Clinical Advisor November/December 2021 by The Clinical Advisor

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

CONFERENCE COVERAGE

Gerontological Advanced Practice Nurses Association Annual Conference LEGAL ADVISOR

Patient Demands Ivermectin

NOVEMBER/DECEMBER 2021

www.ClinicalAdvisor.com

SLEEP MEDICINE

Shift Work Disorder: When and How to Shift Workers’ Gears Approximately 20% of employees work outside of a 9 to 5 schedule.

FEATURE

The Pros and Cons of Medical Cannabis: Current Evidence

DERMATOLOGIC LOOK-ALIKES

Suspicious Nevi

FROM THE DIRECTOR

Director Nikki Kean nikki.kean@haymarketmedia.com Medical editor Kristin Della Volpe

Production editor Kim Daigneau Group creative director Jennifer Dvoretz Senior production manager Krassi Varbanov Account executive Michael Delaney, 551.206.5334 michael.delaney@haymarketmedia.com Publisher Kathleen Hiltz, 201.774.1078 kathleen.hiltz@haymarketmedia.com Vice president, content, medical communications Kathleen Walsh Tulley Chief commercial officer Jim Burke, RPh President, medical communications Michael Graziani Chairman & 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 requests, contact Customer Service at custserv@haymarketmedia.com. 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 24, Number 6. Published 6 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 © 2021

November marks the end of daylight savings time, the time in March when we have to set our clocks forward. Daylight savings time is often praised for giving us an extra hour of sunshine at the end of the day, which is much welcomed after a long cold winter, but it also marks the beginning of sleep problems for many Americans. By putting the clocks forward in the spring, we lose an hour of sleep. For me, this loss of sleep causes daytime sleepiness for a few weeks before my body adjusts to waking up “an hour earlier.” For others, this can lead to the development of sleep disorders and, when the days get shorter in the fall, mood changes from seasonal affective disorder can emerge. Loss of sleep may be even more detrimental for shift workers. As reported by the author of our cover story, approximately 5% to 10% of people who work outside of the traditional 9 to 5 schedule, including health care workers, develop shift work disorder (SWD). Shift work affects the body’s normal circadian rhythms and results in excessive sleepiness. Sleeping less than 7 hours a night can increase the risk of developing cardiovascular disease, metabolic disorders, cognitive impairment, and even cancer. Primary care clinicians play a vital role in screening patients for sleep disorders such as insomnia, sleep apnea, narcolepsy, and SWD. A detailed clinical history, sleep log, and actigraphy can help practitioners diagnose these conditions. With the end of daylight savings time and the onset of shorter days and longer nights, now is the time to get out those light boxes, spend time outdoors when you can, prioritize sleep, and exercise to keep mentally and physically healthy throughout the winter. Seek the care of a mental health or sleep professional for help managing SWD or seasonal affective disorder. As we say goodbye to fall and hello to winter, we here at The Clinical Advisor would like to wish everyone a happy and healthy holiday season and New Year! Nikki Kean, Director The Clinical Advisor

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 1

©ANDREW MERRY / GETTY IMAGES

Spring Forward, Fall Back — Daylight Savings Time and Sleep

Assistant editor Jeanelle Jacobs

CONTENTS NOVEMBER/DECEMBER 2021

NEWS 11

Conference Roundup Highlights from the Gerontological Advanced Practice Nurses Association (GAPNA) Annual Conference.

FEATURES 11 Elder abuse remains under-reported

4 Atypical Celiac Disease: Diagnosing Nonintestinal 1 Cases in Primary Care Celiac disease may present with gastrointestinal (classic) or extraintestinal (atypical or nonclassic) symptoms. 1 Shift Work Disorder: When and How to Shift 3 Workers’ Gears Taking a detailed clinical history, sleep log, and actigraphy can help practitioners diagnose this condition.

14 Case of undiagnosed celiac disease

6 The Pros and Cons of Medical Cannabis: 3 Current Evidence The widespread use of cannabis and the public perception that it is harmless makes screening and patient counseling a priority.

DEPARTMENTS

43 Suspicious mole on the right leg

49 Battle over ivermectin for COVID-19

From the Director Spring Forward, Fall Back — Daylight Savings Time and Sleep

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

Dermatologic Look-Alikes Suspicious Nevi

Legal Advisor Patient Demands Ivermectin

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

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ClinicalAdvisor.com

NEWS ClinicalAdvisor.com/News

Stress Response Affects Functional Connectivity in Bipolar Disorder What is the impact of acute psychosocial stress on changes in amygdala activation and functional connectivity among young adults with bipolar disorder?

Ultra-Processed Foods Associated With Risk for Crohn Disease US health care professionals with the highest intake of ultra-processed food had a nearly 2-fold greater risk of developing Crohn disease than low-intake HCPs.

Medication Rx Lacking for Active OUD in Veterans With Cirrhosis Medication treatments for opioid use disorder are underused in veterans with cirrhosis. The agents are safe and not associated with hepatic decompensation.

Psychosis and Bipolar Disorder Alter Auditory Oddball Responses Investigators assessed the relationship between clinical and cognitive features and oddball neural deviations across the schizophrenia-bipolar spectrum.

Laparoscopic Sleeve Gastrectomy Reduces Epicardial Fat Stores Laparoscopic sleeve gastrectomy led to a statistically significant reduction in epicardial fat thickness, a marker for atherosclerosis, 12 months after surgery.

CLINICAL CHALLENGE ClinicalAdvisor.com/CaseStudy Brady Pregerson, MD Vomiting in 2-Month-Old Infant A 2-month-old infant is brought to the emergency department with a history of vomiting. The parents report that the infant began vomiting 4 days ago, then was better for 2 days, then started vomiting again approximately 16 hours ago with the most recent episode reported as bilious. The infant has no fever or change in bowel movements. See the full case at: clinicaladvisor.com/ case_november_december21

THE WAITING ROOM

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Jim Anderson, MPAS, PA-C, DFAAPA Aggressive Policing as a Public Health Issue Negative health impacts of systemic racism, discrimination, poverty, and other societal forces are known to cause poorer health. Medical providers need to assess the health impact of policing on their patients.

MY PRACTICE ClinicalAdvisor.com/MyPractice Jennifer Kim, DNP, GNP-BC, GS-C, FNAP, FAANP Disaster Response in Long-Term Care Settings Experts discuss strategies for disaster responses in long-term care settings such as a proactive nursing home risk satisfaction model and a unique COVID19 response in a dementia care unit.

4 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 • www.ClinicalAdvisor.com

MIDDLE, BOTTOM IMAGES: © GETTY IMAGES

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

Extremely Itchy Rash A 31-year-old woman of Middle Eastern descent is referred for evaluation of a severely itchy rash affecting her upper back and lower legs. She was diagnosed with eczema approximately 18 months ago; treatment with topical steroids and tacrolimus failed to improve the clinical appearance or itching. Physical examination reveals welldemarcated hyperpigmented macules. CAN YOU DIAGNOSE THIS CASE?

• Acanthosis nigricans • Atopic dermatitis

• Macular amyloidosis • Mycosis fungoides

● See the full case at ClinicalAdvisor.com/DermDx_November_December21

ORTHO DX

In partnership with

TheJopa.org

Journal of Orthopedics for Physician Assistants

Chronic Hip Pain in Child An 11-year-old girl presents with her parents complaining of severe right hip pain and difficulty walking. She denies having a known injury and the pain has progressively increased over the past 4 weeks. She is healthy and active with no underlying medical conditions. On physical examination, she has pain with hip motion but no obvious skin changes or deformity. WHAT IS THE NEXT BEST STEP IN TREATMENT?

• Non-weight-bearing of right lower extremity • External screw fixation • Magnetic resonance imaging of the pelvis • Hip spica cast ● See the full case at ClinicalAdvisor.com/OrthoDx_November_December21

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 5

Data Animal Data In an embryo-fetal development study, oral administration of relugolix to pregnant rabbits during the period of organogenesis (Days 6 to 18 of gestation) resulted in abortion, total litter loss, or decreased number of live fetuses at a dose of 9 mg/kg/day (about half the human exposure at the maximum recommended human dose (MRHD) of 40 mg daily, based on AUC). No treatment related malformations were observed in surviving fetuses. No treatment related effects were observed at 3 mg/kg/day (about 0.1-fold the MRHD) or lower. The binding affinity of relugolix for rabbit GnRH receptors is unknown. In a similar embryo-fetal development study, oral administration of relugolix to pregnant rats during the period of organogenesis (Days 6 to 17 of gestation) did not affect pregnancy status or fetal endpoints at doses up to 1000 mg/kg/day (300 times the MRHD), a dose at which maternal toxicity (decreased body weight gain and food consumption) was observed. A no observed adverse effect level (NOAEL) for maternal toxicity was 200 mg/kg/day (86 times the MRHD). In rats, the binding affinity of relugolix for GnRH receptors is more than 1000-fold lower than that in humans, and this study represents an assessment of non-pharmacological targets of relugolix during pregnancy. No treatment related malformations were observed up to 1000 mg/kg/day. In a pre- and postnatal developmental study in pregnant and lactating rats, oral administration of relugolix to rats during late pregnancy and lactation (Day 6 of gestation to Day 20 of lactation) had no effects on pre- and postnatal development at doses up to 1000 mg/kg/day (300 times the MRHD), a dose in which maternal toxicity was observed (effects on body weight gain). A NOAEL for maternal toxicity was 100 mg/kg/day (34 times the MRHD). 8.2 Lactation Risk Summary There are no data on the presence of relugolix or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Relugolix was detected in milk in lactating rats [see Data]. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen plus progestin therapy and can reduce milk production in breast-feeding women. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for MYFEMBREE and any potential adverse effects on the breastfed child from MYFEMBREE or from the underlying maternal condition. Data Animal Data In lactating rats administered a single oral dose of 30 mg/kg radiolabeled relugolix on post-partum day 14, relugolix and/or its metabolites were present in milk at concentrations up to 10-fold higher than in plasma at 2 hours post-dose. 8.3 Females and Males of Reproductive Potential Based on animal data and the mechanism of action, MYFEMBREE can cause early pregnancy loss if MYFEMBREE is administered to pregnant women.

Pregnancy Testing MYFEMBREE may delay the ability to recognize pregnancy because it may reduce the intensity, duration, and amount of menstrual bleeding. Exclude pregnancy before initiating treatment with MYFEMBREE. Perform pregnancy testing if pregnancy is suspected during treatment with MYFEMBREE and discontinue treatment if pregnancy is confirmed. Contraception Advise women of reproductive potential to use effective non-hormonal contraception during treatment with MYFEMBREE and for 1 week following discontinuation. Avoid concomitant use of hormonal contraceptives with MYFEMBREE. The use of estrogen-containing hormonal contraceptives may increase the risk of estrogen-associated adverse events and is expected to decrease the efficacy of MYFEMBREE. 8.4 Pediatric Use Safety and effectiveness of MYFEMBREE in pediatric patients have not been established. 8.7 Hepatic Impairment MYFEMBREE is contraindicated in women with hepatic impairment or disease. The use of E2 (a component of MYFEMBREE) in patients with hepatic impairment is expected to increase the exposure to E2 and increase the risk of E2-associated adverse reactions. 10. OVERDOSAGE Overdosage of estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness, fatigue, and withdrawal bleeding. Supportive care is recommended if an overdose occurs. The amount of relugolix, estradiol, or norethindrone removed by hemodialysis is unknown. Please see full Prescribing Information for Patient Counseling Information This Brief Summary is based on MYFEMBREE Prescribing Information dated May 2021, which can be found at MYFEMBREE.com. Manufactured by Patheon Inc., 2100 Syntex Court, Mississauga, Ontario L5N 7K9, Canada Manufactured for Myovant Sciences, Inc., Brisbane, CA 94005 Approved: May 2021 214846-MS-000 MYFEMBREE® and its associated logo are trademarks of Myovant Sciences GmbH. ©2021 Myovant Sciences GmbH and Pfizer Inc. All rights reserved. PP-US-REL-CT-2100114 06/21

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10 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 • www.ClinicalAdvisor.com

Conference Roundup Gerontological Advanced Practice Nurses Association (GAPNA) Annual Conference September 30 to October 2, 2021 San Diego, California

SAFETY TOOL ASSESSES RISK FOR ELDER ABUSE Approximately 15.7% of adults 60 years and older are at risk for elder abuse. Researchers developed the Decision Matrix for Elder Safety (DMES) tool to assess abuse risk in older adults, according to findings presented in a poster session at the 2021 GAPNA Annual Conference. Older adults with cognitive, psychological, and physical impairments are at increased risk for elder abuse, with cognitive impairment being the greatest risk factor identified thus far. Different forms of elder abuse include physical, sexual, financial, psychological, and neglect, the study authors noted.

Elder abuse is a societal problem that is frequently undetected and poorly defined.

