Arch Psychiatry Clin Neurosci. 2015;265:419-428). Several limitations should be considered when interpreting this study. First, it is not clear whether there were persons taking over-the-counter PPIs. Second, the APOE4 allele status and educational level of the persons in the study were not known, and these factors could also potentially influence the magnitude of risk. Finally, baseline rates of mild cognitive impairment, a major risk factor for dementia, were not assessed. While this study is not conclusive, it is one more reason to routinely review whether elderly patients taking PPIs need to continue them. Stopping unnecessary PPIs may save money and decrease harms.
ANTENATAL STEROIDS MAY IMPROVE RESPIRATORY OUTCOMES FOR LATE PRETERM BIRTHS Level 1 [likely reliable] evidence The American Congress of Obstetricians and Gynecologists (ACOG) recommends a single The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).
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© EDDIE LAWRENCE / SCIENCE SOURCE
Use of betamethasone in pregnant women may decrease the rate of respiratory complications in late preterm infants.
course of antenatal corticosteroid in pregnant women between 24 and 34 weeks gestation who are at risk of preterm delivery within 7 days (Practice bulletin no. 159 summary: management of preterm labor. Obstet Gynecol. 2016;127:190-191). This intervention has been shown to reduce neonatal mortality and respiratory distress syndrome of the newborn (Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006;:CD004454; Sotiriadis A, Tsiami A, Papatheodorou S, Baschat AA, Sarafidis K, Makrydimas G. Neurodevelopmental outcome after a single course of antenatal steroids in children born preterm: a systematic review and meta-analysis. Obstet Gynecol. 2015;125:1385-1396). While late preterm birth is also associated with increased morbidity and mortality compared to term birth, the fetal lungs have already matured in most cases. The data on antenatal corticosteroid use in pregnant women at 34 to 37 week gestation at high risk of preterm delivery are limited and inconsistent. To further investigate the effects of antenatal corticosteroids on late preterm neonates, the researchers randomized 2,831 women with singleton pregnancy between 34 and 36 5/7 weeks gestation at high risk of late preterm delivery to receive 12 mg of betamethasone or placebo intramuscularly, with 2 doses administered 24 hours apart (Gyamfi-Bannerman C, Thom EA, Blackwell SC, et al. Antenatal betamethasone for women at risk for late preterm delivery. N Engl J Med. 2016;374:1311-1320). Only 59.6% of the women (1,686) received both doses of trial medication, as 38.3% (1,083 women) delivered within
24 hours of the first dose. The primary outcome was a composite of the need for respiratory support, stillbirth, or neonatal death within 72 hours of delivery. Respiratory support ranged from high-flow supplemental oxygen to mechanical ventilation and extracorporeal membrane oxygenation. Severe respiratory complications, which included longer periods of respiratory support, were also evaluated. There were no stillbirths or neonatal deaths within 72 hours. Compared with placebo, betamethasone significantly reduced the rates of the primary outcome (11.6% vs 14.4%; P =.02; number needed to treat [NNT], 36) and severe respiratory complications (8.1% vs 12.1%; P <.001; NNT, 25), according to the study authors. Betamethasone was also associated with a significantly reduced need for resuscitation at birth, surfactant use, transient tachypnea of the newborn, and bronchopulmonary dysplasia. No significant differences were observed in mechanical ventilation, respiratory distress syndrome, apnea, pneumonia, neonatal sepsis, or maternal outcomes. However, hypoglycemia was significantly increased in the betamethasone group, compared to placebo (24% vs 15%; P <.001; NNT, 12). The current trial is the largest and most extensive trial to evaluate antenatal corticosteroids in pregnant women at high risk of late preterm birth to date. The need for respiratory support as well as severe respiratory complications, transient tachypnea of the newborn, and bronchopulmonary dysplasia were all significantly reduced with 1 to 2 doses of betamethasone before birth. The improvement in the primary respiratory outcome is due to differences in need for high-flow nasal cannula and continuous positive airway pressure rather than differences in more invasive interventions such as mechanical ventilation. However, even a few hours of supplemental oxygen can interfere with the initial maternal-infant bonding, and the significance of this was not assessed in this trial. Although the rate of hypoglycemia was significantly increased in the betamethasone group, no adverse events related to hypoglycemia were reported, and there was no increase in the length of hospitalization in neonates with hypoglycemia. Overall, the decreased rate of respiratory complications with betamethasone suggests that this intervention may improve the respiratory status in late preterm infants, even if there is no difference in rates of respiratory distress syndrome. Long-term follow-up will show whether this treatment will have an effect on chronic lung conditions. n
58 THE CLINICAL ADVISOR • FEBRUARY 2017• www.ClinicalAdvisor.com
LEGAL ADVISOR CASE
The frivolous lawsuit
ANN W. LATNER, JD
Mr B was a 46-year-old nurse practitioner working in the busy emergency department (ED) of a hospital. He had been working in the ED for more than a decade, and he was used to the fast-paced environment and the need to triage and assess patients quickly and accurately. Some shifts were worse than others. One weekend, Mr B was stuck doing a Saturday night shift, which was one of the worst in his opinion. The ED was crammed with patients in varying degrees of distress, waiting to be seen. Mr B and the rest of the ED staff were working as fast as possible to make sure that all the patients were treated. One of the patients in the ED that night was Mrs P, aged 63 years. She was initially assessed by one of the triage nurses who told Mr B that the patient came in complaining of a burned mouth and throat, but after examination, only had a sore throat that appeared mildly red. “But she’s saying that her mouth and throat were horribly burned by some unidentified perpetrator and she wants us to report her injuries,” said the nurse, shaking her head. “She’s
A healthcare provider is sued when a patient is determined to believe that she has more than a sore throat.
