June 2020 Clinical Advisor by The Clinical Advisor

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

LEGAL ADVISOR

Nurse Exposed to Ebola Is Cleared for Air Travel DERMATOLOGIC LOOK-ALIKES

Multiple Pustular Eruptions

JUNE 2 020

| www.ClinicalAdvisor.com

CGRP PATHWAY EXAMINED

A Novel Class of Preventive Treatments for Adults With Migraine Migraine is the second most disabling pain condition worldwide.

DERMATOLOGY CLINIC

Ulcerated, Raised, Hypertrophic Nodule on Lower Extremity

FEATURE

When a Headache Isnâ&#x20AC;&#x2122;t a Migraine: A Case of Chiari Malformation

A PEER-REVIEWED FORUM FOR PHYSICIAN ASSISTANTS

LEGAL ADVISOR

Nurse Exposed to Ebola Is Cleared for Air Travel DERMATOLOGIC LOOK-ALIKES

Multiple Pustular Eruptions

JUNE 2 020

| www.ClinicalAdvisor.com

CGRP PATHWAY EXAMINED

A Novel Class of Preventive Treatments for Adults With Migraine Migraine is the second most disabling pain condition worldwide.

DERMATOLOGY CLINIC

Ulcerated, Raised, Hypertrophic Nodule on Lower Extremity

FEATURE

When a Headache Isnâ&#x20AC;&#x2122;t a Migraine: A Case of Chiari Malformation

Director Nikki Kean nikki.kean@haymarketmedia.com Associate editor Madeline Morr Production editor Kim Daigneau

Unsure about a diagnosis or treatment?

Group creative director, medical communications Jennifer Dvoretz Senior production manager Krassi Varbanov Director of audience insights Paul Silver National sales manager Alison McCauley, 973.224.6414 alison.mccauley @ haymarketmedical.com

Ask our

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 the color of the affected area was normal, the skin CLINICAL PEARLS felt quite thick and inflexible. These skin changes stopped abruptly at the collar line, below which POISON IVY PREVENTION the skin was entirely normal. Poison ivy season is starting! I recommend that Abundant evidence of sun damage — includ- people take an old pair of knee-high tube socks ing weathering, telangiectasias, solar lentiginosis, and cut off the foot part above the heel. Pull the and numerous actinic keratoses on prominent socks over the arms up to the start of their sleeve areas of his cheeks and ears — was noted. Similar (assuming they are wearing a T-shirt) and tuck changes were noted on the dorsa of both hands into gloves. Use the socks to protect arms when but were not present on his arms and trunk working in the yard or other high-risk poison because he wore long-sleeved shirts when in the ivy areas. They can be rolled off the arms and sun. Although he had worn a wide-brimmed hat thrown away, or washed and re-used. I remind while in the sun during his adult life, he had never people to always wear gloves, and to remove worn anything, such as a bandana, on his neck. the gloves before touching anything, including Always wear The posterior neck is especially susceptible door handles. This significantly reduces the gloves to to the effects of the sun, evidence of which fre- exposure area of skin to poison ivy. —JUDITH protect the quently manifests as it did in this patient. This MCINTOSH, MSN, Kokomo, Indiana skin from condition is called cutis rhomboidalis nuchae (CRN), which represents thickening and weathweath VERRUCA VULGARIS TREATMENT exposure to ering of the epidermis as well as solar elastosis I always recommend candida albicans skin anti- poison ivy, and of the underlying dermis caused by the sun. gen test injections for patients who are not remove them Although this condition is clear evidence of responding well to liquid nitrogen +/- paring for before touching chronic overexposure to the sun, CRN has no verruca vulgaris. A 0.1-mg injection every month anything. malignant potential, and treatment is neither for about 3 months creates an immune response required nor does it exist. against the warts. I have seen resolution of some Besides being common, CRN is unique in its recalcitrant cases that seemed most impossible! presentation, as well as in the patient population —SARAH LUP, PA-C, Chicago, Illinois it affects (eg, older patients with sun damage confined to the posterior neck), so the differen- RETHINKING PRESCRIBING tial is quite narrow. Punch biopsy would resolve DICLEGIS any confusion. Diclegis is the only FDA-approved prescription CRN puts this patient at higher risk for the medication for nausea and vomiting of pregdevelopmentThe of skin caused by sun expo- nancy that is classified as Category A (safe for se cancers are lette rssquamous sure, such asand basal cell carcinoma, cell mom and baby). Before writing a prescription, from prac successe titioconsider ners arou carcinoma, melanoma, and s,others. the price tag. Diclegis with a coupon obseThis nd the coun rvatpatient ions, andcosts approximately and others with similar histories require regular $345 try for 60 tablets. The pearls with who their to share their skin checks by a qualified dermatology provider most common dosagecolle is 2 tablets/dwan but tcan agues. We clinical chall at least once a year. Although this patient would be more. Some patients may obtain insurance invite you enges to participa be advised to protect himself from the sun, this coverage for this medication, but it will likely te. will do little to ward off any future skin cancers still cost something. Let’s break down Diclegis that will have been caused by sun overexposure CONSUL into its 2 active ingredients: doxylamine sucTAT occurring decades earlier. Application of sun- cinate IONand S pyridoxine hydrochloride (vitamin screen to his neck would prevent IRO worsening of B 6). Unless you are writing a prescription for N PILL 2. Cohen SM, Kwo PY, Lim, his CRN. a celebrity, recommend that your patients ON LIVE S AND THEIR JK. ACG clinical of abnorm Send us R ENZ al liver chemis ECT guideline: your purchase over-the-counter doxylamine YMESinsteadEFF Can takin evaluat tries. Am J Gastroe 3. Iron. ion g iron pills nterol. 2017;1 al Institute Reference letters with succinate and vitamin B 6 to take Nation at night elevate liver —AGNES 12:18-35. of Health nih.gov/Iron.h ques website. https:// enzymes? MURPHY, tm. Access for nausea. —AMBER PA-C, Bolognia JL, Jorizzo JL,tions Rapini RP. Dermatology. 1st ed. NewDEW, PCA and , Americus, livertox. ed April 3, commen 2019. Georgia Birmingham, Michigan York: Mosby, 2003;1380-1381. ts to: Liver enzym es Advisor Forum aspartate aminosuch as alanine amino , CASE FILE transfe The Clinica l Advisor, phatase are transferase (AST), and rase (ALT), S www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 45 275 7th Aven markers of alkaline phosfunction, and hepat ue, 10th CUTIS RHO should be referre ic injury, not hepat Floor, New Albumin, MBO ic York, d to as liver bilirubin, and chemistries. Contributed by Joe Monr IDALIS NY 10001 measures of prothrombin .You oe, MPAS, hepatocellu time are direct A 78-year-old may conta PA-C lar appropriately ct us heavily lined man presented characterized synthetic function and with thick e-mail at edito by skin on enzymes may are as “liver functio r@ be abnormal n tests.” Liver been present for an his posterior neck ened, clinicaladvis liver diseas that had even in patien indet or.com. Although e. The differe ts without the striking erminate period of Letters are ntial for elevat broad with time. skin chang tomatic, edited many be further define potential causative ed enzymes is insiste they were concerning es were asympfor length factors and and d that he be to his relativ d by the patien should risk factors. 1 clarity. The seen es who t’s by a medical histor The Clinical y and the patient had spent dermatology provider. Almost all Advisor’s policy nearl sun, farmi medications ng, ranching, y his whole life small risk of are associated is to print to his in elevat fishing, and the hepatotoxic 2 ed liver chemistries with at least a a histo property in rural tending author’s name Okla ity. Oral with ry homa or of witho iron skin cance . replacement with the letter r and claim He denied doses has little supplementation at typicaut good health. ed to be . liver or serum or No anony in The skin on enzyme elevati no adverse effects on l mous the patien or overdoses, the ons. However, contributio it in high doses lined and thickened t’s nuchal area was ns will of iron poison can cause acute hepato heavily . The multiple overla toxicity as a ing. be accepted. pping rhom lines joined to form result of ferrous sulfate Toxicity occurs after boidal shape ingestion of (approximat ≥3 g s. toxicity with Altho ely 10 tablets ugh aminotransf ). Severe the upper limit erases greate r overdoses and of normal typically than 25 times occurs with high initial larger serum iron dL). Mild levels to usually self-limmoderate cases of iron (>1000 ug/ whereas severe iting and resolve with poisoning are suppo KUSMIN cases become fatal rapidl 3 rtive care, SKY, PA-C y. —LAURA Referenc es

Advisor F

orum

Write us today.

44 THE CLINI

1. Approach to the patient with abnorm and functio n tests. UptoD al liver bioche mical ate.com websit uptodate.com e. https://www. /contents/app roach-to-theabnormal-liver patient-with-biochemical -and-functionApril 2, 2019. tests. Access ed

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

CAL ADVI

SOR • MAY

2019 • www.

ClinicalAdv

isor.com

E-MAIL editor@clinicaladvisor.com

Associate account manager Michael Deverin, 732.343.4921 michael.deverin@haymarketmedia.com Publisher Kathleen Hiltz, 201.774.1078 kathleen.hiltz@haymarketmedia.com Vice president, content, medical communications Kathleen Walsh Tulley General manager, medical communications Jim Burke, RPh President, medical communications Michael Graziani 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/licensing, email Kerry Niessing at kerry.niessing@ haymarketmedia.com or call 646.638.6026. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Features” 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 23, Number 5. Published 10 times a year, by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, call 646.638.6000 (M–F, 9am–5pm, ET). The Clinical Advisor is available on a paid subscription basis at the following annual rates: $75 USA, $85 Canada, $110 for all other foreign, in U.S. dollars, Single copy price: USA $20, Foreign $30. To order or update a paid subscription visit our website at www.ClinicalAdvisor.com or call 800.436.9269. Periodicals postage rate paid at NewYork, NY, and additional mailing offices. Postmaster: Send changes of address to The Clinical Advisor, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2020

2 THE CLINICAL ADVISOR • JUNE 2020 • www.ClinicalAdvisor.com

CONTENTS JUNE 2020

FEATURES 8

7 Progressive shoulder pain

When a Headache Isn’t a Migraine: A Case of Chiari Malformation Primary care providers should be aware that Chiari malformation should be part of the differential diagnosis for the patient with frequent dull or sharp Valsalva-induced headaches.

2 Anti-CGRP: A Novel Class of Preventive Treatments 1 for Adults With Migraine The calcitonin gene-receptor peptide pathway has been studied extensively and is thought to play a significant role in the development of migraine headache via the trigeminovascular system. DEPARTMENTS 6

21 Skin lesion on child from coastal Mexico

Web Roundup A summary of our most recent opinion, news, COVID-19 coverage, and multimedia content from ClinicalAdvisor.com. Dermatology Clinic ■■Ulcerated, Raised, Hypertrophic Nodule on Leg ■■Pigmented Macular Lesion on Hand

25 Differentiating pustular eruptions

31 L ack of proper prevention protocols

Dermatologic Look-Alikes Multiple Pustular Eruptions

Legal Advisor The owners of a bridal store filed a million-dollar lawsuit against a Dallas hospital where a health care worker was exposed to a patient with Ebola, alleging that the hospital negligently failed to prevent the spread of Ebola virus disease in its control and management of the staff.

MORE WAYS TO FIND US!

Like us on Facebook facebook.com/TheClinicalAdvisor Visit us on the web ClinicalAdvisor.com Download the app ClinicalAdvisor.com/App

www.ClinicalAdvisor.com

ClinAd CMF [NP] AD 4.29F.20..qxp_ClinAd[PA]CMF 3.16.10 4/29/20 1:07 PM Page 1

Fast, Easy & Money-Saving Malpractice Insurance For Nurse Practitioners. It Pays To Compare!