The purpose for designing DMES was to “provide a classification tool that assesses elder abuse risk over a continuum as cognitive and functional decline occurs,” said study author Patricia M. Speck, DNSc, CRNP, FNP-BC, DF-IAFN, FAAFS, DF-AFN, FAAN. With logarithmic documentation, advanced practice providers could use DMES to document and expose a pattern of decline and provide opportunities for prevention and intervention. Older patients with severe functional deterioration and full global cognitive decline are at high risk for abuse. When using the DMES tool, the degree of risk for elder abuse is calculated based on varying degrees of cognition and functional decline.Validated tools for functional assessment include the Katz Index of Independence in Activities, which assesses bathing, dressing, toileting, and transferring, Dr Speck said. Lawton Instrumental Activities of Daily Living is used to assess domains such as the ability to manage medications, finances, and transportation as well as the ability to use the phone and shop for oneself. To evaluate cognition, the Mini-Mental State Evaluation (MMSE) is recommended.The MMSE consists of 30 items used to assess orientation, attention, working memory, short-term memory, language, and visual-spatial skills. The Mini-Cog is another simple tool for assessing cognitive impairment. The DMES provides APRNs with a roadmap for evaluating elder abuse risk

and stratifies risk based on cognitive and functional capacity, the researchers noted.

EFFECTS OF URINARY INCONTINENCE ON LONGTERM CARE FACILITIES Urinary incontinence is a common symptom among residents of long-term care (LTC) facilities but is frequently untreated, resulting in a high incidence of falls because of urinary urgency as well as financial costs in terms of staff time and supplies, according to survey responses from directors of nursing at LTC facilities. Nearly 60% of directors said that managing urinary incontinence contributes to nursing assistant turnover, according to a study presented at the 2021 GAPNA Annual Conference. Urinary incontinence affects up to 65% to 70% of patients 65 years and older living in LTC facilities. Urinary incontinence is a common symptom of overactive bladder. The study authors evaluated online survey responses from 71 directors of nursing who worked at skilled nursing facilities with at least 100 beds (≥80% LTC beds) for at least 1 year between February 27, 2020, and May 11, 2020. On average, the facilities housed 115 residents (68% female), 62% of whom had urinary incontinence, 46% with dementia, and 43% with depression. Among patients with urinary incontinence, 75% were frequently or always incontinent and 81% used incontinence products on an ongoing basis. A mean of 14.3 resident falls per month were recorded, 36% of which occurred in patients attempting to access the

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 11

bathroom. The quality measures considered by residents to be most affected by urinary incontinence included: • Falls with major injury (47%) • Urinary tract infection (47%) • Pressure ulcers (41%) Increased need for help with activities of daily living, worsened ability to move independently, catheter use, and antipsychotic medication use were factors also linked to urinary incontinence issues. “The findings show the significant impact of incontinence on falls and CMS [Centers for Medicare and Medicaid] quality measures,” said lead author Diane K. Newman, DNP, ANP-BC, co-director of the Penn Center for Continence and Pelvic Health and adjunct professor of Urology in Surgery at the Perlman School of Medicine in Philadelphia. Medications to treat urge incontinence and overactive bladder were prescribed for 15% of residents; oxybutynin or other anticholinergic/antimuscarinic agents were the most commonly prescribed drugs (59%) followed by mirabegron (15%).Three-quarters of nursing directors were unaware of the link between anticholinergic medications and risk for cognitive issues/dementia. Among patients prescribed urinary incontinence medications, 14% discontinued treatment because of lack of efficacy or safety/tolerability issues. The average monthly cost of urinary incontinence products was $5407 and laundering costs were $5497. Certified nursing assistants on average spent 56% of their time managing urinary incontinence needs, and 59% of respondents said these tasks contributed to nursing assistant turnover.

NURSE-LED PROGRAM BOOSTS MEDICATION ADHERENCE TALKS A single-session, nurse-led clinic staff education program on improving medication adherence led to increases in

Medication nonadherence is associated with 125,000 deaths annually in the US.

knowledge, self-confidence, and selfreported practice behavior change among staff at an urban federally qualified health center (FQHC), according to a qualityimprovement pilot study presented at the 2021 GAPNA Annual Conference. Medication nonadherence is associated with approximately 125,000 deaths annually in the US, 10% of hospitalizations, and nearly $300 billion annually in costs to the US health system, explainedValerie Gruss, PhD, GNP-BC, FAAN, who is a clinical professor at the University of Illinois at Chicago, director of Interprofessional Education at the College of Nursing, and director of Enhancement of Geriatric Care for All-Illinois (ENGAGE-IL). Rates of nonadherence are reportedly higher among minority, low-income, and urban communities. The researchers reviewed the literature and identified 8 randomized controlled trials involving nurse-led interventions that resulted in significant improvements in medication adherence with minimal training required. Based on this research, the study authors developed and implemented a

single workshop designed to enhance staff knowledge, confidence, and commitment to practice change at the Mile Square Health Center in Engelwood, an FQHC which serves a primarily Black population (91%) in which 42% of patients are below the poverty line. Participants attended a single 30-minute workshop virtually (n=6) or via prerecorded video (n=2) in which they were trained on the following tools: • Modified Medication Adherence Rating Scale (MARS) • Barriers and Interventions Checklist (BIC) • Motivational interviewing After the intervention, participants were sent weekly email reminders to engage patients in conversations about medication adherence by using tools learned in the workshop, and surveys were sent to participants 4 weeks after the workshop concluded. A comparison of pre- and post-test intervention surveys showed a 29% increase in staff knowledge, 44% increase in staff confidence in initiating conversations, and 77% increase in the selfreported number of discussions with patients about medication adherence. On a 10-point scale, the participants rated their commitment to practice change as 8.5 and their ability to successfully apply what was learned in the workshop as 8.4. The educational program will continue at this clinic and expand to other sites with modifications based on lessons learned during this pilot program. The researchers recommended adding the modified MARS and BIC to the intake workflow on electronic health records, delegating process steps by staff position, and establishing standard methods of staff communication to ensure adequate patient follow-up. “Assessing medication adherence should be a standard of practice in primary care,” the study authors concluded.

12 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 • www.ClinicalAdvisor.com

Conference Roundup

RECOGNIZING DEPRESSION AS A RISK FACTOR FOR CVD IN OLDER PATIENTS Nearly one-third of nurse practitioners (NPs) did not recognize depression as a risk factor for cardiovascular disease (CVD), according to survey findings presented at the 2021 GAPNA Annual Conference. “Effective depression treatment reduces disability, improves outcomes of comorbid health conditions, and improves quality of life,” said lead author, Lorraine M Novosel, PhD, CRNP, AGPCNP-BC. However, “older adults have but a 50% chance of being diagnosed with depression and are less likely to receive help for depressive symptoms compared with younger adults.” To analyze NPs’ knowledge on depression and CVD, study authors recruited a national sample (N=111) of AANP members and asked them to complete an anonymous review of 4 patient vignettes. Of the sample, 64% reported having 5 or more years working as an NP. The researchers found that 34% of NPs failed to recognize major depressive disorder as a risk for CVD and 2 out of

Nearly one-third of NPs did not recognize depression as a risk factor for CVD.

5 NPs did not recognize CVD as a risk factor for subsequent depression. “Secondary findings suggest an age bias in caring for older adults by practicing NPs and warrants further examination,” the authors said. “This is particularly important given our rapidly growing aging society and the shortage of providers who specialize in older adult care.” Primary care NPs are well-suited to integrate physical and mental health as comprehensive PCPs.The findings indicate a need for professional development among NPs and during NP graduate education geared toward the relationship between CVD risk and depression. “We really need to continue and enhance our education on age-related risks for the best care for our older adult patients,” the authors concluded.

NURSE-LED PROGRAM REDUCES DELIRIUM IN POST-ACUTE CARE Implementation of a nurse-led education and delirium prevention program lead to a decrease in cases of new-onset delirium during post-acute rehabilitation stays at a skilled nursing facility, according to a quality improvement project presented at the 2021 GAPNA Annual Conference. Risk factors for delirium include old age, dementia, history of depression, history of alcohol misuse, use of physical restraint, metabolic abnormalities, infection, recent surgery, and medications. “The outcomes of delirium are numerous and can be quite significant,” the study authors explained. “We often see short and/or long-term cognitive and functional decline, increased length of stay, increased incidence of 30-day readmission, hospitalization, institutionalization, and death.” The goal of the study was to design and implement a delirium prevention protocol in a 116-bed skilled nursing facility in Sonoma County, California.The findings are based on chart audits from new admissions receiving care under Medicare

Part A and staff surveys conducting preand postimplementation. The average patient age was 77 in the preimplementation group (n=25) and 80 years in the postimplementation group (n=23), approximately 60% of patients were female, and approximately 90% were White.The average number of medications was similar in the pre- and postimplementation cohorts. Fracture with or without surgical repair was the most common reason for admission, followed by cardiovascular needs, infection, and stroke, among other conditions. More than half of patients were prescribed psychotropic medications such as antidepressants or antipsychotics at the time of admission (56% preimplementation and 78% postimplementation). Less than 25% of patients in each group were prescribed routine pain medications on admission (24% and 17%, respectively). Following implementation of in-service training on delirium risk factors taught by nursing staff, 65% of patients were identified as at increased risk for delirium using the AWOL risk assessment tool. These patients received an 8-item delirium prevention protocol that included getting patients out of bed for meals, adequate hydration, and tracking urinary output and bowel movements. New-onset delirium was diagnosed in 2 patients in the preimplementation cohort vs 0 patients in the postimplementation group during their post-acute care stay. “Excellent” responses to the intervention were received by nursing staff and certified nurse assistants. “They found the preventative protocol to be easy to use and CNAs, in particular, appreciated the additional education on delirium,” said Rebecca Spear, DNP, ARNP, AGNP-C, Kaiser Permanente, Continuum of Care Skilled Nursing Department in Santa Rosa, California. Study limitations included small sample size of charts reviewed in total and the small sample of survey respondents. ■

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 13

FEATURE: RACHEL ZIGANTI, MPA, PA-C; STEVIE REDMOND, MPA, PA-C

Atypical Celiac Disease: Diagnosing Nonintestinal Cases in Primary Care Atypical CD may present as dermatitis herpetiformis, anemia, elevated transaminases, short stature, and osteopenia/osteoporosis.

Since 1990, celiac diagnoses have increased 5-fold.

eliac disease (CD) is an autoimmune condition resulting from a dysregulated immunologic response to gluten in genetically susceptible individuals.1-3 Nearly all cases of CD occur in individuals with the major histocompatibility complex class II human leucocyte antigen (HLA) DQ2 or DQ8.1 At least one of these heterodimers is present in 30% to 40% of the general population; however, only 3% of patients with HLA-DQ2 or HLA-DQ8 develop CD, and genome-wide association studies have identified more than 100 non-HLA-related genes associated with the disease.1,4

Prevalence of Celiac Disease

Celiac disease affects up to 1% of people in Western countries, and the prevalence is on the rise.1-4 In a cohort study, Catassi et al followed 3511 patients in the US from 1974 to 1989 and found a 2-fold increase in the prevalence of CD, from 1 in every 501 persons to 1 in every 219 persons.3 The findings suggest that immunologic gluten intolerance may develop in adulthood.3 In a more recent cohort study, Catassi et al found that the prevalence of CD continued to rise in the United States, to a prevalence of 1 in 105 persons in 2001, suggesting a 5-fold increase in CD prevalence over a 30-year period.3 Recent epidemiologic studies have shown that this relatively high prevalence extends to countries in North Africa and Asia, particularly in Iran (0.88%), Libya (0.79%), and India (0.7%).1-2 Continues on page 22

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symptoms.

GASTROINTESTINAL DISEASES

Etiology of Celiac Disease

Factors such as gluten production methods, dietary gluten levels, lifetime enteric infections, and physiologic stressors could trigger an imbalance in the immune response to gluten.3 However, the true cause of gluten intolerance is unknown, and environmental factors outside of gluten ingestion may play a role.3,4 Additional potential risk factors include shorter duration of breastfeeding, timing of initial gluten ingestion in infants, and the hygiene hypothesis; however, conflicting evidence on these risk factors is found in the literature.1,3-5 Socioeconomic factors associated with CD are not well studied, but initial research suggests that CD is less commonly diagnosed in populations with lower socioeconomic status.5 A 2015 population study conducted in the UK found that people living in areas of less socioeconomic deprivation, categorized by the Townsend index, had an 80% higher rate of CD diagnosis than those living in the most socioeconomically deprived areas.5 The cause of this discrepancy is unclear; however, it is unlikely that there is a true decreased incidence of CD in socioeconomically deprived areas.5 Rather, the data more likely reflects a lack of access to health care in medically underserved areas.5 The incidence of CD continues to rise in populations of all socioeconomic backgrounds, and primary care providers need to be aware of the often insidious and varied presentation of CD. Symptoms of Celiac Disease