Hospitals are required to conduct an examination that is reasonably calculated to identify a patient’s critical medical condition.
saying she wants to see a specialist, but I don’t see anything wrong with her other than the sore throat. I think she’s a little … off.” Mr B thanked the triage nurse, and he began taking care of the patients with more urgent needs. Several hours later, Mrs P, was ushered into the examination room. She immediately began a litany of complaints. “Why was I sitting here for so long? It’s been four hours! My mouth is on fire! My pain is a 9 out of 10! Where is the doctor?” the patient complained. Mr B introduced himself and told her that he would be treating her that evening. She immediately insisted that she wanted to be seen by a specialist. “Why don’t I just take a look first,” Mr B said calmly. After an examination, the patient’s throat was slightly red. She had no other obvious symptoms. 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 “It looks like you have a bit of a sore throat,” Mr B said. “I can give you a prescription for something to gargle with that will make it feel better.” “I don’t want a prescription,” the patient said angrily, “I want to see a specialist. I want someone to look at the burns in my mouth! And I want you to report the burns to the authorities!” “I’m sorry,” Mr B said as soothingly as he could, “A specialist is not required here, and I see no burns in your mouth.” The patient jumped up, furious, and said, “If this is how you’re going to treat my serious problems, then forget it.” She ran out of the examination room and left the ED. Mr B shook his head, but he did not have time to worry about it—there were still many patients waiting. Mr B did not think about the patient again, until he was notified that he and the hospital were being sued in a federal court.
A federal court found that the plaintiff had failed to state a viable claim under EMTALA against the hospital. Mr B went to see his defense attorney who said, “I don’t think you have anything to worry about—the patient is representing herself pro se! You know what they say—the person who represents himself has a fool for a client!” And indeed, Mrs P’s first legal complaint failed to raise a claim and was dismissed. However, because she was pro se, the court provided her with an opportunity to file an amended complaint. The first amended complaint failed again because the plaintiff made a Fourteenth Amendment argument, and the court pointed out that the Fourteenth Amendment only applies to state action and not private conduct. But again, the court gave her leave to file another amended complaint. Finally, she filed a complaint under the Emergency Medical Treatment and Active Labor Act (EMTALA). Legal background
EMTALA, known as the “Patient Anti-Dumping Act,” was enacted to address concerns that hospitals were dumping patients who were unable to pay for care, either by refusing to provide emergency treatment to these patients or by transferring the patient to other hospitals before the patient’s condition was stabilized. Under the law, hospitals with EDs must provide for “an appropriate medical screening
examination within the capability of the hospital’s ED” to determine if an emergency medical condition exists. Hospitals are required to conduct an examination that is reasonably calculated to identify the patient’s critical medical condition. In this case, Mrs P sued both the hospital and Mr B under EMTALA. The federal court found that Mrs P had failed to state a viable claim under EMTALA against the hospital. The court found that Mrs P was triaged within a reasonable time and that her condition was determined to be non-urgent. The hospital had not violated EMTALA. (It is worth noting that even if Mrs P had burns in her mouth that were not treated or noticed, a hospital is not liable under EMTALA if it negligently fails to detect or misdiagnoses an emergency medical condition. In those cases, plaintiffs must pursue their remedies in state court.) Next, the court looked at the EMTALA claim against Mr B and stated, “insofar as plaintiff attempts to bring a claim against nurse practitioner B for violation of the EMTALA, she may not do so. The EMTALA does not provide a private right of action against hospital employees.” The bottom line is that a hospital may be sued under EMTALA, but a person may not. The court dismissed the claims against the hospital and Mr B. Protecting yourself
Since lawsuits are often one person’s word against another’s, they can happen to anyone, even if nothing was actually done wrong. Some states have enacted methods to try to cut back on frivolous lawsuits, such as having malpractice cases reviewed by a panel of medical experts before a suit can be commenced. However, in many instances, a ridiculous lawsuit (such as the one presented here) can still waste the time and resources of a healthcare provider. There was, unfortunately, little that Mr B could have done to protect himself in this case. He did what he was supposed to do. He assessed the patient, he took notes on her condition, and he noted the time that she had been seen. He also noted that she claimed to have had burns, but an examination revealed only a mild sore throat. Good, detailed notes are always important for protecting yourself. Unfortunately, even good notes did not prevent Mr B from having to go through the experience of being party to a lawsuit. n Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.