Employed Nurse Practitioner Rates Average Annual Premium/$1,000,000 Limits

CM&F

National Competitor

Adult/Geriatric/Telemedicine Psychiatric Family Practice/Pediatric Critical Care/OBGYN

$ 800 $1,100 $1,450 $2,000

$1,200 $1,700 $2,175 $3,000

Average Annual Premium/$1,000,000 Limits

CM&F

National Competitor

Adult/Geriatric/Telemedicine Psychiatric Family Practice/Pediatric Critical Care/OBGYN

$1,200 $1,700 $2,200 $2,700

$1,800 $2,600 $3,400 $4,000

Self-Employed Nurse Practitioner Rates

Healthcare Malpractice Insurance Experts Since 1947 99 Hudson Street, 12th Floor, New York, NY 10013-2815 1-800-221-4904 Fax: 646-390-5163 Email: info@cmfgroup.com APPLY ONLINE TODAY - Most Credit Cards Accepted

Like us at facebook.com/cmfgroupinsurance Follow us on twitter.com/cmfgroup_

Quality, Trust & Value www.NPSave.com

ClinAd CMF [PA] AD 4.29F.20.qxp_ClinAd[PA]CMF 3.16.10 4/29/20 1:03 PM Page 1

Malpractice Insurance For PAs

Personal Protection Is Now More Important Than Ever. Relying On Your Employerâ&#x20AC;&#x2122;s Group Coverage Could Be A Costly Decision.

Like us at facebook.com/cmfgroupinsurance Follow us on twitter.com/cmfgroup_

Quality, Trust & Value www.PA-Protect.com

ClinicalAdvisor.com

NEWS

FEATURE

ClinicalAdvisor.com/News

ClinicalAdvisor.com/Features

Survey of Burnout, Work-Life Balance Among PAs

7 Things to Consider When Transitioning to Telemedicine During COVID-19 The dramatic and rapid expansion in telemedicine has left many clinicians scrambling. Even moreseasoned providers who had already incorporated telemedicine in their practice must learn to move the technology from the periphery to front and center of care.

Compared with other US workers, physician assistants were more likely to experience burnout, but they report better work-life integration.

Smoking Prevention Strategies Released for Teens USPSTF report found that behavioral counseling interventions with a health care clinician can have a moderate effect in preventing tobacco use in school-aged adolescents.

Declines Seen in Immunization in Children During Pandemic

THE WAITING ROOM

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Jim Anderson, MPAS, PA-C, DFAAPA Staying at Home During the COVID-19 Pandemic Two friends reflect on their decision to step back from the front lines of the COVID-19 pandemic to work from home, and whether they made the right choice.

To help keep children protected, the American Academy of Pediatrics has published new guidelines for managing well-care visits safely and efficiently during the COVID-19 pandemic.

Weighing Effects of Immunosuppression for Patients With COVID-19 Reducing hyperinflammation by immunosuppression with corticosteroids or Janus kinase inhibitors in critically ill patients with SARS-CoV-2 should be approached with caution.

Tackling Depression, Anxiety Among Adults With Intellectual Disabilities Individuals who reported loneliness, sleep difficulties, and aggressive behavior and who took mood stabilizers were more likely to meet cutoff scores for anxiety and depression.

CASE STUDY ClinicalAdvisor.com/CaseStudy Brady Pregerson, MD Pain and Swelling in the Knee A 66-year-old man presents with a 3-day history of worsening pain and swelling in his left knee. He denies any injury other than a scrape sustained a week earlier. He denies any fever, redness or warmth to the knee, additional injuries, or other complaints. See the full case at ClinicalAdvisor.com/ CaseStudyJune20

6 THE CLINICAL ADVISOR • JUNE 2020 • www.ClinicalAdvisor.com

EXCLUSIVE TO THE WEB AT

Advisor Dx 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. Check out some of our latest cases below!

DERM DX

Blistering of the Lower Lip A 54-year-old man presents with blistering of his lower lip. The condition has waxed and waned in severity over the past several months. He complains of itching and mild burning at the site of the blisters. His medical history includes complaint of recurrent itchy lesions on his wrists and ankles. CAN YOU DIAGNOSE THIS CONDITION?

• Pemphigus vulgaris • Bullous pemphigoid

• Bullous lichen planus • Herpes simplex

● See the full case at ClinicalAdvisor.com/DermDx_June20

ORTHO DX

In partnership with

TheJopa.org

Journal of Orthopedics for Physician Assistants

Chronic Shoulder Pain A 68-year-old man presents with chronic pain in his left shoulder. He believes that the pain originated more than 10 years ago, and he has progressively lost motion and strength in his shoulder since. Physical examination reveals 90° of active forward flexion and significant weakness with forward flexion in the scapular plane. WHAT IS THE BEST SURGICAL TREATMENT OPTION?

• Arthroscopic rotator cuff repair • Total shoulder arthroplasty • Reverse total shoulder arthroplasty • Shoulder hemiarthroplasty ● See the full case at ClinicalAdvisor.com/OrthoDx_June20

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2020 7

FEATURE: HEATHER JONES, DNP, AGPCNP-C; BETH AMMERMAN, DNP, FNP-BC

When a Headache Isn’t a Migraine: A Case of Chiari Malformation Chiari malformation is a condition characterized by cerebellar tonsillar herniation of ≥5 mm below the level of the foramen magnum.

s B, a 33-year-old white woman, presents with a complaint of severe daily headaches for the past 3 weeks. The patient has a 15-year history of hypertension and intermittent headache. She describes feeling the headaches in the back of her head (suboccipital region), and the pain radiates forward behind her eyes. She describes the headaches as continuous pressure that causes her to have a “fuzzy” feeling in her head. She also reports chronic neck and shoulder pain, upper and lower back pain, and fatigue. Additional symptoms include dizziness, numbness and tingling in her hands, and difficulty with visual focusing, concentration, and memory. The headaches are intensified with coughing, laughing, and bending over, and they prevent her from participating in her yoga practice. The patient reports that the headaches are unresponsive to triptans, nonsteroidal anti-inflammatory drugs, acetaminophen, tramadol, and steroids. Her blood pressure is controlled with oral losartan 50 mg/d. The patient reports taking daily supplements of magnesium, fish oil, and vitamin D.

Examination

Chiari malformation is a rare cause of adult headaches due to tonsillar herniation.

Ms B’s vital signs are normal, and her blood pressure is well controlled at 120/72 mm Hg. Musculoskeletal examination reveals a slightly unsteady gait with dysmetria and reduced lateral range of motion of the neck to the left and right with muscle spasm of the cervical spine. Continues on page 10

8 THE CLINICAL ADVISOR • JUNE 2020 • www.ClinicalAdvisor.com

CHIARI MALFORMATION

Chiari malformations develop in utero when the tonsils of the hindbrain extend into the spinal column, crowding the foramen magnum. Abnormal findings on neurologic examination include a diminished gag reflex with protruding tongue deviation to the right. Hoffman sign is positive bilaterally. Deep tendon reflexes are symmetrically increased 4+ with 2-beat clonus bilaterally. Physical examination is otherwise unremarkable.

and C1 laminectomy. During surgery the cerebellar tonsils were found to be completely occluding the fourth ventricle. After resection, an arachnoid veil was discovered overlying the fourth ventricle, which was also resected allowing for normal flow of cerebrospinal fluid (CSF).

Testing and Diagnosis

Discussion

Considering Ms B’s headache symptoms and her neurologic examination showing signs of spinal cord compression, magnetic resonance imaging (MRI) of the brain and cervical spine are ordered. MRI reveals cerebellar tonsils extending 5 mm below the foramen magnum and a few small nerve root sleeve cysts bilaterally at C6-C7.

Chiari malformation is a medical condition characterized by cerebellar tonsillar herniation of ≥5 mm below the level of the foramen magnum and is a known rare cause of adult-onset headaches.1 Hans Chiari, an Austrian professor and pathologist, first identified hindbrain herniation while performing autopsies in the 1890s.2,3 He classified his findings into 4 categories based on severity of herniation (Table), with type IV being the most severe.4 While types II, III, and IV are typically diagnosed in utero or early childhood due to significant neurologic and physical deviations, Chiari malformation type I, the mildest type, is often not diagnosed until symptom development in early adulthood.4 Some patients go undiagnosed for many years and suffer from headaches and additional symptoms during this time. Chiari I malformation may cause severe headaches that resembleValsalva-induced headaches. Chiari I malformation has been increasingly detected, with a prevalence in some studies of 0.1% to 0.5% percent.5,6 Chiari malformations develop in utero when the tonsils of the hindbrain extend downward out of the skull into the spinal column, crowding the foramen

Treatment

The patient was referred to a neurosurgeon who confirmed the diagnosis of Chiari malformation type I. Ms B subsequently underwent MRI of the thoracic and lumbar spine, which was negative for syrinx (syringomyelia) or tethered spinal cord. The neurosurgeon recommended that Ms B undergo decompression surgery. Because of unrelenting symptoms and severely decreased quality of life, Ms B decided to move forward with surgery. Chiari decompression with microdissection was performed approximately 4 months after her initial symptoms began. The surgery included suboccipital craniectomy with duraplasty TABLE. Classifications of Chiari Malformation4 Chiari Malformation

Description

Type I

• Occurs when the cerebellar tonsils extend into the foramen magnum • Usually first noticed in adolescence or adulthood • Asymptomatic adolescents and adults may develop signs of the disorder later in life

Type II

• Symptoms are generally more severe than in type 1 and usually appear during childhood • Both the cerebellum and brain stem tissue protrude into the foramen magnum • Usually accompanied by a myelomeningocele, resulting in partial or complete paralysis of the area below the spinal opening • Term Arnold-Chiari malformation is specific to type II malformations

Type III

• Rarest and most serious form • Some of the cerebellum and the brain stem herniate through an abnormal opening in the back of the skull • Appears in infancy and can cause debilitating and life-threatening complications • Infants with type III can have many of the same symptoms as those with type II but can also have additional severe neurologic defects such as mental delays, physical delays, and seizures

Type IV

• Involves an incomplete or underdeveloped cerebellum (cerebellar hypoplasia) • In this rare form, the cerebellum is located in its normal position but parts of it are missing, and portions of the skull and spinal cord may be visible

10 THE CLINICAL ADVISOR • JUNE 2020 • www.ClinicalAdvisor.com

Chiari malformation should be part of the differential diagnosis for the patient with frequent dull or sharp Valsalva-induced headaches. Case Outcome

At the patient’s 6-week postoperative follow-up visit, she presented without headache. She denied blurred vision or dizziness, and the numbness and tingling in her hands had resolved. She reported feeling lighter and clearer, and her blood pressure was noted to be lower, resulting in a tapering of her antihypertensive medication. The patient was advised to continue with range of motion exercises for her neck. She was informed that her recovery will be ongoing, and she was instructed to follow up with her neurosurgeon in 6 weeks. ■

The patient’s incision 10 days after surgery.

magnum and impeding the flow of CSF between the head and the spine. This buildup of CSF causes pressure, resulting in sharp headaches and other neurologic symptoms. Other symptoms of Chiari malformation may include ataxic gait, nausea, dizziness, nystagmus, voice changes, dysphagia, facial pain, tinnitus, decreased hearing, neck and shoulder pain, paresthesia and/or weakness in the upper extremities, sleep apnea or insomnia, and heart palpitations.7 The degree of herniation does not reflect the severity of symptoms as some patients with Chiari malformation are asymptomatic.2,3,7 Primary care providers should be aware that Chiari malformation should be part of the differential diagnosis for the patient with frequent dull or sharp Valsalva-induced headaches. Herniation of the hindbrain as demonstrated on MRI of the brain confirms the diagnosis of Chiari malformation. Treatment is based on MRI findings and symptomatology. Suboccipital craniectomy with or without duraplasty is the treatment of choice with the goal of restoring normal flow of CSF to the foramen magnum.7,8 In addition to the Chiari I malformation, Ms B also had nerve root sleeve cysts and an arachnoid veil in the fourth ventricle, both of which contributed to her headaches. An arachnoid veil is webbing of the intradural membranes, which can further impede flow of the CSF.9 Surgical resection of this webbing restores CSF flow. Nerve root sleeve cysts, also known as Tarlov cysts, are usually considered a benign normal deviation and therefore may be underreported on MRI.10 Although they are usually found in the sacral region, these cysts can occur in the cervical spine and can additionally impede the flow of CSF, contributing to symptoms.10