Celiac disease may present with gastrointestinal (classic) or extraintestinal (atypical or nonclassic) symptoms. Classic celiac disease has signs and symptoms similar to those of irritable bowel syndrome, presenting with diarrhea with or without signs of malabsorption, such as steatorrhea, weight loss, flatulence, abdominal pain/distention, and/or vitamin deficiencies.1,6,7 Atypical CD may present as dermatitis herpetiformis, irondeficiency anemia, idiopathic elevated transaminases, constitutional short stature, and osteopenia/osteoporosis.2,4 Other symptoms include dental enamel defects, headache, ataxia, psychiatric disorders, migraine, aphthous ulcers, stomatitis, and recurrent febrile infections with moderate neutropenia.2 A shift in initial symptoms of CD has occurred, with patients increasingly presenting with extraintestinal symptoms.1 Before 1981, diarrhea was the presenting complaint in over 90% of patients with CD, but currently it is the presenting complaint in less than 40%.8 Because extraintestinal manifestations are not recognized as classic CD symptoms, atypical presentations may go undiagnosed.2 The estimated ratio of diagnosed to undiagnosed patients with CD ranges from 1:5 to 1:8.2 Patients with undiagnosed CD are at increased risk for infertility, osteoporosis, gastrointestinal malignancy, and enteropathy-associated T-cell lymphoma.2,9 These risks are diminished with early and consistent treatment.9 The characteristic

histologic changes of the disease, intestinal villi atrophy and crypt hyperplasia, typically resolve upon the elimination of gluten from a patient’s diet.9 In patients who have subclinical or potential disease, the introduction of the gluten-free diet acts as a preventive rather than a therapeutic measure.2 The age at onset of CD demonstrates a bimodal distribution.4 The first peak occurs in the first 2 years of life, shortly after weaning, when gluten is introduced; the second peak occurs in the second and third decades of life.4 Intestinal manifestations are more common during the first peak of onset, whereas extraintestinal symptoms are more common during the second peak of diagnosis.4,10 Because the average length of time from first presenting complaint to diagnosis is 10 years, primary care providers can help improve the early recognition of nonspecific signs of atypical CD.9,11 Autoimmune disorders, particularly type 1 diabetes mellitus, autoimmune thyroid disease, Sjögren syndrome, Addison disease, and systemic lupus erythematosus, are 3 to 10 times more likely to present in patients with CD.2 Gluten-sensitivity enteropathy may present with extraintestinal symptoms, particularly in these patients.2 Evidence suggests that CD patients’ risk of developing additional autoimmune disorders increases with greater gluten exposure.2 Patient populations at high risk for CD include those with Down syndrome, type 1 diabetes, and immunoglobulin A (IgA) deficiency.4 It is important for primary care providers to understand and recognize the common manifestations and presenting symptoms of atypical CD. Dermatitis Herpetiformis Dermatitis herpetiformis is a skin variant of CD, and this extraintestinal presentation falls under the atypical CD umbrella.2 The mean age at diagnosis of dermatitis herpetiformis is 40 to 50 years, and early studies demonstrate a male to female ratio of 2:1.4,12 In contrast, CD demonstrates a male to female ratio of 1.5:1.4,12 The ratio of dermatitis herpetiformis to CD is 1:8 in both Finland and the United Kingdom, making it a common manifestation of atypical CD.12 The characteristic blistering lesions are burning, pleuritic, erythematous papules or vesicles that may be eroded or crusted from excoriation (Figure 1).2,10,12 The eruptions commonly are present on the buttocks and extensor surfaces of the elbows and knees, with a symmetrical distribution often in a herpetiform configuration.2,10,12 Overt gastrointestinal complaints are rare in patients with this skin condition, but duodenal biopsies demonstrate that up to 75% of patients have some degree of villous atrophy; the remaining 25% have inflammatory changes of lymphocytic enteritis.10 The current hypothesis on the pathogenesis of dermatitis herpetiformis suggests that latent or active CD activates an immune complex of high avidity IgA epidermal transglutaminase (TG3)

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FIGURE 1. Characteristic lesions of dermatitis herpetiformis.

antibodies with TG3 enzymes that deposit into the papillary dermis.10,12,13 Diagnosis is based on immunofluorescence biopsy, which demonstrates deposits of IgA in the papillary dermis.2,10,12 The cornerstone of treatment is a strict glutenfree diet complemented by administration of dapsone.12,13 A gluten-free diet is essential because dapsone alone will not control CD if gluten is introduced.12 On average, dapsone may be tapered off after 2 years of a strict gluten-free diet.12 Iron-Deficiency Anemia Iron-deficiency anemia is a common extraintestinal manifestation found in 40% of CD cases.4 Thus, anemia should raise suspicion of CD, especially as an isolated finding or in patients refractory to oral iron therapy.4,9,14,15 The pathophysiology is believed to be associated with decreased oral iron absorption due to villous atrophy and/or chronic inflammation of the duodenum.9,15 In a study of patients undergoing esophagogastroduodenoscopic assessment for iron-deficiency anemia, 15% had CD as the underlying cause.15 A meta-analysis conducted in 2018 found that approximately 1 in 31 patients with irondeficiency anemia had biopsy-confirmed CD, resulting in a 3.2% pooled prevalence.14 A gluten-free diet is necessary to resolve enteropathy and allow absorption of oral iron.9 Oral iron supplementation may be administered in conjunction with a gluten-free diet until iron levels are restored.9 Hypertransaminasemia Liver enzyme abnormalities often affect patients with classic and atypical CD.4,9,15,16 With atypical disease, hypertransaminasemia may be the sole presentation.16 Hypertransaminasemia is present in 40% to 50% of children and adults with classic CD at the time of presentation.4,15,16 The exact mechanisms underlying hypertransaminasemia in CD is poorly understood, but current theories indicate that

increased intestinal permeability may allow antigens and inflammatory cytokines to reach the portal circulation.4,16 Patients with CD-associated hepatic injury/inflammation usually are asymptomatic, but they may present with nonspecific malaise or fatigue.16 Levels of serum aspartate aminotransferase and/ or alanine aminotransferase are mildly to moderately elevated to less than 5 times the upper limit of normal.16 In addition, 66% of patients show histologic changes on liver biopsy; these changes generally are mild and nonspecific.16 Celiac disease is present in approximately 9% of patients with cryptogenic hypertransaminasemia.15,16 Therefore, serologic testing for CD should be pursued in these cases.15,16 Most patients (75% to 95%) will have a normalization of transaminase serum levels within 12 months of starting a gluten-free diet.16 Patients with nonspecific histologic changes also typically experience reversal of liver pathology with adherence to a gluten-free diet.16 Short Stature

In children, short stature may be the main presentation of atypical CD.4,9,17 Approximately 2% to 8% of children presenting with short stature without gastrointestinal complaints have underlying CD.4,9,17 Celiac disease is the most common organic cause of slow growth velocity and is even more common than growth hormone deficiency.9,18 Once endocrine abnormalities are excluded, 19% to 59% of children with short stature and no gastrointestinal complaints will be diagnosed with CD.17 The mechanisms underlying short stature in CD are unclear but may be linked to nutritional deficits.9,18 However, treatment with a gluten-free diet often leads to increased growth to target height within 2 to 3 years.9,18 Osteopenia/Osteoporosis Celiac disease predisposes patients to decreased bone mineral density due to altered absorption of calcium and vitamin D3.4,9 Bone mineral density changes, including osteopenia and osteoporosis, affect approximately 70% of patients at the time of diagnosis.4 In a study that observed 86 consecutive patients with a new diagnosis of biopsy-confirmed CD, 40% had osteopenia and 26% had osteoporosis.9 In addition, the prevalence of CD among patients with osteoporosis is 3.4%.9,19 Osteopenia/osteoporosis may be difficult to recognize in patients with atypical CD due to the frequency of decreased bone mineralization in postmenopausal women and men of the same age, but awareness of osteopenia/osteoporosis as a potential sign of CD may minimize a delay in diagnosis in elderly patients.2 Treatment with a gluten-free diet improved bone mineral density more than expected by the standard of care.19 However, Continues on page 26

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GASTROINTESTINAL DISEASES

unlike pediatric patients, who are expected to fully recover bone mass following a gluten-free diet, bone mineral density may not normalize in adults who experience osteoporosis secondary to CD.9 Therefore, early identification and treatment of CD in adults is imperative to prevent this CD complication.9 Diagnosis of Celiac Disease

In patients with suspected CD, the first step to diagnosis is serologic testing.2,4,20 An antitissue transglutaminase (TG2) antibody (TG2-IgA) level is the preferred serologic test for CD and has a 90% to 98% sensitivity and 95% to 98% specificity for the disease.1,20,21 The antiendomysial antibody (EMA-IgA) test also is available, with a sensitivity of 90% to 97% and specificity of 97% to 100%.1,20 However, EMA-IgA use is limited by cost, complexity, and operator dependency, yielding variation in results.1,6,20 Detection of antigliadin antibodies is not recommended because of lower sensitivity and specificity compared with TG2-IgA and EMA-IgA autoantibodies.20,21 An IgA level also may be needed because IgA deficiency is present in up to 3% of patients with CD and a deficiency will lead to false-negative TG2-IgA and EMA-IgA results.20 In these instances, deamidated gliadin peptides (DGPIgA or DGPIgG) have excellent sensitivity and specificity of 94% and 99% for DGPIgA and 92% and 100% for DGPIgG, respectively.22 Once positive serology has been established, the gold standard of diagnosis is the duodenal biopsy.1-4,20-22 Morphologic changes vary based on patient severity but commonly show partial or complete villous atrophy, increased intraepithelial lymphocytes, increased epithelial apoptosis, and/or crypt hyperplasia.1-4,20 The American Gastroenterological Association proposed a biopsy-avoiding diagnostic pathway for celiac disease in 2019

(Figure 2).23 According to the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guidelines from 2012, celiac disease diagnosis can be made in symptomatic children with a high TG2-IgA antibody titer (>10 times the upper limit of normal) and other positive serologic markers (eg, EMA and HLA-DQ2/DQ8) in a second blood sample without the need for duodenal biopsy.24 Improvement in symptoms through initiation of a glutenfree diet provides further confirmation of the diagnosis. Determination of HLA-DQ2/DQ8 should be used for its negative predictive value to rule out celiac disease in selected clinical scenarios such as in patients who are seronegative with equivocal histologic findings on biopsy.23 Negative genotypes have near 100% negative predictive value for CD and are able to exclude the diagnosis.1,2,4,20 Both TG2-IgA and EMA-IgA correlate with the atrophy of intestinal villi and may produce false-negative results in patients following a gluten-free diet.1,6,20 This is an additional case in which genetic testing for HLA-DQ2/DQ8 may be performed.1,2,4,20,23 If genetic testing is positive, a gluten challenge should be initiated, with intake of at least 3 grams of gluten per day for a minimum of 2 weeks, ideally up to 8 weeks if tolerated, with repeat serology and duodenal biopsy after completion.22 Conclusion

Classic CD known for its gastrointestinal symptoms is most recognizable, but atypical CD is more common, affecting up to 50% of diagnosed cases and even more remaining undiagnosed.2 Atypical CD has a wide array of presentations, including Continues on page 28

Asymptomatic group or at-risk group

Symptomatic group

TG2-IgA* positive

Not celiac disease

TG2-IgA positive

Yes

In a second blood sample: TG2-IgA >10xULN, EMA positive

Yes Celiac disease

TG2-IgA <10xULN or IgA low

Biopsy: histology positive (Marsh 2-3)

Yes Celiac disease

Potential celiac disease * TG2-IgA, tissue transglutaminase immunoglobulin A

FIGURE 2. Suggested biopsy-avoiding diagnostic pathway for celiac disease from the American Gastroenterological Association.

26 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 • www.ClinicalAdvisor.com

TG2-IgA positive >10xULN, IgA normal

GASTROINTESTINAL DISEASES

dermatitis herpetiformis, iron-deficiency anemia, idiopathic elevated transaminases, short stature, and osteopenia/osteoporosis, and may develop in patients of all ages, making diagnosis difficult.1-4 Patients who remain undiagnosed are at increased risk for long-term complications, including infertility, osteoporosis, gastrointestinal malignancy, and enteropathy-associated T-cell lymphoma.2,9 With early detection and adherence to a gluten-free diet, these risks may be diminished with resolution of symptoms.9 This places important emphasis on the primary care provider’s ability to recognize common extraintestinal presentations of atypical CD, which are often associated with nonspecific complaints. ■

12. Reunala T, Salmi TT, Hervonen K, Kaukinen K, Collin P. Dermatitis herpetiformis: a common extraintestinal manifestation of coeliac disease. Nutrients. 2018;10(5):602. 13. Kárpáti S. Dermatitis herpetiformis. Clin Dermatol. 2012;30(1):56-59. 14. Mahadev S, Laszkowska M, Sundström J, et al. Prevalence of celiac disease in patients with iron deficiency anemia-a systematic review with metaanalysis. Gastroenterology. 2018;155(2):374-382.e1. 15. Hernandez L, Green PH. Extraintestinal manifestations of celiac disease. Curr Gastroenterol Rep. 2006;8(5):383-389. 16. Rubio-Tapia A, Murray JA. The liver in celiac disease. Hepatology. 2007;46(5):1650-1658. 17. van Rijn JC, Grote FK, Oostdijk W, Wit JM. Short stature and the probability of coeliac disease, in the absence of gastrointestinal symptoms.

Rachel Ziganti, MPA, PA-C, is a physician assistant working with the Department of Rheumatic and Immunologic Diseases of the Cleveland Clinic in Cleveland, Ohio; Stevie Redmond, MPA, PA-C, is director of education and associate professor in the Physician Assistant Department at Augusta University in Augusta, Georgia.

Arch Dis Child. 2004;89(9):882-883. 18. Gadewar S, Fasano A. Celiac disease: is the atypical really typical? Summary of the recent National Institutes of Health Consensus Conference and latest advances. Curr Gastroenterol Rep. 2005;7(6):455-461. 19. Stenson WF, Newberry R, Lorenz R, Baldus C, Civitelli R. Increased prevalence of celiac disease and need for routine screening among patients

References

with osteoporosis. Arch Intern Med. 2005;165(4):393-399.