60 THE CLINICAL ADVISOR • FEBRUARY 2017 • www.ClinicalAdvisor.com
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.
Ocimum sanctum, or holy basil, has been used for thousands of years and is considered a sacred herb in many parts of the world, hence, its name.1 Often dubbed ‘the elixir of life’ and ‘the queen of herbs,’ the uses of holy basil range from an anti-inflammatory, to an expectorant, to a tonic for energy and memory enhancement.2 The plant is typically found in the tropics and subtropical areas, often in homes to be used in religious ceremonies.2 The essential oils of the leaves are very aromatic and contain a wide array of important metabolites.
Background Believed to have first been grown in the wild in northern India, holy basil reaches a height of almost two feet and has many branches, making it almost seem like a shrub.3 The branches have hairy stems that bear leaves of approximately two inches long that are dark green to almost purple with a pungent scent. When holy basil flowers, the tiny lavender blooms are tightly displayed on a linear spire.
Science One of the most important claims of holy basil is as an immune booster. In a double-blind trial of healthy volunteers, participants were given standardized capsules of ethanolic extracts of basil leaves or placebo.1 In the 4-week, post-study phase, participants’ blood samples were analyzed for the content of Th1 and Th2 cytokines (interferon-gamma and interleukin-4) and the results were compared to baseline
data. The results showed statistically significant increases in the levels of these two potent immune mediators over baseline in the basil group, when compared to baseline and the placebo group.1 Since the rapidly expanding problem of antimicrobial resistance is being felt worldwide, researchers are constantly searching for alternate compounds with bactericidal action. One study examined the action of Ocimum essential oil on three major pathogens: Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus), Escherichia coli, and Pseudomonas aeruginosa.4 Using oil concentrations of 2.25% and 4%, complete growth inhibition of S aureus and E coli was achieved and partial inhibitory action was seen in P aeruginosa. It should be noted, however, that while these results are impressive, the study only showed bacteriostatic activity and not bactericidal action. Another feature of holy basil is its apparent modulatory effects on the clinical aspects of metabolic syndrome.5 Researchers in this study recruited 100 volunteers with
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ALTERNATIVE MEDS UPDATE known elevations in blood glucose, lipids, and blood pressure. The participants were randomly assigned to take either placebo or holy basil extract twice daily for three months. Compared to baseline and the placebo group, the holy basil group showed impressively significant reductions in blood sugar levels, lipid profiles, and blood pressure. The mechanism of action of holy basil on these parameters is believed to be largely due to the herb’s potent anti-inflammatory effect. Holy basil’s protective action is due, in part, to its free radical scavenging effect. This also reduces oxidative cellular and chromosomal damage from radiation.6 These actions ultimately help reduce end-organ damage and improve post-radiation recovery. Limited clinical studies have shown promise with being able to deliver higher doses of therapeutic radiation in patients taking holy basil without increasing the unwanted side effects of the radiation.6 The protective mechanisms are thought to be due to the increase in antioxidant activity, alteration in gene expression, induction of apoptosis, and the inhibition of angiogenesis and metastasis.7 A substantial part of this protective action is due to enhancement of the liver enzyme systems that detoxify and cleanse the bloodstream of damaging substances.
Safety, interactions, side effects
can be purchased for as little as $4. Dried leaves are usually dosed by steeping one-half teaspoon in hot water to make a tea and consuming two to three times daily.6
Holy basil is found as either chopped and dried leaves, tea, or tincture.
Holy basil’s protective mechanisms are thought to be due to the increase in antioxidant activity and alteration in gene expression.
Holy basil is not recommended for pregnant or nursing mothers or young children. It should also be used with caution in patients with diabetes due to its potential for inducing hypoglycemia.6 Allergic reactions are always a concern with any compound. Persons with allergic histories should be cautious with first-time use of holy basil.