Heather Jones, DNP, AGPCNP-C, is a certified adult gerontology primary care nurse practitioner and a clinical instructor in the Department of Health Behavior and Biological Sciences at the University of Michigan in Ann Arbor. She also works in clinical practice. Beth Ammerman, DNP, FNP-BC, is a certified family nurse practitioner and a clinical assistant professor in the Department of Health Behavior and Biological Sciences at the University of Michigan in Ann Arbor. She also works in clinical practice. References 1. Sarnat HB. Disorders of segmentation of the neural tube: Chiari malformation. In: Aminoff MJ, Boller F, Swaab DF, Sarnat HB, Curatolo P, eds. Handbook of Clinical Neurology: Malformations of the Nervous System. Elsevier. 2007;87:89-103. 2. Loukas M, Noordeh N, Shoja MM, Pugh J, Oakes WJ, Tubbs RS. Hans Chiari (1851-1916). Childs Nerv Syst. 2008;24(3):407-409. 3. Massimi L, Peppucci E, Peraio S, Di Rocco C. History of Chiari type 1 malformation. Neurol Sci. 2011;32(Suppl 3): S263-265. 4. Chiari malformation fact sheet. National Institutes of Health website. https:// www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/ChiariMalformation-Fact-Sheet#4. Modified March 13, 2020. Accessed April 22, 2020. 5. Piper RJ, Pike M, Harrington R, Magdum SA. Chiari malformations: principles of diagnosis and management. BMJ. 2019;365:I1159. 6. Khoury C. Chiari malformations. UpToDate website. https://www.uptodate.com/ contents/chiari-malformations?search=chiari%20malformation&source=search_ result&selectedTitle=1~122&usage_type=default&display_rank=1. Updated June 21, 2019. Accessed May 7, 2020. 7. Gilmer HS. Chiari malformation program: education, treatment and support. Michigan Head & Spine Institute. https://www2.mhsi.us/images/ education/MHSIchiariBooklet.pdf. Accessed April 23, 2020 8. Baisden J. Controversies in Chiari I malformations. Surg Neurol Int. 2012;3(Suppl3):S232-S237. 9. Jain M, Sahu NK, Naik S, Bag ND. Symptomatic Tarlov cyst in cervical spine. BMJ Case Reports. 2018;11(1):e228051. 10. Ciappetta P, Signorelli F, Visocchi M. The role of arachnoid veils in Chiari malformation associated with syringomyelia. Acta Neurochir Suppl. 2019;125:97-99.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2020 11

FEATURE: AMY L. DIX, MPAS, PA-C, AQH, MSCS; LAUREN J. BARTON, MHS, PA-C; SAMUEL F. HUNTER, MD, PHD

Anti-CGRP: A Novel Class of Preventive Treatments for Adults With Migraine The FDA-approved anti-calcitonin gene-related peptide monoclonal antibodies were developed explicitly for the prevention of migraine.

Monoclonal antibodies (red) block the CGRP receptor (blue), lessening migraine attacks.

12 THE CLINICAL ADVISOR • JUNE 2020 • www.ClinicalAdvisor.com

igraine is a disabling, chronic neurologic disorder that affects more than 1 billion people worldwide.1,2 The 2016 Global Burden of Disease report revealed that migraine is the second most disabling condition worldwide, exceeded only by low back pain.2 In the United States, the Centers for Disease Control and Prevention report that 20% of women and 9.7% of men aged ≥18 years have had a severe headache or migraine in the past 3 months.3 Chronic migraine (CM) and episodic migraine (EM) negatively affect the quality of life of approximately 1 in 6 individuals in the United States,4 and migraine ranks as the number one cause of years lived with disability within the 15- to 49-year-old age group.5 The International Headache Society has established criteria for the classification of CM and EM.6 Diagnostic criteria for CM includes headache on ≥15 days per month for more than 3 months, which on at least 8 days per month, has the features of migraines: • Migraine without aura • Migraine with aura • Believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative • EM is defined as headache occurring on <15 days per month.6 Individuals with migraine headaches use opioids twice as often as those without migraines.7 Migraine headaches place a significant burden on already vulnerable populations such as the unemployed, uninsured or underinsured, lower

income individuals and families, the elderly, and the disabled, suggesting a serious public health concern that requires improvement.4 Indirect and direct healthcare costs for patients with migraine are significantly higher — on average $8924 more annually — than those for migraine-free individuals.8

sensory pathways contribute to the development of migraine.17 Researchers have progressed toward further understanding of both CM and EM headaches as well as their relationship with the CGRP pathway.18 Review of Anti-CGRP Therapies

Traditional Preventive Therapies

Undertreatment of migraine represents a great challenge; an estimated 66% of candidates for prophylactic migraine intervention go untreated.9,10 Several preventive treatments for frequent CM or EM — including divalproex sodium, topiramate, gabapentin, propranolol, and similar agents with antihypertensive, antidepressant, or antiepileptic actions — have been used for decades.11-13 These agents, however, have not been found to be uniformly efficacious. In a study of 1165 patients living with migraine, only 13.9% of patients on antidepressants (n=205), 11.2% on antiepileptics (n=125), and 11.5% on beta-blockers (n=130) said they found satisfactory resolution of their migraines through pharmacologic intervention.14 Nearly 50% of the patients discontinued their migraine therapy due to lack of efficacy or the side effects associated with treatment.14 In 2010, the US Food and Drug Administration (FDA) approved onabotulinumtoxinA (Botox®) for the prevention of migraines.15,16 This alternative treatment avoids the unpleasant adverse effects that traditionally deter patient adherence to standard pharmacologic treatments including nausea, vomiting, somnolence, dizziness, paresthesia, memory impairment, appetite loss, and taste abnormalities.15 New, rationally designed migraine prophylaxis has been pursued since the 1990s.The calcitonin gene-related peptide (CGRP) pathway plays a significant role in the pain and other symptoms associated with the development of migraine headache.17 Trigeminal nerve dysfunction and hypersensitive

Anti-CGRP monoclonal antibodies (anti-CGRP mAbs) are the first approved pharmacologic treatments developed explicitly for the prevention of migraine.18-20 Since 2018, the FDA has approved 4 new preventive therapies to treat migraine: erenumab (Aimovig®), fremanezumab (Ajovy®), galcanezumab (Emgality®), and eptinezumab (Vyepti™) (Table 1).21-24 The FDA approved these new agents globally for migraine, whether CM or EM, as significant benefit and safety were documented in both CM and EM treatment trials.The adult migraine indication shows that the FDA supports a wide spectrum of anti-CGRP utility in these populations. One agent also achieved approval for cluster headache.23 Approval of these agents validates the improved understanding and awareness of the underlying causes of migraine and presents a new opportunity for further education and better management of migraine as a chronic neurologic condition. Erenumab-aooe

Erenumab-aooe was the first of the anti-CGRP mAbs to be approved for the preventive treatment of migraine in adults.21 Erenumab, a completely human immunoglobulin G2 (IgG2) mAb that binds at the CGRP receptor, acts as an antagonist, inhibiting CGRP ligand activation of the receptor.25 Erenumab does not show cross-reactivity at adrenomedullin, calcitonin, and amylin receptors and lacks agonist activity at other CGRP receptor types.25 The drug requires 3 months to reach steady state.21

TABLE 1. New CGRP Monoclonal Antibody Therapies Erenumab21

Fremanezumab22

Galcanezumab23

Eptinezumab24

Dosing

70 mg SC monthly OR 140 mg SC (two 70- mg doses) monthly

225 mg/1.5 mL single-dose syringe monthly OR 675 mg/4.5 mL (3 225/1.5 mL single-dose syringes) SC quarterly

240 mg SC loading dose (two 100 mg/mL IV over 120-mg SC doses monthly), 30 min quarterly then 120 mg SC monthly

Route of Administration

Autoinjector (SC)

Single-dose syringe (SC)

Autoinjector (SC)

IV quarterly

Type of Monoclonal Antibody

Fully human, IgG2

Humanized, IgG2 δa/κ

Humanized, IgG4

Humanized, IgG1

CGRP Target

Receptor

Ligand

CGRP, calcitonin gene-related peptide; IV, intravenous; SC, subcutaneous

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2020 13

PREVENTIVE TREATMENTS FOR MIGRAINE

STRIVE (Study to Evaluate the Efficacy and Safety of Erenumab [AMG 334] in Migraine Prevention; ClinicalTrials.gov Identifier: NCT02456740) evaluated the effectiveness of erenumab 70 mg and 140 mg for the management of CM.26 The primary end point was change in mean monthly migraine days (MMD) at 3 months. Prior to treatment, patients had an average baseline of 18 MMD. The results of the trial showed that MMD was reduced by 6.6 days for both the 70-mg and 140-mg doses (Table 2).26 Secondary end points included the ability of erenumab to reduce mean MMD by ≥50% from baseline at the end of the trial. At 3 months, 41.2% of patients on erenumab 140 mg achieved a 50% reduction in MMD, and 40% of patients on erenumab 70 mg had a 50% reduction in MMD.26 Extension trials have shown promise at the 3-year mark indicating continued improvement with erenumab for the treatment of CM.18,27 The efficacy of erenumab in the treatment of EM also was studied at both 70-mg and 140-mg doses in ARISE (Study to Evaluate the Efficacy and Safety of Erenumab [AMG 334] Compared to Placebo in Migraine Prevention; ClinicalTrials. gov Identifier: NCT02483585). Patients in this trial had a baseline of 8.3 MMD.18 Treatment reduced MMD by 3.2 days at the 70-mg dose and by 3.7 days at the 140 mg-dose compared with baseline MMD.18

At 4 to 6 months on erenumab 140 mg, 50% of patients were able to achieve a ≥50% reduction in MMD; on erenumab 70 mg, 43.3% of patients demonstrated a ≥50% reduction.18 Reduction in the number of acute migraine-specific medication days was demonstrated in both STRIVE and ARISE (Table 3). Across both CM and EM trials with erenumab, the most frequently reported adverse reaction was injection site irritation, which occurred in 6% of patients receiving 70 mg/mo (n=787) and 5% of patients receiving 140 mg/mo (n=507) compared with 3% of patients receiving placebo (n=890).21 The frequency of complaints of constipation in patients on 70 mg was found to be similar to placebo at 1% compared with 3% for patients on 140 mg. Cramps and muscle spasms occurred in <1% of patients at the 70-mg dose, 2% at the 140-mg dose, and <1% in patients taking placebo.21 Fremanezumab-vfrm

Unlike erenumab, which targets the CGRP receptor, fremanezumab-vfrm is a fully humanized IgG2a δa/κ mAb that selectively targets CGRP ligand isoforms.This agent inhibits activation of the Aδ myelinated afferents in the trigeminovascular system originating from meningeal nociceptors.28 Continues on page 16

TABLE 2. Reduction in Monthly Migraine Days by Medication and Dose

Chronic Migraine, d

Episodic Migraine, d

Erenumab18,19,26

Fremanezumab20,30

Galcanezumab32,34

Eptinezumab36,37

70 mg: 6.6

Monthly: 4.6

120 mg: 4.8

300 mg: 8.2

140 mg: 6.6

Quarterly: 4.3

240 mg: Not approved

100 mg: 7.7

70 mg: 3.2

Monthly: 3.6 At 6 months: 4.9

120 mg: 4.7

300 mg: 4.3

140 mg: 3.7

Quarterly: 3.9 At 6 months: 5.0

240 mg: Not approved

100 mg: 3.9

TABLE 3. Responder Rates (≥50%) by Drug and Dose

Chronic Migraine

Episodic Migraine

Erenumab18,19,26

Fremanezumab20,30

Galcanezumab32-34

Eptinezumab36.37

70 mg: 40%

Quarterly: 37.6%

Loading dose of 240 mg followed by 120 mg: 28%

300 mg: 51%

140 mg: 41.2%

Monthly: 40.8%

240 mg monthly was not approved by FDA

100 mg: 48%

70 mg: 43.3%

Quarterly: 44.4%

EVOLVE-1: loading dose of 240 mg followed by 120 mg: 61%

300 mg: 51%

140 mg: 50%

Monthly: 47.7%

EVOLVE-2: loading dose of 240 mg followed by 240mg: 59%

100 mg: 45%

14 THE CLINICAL ADVISOR • JUNE 2020 • www.ClinicalAdvisor.com

For 1st-line constipation relief

The gentle power of MiraLAXÂŽ (PEG 3350) is prized by both doctors and patients.1-3 AGA recommends PEG laxatives as a first-line treatment 4

#1 GI-recommended laxative

96% patient satisfaction rate3

AGA=American Gastroenterological Association. References: 1. Schiller LR, Emmett M, Santa Ana CA, Fordtran JS. Osmotic effects of polyethylene glycol. Gastroenterology. 1988;94(4):933-941. 2. Hammer HF, Santa Ana CA, Schiller LR, Fordtran JS. Studies of osmotic diarrhea induced in normal subjects by ingestion of polyethylene glycol and lactulose. J Clin Invest. 1989;84(4):1056-1062. 3. Survey of 672 consumers, August 2017, Bayer Consumer Health. 4. Bharucha AE, Dorn SD, Lembo A, Pressman A; American Gastroenterological Association. American Gastroenterological Association medical position statement on constipation. Gastroenterology. 2013;144(1):211-217.