1. Ungaro R, Babyatsky MW. Celiac disease. In Murray MF, Babyatsky MW,

20. McQuaid KR. Malabsorption. In: Papadakis MA, McPhee SJ, Rabow

Giovanni MA, Alkuraya FS, Stewart DR, eds. Clinical Genomics: Practical

MW. eds. Current Medical Diagnosis and Treatment 2020. New York, NY:

Applications in Adult Patient Care, 1e. McGraw-Hill; 2014. Accessed

McGraw-Hill; 2020:649-650. October 26, 2021. https://accessmedicine.

October 26, 2021. https://accessmedicine.mhmedical.com/Content.aspx?

mhmedical.com/content.aspx?bookid=2683&sectionid=225047731

bookid=1094&sectionid=61902785

21. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG clinical

2. Admou B, Essaadouni L, Krati K, et al. Atypical celiac disease: from recognizing

guidelines: diagnosis and management of celiac disease. Am J Gastroenterol.

to managing. Gastroenterol Res Pract. 2012;2012:637187.

2013;108(5):656-676.

3. Catassi C, Kryszak D, Bhatti B, et al. Natural history of celiac disease autoimmunity

22. Sugai E, Vázquez H, Nachman F, et al. Accuracy of testing for antibodies

in a USA cohort followed since 1974. Ann Med. 2010;42(7): 530-538.

to synthetic gliadin-related peptides in celiac disease. Clin Gastroenterol

4. Caio G, Volta U, Sapone A, et al. Celiac disease: a comprehensive current

Hepatol. 2006;4(9):1112-1117.

review. BMC Med. 2019;17(1):142.

23. Husby S, Murray JA, Katzka DA. AGA clinical practice update on diagnosis

5. Zingone F, West J, Crooks CJ, et al. Socioeconomic variation in the incidence

and monitoring of celiac disease—changing utility of serology and histologic

of childhood coeliac disease in the UK. Arch Dis Child. 2015;100(5):466-473.

measures: expert review. Gastroenterology. 2019;156(4):885-889.

6. Trier JS. Intestinal malabsorption. In Greenberger NJ, Blumberg RS, Burakoff

24. Husby S, Koletzko S, Korponay-Szabó IR, et al. European Society for Pediatric

R. eds. CURRENT Diagnosis & Treatment: Gastroenterology, Hepatology, &

Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of

Endoscopy, 3e. McGraw-Hill; 2016. Accessed October 26, 2021. https://access-

coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54(1):136-160.

medicine.mhmedical.com/content.aspx?bookid=1621&sectionid=105183794 7. Binder HJ. Disorders of absorption. In Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill; 2018. Accessed October 26, 2021. https://accessmedicine. mhmedical.com/content.aspx?bookid=2129&sectionid=192282356 8. Nadhem ON, Azeez G, Smalligan RD, Urban S. Review and practice guidelines for celiac disease in 2014. Postgrad Med. 2015;127(3):259-265. 9. Lionetti E, Catassi C. New clues in celiac disease epidemiology, pathogenesis, clinical manifestations, and treatment. Int Rev Immunol. 2011;30(4):219-231. 10. Rodrigo L, Beteta-Gorriti V, Alvarez N, et al. Cutaneous and mucosal manifestations associated with celiac disease. Nutrients. 2018;10(7):800. 11. Majsiak E, Cichoz·-Lach H, Gubska O, Cukrowska B. [Celiac disease disease of children and adults: symptoms, disease complications, risk groups

Want More? Sign up for our daily Clinical Advisor email to get more features, cases, meeting coverage, and news. To sign up, go to ClinicalAdvisor.com/ registration

and comorbidities]. Pol Merkur Lekarski. 2018;44(259):31-35.

28 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 • www.ClinicalAdvisor.com

Newsline DEMENTIA AND MILD cognitive impairment (MCI) were found to be less common among patients who were prescribed direct oral anticoagulants (DOACs) to treat atrial fibrillation (AF) as opposed to those who were prescribed vitamin K antagonists (VKAs), according to findings published in BMJ Journals. The study was comprised of 39,200 patients (44.6% women; median age, 76 years) who were diagnosed with AF from 2012 to 2018. Approximately half of patients (53%, n=20,687) were prescribed VKAs and the rest were prescribed DOACs (47%, n=18,513) at baseline, with 11% (n=4477) switching oral anticoagulants (most commonly fromVKAs to DOACs) during the course of the study. Patients who were prescribed VKAs had more comorbidities (heart failure,

other vascular diseases, and chronic renal disease) compared with those who were prescribed DOACs, the study authors noted. Other between-group differences included lower rates of use of antiplatelet drugs (58.7% vs 68.7%), diuretics (43.5% vs 49.5%), and ACE inhibitors (37.8% vs 42.6%) in the DOACs vs VKAs group. In contrast, patients in the VKAs group were more likely to be prescribed beta-blockers (69.2% vs 66.0%), antidepressants (19.1% vs 17.7%), and proton pump inhibitors (46.7% vs 44.6%) compared with the DOAC cohort, the study authors noted. A total of 1258 patients (3.2%) were diagnosed with incident dementia, equating to an incidence rate of 16.5 per 1000 person-years. Treatment with DOACs was associated with a 16% reduction in

Dementia, Mild Cognitive Impairment Less Common in Patients With AF Given DOACs

AF treatment with DOACs was associated with a 16% reduction in dementia diagnosis in comparison with vitamin K antagonists.

dementia diagnosis (adjusted HR, 0.84; 95% CI, 0.73-0.98) and a 26% reduction in MCI (HR 0.74; 95% CI, 0.65-0.84) compared with treatment with VKAs. “While further evidence, including from randomized controlled trials, would strengthen this finding, it may be relevant to consider cognitive risk profile when prescribing DOACs for AF among older individuals,” the study authors concluded.

Physical Therapy Tied to Lower Long-Term Opioid Use Post-TKR PHYSICAL THERAPY interventions are associated with a lower risk for long-term opioid use after total knee replacement (TKR), according to a study published in JAMA Network Open. Kosaku Aoyagi, PT, PhD, from the Boston University School of Medicine, and colleagues used data from the OptumLabs Data Warehouse to identify 67,322 individuals (aged ≥40 years) who underwent TKR from 2001 through 2016. Associations between physical therapy interventions before and after TKR and longterm opioid use after TKR were evaluated. The researchers found that receipt of any physical therapy before TKR was associated with lower odds of long-term

opioid use in both opioid-naive (adjusted odds ratio [aOR], 0.75) and opioid-experienced (aOR, 0.75) patients. Similarly, receipt of any post-TKR physical therapy was associated with lower odds of long-term use of opioids in the opioid-experienced cohort (aOR, 0.75), with more physical therapy sessions tied to a lower risk (6 to 12 sessions: aOR, 0.82; ≥13 sessions: aOR, 0.71 vs 1 to 5 sessions). Physical therapy initiation at 31 to 60 days post-TKR or 61 to 90 days post-TKR was associated with greater odds of long-term opioid use in both the opioidnaive and opioid-experienced group vs initiation of physical therapy within 30 days after TKR.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 29

Newsline

Link Found Between HIV Infection and Impaired Pulmonary Gas Exchange

Participants with HIV and COPD had the greatest impairment in diffusing capacity of the lungs for carbon monoxide.

IMPAIRED pulmonary gas exchange was found to be independently associated with HIV infection, regardless of emphysema severity, according to results of a post-hoc analysis published in the Journal of Acquired Immune Deficiency Syndromes. The study aimed to determine whether there is an association between HIV infection and diffusing capacity of the lungs for carbon monoxide (DLCO) — a reflection of abnormalities at the alveolar-capillary surface — independent of emphysema, as well as identify the influence HIV infection has on DLCO impairment in participants with and without comorbid chronic obstructive pulmonary disease (COPD). The investigators, who were led by Sarath Raju, MD, MPH, of the Division of Pulmonary and Critical Care Medicine at Johns Hopkins University in Baltimore, Maryland, used crosssectional data from the Study of HIV in the Etiology of Lung Disease (SHIELD), a longitudinal cohort study conducted

between 2012 and 2015 that assessed the relationship between HIV infection and DLCO in participants with and without HIV infection. In addition, participants who were aged 18 years and older and/ or had a history of injection drug use underwent DLCO measurement and a computed tomography scan of the chest. The analysis included a total of 339 participants, 229 of whom had HIV infection.After adjustment for confounders, including emphysema severity, HIV infection was found to be associated with decreased DLCO (mean difference [ß], -4.02%; P =.020) and an increased odds of DLCO impairment (odds ratio, 1.93; P =.017). Of note, among participants without COPD, HIV infection was independently associated with decreased DLCO (ß, -3.89%; P =.049). Participants with HIV infection and comorbid COPD exhibited the greatest DLCO impairment compared with those without either condition (ß, -14.81; P <.001). “HIV is associated with impaired pulmonary gas exchange independent of emphysema severity. Our data also suggest a potentially additive influence between HIV and COPD on DLCO impairment,” noted the investigative team. Based on these findings, the investigators suggested that “a history of opportunistic infections may be a larger contributor to long-term lung injury, given that the greatest DLCO impairment was observed amongst those with [decreased] CD4+ T-cell counts.” In addition, “further studies should investigate other factors, including pulmonary vascular disease, which may contribute to DLCO impairment among [individuals with HIV infection],” the investigators concluded.

30 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 • www.ClinicalAdvisor.com

FDA Adds Checklist to Safety Guidelines for Breast Implants THE FOOD and Drug Administration (FDA) has taken several steps to improve the communication of risks associated with breast implants to patients and to help those who are considering the procedure make an informed decision, according to a statement released by the agency. Core to new labeling is the development of the patient decision checklist. “The checklist must be reviewed with the prospective patient by the health care provider to help ensure the patient understands the risks, benefits, and other information about the breast implant device.The patient must be given the opportunity to initial and sign the patient decision checklist and it must be signed by the physician implanting the device.” The General and Plastic Surgery Devices Advisory Panel recommended box warnings and a checklist as a part of the consent process.The panel also called for revisions to the magnetic resonance imaging screening recommendations for silent ruptures of silicone-filled implants and greater transparency about materials contained in breast implants.The recommendations were incorporated into the FDA’s final guidance for breast implants issued in September 2020. “A medical device’s labeling is intended to enhance, but not replace, the physician-patient discussion of the risks and benefits of breast implants that uniquely pertain to individual patients,” the FDA said. The agency has restricted the sale of implants only to health care providers who use the patient decision checklist. ■

FEATURE: KIMBERLY SAPRE, DMSc, PA-C, CAQ-EM

Shift Work Disorder: When and How to Shift Workers’ Gears Approximately 5% to 10% of shift workers suffer from shift work disorder, a circadian sleep-wake cycle disorder defined by poor quality sleep.

Patients with SWD often sleep less than 7 hours a night.

n the United States, 20% of employees work during shifts that are outside of the traditional 9:00 AM to 5:00 PM schedule, including many in the health care industry.1-3 Work schedules may include early morning, evening, night, or rotating shifts.4,5 Approximately 5% to 10% of shift workers suffer from shift work disorder (SWD), a circadian sleep-wake cycle disorder defined by poor quality sleep that results in excessive sleepiness and insomnia.1-4 The lack of restful sleep increases the risk for drowsy driving, cardiovascular disease, metabolic disorders, cancer, and cognitive impairment.1-9 People working night shifts and rotating shifts are at higher risk for the disorder, with a prevalence of 14% and 8%, respectively.10 Primary care clinicians play an essential role in screening patients for SWD. A detailed clinical history, sleep log, and actigraphy help practitioners diagnose the condition.1-4 Patients with SWD often sleep less than the 7 hours recommended by the American Academy of Sleep Medicine (AASM) and the Sleep Research Society.6 Pathophysiology

The cause of SWD is the inability to sleep due to imbalance of the circadian rhythm and internal homeostatic sleep drives.2,4,5 The circadian rhythm is regulated by the suprachiasmatic nucleus (SCN), also known as the ‘master pacemaker,’ which is located in the hypothalamus.5,8 When light enters the eyes, photoreceptors send signals to the SCN to suppress the release of melatonin from the www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 31

SLEEP MEDICINE

Shift work requires eating, socializing, and physical activity during hours that are at odds with the daily circadian rhythm, causing dysregulation. pineal gland, preventing the urge to sleep during the day.5,7 In shift workers who must sleep during the day, sleep eventually occurs due to the build-up of internal sleep pressure, but the circadian misalignment causes a decrease in sleep duration and inadequate sleep.4,5 In addition to light exposure, activity and meal timing signal the SCN to regulate the sleep/wake cycle.7 Shift work requires eating, socializing, and physical activity during hours that are at odds with the daily circadian rhythm, causing dysregulation of physiologic processes.5,7

driving,5,9 and drowsy driving is reported to be the cause of 16.5% of fatal crashes.9 Those sleeping fewer than 6.75 hours had a 73% increased risk of falling asleep during the Multiple Sleep Latency Test.6 Recent research suggests that workers with a lower socioeconomic status (SES) have an even higher risk for health problems due to SWD.14 Workers with lower SES may have additional causes for insufficient sleep, such as increased exposure to environmental pollutants, psychosocial pressures, and neighborhood stressors.14