How supplied, dose, cost
As with all homeopathic remedies, there are many pros and cons. There does not appear to be a substantial downside to the use of holy basil. However, there are still many holes in the research before healthcare providers can safely recommend its use. The concern always exists, especially in cases of cancer and other life-threatening diseases, that patients could unknowingly rely too heavily on this remedy and possibly feel that it could replace traditional therapy. As long as healthcare providers thoroughly educate their patients as to the adjunctive place of holy basil in a treatment regimen, cautious use seems both safe and likely beneficial. n References 1. Mondal S, Varma S, Bamola VD, et al. Double-blinded randomized controlled trial for immunomodulatory effects of Tulsi (Ocimum sanctum Linn.) leaf extract on health volunteers. J Ethnopharmacol. 2011;136:452-456. 2. Cohen MM. Tulsi-Ocimum sanctum: A herb for all reasons. J Ayurveda Integr Med. 2014;5:251-259. 3. Renter E. Holy basil benefits: Growing your own medicine. Available at http://naturalsociety.com/holy-basil- benefits-growing-your-own-medicine. Posted March 7, 2013. Accessed January 10, 2017. 4. Yamani HA, Pang EC, Mantri N, Deighton MA. Antimicrobial activity of Tulsi (Ocimum tenuiflorum) Essential Oil and their major constituents against three species of bacteria. Front Microbiol. 2016;7:681. 5. Devra DK, Mathur KC, Agrawal RP, Bhadu I, Goyal S, Agarwal V. Effect of Tulsi (Ocimum sanctum Linn.) on clinical and biochemical parameters of metabolic syndrome. Journal of Natural Remedies. 2012;12: 63-67.
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6. Tulsi (Ocimum sanctum) as radioprotector in head and neck cancer patients undergoing radiation therapy. Biomedicine. 2012; 32:39-44. 7. Baliga MS, Rao S, Rai MP, D’Souza P. Radioprotective effects of the Ayurvedic medicinal plant Ocimum sanctum Linn. (holy basil): A memoir. J Cancer Res Ther. 2016;12:20-27.
Holy basil is usually found as either chopped and dried leaves, tea, or tincture. Essential oil of holy basil is also becoming very popular. Holy basil products cost from $15 to $45, depending on the quantity and concentration. Also, ‘growing your own’ is becoming increasingly attractive and a packet of several hundred non-GMO seeds
COMMENTARY Judi Greif, MS, RN, APN-C, is a family nurse practitioner residing in East Brunswick, N. J.
Health care under President Trump On his website in an article entitled, “Healthcare Reform to Make America Great Again,” President Donald Trump stated, “On day one of the Trump administration, we will ask Congress to immediately deliver a full repeal of Obamacare.” In fact, both houses of Congress had voted for a repeal before the inauguration had taken place. In the Senate, the vote was 51 to 48. The House of Representatives followed suit and voted 227–198 to instruct committees to draft legislation that would repeal the 2010 Affordable Care Act (ACA). With these actions and the nomination of orthopedist and Representative Tom Price (R, Georgia), an ardent opponent of the ACA, as the
As healthcare providers, we have an obligation to our patients— especially to those who are most vulnerable.
proposed Secretary of Health and Human Services, it is likely that the administration is on a path to dismantle President Obama’s signature healthcare plan — one that covers 20 million Americans. The healthcare community is deeply divided on the future of the ACA and what reforms will mean to patients. While no formal replacement plan has been proposed, an examination of Price’s legislative record, as well as some of the proposals that he and others have put forth, may provide a glimpse into the future. Price’s alternative to the ACA, called the “Empowering Patient First Act,” states that there should not be “a government takeover of health care.” He vowed in his hearing that he would not “pull the rug out” from under those covered by the ACA. He favors returning control to individual states, such as providing them with block grants for Medicaid funding and creating state-run “high risk pools.” It is likely that Price’s vision of health coverage would not continue to support women’s health services, as his plan does not guarantee prenatal care and he is opposed to abortion and funding for contraception. Although the American Medical Association has “strongly” supported Price, “for his service as a physician, state legislator, and member of the U.S. Congress” and has called him a “leader in … policies to advance patient choice
and market-based solutions as well as reduce excessive regulatory burdens,” this organization only represents approximately 25% of all physicians, and his nomination has spurred strong reaction among many clinicians. An online open letter entitled, “The AMA Does Not Speak for Us,” which gathered more than 5,500 signatures, stated, “Dr. Price’s proposed policies threaten to harm our most vulnerable patients and limit their access to health care.” National Nurses United, representing 185,000 members, stated, “If confirmed, it is clear that Rep. Price will pursue policies that substantially erode our nation’s health and security … throwing our most sick and vulnerable fellow Americans at the mercy of the healthcare industry.” Let us hope that President Trump’s desire to reform the ACA will retain its best components and improve on its shortcomings. As healthcare providers, we have an obligation to our patients — especially to those who are most vulnerable. A spokesperson for the Trump transition team told the New York Times that Price will “work to restore the patient-doctor relationship.” However, how can you have a patient–doctor relationship when the patient cannot afford to go to the doctor? n For the full version of this Commentary, please log onto ClinicalAdvisor.com
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