Doctor recommended, patient approved

The Bayer Cross, MiraLAX, and the MiraLAX Pink Cap are registered trademarks of Bayer. ÂŠ 2019 Bayer

1022320ha_a.indd 1

January 2019

3890-PP-MLX-BASE-US-0613

3/2/19 1:25 AM

PREVENTIVE TREATMENTS FOR MIGRAINE

Fremanezumab may be administered either as a single injection of 225 mg/1.5 mL/mo in a prefilled syringe or as 3 singledose syringes (totaling 675 mg/4.5 mL) every 3 months. Fremanezumab has been approved by the FDA in both dosing strategies for the treatment of migraine in adults (including both CM and EM).22 A trial of fremanezumab in patients with cluster headache failed to meet the primary outcome.29 Fremanezumab requires about 6 months to reach steady state plasma concentrations.22 At the time of publication, an autoinjector, rather than the original prefilled syringe, is under FDA review. In the HALO trial (Efficacy and Safety of Subcutaneous Administration of Fremanezumab [TEV-48125] for the Preventive Treatment of Migraine; ClinicalTrials.gov Identifier: NCT02638103) for EM, the primary end point was change in MMD from baseline during the 12-week period with quarterly or monthly dosing. From a baseline of 8.9 MMD, monthly treatment reduced EM MMD by 3.6 at 12 weeks and 4.9 at 6 months. For quarterly dosing from a similar baseline (9.2 MMD), EM MMD was reduced by 3.9 at 12 weeks and by 5.0 at 6 months.30 Similarly, in the fremanezumab trial for the prevention of CM (Comparing Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of TEV-48125 Versus Placebo for the Preventive Treatment of Chronic Migraine, ClinicalTrials. gov Identifier: NCT02621931), the primary end point was change in MMD from baseline during the 12-week study period with either quarterly or monthly dosing. From a baseline of 16.2 MMD, monthly dosing showed an average reduction of 4.6 MMD; the reduction in MMD for quarterly dosing was 4.3.20 Galcanezumab-gnlm

Unlike erenumab or fremanezumab, galcanezumab-gnlm uses a humanized IgG4 mAb to modify CGRP function. Similar to fremanezumab, galcanezumab binds, inactivates, and depletes or sequesters the CGRP ligand itself. The binding site of fremanezumab represents the domain of CGRP known to interact with the CGRP receptor. Galcanezumab is administered via an autoinjector with a loading dose of 2 injections (total of 240 mg) on the first day followed by subcutaneous injections of 120 mg/mo thereafter.23 Galcanezumab has also emerged as the first CGRP treatment to achieve approval for management of episodic cluster headache in adults.31 The REGAIN trial (Evaluation of Galcanezumab in the Prevention of Chronic Migraine; ClinicalTrials.gov Identifier: NCT02614261) evaluated the effectiveness of galcanezumab at both 120-mg and 240-mg doses.32 The primary end point was change from baseline in monthly migraine headache days (MHD) over 3 months. From a baseline of 19.4 MHD, the 120mg dose decreased MHD by 4.8; however, a higher incidence of drug injection-site reactions and sinusitis was seen at this dose.32

POLL POSITION Which of the anti-CGRP agents binds to the CGRP receptor, not the ligand? 5.26% ■ Fremanezumab ■ Galcanezumab ■ Erenumab

14.04% 59.65% 21.05%

■ Eptinezumab

For more polls, visit ClinicalAdvisor.com/Polls.

Now used as a loading dose, the higher 240-mg dose was not approved as a monthly dosing regimen.The loading dose was derived from pharmacokinetic modeling indicating that this initial dose would reach steady state rapidly. This dosing approach is unique to galcanezumab in the subcutaneous class.32 From the subcutaneous depot, galcanezumab reaches steady state within 1 week as opposed to the 3 to 6 months required by the other subcutaneous agents.21,22 The EVOLVE-1 (Evaluation of Galcanezumab in the Prevention of Episodic Migraine; ClinicalTrials.gov Identifier: NCT02614183) study assessed the safety and efficacy of galcanezumab at both 120-mg and 240-mg doses.33 The primary end point was change in MHD over months 1 to 6. From a baseline of 9.2 MHD, MHD fell 4.7 for the 120-mg dose.33 EVOLVE-2 (Evaluation of Efficacy & Safety of Galcanezumab in the Prevention of Episodic Migraine; ClinicalTrials.gov Identifier: NCT02614196), which had a similar protocol for EM, had nearly identical findings; only the 120-mg dose was approved.34 Eptinezumab-jjmr

Eptinezumab-jjmr, the fourth CGRP antagonist, was approved by the FDA in February 2020 as the first anti-CGRP agent for intravenous therapy, which differs distinctively from the other agents.35 In the PROMISE 1 (A Multicenter Assessment of ALD403 in Frequent Episodic Migraine, ClinicalTrials.gov Identifier: NCT02559895) study, reductions in MMD from a baseline of 8.6 were seen for placebo (-3.2) and eptinezumab 100 mg ( 3.9 [-45%]) and 300 mg (-4.3 [-50%]) by week 12.36 In the PROMISE-2 (Evaluation of ALD403 [Eptinezumab] in the Prevention of Chronic Migraine; ClinicalTrials.gov Identifier:

16 THE CLINICAL ADVISOR • JUNE 2020 • www.ClinicalAdvisor.com

NCT02974153) study, eptinezumab at monthly doses reduced MMD from a baseline of 16.1 MMD for placebo (-5.6 [-35%]), 100 mg (-7.7 [-48%]), and 300 mg (-8.2 [-51%]) by week 12.37 Eptinezumab is infused over approximately 30 minutes, and benefits can be seen as early as 1 day following intravenous infusion.37 The usual 100-mg dose can be increased if needed to 300 mg. Unlike the aforementioned agents with minimal immunogenicity, the incidence of antibodies was found to be approximately 21% in PROMISE-1; of these, 41% developed neutralizing antibodies (NAB).36 In PROMISE-2, 18% developed antibodies, and 35% of those were NAB.37 Essentially, 8% to 10% of patients receiving eptinezumab develop NAB.The impact of immunogenicity remains to be clarified, but the approved 300-mg dose may mitigate the effect of the neutralization in some patients. For this anti-CGRP mAb class, adverse effects listed in the prescribing information of these parenteral prophylactic mAbs include constipation, injection site reactions, and muscle cramps.21-24 Comparison With Established Strategies

Over the past few years, several notable systematic reviews have analyzed the efficacy of more commonly prescribed prophylactic agents for CM and EM, including gabapentin, topiramate, valproate, and onabotulinumtoxinA.11-15 A review of gabapentin administered in a 900-mg daily dose and titrated to 1800 mg demonstrated no significant difference in migraine frequency compared with placebo.11 A review of topiramate in doses ranging from 50 to 200 mg found only a 1-headache-day-per-month reduction compared with placebo.12 Valproate preparations, including valproic acid, sodium valproate, and divalproex sodium, have been approved as oral prophylactic agents, and an intravenous formulation (Depacon®) has also been approved for aborting acute migraine. Research involving valproate has produced some conflicting data. In a preventive study, 42% of subjects responded in the treatment group compared to 21% in the placebo group.13 However, the prophylactic study with the largest sample size found no significant difference.13 A third study found a statistically significant reduction of 4 migraine days per month with valproate compared with placebo.13 A review of onabotulinumtoxinA for headache prevention found only a single study sufficient for analysis and no significant differences from placebo.14 Another systematic review found only 2 studies adequate for analysis with both lacking any significant reduction in migraine headache days compared with placebo.15 Traditional agents for first-line prophylaxis of CM or EM (antiepileptics, antihypertensives, antidepressants) infrequently show a difference from placebo.When significant differences were found, the magnitude of the effect was less efficacious than the CGRP mAb class. Furthermore, the adverse effect profile of these traditional first-line drugs may be intolerable, negatively affecting patient adherence.14

The Need for Wider Intervention in Migraine

Uncontrolled migraine significantly impairs quality of life; therefore, both headache specialists and primary care professionals may provide access to newer prophylactic and abortive therapies. Patients with severe migraine now have wider preventive and abortive options including the anti-CGRP mAbs, small molecule CGRP antagonists, and ditans. Both nurse practitioners (NPs) and physician assistants (PAs) serve on the front line of primary care, urgent care, and emergency medicine — all contact points of migraineurs. Only 4.5% of patients with CM and 26.3% of patients with EM succeed in navigating the myriad barriers to receiving appropriate headache care.1,38 NPs and PAs serve as valuable team members in communities, improving care and access for patients, especially within the underserved migraine community. Being clinically informed allows primary care practitioners to make collaborative decisions with patients and to appropriately employ specialty care neurology and headache medicine. For patients who have tried standard preventive medications such as antiepileptics, beta-blockers, and antidepressants, a newly approved parenteral anti-CGRP may be a better option. Some insurance carriers may require referral to a neurology specialist to secure authorization; however, the simplicity and efficacy of the class has resulted increasingly in payors permitting prescriptions from a wide group of clinicians. Patient access to and coverage of these medications through health insurance plans must be present for CM and EM prevention. Since the introduction of anti-CGRP mAb use in clinical practice, a significant reduction in MMD or MHD has resulted, translating to fewer hospital admissions and emergency department visits as well as less use of ineffective therapies and missed work. ■ At the time the article was written, Amy L. Dix, MPAS, PA-C, AQH, MSCS, was working at the KC MS and Headache Center in Overland Park, Kansas. She is currently employed by EMD Serono, Inc. Lauren J. Barton, MHS, PA-C , practices in Hospital Medicine at Einstein Healthcare Network in North Philadelphia. Samuel F. Hunter, MD, PhD, is a neurologist in Franklin,Tennessee. Disclosures: Dr Hunter has disclosed that he has received honoraria, consulting fees, and research support from Novartis. Ms Dix has disclosed that she is an employee of EMD Serono, Inc. Ms Barton have no financial information to disclose. References 1. Dodick DW, Loder EW, Manack Adams A, et al. Assessing barriers to chronic migraine consultation, diagnosis, and treatment: results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. Headache. 2016;56(5):821-834. Continues on page 20

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2020 17

PREVENTIVE TREATMENTS FOR MIGRAINE

2. Vos T, Abajobir AA, Abate KH, et al; GBD 2016 Disease and Injury Incidence

preventive treatment of chronic migraine: a randomised, double-blind, placebo-

and Prevalence Collaborators. Global, regional, and national incidence,

controlled phase 2 trial. Lancet Neurol. 2017;16(6):425-434.

prevalence, and years lived with disability for 328 diseases and injuries for 195

20. Silberstein SD, Dodick DW, Bigal ME. Fremanezumab for the preventive

countries, 1990-2016: a systematic analysis for the Global Burden of Disease

treatment of chronic migraine. N Engl J Med. 2017;377(22):2113-2122.