Adverse Health Outcomes

Shift work is a risk factor for hypertension, coronary heart disease, stroke, diabetes, obesity, and some types of cancers.1-8 The dysregulation of sleep affects the hormones leptin and ghrelin, which signal to the body to stop food intake and stimulate hunger, respectively.7 The altered eating patterns of shift workers — eating on an altered schedule, quickly devouring food, and skipping meals — dysregulates the hormonal balance and increases the risk for metabolic syndrome (abdominal obesity, hypertension, hyperlipidemia, and diabetes).7,11 Working nontraditional hours also can increase the risk of engaging in unhealthy behaviors such as smoking, excessive alcohol use, and decreased exercise, which also can lead to obesity.4,8 In 2007, the International Agency for Research on Cancer and the World Health Organization designated shift work as a possible carcinogen.12 A meta-analysis of 57 studies with more than 5.1 million participants noted that night shift workers have a 15% increased risk for cancer compared with those who work traditional hours, and the risk is cumulative over the years of shift work.13 Rotating shifts, which cause severe circadian disruption, pose the highest risk for cancer compared with fixed shifts (odds ratio [OR], 1.14; 95% CI,1.04-1.24).13 Shift workers are at particularly increased risk for breast (OR, 1.22; 95% CI, 1.08-1.32) and prostate cancers (OR, 1.26; 95% CI, 1.05-1.52).13 Carcinogenesis is attributed to decreased levels of nighttime melatonin, as well as decreased vitamin D level and circadian misalignment.13 Poor sleep causes fatigue and drowsiness, resulting in cognitive decline, which increases the incidence of work accidents and mistakes.3-5 Worker and public safety are at risk because shift workers include those in health care, protective services, and transportation roles.4 Shift work decreases overall mental performance; for example, 10 years of shift work equates to 6.5 years of age-related mental decline (2.5-point decrease on 0-100 scale).3,4 People with SWD often are tired while

Evaluation and Diagnosis

Patient History Patients with SWD often present with complaints of excessive fatigue, insomnia, poor sleep quality, and inability to stay asleep.1,2,4,5 It is imperative to distinguish SWD from other sleep disorders, such as obstructive sleep apnea, narcolepsy, restless legs syndrome, periodic limb movement disorder, and parasomnias.4,15 The assessment of excessive snoring and apneic breathing is more consistent with obstructive sleep apnea, whereas complaints of hallucinations or nightmares affecting sleep are more consistent with parasomnias.15 The inability to sleep because of a constant urge to move the legs is consistent with restless legs syndrome.15 Patients with SWD also may suffer from comorbid sleep disorders, which are 18.8% more prevalent in those with SWD than those working traditional schedules.16 A complete clinical history, including medical, psychiatric, medication, sleep patterns, and work schedule histories, is essential.1,2,4.5 A comprehensive social history, including the use of tobacco, alcohol, and illicit drugs; physical exercise; and daily caffeine/energy drink consumption, also should TABLE 1. Validated Patient Self-Assessments for Shift Work Disorder Insomnia Severity Index (ISI) • 7 questions about the inability to sleep • Score ≥10 is positive for clinical insomnia Epworth Sleepiness Scale (ESS) • 8 questions about the inability to stay awake • Score ≥10 is positive for clinical excessive sleepiness Munich Chronotype Questionnaire for Shift Workers (MCTQShift) • Questionnaire assessing chronotype based on sleeping behavior • No specific rating to determine chronotype; use clinical judgment

32 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 • www.ClinicalAdvisor.com

Patients with SWD are risk for multiple medical conditions; clinicians should screen for diabetes, hypertension, hyperlipidemia, and cancer. be documented.8 There are 3 different, validated patient selfassessments for the evaluation of SWD (Table 1).1,4,5 Primary care providers receive little medical training about obtaining a sleep history from patients. One mnemonic device that can be helpful is BAMS-RN (Bedtime, Awakenings, Maladaptive sleep behaviors, Snoring, Rise time, and Naps).1 The patient completes a sleep log detailing sleep patterns for at least 7 days, describing bedtime, length of sleep, number of awakenings, caffeine or alcohol use at bedtime, snoring, and number of naps taken throughout the day.1,4

TABLE 2. International Classification of Sleep Disorders-Third Edition (ICSD-3) Criteria for Diagnosis of Shift Work Disorder15 All symptoms below must be attributed to the current shift work schedule 1. Misalignment of circadian rhythm internal factors and external factors affecting sleep patterns 2. Insomnia or excessive daytime sleepiness and shifts are worked during usual sleep time 3. Symptoms present for 3 months 4. Symptoms cause significant impairment in daily functions 5. Sleep log and actigraphy for ≥7 days demonstrating sleep disturbances

Diagnostic Tests

There are no laboratory or radiologic tests to confirm SWD. The AASM recommends actigraphy for at least 7 days in conjunction with a detailed history and sleep log (Table 2).1,4,15 An actigraphy monitor is a clinically validated device worn on the wrist to monitor sleep and wake cycles.1,4 It must be worn at all times — not just while working.2,4 Activity monitors are available on many smartwatches; however, the US Food and Drug Administration (FDA) has not approved these devices for clinical use. Nonetheless, if patients are unable to afford actigraphy, smartwatches are a viable substitution to facilitate monitoring.As patients with SWD are at higher risk for multiple medical conditions, clinicians should continue to recommend screening for diabetes, hypertension, hyperlipidemia, and cancer.1-8 Psychological screenings assessing risk for depression, anxiety, and other psychological disorders also should be performed during each visit.8 Polysomnography is not recommended for diagnosis of SWD but may help rule out other sleep disorders.15

6. Symptoms not explained by other medical conditions, medications, substance abuse, or other sleep disorder

TABLE 3. Nonpharmacologic Treatment of SWD14 Maintain a regular sleep schedule and obtain ≥7 hours of sleep per night • Anchor sleep: sleep at a regular interval of time on work and off days Practice good sleep hygiene • No alcohol, caffeine, or eating up to 2 hours before bed • No cell phone use, eating, or watching television in bed • Maintain a cool and dark environment in the bedroom Night shifts: exposure to bright light (2000-20,000 lux) for wakefulness during the first half of shift and refrain from light after shift (wear sunglasses) Napping • Nap approximately 30 minutes before the shift and limit napping to ≤60 minutes • Nap 20-30 minutes during the shift, followed by light therapy Maintain healthy eating habits and routine physical exercise

Clinical Management

Although the first recommendation for a patient diagnosed with SWD is to refrain from shift work, in most patients, quitting a job or changing the schedule is not an option.1,5 However, the following adjustments in shift work may be helpful5: • Maintaining a fixed shift schedule • Working <10 hours per shift • Working <4 shifts consecutively • Having at least 11 hours off between shifts • Scheduling shifts to follow a clockwise rotation The clinical management of SWD is tailored to the patient based on symptoms.The AASM recommends both behavioral changes (Table 3) and medications (Table 4) for treatment of the disorder.6 Nonpharmacologic treatments entail lifestyle adjustments.The patient’s family and those living in the home must be aware of the adjustments and should offer support.17

TABLE 4. Pharmacologic Treatment of SWD1,4,5 Medication Dose, mg Common Adverse Effects Promote sleepa

Melatonin

1-10

None

Zolpidem

Headache, drowsiness, dizziness

Temazepamb

7.5-15

Drowsiness, fatigue, dizziness

Triazolam

0.125-0.25 Drowsiness, headache, dizziness

Modafinil Promote wakefulnessc Armodafinil

200

Headache, nausea, nervousness

150

All medications that promote sleep may cause residual sedation. Food and Drug Administration black box warning – concomitant use with opioids may result in severe respiratory depression, coma, or death. c Take tablets 1 hour before work shift. a

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 33

SLEEP MEDICINE

There is no evidence indicating that any specific treatment has better efficacy. The goal of treatment is to realign the circadian rhythm, promote sleep, and reduce daytime sleepiness.17 Pharmacologic treatments are prescribed based on the patient’s complaints to treat insomnia and/or promote wakefulness.5 None of the treatments recommended for insomnia have been studied in SWD, but both treatments recommended to promote wakefulness are FDA-approved in patients with SWD.1,4,5 Pharmacological treatments offer immediate benefits, but all sleep-promoting agents may cause residual drowsiness affecting work performance.4,5 In addition, modafinil and armodafinil may exacerbate psychiatric conditions and must be prescribed carefully in those with a history of mania or psychosis.5

6. Watson NF, Badr MS, Belenky, G, et al. Joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society on the recommended amount of sleep for a healthy adult: methodology and discussion. J Clin Sleep Med. 2015;11(8):931-952. 7. James SM, Honn KA, Gaddameedhi S, Van Dongen HPA. Shift work: disrupted circadian rhythms and sleep-implications for health and well-being. Curr Sleep Med Rep. 2017;3(2):104-112. 8. Moreno CRC, Marqueze EC, Sargent C, Wright KP, Ferguson SA, Tucker P. Working Time Society consensus statements: evidenced-based effects of shift work on physical and mental health. Ind Health. 2019;57(2):139-157. 9. Bhat A, Marciarille AM, Stevens D, Ingram DG. Drowsy driving considerations in non-commercial drivers for the sleep physician. J Clin Sleep Med. 2019;15(7):1069-1071. 10. Drake CL, Roehrs T, Richardson G, Walsh JK, Roth T. Shift work sleep

Patient Education

disorder: prevalence and consequences beyond that of symptomatic day

Shift work disorder puts patients at risk for drowsy driving. Patients must refrain from drowsy driving and arrange transportation when they experience excessive sleepiness. Assessment of the patient’s risk for a vehicular accident should include discussion of previous accidents or near misses.4 Educate family members about signs of comorbid disorders, such as apneic episodes, snoring, periodic limb movement, or restless legs syndrome.4,16 Encourage patients to seek support from family members for lifestyle adjustments.

workers. Sleep. 2004;27(8):1453-1462. 11. Costa G. Shift work and health: current problems and preventive actions. Saf Health Work. 2010;1(2):112-123. 12. International Agency for Research on Cancer. Night Shift Work. 2020;124. Accessed October 25, 2021. https://publications.iarc.fr/593 13. Lui W, Zhou Z, Dong D, Sun L, Zhang G. Sex differences in the association between night shift work and the risk of cancers: a meta-analysis of 57 articles. Dis Markers. 2018:7925219. 14. Jackson CL, Redline S, Emmons KM. Sleep as a potential fundamental contributor to disparities in cardiovascular health. Annu Rev Public Health.

Follow-up

2015;36:417-440.

After the initial diagnosis, patients should return for follow-up after a month to discuss the effectiveness of treatments and undergo screening tests.1,2,4,5 If Epworth Sleepiness Scale score remains high or is increasing, clinicians should refer patients to a sleep specialist for a Maintenance of Wakeful Test.1,4 If clinicians are concerned about narcolepsy, parasomnias, or obstructive sleep apnea, they should refer patients to a sleep specialist for polysomnography.2,4 ■

15. Sateia MJ. International Classification of Sleep Disorders-third edition.

Kimberly Sapre, DMSc, PA-C, CAQ-EM, practices emergency medicine in Falls Church,Virginia. She has 10 years of experience as a PA with previous experience in neurosurgery and interventional pain medicine. References 1. Wickwire EM, Geiger-Brown J, Scharf SM, Drake CL. Shift work and shift work sleep disorder: clinical and organizational perspectives. Chest.

Chest. 2014;146(5):1387-1394. 16. Kerkhof GA. Shift work and sleep disorder comorbidity tend to go hand in hand. Chronobiol Int. 2018;35(2):219-228. 17. Richter K, Acker J, Adam S, Niklewski G. Prevention of fatigue and insomnia in shift workers—a review of non-pharmacological measures. EPMA J. 2016;7(1):16.

Case Study Library

2017;151(5):1156-1172. 2. Reid KJ, Abbott SM. Jet lag and shift work disorder. Sleep Med Clin. 2015;10(4):523-535. 3. Jehan S, Zizi F, Pandi-Perumal SR, et al. Shift work and sleep: medical implications and management. Sleep Med Disord. 2017;1(2):00008. 4. Cheng P, Drake C. Shift work disorder. Neurol Clin. 2019;37(3):563-577. 5. Wright KP, Bogan RK, Wyatt JK. Shift work and the assessment and manage-

Check out all of our case studies in obesity, diabetes, and other important topics in primary care — along with our clinical challenges — by visiting us at: ClinicalAdvisor.com/Case-Study

ment of shift work disorder (SWD). Sleep Med Rev. 2013;17(1):41-54.

34 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 • www.ClinicalAdvisor.com

FEATURE: MELISSA KALENSKY, DNP, FNP-BC, PMHNP-BC, CNE

The Pros and Cons of Medical Cannabis: Current Evidence The widespread use of cannabis and the public perception that it is harmless make screening and patient counseling a priority.

Over 90% of US citizens approve of legalizing cannabis.

annabis is one of the most commonly used drugs in the United States. More than 48.2 million people in the US aged 12 years and older (17.5%) have used cannabis in the last year.1 Although evidence suggest that some medical conditions may benefit from cannabis use, there is a lack of high-quality randomized controlled trials examining the potential therapeutic uses of cannabis and a lack of prospective studies looking at associated adverse effects. The risks and benefits of any cannabinoidcontaining compound need to be carefully weighed for each patient. This includes consideration of potential effects on comorbidities and drug-drug interactions.The increasingly widespread use of cannabis makes screening and counseling patients about the potential risks vs benefits a priority.

Pharmacology

Cannabis sativa and Cannabis indica are the 2 most commonly used strains of cannabis, a plant containing approximately 540 chemical compounds, of which more than 100 are classified as cannabinoids.2 The compound generally responsible for producing intoxication (high) is delta-9-tetrahydrocannabinol (THC); cannabidiol (CBD) does not produce this effect but may have therapeutic effects.3 Cannabis can be found in natural and synthetic formulations that contain psychoactive and inactive compounds. Cannabis concentrates can be inhaled or vaporized. Products for oral ingestion 36 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 • www.ClinicalAdvisor.com

include pills, teas, edibles, tinctures, and gummies. Lozenges, lollipops, and dissolvable strips can be taken sublingually. Topical products include oils, lotions, and bath salts.4 The potency of THC content in samples of recreational cannabis has increased dramatically, from less than 4% in the early 1990s to more than 15% in 2018; some current variants and cannabis concentrates can have much higher THC levels.4 In the last 2 decades, the percentage of nonpsychoactive components has steadily decreased, resulting in an increase in the psychoactive to nonpsychoactive component ratio from 14 times in 2001 to 80 times in 2017.5 The result is that some currently available products may have a greater ability to produce a high. Psychoactive Drug Components

The absorption and distribution of THC is highly variable depending on the route of administration and individual patient characteristics.When consumed via inhalation (smoking or vaping), the onset of action is typically within 10 minutes; systemic bioavailability is 11% to 45%.6 When THC is consumed orally there is a greater variability in onset and effects due to first-pass metabolism through the liver and significant degradation by gastric acid. Peak THC levels have been reported at 1 to 6 hours after oral ingestion; systemic bioavailability is 4% to 20%.6 The metabolism of cannabis occurs via 2 hepatic cytochrome oxidases, CYP2C9 and CYP3A4. Its plasma half-life ranges from 1 to 3 days in occasional users to up to 13 days in chronic users, and it is eliminated through feces (65%) and urine (20%).6 The elimination half-life can be substantially longer in regular cannabis users because cannabis is highly lipophilic. With regular use, cannabis accumulates in adipose tissues over time, resulting in a slow release when blood levels are low and accounting for a positive urine drug screening for up to 6 weeks after last consumption vs 4 weeks in occasional users.7 Receptors and Reward Pathways

Endogenous cannabinoid receptors are found in the brain, spine, and peripheral nervous system, with components of cannabis acting as a partial agonist at both cannabinoid receptor type 1 (CB1) and type 2 (CB2) sites.8 Within the central nervous system, THC strongly binds to CB1 receptors accounting for its psychoactive properties; CBD does not.8 Cannabis impacts the release of several neurotransmitters such as acetylcholine, norepinephrine, γ-aminobutyric acid, and serotonin within multiple regions of the brain. Areas impacted include the frontal cortex, basal ganglia, cerebellum, hippocampus, and cerebral cortex, accounting for some of the drug’s clinical effects.6,8,9 Binding within the peripheral tissues occurs at CB2 receptors, primarily located within cells in the immune system

(B lymphocytes and splenic macrophages), peripheral nerve terminals, and the vas deferens.8 The mechanism of action in the periphery is less clear, but cannabinoids may play a role in the regulation of immune and/or inflammatory reactions.8 Both CB1 and CB2 cells are found in the cardiovascular system.6 Like alcohol and other psychoactive substances, cannabis is processed through the mesolimbic dopamine pathway, the same circuitry involved in the regulation of reinforcement and reward.9 This pathway is associated with reinforcement of adaptive behaviors and the natural high associated with joy or accomplishment. Cannabis binding bypasses the brain’s neurotransmitters and directly stimulates the release of dopamine within the reward pathway, triggering an artificial high. Longterm cannabis use eventually causes changes in this reward circuit. Over time, this results in an increase in impulsiveness to use the substance, which provides a reward, and a decrease in the pleasure or gratification associated with it, accounting for clinical symptoms related to tolerance.9 Physiologic Effects of Cannabis Use

Acute Intoxication Physiologic effects of acute intoxication may include euphoria, tachycardia, hypertension, conjunctival injection, dry mouth, increased appetite, impaired judgment, and paranoid delusions.10 Acute neuropsychiatric effects can be highly variable in presentation and appear to be dose dependent. At low doses, mood is described as euphoric, with decreased depression, anxiety, and tension; conversely, at higher doses there is increased anxiety, dysphoria, and panic.10 Other neurologic or psychiatric effects may include10-12: • Slowed reaction times and impaired motor coordination • Impaired attention, concentration, short-term memory, and risk assessment • Distortions in time and spatial perception • Increased intensity of visual/auditory perception • Depersonalization, hallucination, grandiosity, paranoia, and/ or other signs of psychosis These effects are additive when combined with other central nervous system (CNS) depressants. Mood-altering effects typically resolve within hours, but residual effects of a dose of cannabis might last for 24 hours. In laboratory studies of cognitive and behavioral effects, evidence suggests that the effects of cannabis increase as the dose consumed or level of THC in blood increases. Evidence also suggests that effects of cannabis on driving simulator performance and collision risk increase as dose consumed and levels in the body increase.13 Cardiovascular Effects The heart and vascular smooth muscle contain CB1 and CB2 receptors; thus, dose-dependent increases in heart rate

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MEDICAL CANNABIS UPDATE

and blood pressure can occur with acute intoxication.11,12 Orthostatic hypotension is a common side effect in older adults.14 Other potential physiologic changes can include increased platelet aggregation, arterial vasospasm, and increased cerebral vascular tone, which can result in decreased cerebrovascular blood flow.12 In the hours after ingestion, cannabis increases the risk for major cardiovascular events, such as hypertensive emergency, myocardial infarction, transient ischemic attack, and cerebrovascular accident.11 Chronic use in individuals with a history of angina may lower the angina threshold and, thus, precipitate chest pain.12 There also is evidence to suggest a link to new cardiac arrhythmia secondary to ischemia.12 Atrial fibrillation, ventricular fibrillation, and Brugada pattern (ventricular arrhythmia) are the most commonly associated arrhythmias; when such arrhythmias occur, the mortality rate is estimated at 11%.12,15 Pulmonary Effects Inhalation of cannabis and associated respiratory irritants can cause acute or chronic cough, increased mucous production, and shortness of breath.16 Pneumomediastinum can be an acute complication associated with holding ones breath in during inhalation.17 Evidence suggests that long-term cannabis use may lead to large airway inflammation, increased airway resistance, and lung hyperinflation.11 In individuals with underlying pulmonary disease, such as asthma or chronic obstructive pulmonary disease (COPD), this may increase the risk for respiratory infection and acute exacerbations of chronic disease. Although cannabis is known to contain potential carcinogens, the connection between lung carcinoma and cannabis use remains less clear.14 By comparison, cannabis contains 50% more benzopyrene and 75% more benzanthracene than tobacco.11 Evidence also suggests cannabis is associated with 4 times more deposition of tar than tobacco products, suggesting that an underlying link to carcinoma is possible, although there is no definitive evidence linking cannabis to increased head, neck, or lung cancer.4,11,14 Prolonged Neuropsychiatric Effects Cannabis use in children has the potential to alter brain development and can be linked to poor educational outcomes, such as increased drop-out rates.11 Use in adolescents is correlated with cognitive impairment and lower IQ scores.11 In adults, use causes memory impairment and difficulty learning new information.18 In some individuals, cannabis increases the risk of developing or worsening of depression, anxiety, and post-traumatic stress disorder.11 Cannabis use is linked with the development of psychosis, particularly among youth who have preexisting genetic vulnerability, and may advance onset

Case Presentation A 32-year-old mother of 3 presents to the emergency department with a 10-day history of persistent nausea with intermittent nonbiliary, nonbloody emesis, and diffuse abdominal pain. She denies alcohol or “illicit” drug use but does admit to smoking cannabis 2 to 3 times a day for the last several years. Her vital signs are within normal limits, her electrocardiogram is normal, and her laboratory tests (complete blood cell count, comprehensive metabolic panel, lipase, and serial troponins) are normal. Computed tomography of the abdomen shows no acute pathology. She has received 2 liters of normal saline, as well as multiple doses of intravenous ondansetron and metoclopramide, without improvement in nausea and continued active emesis.

of first psychotic episode by 2 to 6 years in such individuals.11,18 Long-term use has been linked with the development of amotivational syndrome and reports of decreased life satisfaction.18 Cannabis Hyperemesis Syndrome There are no clinically established diagnostic or treatment guidelines for cannabis hyperemesis syndrome (see Case Presentation), but there are definitive patterns in clinical presentation. Patients typically present with intense and unremitting abdominal pain with persistent nausea and vomiting, often with reports of multiple episodes over months to years.19 Clinical history reveals a heavy use of cannabis daily over a prolonged period of time. Often patients report the only effective alleviating factor for associated abdominal pain is the use of hot baths or showers. Generally, symptom presentation occurs in 3 phases: prodromal, acute nausea and diffuse abdominal pain, the intensity of which often causes fear of vomiting; hyperemetic, multiple episodes of vomiting, driving the patient to seek medical care; and recovery, during which normal eating patterns resume.19 Cannabis has dose-dependent biphasic effects.At a low dose, it acts as an antiemetic; at higher doses, it becomes proemetic.19 Clinical priorities lay in achieving cessation of hyperemesis, addressing any secondary issues, such as dehydration, electrolyte disturbance, acute kidney injury, or rhabdomyolysis, and advising the patient about long-term cessation of cannabis use.19 It is unclear why traditional antiemetics are ineffective in addressing nausea and emesis associated with cannabis use. However, it is known that cannabis is active within the dopaminergic pathways of the brain; clinically, dopamine-blocking agents such as intravenous haloperidol (5 mg) often are more

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Continues on page 40

MEDICAL CANNABIS UPDATE

effective in treating nausea in these patients.19 Other treatments, including topical capsaicin (applied to the stomach), corticosteroids, benzodiazepines, and tricyclic antidepressants have been studied but none have demonstrated consistently effective symptom relief.19 Potential Drug Interactions, Toxicity, and Overdose

The large volume of chemical compounds within cannabis makes examining potential drug-drug interactions challenging, and knowledge in this area is largely theoretical. Cannabinoids bind at a wide variety of sites to impact gene expression.20 It is presumed that specific chemical components and formulations affect actions and that the duration of exposure may dictate potential drug interactions.The primary metabolism of cannabinoid compounds is via cytochrome P450 (CYP450): THC (CYP2C9/CYP3A4), CBD (CYP2C19/CYP3A4), and cannabinol (CYP2C9/CYP3A4).20 Any prescription drug processed through one or more of these CYP450 pathways, including commonly used medications (eg, NSAIDs, opioids, statins, anticonvulsants, selective serotonin reuptake inhibitors, and antibiotics) has the potential to cause a drug-drug interaction. Generally, data demonstrate that even low doses of alcohol increase plasma levels of THC.20 When cannabis is used in combination with opioid pain medications, there may be increased opioid analgesic effects without correspondingly increased plasma levels.20 Cannabinoids also may work synergistically with gabapentin to improve therapeutic window and effects.20 Adverse effects are more common when cannabis is orally ingested, and symptoms can last up to 12 hours. Naturally

POLL POSITION Which condition has evidence of medical cannabis demonstrating some clear improvement in symptoms?

■ Parkinson disease ■ Major depression

22.63%

18.25%

■ Spasticity of multiple sclerosis ■ Post-traumatic stress disorder

56.93%

For more polls, visit ClinicalAdvisor.com/Polls.