Study 2016. Lancet. 2017;390(10100):1211-1259.

21. Aimovig [package insert]. Thousand Oaks, CA: Amgen; 2020.

3. National Health Interview Survey, 2015. CDC Website. https://www.cdc.

22. Ajovy [package insert]. North Wales, PA:Teva Pharmaceuticals USA, Inc; 2020.

gov/nchs/nhis/index.htm. Reviewed April 30, 2020. Accessed May 12, 2020.

23. Emgality [package insert]. Indianapolis, IN: Eli Lilly; 2018.

4. Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and

24. Vyepti [package insert]. Bothell, WA: Lundbeck Seattle BioPharmaceuticals,

severe headache in the United States: figures and trends from government

Inc; 2020.

health studies. Headache. 2018;58(4):496-505.

25. Shi L, Lehto SG, Zhu DX et al. Pharmacologic characterization of AMG

5. Steiner TJ, Stovner LJ,Vos T, Jensen R, Katsarava Z. Migraine is first cause of disab ili

334, a potent and selective human monoclonal antibody against the calcitonin

ty in under 50s: will health politicians now take notice? J Headache Pain. 2018;19(1):17.

gene-related peptide receptor. J Pharmacol Exp Ther. 2016;356(1):223-231.

6. Headache Classification Committee of the International Headache Society

26. Ashina M, Tepper S, Brandes JL, et al. Efficacy and safety of erenumab

(IHS). The International Classification of Headache Disorders, 3rd edition.

(AMG334) in chronic migraine patients with prior preventive treatment

Cephalalgia. 2018;38(1):1-211.

failure: a subgroup analysis of a randomized, double-blind, placebo-controlled

7. Buse DC, Pearlman SH, Reed ML, Serrano D, Ng-Mak DS, Lipton RB.

study. Cephalalgia. 2018;38(10):1611-1621.

Opioid use and dependence among persons with migraine: results of the

27. Dodick DW, Ashina M, Brandes JL ARISE: a phase 3 randomized trial of

AMPP study. Headache. 2012;52(1):18-36.

erenumab for episodic migraine. Cephalalgia. 2018;38(6):1026-1037.

8. Bonafede M, Sapra S, Shah N, Tepper S, Cappell K, Desai P. Direct and

28. Melo-Carrillo A, Strassman AM, Nir RR, et al. Fremanezumab — a human-

indirect healthcare resource utilization and costs among migraine patients in

ized monoclonal anti-CGRP antibody — inhibits thinly myelinated (Aδ) but not

the United States. Headache. 2018;58(5):700-714.

unmyelinated (C) meningeal nociceptors. J Neurosci. 2017;37(44):10587-10596.

9. Lipton RB, Bigal ME, Diamond M, et al; AMPP Advisory Group. Migraine

29. Chan C, Goadsby PJ. CGRP pathway monoclonal antibodies for cluster

prevalence, disease burden, and the need for preventive therapy. Neurology.

headache [published online April 2, 2020]. Expert Opin Biol Ther. doi:10.1080/1

2007;68(5):343-349.

4712598.2020.1751114

10. Hepp Z, Dodick DW, Varon SF, et al. Persistence and switching patterns of

30. Dodick DW, Silberstein SD, Bigal ME, et al. Effect of fremanezumab

oral migraine prophylactic medications among patients with chronic migraine:

compared with placebo for prevention of episodic migraine: a randomized

a retrospective claims analysis. Cephalalgia. 2017;37(5):470-485.

clinical trial. JAMA. 2018;319(19):1999-2008.

11. Linde M, Mulleners WM, Chronicle EP, McCrory DC. Gabapentin or pre-

31. FDA approves first treatment for episodic cluster headache that reduces

gabalin for the prophylaxis of episodic migraine in adults. Cochrane Database

the frequency of attacks new reference [news release]. US Food and Drug

Syst Rev. 2013;(6):CD010609.

Administration. June 4, 2019. Accessed April 24, 2020.

12. Linde M, Mulleners WM, Chronicle EP, McCrory DC. Topiramate for

32. Detke HC, Goadsby PJ, Wang S, Friedman DI, Selzler KJ, Aurora SK.

the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev.

Galcanezumab in chronic migraine: the randomized, double-blind, placebo-

2013;(6):CD010610.

controlled REGAIN study. Neurology. 2018;91(24):e2211-e2221.

13. Linde M, Mulleners WM, Chronicle EP, McCrory DC. Valproate (valproic

33. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR.

acid or sodium valproate or a combination of the two) for the prophylaxis of

Evaluation of galcanezumab for the prevention of episodic migraine: the

episodic migraine in adults. Cochrane Database Syst Rev. 2013;(6):CD010611.

EVOLVE-1 randomized clinical trial. JAMA Neurol. 2018;75(9):1080-1088.

14. Blumenfeld AM, Bloudek LM, Becker WJ, et al. Patterns of use and reasons

34. Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy

for discontinuation of prophylactic medications for episodic migraine and

and safety of galcanezumab for the prevention of episodic migraine: results

chronic migraine: results from the second international burden of migraine

of the EVOLVE-2 phase 3 randomized controlled clinical trial. Cephalalgia.

study (IBMS-II). Headache. 2013;53(4):644-655.

2018;38(8):1442-1454.

15. Herd CP, Tomlinson CL, Rick C, et al. Botulinum toxins for the prevention

35. FDA approves new treatment for adults with migraine. US Food and

of migraine in adults. Cochrane Database Syst Rev. 2018;6:CD011616.

Drug Administration. December 23, 2019. Accessed April 24, 2020.

16. Ashkenazi A, Blumenfeld A. OnabotulinumtoxinA for the treatment of

36. Ashina M, Saper J, Cady R, et al. Eptinezumab in episodic migraine: a

headache. Headache. 2013;53(Suppl2):54-61.

randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalalgia.

17. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine:

2020;40(3):241-254.

studies characterizing cerebrovascular and neuropeptide changes seen in

37. Lipton RB, Goadsby PJ, Smith J, et al. Efficacy and safety of eptinezumab in

humans and cats. Ann Neurol. 1993;33(1):48-56.

patients with chronic migraine: PROMISE-2. Neurology. 2020:94(13):e1365-e1377.

18. Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab

38. Lipton RB, Serrano D, Holland S, Fanning KM, Reed ML, Buse DC. Barriers

for episodic migraine. N Engl J Med. 2017;30;377(22):2123-2132.

to the diagnosis and treatment of migraine: effects of sex, income, and head-

19. Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for

ache features. Headache. 2013;53(1):81-92.

20 THE CLINICAL ADVISOR • JUNE 2020 • www.ClinicalAdvisor.com

Dermatology Clinic CASE #1

Ulcerated, Raised, Hypertrophic Nodule on Leg YELENA DOKIC, BSA; ELEANOR JOHNSON, BS; CHRISTOPHER RIZK, MD

A 53-year-old man presents to the clinic with ulcerated, scarred, and hypertrophic plaques on both lower extremities. He is a refugee from Sudan who arrived in the United States a month earlier. He reports that the lesions started as red bumps that slowly expanded and developed a raised border. Several of his family members in Sudan have had similar lesions in the past, and he is concerned that he may have developed the same condition. What is your diagnosis? Turn to page 22

CASE #2

Pigmented Macular Lesion on Hand YASMIN KHALFE, BA; EMILY BURNS, BA; CHRISTOPHER RIZK, MD

An 8-year-old boy presents with a 2-month history of an asymptomatic rash on the dorsum of his right hand. He and his family have recently moved from a coastal region in Mexico. Medical and family history are otherwise unremarkable. On examination, he has a 2-cm pigmented macular lesion with an irregular outline centrally located on the dorsal aspect of his right hand.The remainder of the physical examination is normal. Dermoscopy rules out a nevoid lesion, and septated filaments are observed on potassium hydroxide (KOH) test. What is your diagnosis? Turn to page 23 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2020 21

Dermatology Clinic CASE #1

Cutaneous Leishmaniasis

Leishmaniasis is a disease caused by intracellular protozoan parasites predominantly found in tropical areas of the world. Leishmania-like species have been discovered in amber dating back more than 100 million years.1 Archeologists discovered evidence of leishmaniasis in samples from Egyptian mummies as well as tablets from ancient Arabic societies.1 William Boog Leishman, a Scottish pathologist, discovered ovoid bodies in smears taken from the spleen of a soldier who died from emaciation and splenomegaly while in Calcutta, India, in 1900.1 Around the same time, Charles Donovan, a physician and professor of physiology, discovered similar ovoid bodies in splenic smears from Indian patients who had fever and splenomegaly.1 These 2 physicians are credited with the discovery of the parasite that causes visceral leishmaniasis.1 Leishmaniasis is categorized into 3 types: cutaneous, mucocutaneous, and visceral. Cutaneous leishmaniasis can be found in many places around the world, specifically in Latin America, Africa, Asia, and southern Europe. An estimated 350 million people are at risk for the disease; the worldwide prevalence is 12 million, with an annual incidence of cutaneous leishmaniasis of 1.5 million cases.2 The condition is particularly prevalent in the Middle East and North African countries, such as Afghanistan, Iran, Iraq, Morocco, Pakistan, Saudi Arabia, Sudan, Syria, and Yemen.3 Transmitted via an insect bite of infected female phlebotomine sand flies, leishmaniasis is caused by intracellular protozoan parasites of the genus Leishmania.4 Specifically, when a sand fly bites a host, it transmits the parasite in the promastigote form through its proboscis.These promastigotes are then phagocytosed by the host macrophages, transformed into amastigotes and multiply, and then spread to different tissues of the body. Sandflies can then have a blood meal on an infected host and become infected with amastigotes, which migrate to the gut of the sand fly to multiply. These amastigotes develop into promastigotes and then migrate to the sand fly’s proboscis to repeat the process when having a blood meal on the next host.4 The amastigotes within the macrophages are termed Leishman-Donovan bodies and can be visualized histologically.2 Initially, a wide variety of inflammatory cells are present at the site of infection. Histologic appearance of chronic lesions is characterized based on the strength of the immune

response of the host. If the immune response is sufficient, then epithelioid granulomata with few parasites are seen. If the immune response is poor, then a diffuse macrophage infiltrate with many parasites is seen.The immune response is T-cell-mediated, but the outcome differs in Th1 lymphocyte vs Th2 lymphocyte responses. Generally, the Th1 lymphocyte response leads to better outcomes.2,5 The cutaneous form of leishmaniasis is caused by approximately 14 different species of protozoa within the genus Leishmania, including L mexicana, L brasiliensis, L donovani, among others.2 Knowing the species of Leishmania that infected a patient can be useful because certain species are associated with prolonged, more severe courses of disease.