2.19%

occurring cannabinoids act as partial agonists at CB1/CB2 receptors, limiting fatal overdoses.21 However, children have an increased risk for overdose, most commonly through unintentional oral ingestion, and they are significantly more likely than adults to experience severe or life-threatening symptoms including hyperkinesis, respiratory depression, lethargy, coma, and death.22 Duration of symptoms in children can vary from 4 to 48 hours postingestion, with treatment involving supportive care.22 Synthetic cannabinoids act as pure agonists with very high affinity at the CB1 receptor and, thus, their effects are more intense and longer lasting.23 Synthetic formulations are not detectable on routine laboratory screening tests. If potential ingestion is suspected, cannabis toxicity should be included within a differential diagnosis, regardless of a negative toxicology screening. Synthetic compounds have a greater potential for serious neuropsychiatric toxicity, producing hallucinations, delirium, and/or psychosis in up to 66% of individuals.23 Life-threatening toxicity, most characteristically manifesting as severe agitation or seizures, is possible at any age.23 Considerations in Recommending Medical Cannabis

The US Food and Drug Administration (FDA) has approved medical cannabis for 3 clinical syndromes.24 Naturally derived cannabis, labeled as cannabidiol (Epidiolex), is approved for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients 2 years and older. The agent is approved in the United Kingdom for treatment of seizures associated with tuberous sclerosis complex.25 The synthetic cannabinoid dronabinol (Marinol and Syndros) is approved for the management of anorexia with associated weight loss in patients with AIDS and nausea associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.24 Nabilone (Cesamet) is also a synthetic cannabinoid approved for the treatment of nausea associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.24 Potential Off-Label Therapeutic Uses

The use of cannabinoids in the treatment of chronic pain (fibromyalgia, rheumatoid arthritis, central pain in multiple sclerosis, and neuropathic pain) is supported by study evidence, with no serious adverse events related to its use.2,26 There has been clear efficacy established in the improvement of chemotherapy-induced nausea and vomiting with medical cannabis products that are not FDA-approved, particularly with ingestible products vs inhaled products.11,26 The treatment of seizures beyond those associated with Lennox-Gastaut syndrome and Dravet syndrome is perhaps

40 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 • www.ClinicalAdvisor.com

TABLE. Available Evidence of Cannabis Efficacy6,8,24,26 Not Enough Evidence to Recommend Routine Clinical Use

No Clear Evidence of Clinical Benefits

Evidence Demonstrates Some Clear Improvement in Symptoms

Available Evidence Supports Improvement in Some Cases

Alzheimer disease

Acute pain

Chemotherapy-induced nausea/vomiting

Seizures

Parkinson disease

Glaucoma

Chronic pain

Cachexia related to HIV/cancer

PTSD

Tremor in MS

Spasticity in MS

Schizophrenia

Major depression

Generalized anxiety

Psychosis

Huntington disease

Social anxiety

Sleep disorders

MS, multiple sclerosis; PTSD, post-traumatic stress disorder

the most discussed applications for cannabis, but data are highly variable, ranging from no improvement to an estimated 50% reduction in symptoms.26 In the treatment of mental health disorders, studies have shown improvement in generalized and social anxiety disorders but no clear benefits in major depression and variability in the efficacy for psychotic disorders.26 No clear benefit has been found in the treatment of acute postoperative or dental pain, and use improves intraocular pressure in those with glaucoma only transiently. 264 The application in Alzheimer disease is purely theoretical, minimal data is available in Parkinson’s disease, and no efficacy has been established in the treatment of Huntington disease (Table).26 No cannabis formulation has yet proven to have greater efficacy than other FDA-approved medications options for these conditions.26 Use in Pregnancy and Breastfeeding

Minimal data exist on the safety and effects of cannabis use in pregnancy. Both the American College of Obstetrics and Gynecology and the American Academy of Pediatrics advise against cannabis use during pregnancy and breastfeeding, citing concern for adverse neurodevelopmental effects.27,28 Some psychoactive components of cannabis likely cross the placental barrier, with fetal plasma concentrations estimated to be 10% to 30% of maternal serum concentrations.29 With the highly lipophilic nature of THC, it is important to counsel patients that fetal exposure may occur for 4 to 6 weeks after maternal cessation.29 Based on the available evidence, complications of use during pregnancy may include higher rates of maternal anemia, up to twice the rate of preterm births, reduced birth weight,

increased likelihood of neonatal intensive care unit stays, and learning/attention deficits into childhood.30 Studies suggest that THC accumulates in breast milk. Peak levels occur approximately 4 hours after maternal inhalation and detectable levels persist for at least 6 days after last maternal use.31 Lack of federal regulation in cannabis supply and distribution also raises concern for the potential secondary exposure to pesticides, heavy metals, bacteria, and fungi through cannabis use.32 Conclusion

Research on use of cannabis in the treatment of medical conditions is emerging at a rapid pace.The expanding number of states that have legalized recreational marijuana use is likely to increase the number of patients who present in the primary care setting seeking information on cannabis use for medical conditions. Clinicians will need to remain updated on evolving evidence to provide tailored patient education on the benefits and risks associated with cannabis use. ■ Melissa Kalensky, DNP,APRN, FNP-BC, PMHNP-BC, CNE, is an assistant professor at Rush University College of Nursing in Chicago.

Read the online version of this article for a link to information on cannabis use disorder, intoxication, withdrawal, and other cannabis-related disorders.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 41

MEDICAL CANNABIS UPDATE

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research-reports/marijuana/letter-director

MMWR Morb Mortal Wkly Rep. 2016;15;65(27):692-695.

5. ElSohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes

24. US Food and Drug Administration. FDA and cannabis: research

in cannabis potency over the last 2 decades (1995–2014): analysis of current

and drug approval process. Published 2020. Accessed August 19, 2021.

data in the United States. Biol Psychiatry. 2016;79(7):613-619.

https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-

6. Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers.

research-and-drug-approval-process

2007;4(8):1770-1804.

25. Jazz Pharmaceuticals. GW Pharmaceuticals receives approval for

7. Drug and Alcohol Services South Australia. Urine drug screening: its use

EPIDYOLEX® (cannabidiol) from the MHRA for the treatment of seizures

in determining patient progress. November 2016. Accessed August 24, 2021.

associated with tuberous sclerosis complex. Press release. Accessed

https://www.sahealth.sa.gov.au/wps/wcm/connect/8e72130045dc95aaaad6ea

October 20, 2021. https://investor.jazzpharma.com/news-releases/

574adac1f8/Urine+Drug+Screening+21+11+2016.pdf?MOD=AJPERES&CA

news-release-details/gw-pharmaceuticals-receives-approval-epidyolexr-

CHEID=ROOTWORKSPACE-8e72130045dc95aaaad6ea574adac1f8-l.pEszj

cannabidiol-mhra

8. Chayasirisobhon S. Mechanisms of action and pharmacokinetics of cannabis.

26. Abrams D, Fug-Berman A, Wood, S, et al. Medical cannabis: evidence on

Perm J. 2020;25:19-200.

efficacy. District of Columbia, Department of Health. Accessed August 19,

9. Stahl SM. Stahl’s Essential Psychopharmacology. 4th ed. Cambridge University

2021. https://dchealth.dc.gov/sites/default/files/dc/sites/doh/publication/attach-

Press; 2013.

ments/Medical%20Cannabis%20Clinical%20Efficacy%20V2.pdf

10. American Psychiatric Association. Diagnostic and Statistical Manual of

27. The American College of Obstetricians and Gynecologists. ACOG com-

Mental Disorders. 5th ed. American Psychiatric Association; 2017.

mittee opinion: marijuana use during pregnancy and lactation. Obstet Gynecol.

11. Volkow ND, Baler RD, Compton WM, Weiss SRB. Adverse health effects

2017;130(4):e205-209.

of marijuana use. N Engl J Med. 2014;370(23):2219-2227.

28. Ryan, SA, Ammerman, SD, O’Connor, ME. Marijuana use during

12. Subramaniam V, Menezes A, DeSchutter A, Lavie C. The cardiovascular

pregnancy and breastfeeding: implications for neonatal and childhood

effects of marijuana: are the potential adverse effects worth the high?

outcomes. Pediatrics. 2018;142 (3):e20181889.

Mo Med. 2019;116(2):146-153.

29. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabi-

13. Brands B, Di Ciano P, Mann RE. Cannabis, impaired driving, and road safety:

noids. Clin Pharmacokinet. 2003;42(4):327-360.

an overview of key questions and issues. Front Psychiatry. 2021;12:641549.

30. Gunn JKL, Rosales CB, Center KE, et al. Prenatal exposure to cannabis and

14. National Academies of Sciences, Engineering, and Medicine. The health

maternal and child health outcomes: a systematic review and meta-analysis.

effects of cannabis and cannabinoids: the current state of evidence and rec-

BMJ Open. 2016;6(4):e009986.

ommendations for research. National Academies Press; 2017. Accessed July

31. Bertrand KA, Hanan NJ, Honerkamp-Smith G, Best BM, Chambers CD.

26, 2021. https://pubmed.ncbi.nlm.nih.gov/28182367/

Marijuana use by breastfeeding mothers and cannabinoid concentrations in

15.Kariyanna PT, Wengrofsky P, Jayarangaiah A, et al. Marijuana and cardiac

breast milk. Pediatrics. 2018;142(3):e20181076.

arrhythmias: a scoping study. Int J Clin Res Trials. 2019;4(1):132.

32. Centers for Disease Control and Prevention. Breastfeeding.

16. Turner AR, Agrawal S. Marijuana. In: StatPearls [Internet]. Treasure Island

Marijuana: is it safe for mothers who use marijuana to breastfeed?

(FL): StatPearls Publishing; September 2, 2020. Accessed August 26, 2021.

Published 2020. Accessed August 19, 2021. https://www.cdc.gov/

17. Kouritas VK, Papagiannopoulos K, Lazaridis G, et al. Pneumomediastinum.

breastfeeding/breastfeeding-special-circumstances/vaccinations-

J Thorac Dis. 2015;7(Suppl 1):S44-S49.

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18. Stuyt E. The problem with the current high potency THC marijuana from

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the perspective of an addiction psychiatrist. Mo Med. 2018;115(6):482-486.

20the%20infant

42 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 • www.ClinicalAdvisor.com

Dermatologic Look-Alikes Suspicious Nevi SARAH K. FRISKE, BBA; TARA L. BRAUN, MD; CHRISTOPHER RIZK, MD

CASE #1

CASE #2

A 65-year-old White man with a history of nonmelanoma skin cancers presents to the dermatology clinic with a mole on his right leg that has been present for 6 months. The patient notes that the lesion is not painful, itchy, or bleeding. He reports that the mole started as a small lesion but has grown steadily over the last half year. The patient states that he goes sailing several times a year and reports a history of several blistering sunburns. Physical examination reveals a 1.2- × 1.3-cm hyperpigmented lesion with irregular borders and color variegation on the patient’s right lower leg.

A 15-year-old adolescent with a birthmark on her chest presents to the dermatology clinic for evaluation.The lesion was first noticed at birth and has grown as the patient has aged, becoming increasingly thick and dark over the years. The patient reports that the lesion is not painful, itchy, or bleeding but she is somewhat bothered by its appearance. On physical examination, there is a well-demarcated, oval, dark brown plaque with a pebbly texture on the patient’s right upper chest. She has no similar lesions elsewhere on her body.The patient is otherwise in good health with no history of allergies or major illnesses.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 43

Dermatologic Look-Alikes CASE #1

Melanoma

Melanoma has an extensive history with descriptions of the disease dating back to the writings of Hippocrates in the 5th century BC and archeological evidence of diffuse melanotic metastases identified in preColumbian mummies radiocarbon dated to approximately 2400 years ago.1 Coining of the term “melanose” is first credited to Rene Laënnec, who recognized the disease to be independent from black carbon lung deposits, which were frequently found in autopsies during the early 1800s.2 In 1820,William Norris, MD, furthered the awareness of melanoma with a detailed report of the etiology and progression of the disease including documentation of the proclivity for widespread metastasis.3 Additional key events in the history of melanoma include Sir Robert Carswell’s coining of the term “melanoma” in 1838 and Australian mathemetician Henry Lancaster’s discovery of the association between sunlight and increased incidence of melanoma in 1956.3 Americans have a 1 in 59 lifetime risk of developing invasive melanoma.4 The incidence rate has increased exponentially from 6.8 per 100,000 in 1973 to 22.0 per 100,000 in 2018.5 The rate of melanoma is higher in women than in men until approximately age 40, after which risk for melanoma increases in men who then have an incidence almost 3 times that of women.4 The rate of melanoma is significantly higher in White populations than in non-White populations (2.6% vs 0.35%).6

Melanoma more severely affects people with a family history of dysplastic and melanocytic nevi. Although the specific etiology of melanoma remains unknown, research suggests an interaction between genes and the environment. Normal melanocyte development and function is tightly regulated by signal transduction pathways that translate extracellular messages, activating intracellular tyrosine kinases and phosphorylation responses.7 BRAF, a serine/ threonine kinase encoded by the BRAF gene, can interrupt these pathways when mutated, causing growth factor–independent cellular proliferation.7 In addition, the microphthalmia transcription factor (MITF) gene is an important regulator of

melanocyte differentiation, proliferation, and the cell cycle.7 Amplification of this gene was identified in 20% of human melanoma clinical specimens, suggesting its potential role as an oncogene.7 Melanomas also often display dysregulation in the cyclin D/CDK4 complex, leading to loss of inhibitor p16 and loss of control of G1/S cell cycle transition.7,8 Environmentally, UV radiation has ionizing effects that influence the p53 tumor suppressor gene, leading to melanoma development.4 Risk factors for melanoma include sun exposure and frequent tanning bed usage, with melanoma mortality directly correlating with UV exposure.4 Melanoma has been shown to cluster in families and more severely affects individuals with a history of dysplastic and melanocytic nevi.4 In addition, melanoma development has been linked to phenotypic features including fair complexions, red hair, freckles, and a tendency to sunburn easily.4 Individuals who are immunosuppressed are 8 times more likely to develop melanoma. Consequently, special precautions should be taken for organ transplant recipients and patients with cancer.4,9,10 When performing a physical examination, clinicians should note the presence of multiple nevi, giant congenital nevi, and atypical/dysplastic nevi because these conditions pose a risk of developing into melanoma.11 Melanoma typically presents with at least 1 of 5 characteristic criteria defined in the ABCDE system: asymmetry, border irregularity, color variegation, diameter larger than 6 mm, and evolving appearance.10,11 Dermoscopy can assist in the evaluation of suspicious-appearing lesions, with findings of atypical pigment networks, asymmetry, and blue-white veils being especially concerning for malignancy.12 Additional imaging techniques that help differentiate melanoma from benign moles include in vivo reflectance confocal laser microscopy, computer-aided multispectral digital analysis, and electrical impedance spectroscopy.9,12 Bleeding, itching, or ulceration of moles also can indicate melanoma.11 If a lesion is concerning for melanoma, the lesion should be sampled with either partial biopsy (punch or shave) or, ideally, with excisional biopsy of the entire specimen with narrow margins.10,11 Histologic subtypes of melanoma are as follows: superficial spreading, nodular, acral lentiginous, lentigo maligna, desmoplastic, and amelanotic. Reported histologic features include dermal mitotic rate, microsatellitosis, tumor-infiltrating lymphocytes, angiolymphatic invasion, neurotropism, and pure desmoplasia. Tumor thickness based on Breslow staging, lymph node involvement, and the presence of metastasis are important factors on laboratory workup.10 The differential diagnosis for melanoma includes seborrheic keratosis, benign nevus, lentigo, blue nevus, angiokeratoma, traumatic hematoma, hemangioma, and pigmented actinic keratosis.11 Melanoma can be distinguished from these other