The differential diagnosis of leishmaniasis can be broad, primarily due to considerable variation in presentation of the lesions. Risk factors for cutaneous leishmaniasis include living in or visiting endemic regions or urban areas, warmer climate, environmental factors such as proximity of housing to dams and cowsheds, cracks in the walls of houses that encourage sand fly aggregation, and a suppressed immune system such as in individuals with HIV.6 Additionally, travelers and military personnel are at risk.7 Clinically, leishmaniasis appears initially as a small papule. If the lesion enlarges and develops an area of central necrosis, resembling the appearance of a volcano, then the lesion is termed a “wet” lesion.2,7 However, if the initial small papule either remains smooth or becomes hyperkeratotic, then the lesion is called a “dry” lesion.2,7 The outcome associated with a wet or a dry lesion can vary with different species of Leishmania.The edge of the lesion is thickened, and ulceration rarely extends into the subcutaneous tissue. Lesions develop on exposed areas of the skin where the sand fly can get access for a blood meal; however, satellite lesions may also develop due to the local spread of parasites. The size of the lesion is typically <5 cm in diameter but can reach up to 10 cm.2 The differential diagnosis of leishmaniasis can be broad, primarily due to considerable variation in presentation of the lesions. Several conditions that may mimic leishmaniasis include infected insect bites, ulceroglandular tularemia, cutaneous anthrax, cutaneous tuberculosis, and leprosy.2,7 It is also important to include noninfectious conditions such as basal cell carcinoma, squamous cell carcinoma, cutaneous lymphoma, and pyoderma gangrenosum within the differential.2,7

22 THE CLINICAL ADVISOR • JUNE 2020 • www.ClinicalAdvisor.com

A diagnosis is made by performing a 4-mm punch biopsy at the edge of the lesion and histologic examination. Classically, the presence of amastigotes within macrophages is specific for a diagnosis of leishmaniasis.7 The amastigotes may also be visualized in skin scrapings or smears. Polymerase chain reaction is being used increasingly as a method to detect Leishmania DNA and make the diagnosis, as it is the most sensitive technique.7 Prevention is essential for controlling leishmaniasis.This can be accomplished by the use of nets and insecticide, especially while sleeping.7 Once an individual has developed cutaneous leishmaniasis, treatment methods include pentavalent antimonials (meglumine antimoniate and sodium stibogluconate), paromomycin, miltefosine, and pentamidine.2,7 The size of the lesion should decrease after several weeks of treatment. If left untreated, it may take several months to a year for the ulcers to self-heal. Disfiguring scars can often appear. Therefore, the goals of treatment are to prevent local dissemination of parasites, decrease the size of the scar, and accelerate the healing process.7,8 The patient in this case underwent a punch biopsy of his lesion, and histologic examination revealed Leishman-Donovan bodies.The Centers for Disease Control and Prevention was notified, and the patient was referred to an infectious disease specialist for treatment. Yelena Dokic, BSA, and Eleanor Johnson, BS, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is a dermatologist affiliated with Elite Dermatology in Houston,Texas. References 1. Steverding D. The history of leishmaniasis. Parasit Vectors. 2017;10(1):82. 2. Bailey MS, Lockwood DN. Cutaneous leishmaniasis. Clin Dermatol. 2007;25(2):203-211. 3. Postigo JAR. Leishmaniasis in the World Health Organization Eastern Mediterranean region. Int J Antimicrob Agents. 2010;36(Suppl 1): S62-S65. 4. Gossage SM, Rogers ME, Bates PA. Two separate growth phases during the development of Leishmania in sand flies: implications for understanding the life cycle. Int J Parasitol. 2003;33(10):1027-1034. 5. Ghersetich I, Menchini G, Teofoli P, Lotti T. Immune response to Leishmania infection in human skin. Clin Dermatol. 1999;17(3):333-338. 6. Desjeux P. The increase in risk factors for leishmaniasis worldwide. Trans R Soc Trop Med Hyg. 2001;95(3):239-243. 7. Murray HW, Berman JD, Davies CR, Saravia NG. Advances in leishmaniasis. Lancet. 2005;366(9496):1561-1577. 8. Shin JY, Lee YB, Cho BK, Park HJ. New world cutaneous leishmaniasis treated with intralesional injection of pentavalent antimony. Ann Dermatol. 2013;25(1):80-83.

CASE #2

Tinea Nigra

Tinea nigra is an uncommon superficial fungal infection. It is strictly limited to the stratum corneum and is caused by dematiaceous fungi.The characteristic causative organism of tinea nigra is Hortaea werneckii, a fungus that grows as a black yeast and can transform into a mold.1,2 The fungus is halophilic and favors hypersaline environments up to 30% NaCl, such as coastal regions.3 Other fungi that have been considered to cause tinea nigra are Cladosporium castellanii, Cladophialophora saturnica, and Phoma hibernica.4-7 The condition was first described in 1973 in Venezuela.4 Although tinea nigra is generally not associated with other manifestations in the body, H werneckii was reportedly isolated from a splenic abscess in 2 patients in 2005.8 Most cases of tinea nigra have been reported in Latin America, Asia, Africa, and the Pacific Islands.2,9-13 Tinea nigra has less commonly been reported in Europe and the United States.2 The condition is more commonly seen in children and adolescents. The most important predisposing factor for tinea nigra is hyperhidrosis, and it is most commonly found in the palmoplantar regions of the body.2 Initially, the organism most likely attaches to its host through minor trauma. The incubation time of H werneckii is unknown but may vary from weeks to years.12 It is seen less commonly on the arms, legs, neck, trunk, and dorsal aspects of the hands.1,2,9,10,14 Typically, tinea nigra is unilateral and appears as a brown to gray macule or plaque that is hyperpigmented and circumscribed. The lesion can become darker at the borders with an irregular outline. Some patients have observed that the macules change color throughout the day.2 Patients are typically asymptomatic, but occasionally patients report pruritus.1,2 Diagnosis of tinea nigra is based on clinical physical findings and confirmed with a laboratory diagnosis of fungal infection. This can be performed by direct mycological examination with 10% to 20% KOH preparation. KOH prep testing of the affected skin scraping reveals dematiaceous, septate hyphae with colors that vary from brown to black on microscopic examination.1,2,9,10,15 Dermoscopy is also useful for distinguishing tinea nigra from a melanocytic lesion. Tinea nigra will show a nonmelanocytic-pattern macule with superficial brown pigmentation in specks. Seeing the characteristic fungal growth pattern can help differentiate the infection from nevi, particularly melanoma.1

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2020 23

Dermatology Clinic Culturing of the affected skin on Sabouraud glucose agar with or without antibiotics, incubated at 28 °C, usually reveals fungal growth within 5 to 6 days.1 The fungus grows in 2 phases: the initial yeast-like phase shows smooth colonies that can be creamy in appearance and dark green to black in color, and the mold phase shows fungus as filaments with wooly or smooth appearance and filamentous hyphae.1 The differential diagnosis for tinea nigra should include melanocytic nevi, lentigines, palmar lichen planus, fixed drug eruptions, and melanoma.16,17 These can be distinguished from tinea nigra by fungal culture, KOH prep, or skin biopsy. Light brown, wavy, and thick hyphae with occasional dark hyphae differentiate tinea nigra from other fungal infections, particularly those caused by conidia, which appear more uniformly heavily pigmented.2 On

3. Kogej T, Stein M, Volkmann M, Gorbushina AA, Galinski EA, GundeCimerman N. Osmotic adaptation of the halophilic fungus Hortaea werneckii: role of osmolytes and melanization. Microbiology. 2007;153(12):4261-4273. 4. Borelli D, Marcano C. Cladosporium castellanii nova espécie agente de tinea nigra. Castellania. 1973;1:151-154. 5. Crous PW, Braun U, Schubert K, Groenewald JZ. Delimiting Cladosporium from morphologically similar genera. Stud Mycol. 2007;58:33-56. 6. Bakerspigel A. The isolation of Phoma hibernica from a lesion on a leg. Sabouraudia. 1969;7(3):261-264. 7. Badali H, Carvalho VO, Vicente V, et al. Cladophialophora saturnica sp. nov., a new opportunistic species of Chaetothyriales revealed using molecular data. Med Mycol. 2009;47(1):51-62. 8. Ng KP, Soo-Hoo TS, Na SL, et al. The mycological and molecular study of Hortaea werneckii isolated from blood and splenic abscess. Mycopathologia. 2005;159(4):495-500.

Tinea nigra appears as a hyperpigmented brown to gray macule or plaque that is circumscribed, often darker on the edges.

9. Perez C, Colella MT, Olaizola C, Hartung de Capriles C, Magaldi S, MataEssayag S. Tinea nigra: report of twelve cases in Venezuela. Mycopathologia. 2005;160(3):235-238. 10. Severo LC, Bassanesi MC, Londero AT. Tinea nigra: report of four cases observed in Rio Grande do Sul (Brazil) and a review of Brazilian literature. Mycopathologia. 1994;126(3):157-162. 11. Cabrera R, Sabatini N, Urrutia M, Sepúlveda R. [Tinea nigra: a

hematoxylin and eosin stain, hyphae and spores are seen at the stratum corneum.1 Due to the irregular borders, pigmentation, and growth of the lesion, tinea nigra may be mistaken for melanoma.13 An accurate diagnosis is important in order to prevent unnecessary diagnostic and excisional surgery as well as scarring. Treatment of tinea nigra include topical antifungals bifonazole, clotrimazole, ketoconazole, terbinafine, and ciclopirox olamine gel.2,18-21 Oral itraconazole was first reported to be effective in a case correspondence.22 Topical keratolytic agents such as 3% salicylic acid or Whitfield ointment (6% benzoic acid and 3% salicylic acid) may also be beneficial.2 Oral griseofulvin has not been found to be effective.1 No randomized controlled clinical trials have evaluated treatments for tinea nigra. Overall, tinea nigra is found to clear quickly and effectively with these treatments. The patient in this case was prescribed topical ketoconazole cream for 4 weeks, and the lesion regressed. ■

allochthonous case report in Chile]. Rev Chilena Infectol. 2013;30(1):90-93. 12. Pegas JR, Criado PR, Lucena SK, de Oliveira MA. Tinea nigra: report of two cases in infants. Pediatr Dermatol. 2003;20(4):315-317. 13. Uezato H, Gushi M, Hagiwara K, Kayo S, Hosokawa A, Nonaka S. A case of tinea nigra palmaris in Okinawa, Japan. J Dermatol. 2006;33(1):23-29. 14. Gupta AK, Chaudhry M, Elewski B. Tinea corporis, tinea cruris, tinea nigra, and piedra. Dermatol Clin. 2003;21(3):395-400. 15. Veasey JV, Avila RB, Miguel BAF, Muramatu LH. White piedra, black piedra, tinea versicolor, and tinea nigra: contribution to the diagnosis of superficial mycosis. An Bras Dermatol. 2017;92(3):413-416. 16. Tseng SS, Whittier S, Miller SR, Zalar GL. Bilateral tinea nigra plantaris and tinea nigra plantaris mimicking melanoma. Cutis. 1999;64(4):265-268. 17. Hall J, Perry VE. Tinea nigra palmaris: differentiation from malignant melanoma or junctional nevi. Cutis. 1998;62(1):45-46. 18. Sarangi G, Dash D, Chayani N, Patjoshi SK, Jena S. Bilateral tinea nigra of palm: a rare case report from Eastern India. Indian J Med Microbiol. 2014;32(1):86-88. 19. Burke WA. Tinea nigra: treatment with topical ketoconazole. Cutis. 1993;52(4):209-211.

Yasmin Khalfe, BA, and Emily Burns, BA, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is a dermatologist at Elite Dermatology in Houston,Texas.

20. Rossetto AL, Cruz RC, Haddad Junior V. [Double-blind study with topical isoconazole and terbinafine for the treatment of one patient with bilateral tinea nigra plantaris and suggestions for new differential diagnosis.] Rev Inst Med Trop Sao Paulo. 2013;55(2):125-128.

References

21. Rosen T, Lingappan A. Rapid treatment of tinea nigra palmaris with

1. Bonifaz A, Badali H, de Hoog GS, et al. Tinea nigra by Hortaea werneckii, a

ciclopirox olamine gel, 0.77%. Skinmed. 2006;5(4):201-203.

report of 22 cases from Mexico. Stud Mycol. 2008;61:77-82.

22. Gupta G, Burden AD, Shankland GS, Fallowfield ME, Richardson MD.

2. Bonifaz A, Gómez-Daza F, Paredes V, Ponce RM. Tinea versicolor, tinea nigra,

Tinea nigra secondary to Exophiala werneckii responding to itraconazole.

white piedra, and black piedra. Clin Dermatol. 2010;28(2):140-145.

Br J Dermatol. 1997;137(3):483-484.

24 THE CLINICAL ADVISOR • JUNE 2020 • www.ClinicalAdvisor.com

Dermatologic Look-Alikes Multiple Pustular Eruptions ALEXANDRIA BROWN, BSA; SHRAVYA POTHULA, BS; EMILY BURNS, BA; CHRISTOPHER RIZK, MD

CASE #1

CASE #2

A 50-year-old man presents with a 2-day history of fever, malaise, and erythematous skin with widespread pustules. He reports a history of psoriasis and is concerned about the recent development of skin pustules.The patient is also febrile and has an upper respiratory tract infection. Biopsy of a pustular lesion is performed. On histopathologic examination, the lesion displays neutrophilic infiltration and psoriasiform changes of the epidermis. Laboratory testing reveals leukocytosis and an elevated erythrocyte sedimentation rate (ESR).

A 21-year-old woman presents to the dermatology clinic with fever and a generalized pustular rash on her torso that developed 2 days ago. The rash is pruritic and has sterile, nonfollicular, pinhead-sized pustules over an erythematous, edematous base. She reports the rash first appeared in the axillary folds and then spread to her arms and trunk. Last week, she was prescribed amoxicillin for a urinary tract infection and has been taking ibuprofen as needed for symptomatic relief. She states that she has not had a similar rash before.

www.ClinicalAdvisor.com â&#x20AC;˘ THE CLINICAL ADVISOR â&#x20AC;˘ JUNE 2020 25

Dermatologic Look-Alikes CASE #1

Generalized Pustular Psoriasis

Generalized pustular psoriasis (GPP) is a severe form of psoriasis characterized by diffuse pustules and plaques with erythema of the underlying skin. The course of the disease varies, with waxing and waning symptoms potentially occurring for a number of years.1 GPP is a rare subtype of psoriasis that can be found in all racial and ethnic groups and in both sexes. Patients may or may not report a prior diagnosis of plaque psoriasis. The disease can occur at any age but is most prevalent between the ages of 40 and 59 years. Common associations include inflammatory polyarthritis, diabetes, hypertension, and dyslipidemia.2,3 Based on appearance and history, GPP is classified into the following subtypes: von Zumbusch, impetigo herpetiformis, and infantile and juvenile GPP.3-5 GPP of von Zumbusch occurs acutely and is accompanied by malaise, fever, leukocytosis, and an elevated ESR.1,4,5 The pustules are typically 2 to 3 mm in size and occur at the periphery of an erythematous base. Extracutaneous involvement can include acute renal failure, interstitial pneumonitis, cholestasis, and cholangitis. These manifestations may warrant inpatient monitoring.5 Impetigo herpetiformis, also known as GPP of pregnancy, may present late in pregnancy, with the lesions resolving in the postpartum period. Lesions typically begin in axillary, groin, submammary, popliteal, and antecubital areas symmetrically. The lesions then spread radially and typically spare the palms, soles, and face. Cases may be severe, with symptoms and signs including malaise, fever, nausea, leukocytosis, and an increased ESR. Hypocalcemia resulting in tetany has also been observed.4,5 Infantile and juvenile GPP is similar to adult-onset GPP but typically has a more benign course and more frequently resolves spontaneously.3 These cases are exceptionally rare.5 Although the etiology of GPP is unknown, potential triggers of disease include drugs, infections, psychological stress, pregnancy, and hypocalcemia.2 Both bacterial and viral infections have been cited as potential inciting factors for GPP. In particular, GPP may occur alongside an upper respiratory tract infection due to the activation of neutrophils.4 Conditions resulting in fluctuating hormone levels, such as stressful life events and pregnancy, are associated with the development of GPP.2,3 Systemic corticosteroid withdrawal in patients with plaque psoriasis may also incite GPP.2,3 Other drugs that have been implicated in the disease include antihypertensive agents, antibiotics, bupropion, terbinafine, and various biologic agents.3 A pustular reaction to a new

drug, however, warrants consideration of acute generalized exanthematous pustulosis (AGEP). Histologic examination of GPP reveals epidermal spongiform pustules of Kogoj, neutrophilic infiltrate, dilated tortuous vessels, Munro microabscesses, parakeratosis, epidermal edema, and epidermal hyperplasia.4,5 Previously, GPP was considered a subtype of plaque psoriasis; however, recent research has identified unique genetic factors distinct to GPP.5 Mutations in the IL36RN gene, which codes for interleukin-36 receptor antagonist (IL-36RA) protein, result in increased proinflammatory pathways including overproduction of IL-36 and IL-1 cytokines. GPP with this genetic mutation is called “deficiency in IL-36RA” or “DITRA”.4,5 Notably, not all patients presenting with GPP have with this genetic variant.4 Treatment of GPP depends on a number of factors. Recurrences are common, so long-term therapy is recommended. In adults with GPP, treatment with a retinoid such

Potential triggers of generalized pustular psoriasis include drugs, infections, stress, pregnancy, and hypocalcemia. as acitretin is most efficacious for nonacute flares. Retinoids are associated with capillary leak syndrome, and they are contraindicated in pregnant women due to teratogenic effects.4-6 Other first-line treatments include infliximab, methotrexate, and cyclosporine. In patients with severe acute disease, cyclosporine and infliximab are first-line agents due to their rapid onset.4 First-line therapies for pregnant patients include oral corticosteroids, cyclosporine, and infliximab. First-line therapies for juvenile and infantile pustular psoriasis include acitretin, cyclosporine, methotrexate, and etanercept. However, acitretin has been linked to various skeletal toxicities, so this association should be considered when treating children.4,5 Second-line therapies for all subtypes include topical corticosteroids, phototherapy (psoralen plus ultraviolet A), adalimumab, and etanercept.4-6 The presentation of GPP varies from fairly benign to extremely severe. Patients with severe GPP and comorbid conditions may be unable to tolerate first-line treatments. In a case report by Jeon and Nakamura, treatment with a phosphodiesterase type 4 (PDE-4) inhibitor was found to be effective for a patient with GPP, hepatitis C virus infection, liver cirrhosis, and hepatocellular carcinoma, as cyclosporine and infliximab are contraindicated

26 THE CLINICAL ADVISOR • JUNE 2020 • www.ClinicalAdvisor.com

Continues on page 28

Dermatologic Look-Alikes in patients with liver disease.7 In the case described, GPP was found to be markedly reduced at 3 weeks and absent at 6 weeks.7 PDE-4 inhibitors decrease tumor necrosis factor and interleukin levels, which counteracts the dysregulation of IL-36 and IL-1 cytokines in patients with DITRA.7 Other therapies targeting immunologic pathways, such as ustekinumab (a monoclonal antibody against IL-12 and IL-23), show promise for the management of GPP.4 In the future, biologic therapies may replace or further supplement traditional systemic therapies as first-line treatments of GPP. Due to the rarity of GPP, the current literature lacks high-quality randomized controlled trials; therefore, these recommendations are based on case reports and clinical experience.6,8 The differential diagnosis of GPP includes AGEP, palmoplantar pustular psoriasis, pustular erythema multiforme, annular pustular psoriasis, and dermatitis with secondary infection. Differentiating GPP from AGEP is particularly important when making the diagnosis.AGEP is associated with antibiotic use and tends to improve more quickly than GPP.5 Diagnostic criteria of GPP include: • Multiple pustules on erythematous skin; • Constitutional symptoms; • Spongiform pustules on histologic examination; and • Laboratory abnormalities such as elevated ESR, elevated C-reactive protein, or leukocytosis.6 The patient in the case described earlier was prescribed oral cyclosporine resulting in resolution of GPP.

CASE #2

Acute Generalized Exanthematous Pustulosis

Acute generalized exanthematous pustulosis (AGEP) is a rare adverse skin reaction usually caused by medication or acute infection. As numerous diseases may present with pustular eruptions, it is imperative that the diagnosis of AGEP is determined by a thorough history and recognition of its unique clinical and histologic features. In the past, widespread pustular eruptions were often classified as GPP, but further research has shown that AGEP has its own set of histopathologic and clinical features and should be classified as a separate entity.9 The incidence of AGEP has been estimated to range from 1 to 5 cases per million persons per year, with no difference based on sex.9 A personal or family history of psoriasis is not

usually associated with AGEP. Removal of the offending drug often protects against recurrence, as 87% to more than 90% of cases have been associated with medications.9,10 Some of the frequent offending agents include aminopenicillins, macrolides, and clindamycin antibiotics; antimalarial agents; and calcium channel blockers. Infectious causes of AGEP are more rare and include parvovirus B19, mycoplasma, cytomegalovirus, Coxsackie B4, Chlamydia pneumoniae, Escherichia coli, echinococcus, and spider bites.11 The clinical hallmark of AGEP is the sudden onset of dozens of sterile, nonfollicular pustules with an edematous, erythematous background within hours to days of taking an inciting medication. This acute rash initially develops in skin folds (axillary, inguinal, and submammary areas) or on the face and spreads quickly to the trunk and limbs within a few hours.11 The skin lesions will often

The hallmark of AGEP is the sudden onset of sterile, nonfollicular pustules within hours of taking an inciting medication. be pruritic, and patients may experience fever, headache, neutrophilia, and possibly eosinophilia.The lesions tend to resolve within 1 to 3 days of stopping the offending medication. However, a postpustular desquamation period usually follows and fully resolves within 15 days. Although systemic complications are rare, severe cases have been reported involving the liver, lung, kidney, and/or bone marrow.9 Biopsy of a pustule and histopathologic examination are crucial for distinguishing AGEP from other pustular eruptions. Typically, examination will reveal subcorneal and/or intraepidermal pustules, spongiosis of the stratum spinosum, edema of the papillary dermis, necrotic keratinocytes, and infiltration of neutrophils and possible eosinophils.11 Although pustular eruptions can be found in a wide spectrum of cutaneous diseases, most can be easily differentiated from AGEP with a thorough physical examination, history, and histopathologic findings. Differential diagnosis of AGEP includes bacterial folliculitis, localized pustular contact dermatitis, GPP, drug hypersensitivity syndrome (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). The presentation of DRESS includes a morbilliform rash, with possible pustules, that spreads from the face to the rest of the body. DRESS, however, has a 2- to 6-week latent period, a less-pronounced pustular component, and more commonly has systemic and mucous membrane involvement compared with AGEP.11 Furthermore, SJS and TEN characteristically

28 THE CLINICAL ADVISOR • JUNE 2020 • www.ClinicalAdvisor.com

Generalized Pustular Psoriasis (GPP)1-8

Acute Generalized Exanthematous Pustulosis (AGEP)9-15

Etiology

• Unknown • Associated with deficiency in IL-36RA • Drugs, infections, psychological stress, pregnancy, and hypocalcemia

• Usually drug related • Can be associated with bacterial or viral infections

Clinical Characteristics

• Confluent, sterile pinhead-sized (2-3 mm in diameter) pustules on erythematous background • Generalized distribution • Elevated erythrocyte sedimentation rate, leukocytosis, or elevated C-reactive protein • Constitutional symptoms including fever and malaise

• Diffuse, sterile pinhead-sized pustules on an erythematous, edematous background • Predominantly in skin folds and face • Occurs hours to days after administration of offending drug

Histology

• Epidermal spongiform pustules of Kogoj • Neutrophilic infiltration • Munro microabscesses • Parakeratosis • Dilated, tortuous blood vessels

• Subcorneal spongiform pustules • Edematous papillary dermis • Necrotic keratinocytes • Exocytosis of eosinophils in pustules or dermis

Associations

• Plaque psoriasis • Pregnancy • Inflammatory polyarthritis • Diabetes, hypertension, dyslipidemia

• Prior reaction to offending agent

Diagnosis and Treatment

First line: • Acitretin, cyclosporine, methotrexate, infliximab

• Discontinue offending agent • Symptomatic treatment (antipyretics, antihistamines, topical corticosteroids)

Second line: • Adalimumab, etanercept, phototherapy, topical corticosteroids

have full-thickness epidermal necrosis and detachment with sparse inflammatory infiltrate, while epidermal detachment is much more superficial in AGEP.11 Severe cases of AGEP may be difficult to differentiate from these entities, but one of the most important clinical factors for the diagnosis of AGEP is the shorter resolution time.12 Acute GPP can often present with a clinical picture and histopathologic findings similar to those seen with AGEP, making differentiation especially difficult. While AGEP tends to distribute to the face and/or skin folds, GPP has a more generalized distribution pattern.10 Key histologic features distinguishing AGEP from GPP is the presence of eosinophils in the pustules or dermis, necrotic keratinocytes, and the absence of dilated, tortuous blood vessels. Additionally, psoriatic characteristics like papillomatosis and acanthosis are usually present in GPP but absent in AGEP.13 Although distinguishing AGEP from GPP may be difficult, it is important to do so in order to identify the offending agent and provide the correct treatment. In 2001, a multinational epidemiologic case-control study on severe cutaneous adverse reactions (EuroSCAR study group)

presented the AGEP validation score. This scoring system helps standardize the process of diagnosing AGEP. It takes into account the morphology of skin lesions, clinical course, presence of fever, and laboratory and histopathologic findings.9 In cases of polymedication, a patch test, skin allergy test, and/or in vitro testing may be performed in order to identify the offending agent. The patch test must be performed after complete resolution of the lesion. Positive results show small pustules at the location of testing.14 However, due to their lack of specificity and sensitivity, these tests have not been widely adopted for the diagnosis of AGEP. AGEP often has a benign, self-limited course after cessation of the offending agent. If a patient requires treatment for an underlying condition, an alternative medication should be prescribed. Systemic corticosteroids are usually not necessary; however, antipyretics, antihistamines, and local corticosteroids may be given for symptomatic relief. Additionally, superinfection of skin lesions, high fever, and organ involvement can sometimes lead to life-threatening situations in elderly or immunocompromised patients. Rapid administration of systemic corticosteroids, antibiotics, supportive care, and/or

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2020 29

Dermatologic Look-Alikes organ-specific interventions are critical in the treatment of these complications.15 For the patient in the case described, a biopsy of the lesions was performed and results of histopathologic examination were consistent with AGEP.Amoxicillin was determined to be the likely culprit, and the patient was advised to discontinue that medication. After discontinuing amoxicillin, the lesions resolved with no recurrence. ■

psoriasis: a review and update on treatment. J Eur Acad Dermatol Venereol, 2018;32(10):1645-1651. 6. Robinson A, Van Voorhees AS, Hsu S, et al. Treatment of pustular psoriasis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2012;67(2):279-288. 7. Jeon C, Nakamura M, Sekhon S, et al. Generalized pustular psoriasis treated with apremilast in a patient with multiple medical comorbidities. JAAD Case Reports. 2017;3(6):495-497. 8. Kim H-S, You H-S, Cho H-H, et al. Two cases of generalized pustular psoria-

Alexandria Brown, BSA, Shravya Pothula, BS, and Emily Burns, BA, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is a certified dermatologist at Elite Dermatology in Houston,Texas.

sis: successful treatment with infliximab. Ann Dermatol. 2014;26(6):787-788. 9. Sidoroff A, Halevy S, Bavinck JN, Vaillant L, Roujeau JC. Acute generalized exanthematous pustulosis (AGEP) - a clinical reaction pattern. J Cutan Pathol. 2001;28(3):113-119. 10. Roujeau JC, Bioulac-Sage P, Bourseau C, et al. Acute generalized exanthema-

References

tous pustulosis. Analysis of 63 cases. Arch Dermatol. 1991;127(9):1333-1338.

1. Sousa AS, Lara OA, Papaiordanou F, Marchioro GS,Tebcherani AJ. Acute gen-

11. Feldmeyer L, Heidemeyer K, Yawalkar N. Acute generalized exanthema-

eralized exanthematous pustulosis x Von Zumbusch’s pustular psoriasis: a diag-

tous pustulosis: pathogenesis, genetic background, clinical variants and therapy.

nostic challenge in a psoriatic patient. An Bras Dermatol. 2015;90(4):557-560.

Int J Mol Sci. 2016;17(8):1214-1221.

2. Choon SE, Lai NM, Mohammad NA, Nanu NM, Tey KE, Chew SF. Clinical

12. Kardaun SH, Kuiper H, Fidler V, Jonkman MF.The histopathological spectrum

profile, morbidity, and outcome of adult-onset generalized pustular

of acute generalized exanthematous pustulosis (AGEP) and its differentiation

psoriasis: analysis of 102 cases seen in a tertiary hospital in Johor, Malaysia.

from generalized pustular psoriasis. J Cutan Pathol. 2010;37(12):1220-1229.

Int J Dermatol. 2014;53(6):676-684.

13. Orime M. Immunohistopathological findings of severe cutaneous adverse

3. Boehner A, Navarini, AA, Eyerich, K. Generalized pustular psoriasis –

drug reactions. J Immunol Res. 2017;2017:1-5.

a model disease for specific targeted immunotherapy, systematic review.

14. Wolkenstein P, Chosidow O, Fléchet ML, et al. Patch testing in severe

Exp Dermatol. 2018;27(10):1067-1077.

cutaneous adverse drug reactions, including Stevens-Johnson syndrome and

4. Benjegerdes K, Hyde K, Kivelevitch D, Mansouri B. Pustular psoriasis: pathophysi-

toxic epidermal necrolysis. Contact Dermatitis. 1996;35(4):234-236.

ology and current treatment perspectives. Psoriasis (Auckl). 2016;6:131-144.

15.Thienvibul C,Vachiramon V, Chanprapaph K. Five-year retrospective review of

5. Hoegler KM, John AM, Handler MZ, Schwartz RA. Generalized pustular

acute generalized exanthematous pustulosis. Dermatol Res Pract. 2015;2015:1-8.

Become a Peer Reviewer for

The Clinical Advisor is seeking highly qualified peer reviewers to review our manuscript submissions. All of our feature articles, case studies, and clinical challenges undergo medical peer review. Each review is double-blinded to ensure confidentiality. If you are interested, please provide a list of the subject areas in which you have expertise, and submit your resume/curriculum vitae to the editor at editor@ClinicalAdvisor.com

30 THE CLINICAL ADVISOR • JUNE 2020 • www.ClinicalAdvisor.com

LEGAL ADVISOR CASE

Shop Closes After Ebola Exposure After treating an Ebola patient, a nurse is cleared for airplane travel. BY ANN W. LATNER, JD

The facts in this case made national headlines when they occurred in late 2014 during the Ebola virus disease (EVD) outbreak. Although most of the 11 affected individuals had contracted the disease outside of the United States, 2 people contracted EVD in the United States; both were nurses who treated an Ebola patient, and both recovered. This case was originally filed in Texas in 2016, then made its way through the trial court and appeals court until the Texas Supreme Court made its final decision in 2020. Ms V was a 29-year-old nurse working in the intensive care unit of a Dallas, Texas, hospital in the fall of 2014. One of her patients was a Liberian man who, while visiting his family in Dallas, had become ill with EVD. Because of the rarity of Ebola in the United States, proper protocols had not been developed or put in place at the hospital. Nurses were told that if personal protective equipment (PPE) left their necks exposed, they should use surgical tape to cover themselves. Despite the best efforts of the healthcare team, the patient died in October. Healthcare workers who had been exposed to the

Healthcare workers exposed to the patient were told to self-monitor, but no specific guidance was given.

patient were told to self-monitor, but no specific guidance was given. Two days after the patient’s death, Ms V flew to her hometown in Ohio to shop for a wedding dress with her bridesmaids. While there, Ms V visited a bridal store as part of this trip. Prior to flying to Ohio, the nurse had asked a contact at the Texas Health Department about travel restrictions due to her exposure to EVD; she was told that travel was permitted. Three days later, MsV was scheduled to fly back to Dallas when her flight got delayed.While she waited, she checked her temperature numerous times and reported the results to the Texas Health Department. When the rescheduled flight was ready to take off, Ms V’s temperature was 99.5° F. She reported her temperature to her contact at the health department, who spoke to a representative at the Centers for Disease Control and Prevention 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.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2020 31

LEGAL ADVISOR (CDC). As her temperature was below the 100.4° F threshold used by the CDC to define fever, and because Ms V showed no symptoms, she was cleared to fly back to Dallas. Two days later, Ms V was diagnosed with EVD. Texas health authorities contacted Ohio health authorities, and upon learning of Ms V’s visit to the bridal store, the Ohio health authorities ordered it to temporarily close to prevent the spread of the virus. The store was thoroughly cleaned and reopened for business a month later.

The hospital moved to dismiss the case as the bridal store did not submit an expert report as required by a Texas statute. However, the story of Ms V’s visit had made the news, and the fear of catching Ebola caused potential customers to avoid the store. Despite efforts to keep the business going, the owners of the store were eventually forced to close. The owners of the bridal store filed a million-dollar lawsuit against the Dallas hospital where Ms V worked, alleging that the hospital negligently failed to prevent the spread of EVD in its control and management of the staff. Specifically, the bridal store owners alleged that the hospital was negligent by failing to: • Recognize the danger of the Ebola virus coming to its hospitals • Develop and implement policies and procedures on how to respond to the presence of the Ebola virus in the patient population • Ensure that all health care providers were trained on policies and procedures on how to recognize, appreciate, contain, and treat the Ebola virus in the patient population • Train nurses on proper protection from Ebola • Ensure that the hospital had appropriate personal protective equipment • Notify the appropriate authorities and employ qualified people to manage patients with Ebola • Instruct and warn its nurses about the dangers of travel and interacting with the public following potential exposure to the Ebola virus • Protect the public from foreseeable harm when it unnecessarily exposed its nurses to the Ebola virus in an unsafe manner and failed to prevent or warn the exposed nurses from interacting with the public. The hospital moved to dismiss the case because the bridal store did not submit an expert report supporting its allegations as required by a Texas statute.

Legal Background

The trial court denied the hospital’s motion to dismiss, and the hospital appealed. The court of appeals reversed, holding that the bridal shop’s claim against the hospital is a health care liability claim and, thus, an expert report is required. The court of appeals dismissed the case. The bridal shop appealed to the Texas Supreme Court, which granted review. The first issue the court analyzed was whether the bridal shop is considered a “claimant” by the Texas Medical Liability Act, which requires an expert report. The court concluded that the Act’s definition of “claimant” includes corporations, regardless of whether the injury alleged was economic or physical. Because the bridal shop had alleged that the hospital was negligent in controlling the spread of Ebola, the hospital fell short of implementing health care-related safety standards. The court held that the claim constituted health care liability under the Texas Medical Liability Act. Because the bridal shop did not submit the required report by an expert detailing the support for and factual basis for the claim, the case was dismissed. Protecting Yourself

This case failed on a technicality. We will never know whether the bridal shop could have found an expert to support its claim. The case is of interest in the context of the current novel coronavirus (COVID-19) pandemic. Can a nurse or hospital be sued if they failed to take enough precautions to prevent the spread of COVID-19 from hospital patients to the public? With the number of COVID cases so vastly different than that seen during the Ebola outbreak in 2014, a flood of cases could cripple an already suffering healthcare system. As always, do your best even in the worst circumstances to protect your patients and yourself. ■ Ann W. Latner, JD, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.

32 THE CLINICAL ADVISOR • JUNE 2020 • www.ClinicalAdvisor.com

Do you have a

Clinical Pearl that you would like to share with your colleagues? Please submit your pearl to: editor@ClinicalAdvisor.com

Complimentary June CME/CE THE CHOICE IS YOURS! Instead of One CME/CE Option Each Month, You Can Choose From Many The same high-quality CME/CE you are accustomed to reviewing in our issues is available online, with more to choose from! CHECK OUT THIS MONTH’S FEATURED CME/CE ACTIVITIES:

Innovative HF Delivery Models: Putting Patients at the Center of Care 0.50 CME/CNE Credit

Navigating the Potential Pitfalls of an ART Regimen 0.25 CME Credit

A Gut Check: Altering the GI Microbiome to Fight the C diff Invasion—Case 3: A 65-Year-Old Man With a History of CDI and Compromised Immunity 0.50 CME Credit CME/CE activities powered by myCME, a leader in online continuing education

Go digital! Access these featured activities— plus many more—on The Clinical Advisor website.

Visit ClinicalAdvisor.com/CE

June 2020 Clinical Advisor

Articles inside

Dermatology Clinic

Legal Advisor

Web Roundup

When a Headache Isn’t a Migraine: A Case of Chiari Malformation