44 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 • www.ClinicalAdvisor.com

conditions via histology and melanocytic and proliferative biomarkers including Melan-A and MART-1, which recognize a specific melanoma antigen. Additional clinical markers include HMB-45, S100, and MITF, which display high levels of expression in melanocytic tumors.8 For confirmed cases of melanoma, the American Joint Committee on Cancer has developed a standardized staging system based on tumor, node, and metastasis to allow clinicians to categorize patients into stages strongly linked to survival and prognosis.8,10 The recommended treatment for localized melanoma is surgical removal of the tumor and surrounding tissue. Depending on lymph node biopsy results, affected lymph nodes also should be removed. Surgical removal is not sufficient for metastatic melanoma, and drug therapies are recommended. Systemic treatments available for metastatic melanoma include targeted therapies, such as BRAF inhibitors, as well as immunotherapies, such as anticytotoxic T-lymphocyte-associated antigen 4 antibodies and antiprogrammed cell death-1 antibodies.8 The patient in this case was diagnosed with biopsy-proven noninvasive melanoma and was treated with wide local excision.

CASE #2

Congenital Melanocytic Nevi

Congenital melanocytic nevi (CMN) result from the benign proliferation of melanocytic cells during intrauterine life. Historic information about the identification of CMN is limited. In the late nineteenth and early twentieth century, an increase in reports of children with giant CMN who later developed melanoma sparked an increased interest in studying, identifying, and classifying congenital nevi to better understand the condition’s potential link to melanoma.13 The prevalence of CMN varies from 0.5% to 31.7% depending on the study consulted.14 Female infants are more likely to develop CMN than male infants, with a female to male incidence ratio of 3 to 2. Lesions generally are smaller than 3 cm to 4 cm, but larger lesions can occur. Such giant CMN have an incidence of 1 in 20,000 to 500,000 newborns.13,14 The pathophysiology of CMN is linked to sporadic somatic mutations in utero; familial patterns are rare.The underlying mechanism is attributed largely to defects in the neuroblastomaras (NRAS) proto-oncogene, which encodes an isoform of

RAS GTPase that normally activates BRAF serine-threonine kinase.15 Once phosphorylated, the mitogen-activated protein kinase signaling pathway can direct cell cycle, transcription, and differentiation. However, defects in RAS protein can lead to unregulated growth and the development of benign melanocytic cells in epidermal nests. Studies also have demonstrated a consistent relationship between CMN size and number of NRAS mutations, with the number of such mutations being higher in giant CMN.14-16 Unlike in melanoma, minimal data support pathologic contributions from BRAF mutations in CMN.16

Congenital melanocytic nevi often are removed to reduce the risk for melanoma development or cosmetic purposes. The high degree of NRAS mutations studied in nevi present at birth reveals that UV radiation is not a prerequisite for NRAS mutations. Other somatic mutations, such as those in SOX10, also could work together with NRAS mutations to promote development of CMN. Deficiencies of SOX10 have been shown to prevent congenital nevi and suppress neural crest stem cell properties.14-16 Risk factors for CMN are poorly defined.14 One study found no significant influence of the following factors on the rate of CMN: gender, twin pregnancies, parental consanguinity, type of delivery, socioeconomic level, parental ages, birth order, fetal presentation, type of delivery, and postnatal mortality. In addition, no link between CMN rates and history of first-trimester vaginal bleeding, maternal chronic illnesses or immunizations, drug intake, or radiation exposure was found.17 Congenital nevi typically are distinguished by their presentation in newborns and their round to oval shape with welldemarcated, regular borders. However, CMN are noted to change in appearance from the neonatal period to adulthood. During the newborn period, CMN appear as lightly colored, hairless, flat, or raised moles.The appearance during the initial days of life also has been compared to an irregular café au lait spot. Later in the child’s life, CMN can become a darker brown, slightly elevated spot with long, coarse pigmented hairs. CMN can present with a papular, rugose, pebbly, verrucous, or even cerebriform exterior. CMN typically are classified by their size in adulthood with diameters of less than 1.5 cm for small CMN, between 1.5 cm and 19.9 cm for medium CMN, and 20 cm or larger for giant CMN. When distinguishing these lesions from benign acquired nevi, CMN stand out with a

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 45

Dermatologic Look-Alikes Melanoma1-12

Congenital Melanocytic Nevus13-22

Dermatologic presentation

• Pigmented lesion with asymmetry, border irregularity, color variegation, diameter larger than 6 mm, and evolution and/or elevation • Dermoscopic findings of atypical pigment networks, asymmetry, and blue-white veils

• Round to oval shape with well-demarcated, regular borders • In newborns, lesions often appear lightly colored and hairless, with a flat or raised appearance • Lesions progressively darken and acquire coarse pigmented hair as a child grows • Textures include papular, rugose, pebbly, verrucous, or cerebriform

Associations

• Persistent itching, bleeding, or crusting of lesion • Local inflammation • Metastatic spread indicated by seizures, headaches, vision changes, coughing, hemoptysis, shortness of breath, fever, chills, and weight loss

• With giant CMN, scoliosis, spina bifida, atrophy, asymmetry, clubfoot, elephantiasis, cranial bone hypertrophy, and increased risk for neurocutaneous melanosis and leptomeningeal melanocytosis • Satellite and other benign lesions

Etiology

• Contributing factors include disruption of cell signaling, differentiation, and proliferation pathways • Exposure to UV radiation through direct sun or tanning bed usage

• In utero sporadic somatic mutations • Contributing factors include disruption of cell signaling, differentiation, and proliferation pathways • Direct relationship between number of NRAS mutations and CMN size

Characteristic location

• In men, occur most frequently on the trunk • In women, occur most frequently on lower extremities • Specific subtypes may present on palms, soles, nail beds, mucous membranes, scalp, and penis

• Most commonly appears on trunk and extremities • Less frequently appears on head, neck, hands, and feet

Histology

• Histologic subtypes of melanoma are as follows: superficial spreading, nodular, acral lentiginous, lentigo maligna, desmoplastic, and amelanotic • Important for staging: Breslow thickness, dermal mitotic rate, peripheral margin status, deep margin status, histologic ulceration, microsatellitosis, tumor infiltrating lymphocytes, neurotropism, and pure desmoplasia

• Presence of nevomelanocytes in the lower two-thirds of the dermis and subcutaneous tissues • Single-file array of nevomelanocytes within collagen bundles • Nevomelanocytes within hair follicles, sebaceous glands, eccrine apparatus, vessel walls, and nerves

Diagnosis

• History and physical examination • Excisional biopsy of entire specimen (preferred) or partial biopsy • Histologic findings (cytologic atypia, amplified cellularity, angiolymphatic invasion, melanocytic biomarkers)

• History and physical examination at birth • Evolution of size and appearance after childhood development • Histologic findings (nevus cells in lower two-thirds of dermis, single-file array, involvement of nevus with sebaceous glands, blood vessels, eccrine glands)

Treatment

• Surgical excision of tumor • Lymph node removal if biopsy results deem appropriate • Systemic therapies available for metastatic melanoma include targeted therapies (eg, BRAF inhibitors) and immunotherapies (eg, CTLA-4 antibodies and anti-PD-1 antibodies)

• No treatment (observation) • Full-thickness or partial-thickness excision • Dermatome shaving and dermabrasion • Anecdotal data on chemical peels, cryotherapy, and electrotherapy • Trade-off between cosmetic treatment goals and prevention of future melanoma largely guide treatment recommendations

CMN, congenital melanocytic nevus; CTLA-4, cytotoxic T-lymphocyte–associated antigen 4; NRAS, neuroblastoma-ras proto-oncogene; PD-1, programmed cell death-1

larger size, penetration of deeper layers of the skin, and the presence of a mottled heterogeneous morphology. Eventually, most CMN evolve to form elevated plaques. CMN most often are found on the trunk or extremities but also may be found on the head, neck, hands, and feet.13,14,18 CMN have distinct histopathologic features. First, the lower two-thirds of the dermis and the subcutaneous tissue should contain nevomelanocytes. The presence of a single-file array of nevomelanocytes between the collagen bundles of the dermis is a unique indicator of CMN. Histologic analysis of hair

follicles, sebaceous glands, eccrine apparatus, vessel walls, and nerves should reveal extensions of nevomelanocytes around these structures.13,18 When diagnosing CMN, clinicians should be aware of potential associations with giant CMN, such as scoliosis, spina bifida, clubfoot, asymmetry, atrophy, elephantiasis, and cranial bone hypertrophy. Studies also noted that patients with giant CMN or numerous CMN have an increased risk for neurocutaneous melanosis.18 Satellite lesions are present in up to 78% of giant CMN cases.13

46 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 • www.ClinicalAdvisor.com

The differential diagnosis for CMN includes acquired nevi, café au lait spots, melanoma, desmoplastic malignant melanoma, blue nevi, and Becker nevus.14,19-21 Diagnosis is made by total body skin examination at birth with dermoscopic evaluation; if concerning features are present, diagnosis is made via biopsy.21 Treatment options for CMN are varied with respect to goals, advantages, and disadvantages. CMN often are removed to either reduce the chance for development of melanoma or for cosmetic purposes. The first-line treatment recommendation is excision, which results in high satisfaction rates, but data are limited on the efficacy of excision in preventing future melanoma. Small- to medium-sized lesions that are clinically consistent with CMN do not need to be removed prophylactically in the absence of concerning features as these lesions have a less than 1% chance of developing into melanoma during a patient’s lifetime. Giant CMN have an approximately 5% chance of developing into melanoma over a lifetime; thus, patients with such lesions may benefit from prophylactic partial or complete surgical removal and require diligent surveillance for the development of melanoma and neurocutaneous melanocytosis.21-22 Excision can be either full or partial thickness removal depending on penetration level and size. Dermatome shaving shows potential in reducing the risk for melanoma by removing some CMN cells but has the disadvantage of creating a scar. Abrasive removal methods such as dermabrasion can reduce pigmentation during the newborn period whereas curettage results are relatively poor. Other potential treatment options include chemical peels, cryotherapy, electrosurgery, and radiation; however, information about these options is anecdotal at best, which results in their limited use in practice.12,22 The patient in this case was diagnosed with CMN via clinical history and examination. After she and her parents were counseled about the risks and benefits of surgical excision, the patient decided to monitor the lesion at this time. ■

3. Rebecca VW, Sondak VK, Smalley KS. A brief history of melanoma: from mummies to mutations. Melanoma Res. 2012;22(2):114-122. 4. Rigel DS. Epidemiology of melanoma. Semin Cutan Med Surg. 2010;29(4):204-209. 5. Centers for Disease Control and Prevention. Cancer statistics at a glance. Accessed October 18, 2021. https://www.cdc.gov/cancer/skin/statistics/ index.htm 6. American Cancer Society. Key Statistics for melanoma skin cancer. Accessed October 18, 2021. https://www.cancer.org/cancer/melanoma-skincancer/about/key-statistics.html 7. Wagner AJ, Fisher DE. Melanocyte signaling pathways and the etiology of melanoma. Drug Discovery Today: Disease Mechanisms. 2005;2(2):179-183. 8. Davis LE, Shalin SC, Tackett AJ. Current state of melanoma diagnosis and treatment. Cancer Biol Ther. 2019;20(11):1366-1379. 9. Schadendorf D, van Akkooi ACJ, Berking C, et al. Melanoma. Lancet. 2018;392(10151):971-984. 10. Ward WH, Lambreton F, Goel N, Yu JQ, Farma JM. Clinical presentation and staging of melanoma. In: Ward WH, Farma JM, eds. Cutaneous Melanoma: Etiology and Therapy [Internet]. Codon Publications; 2017. 11. Goldstein BG, Goldstein AO. Diagnosis and management of malignant melanoma. Am Fam Physician. 2001;63(7):1359-1368. 12. Rigel DS, Russak J, Friedman R. The evolution of melanoma diagnosis: 25 years beyond the ABCDs. CA Cancer J Clin. 2010;60(5):301-316. 13. Viana AC, Gontijo B, Bittencourt FV. Giant congenital melanocytic nevus. An Bras Dermatol. 2013;88(6):863-878. 14. Alikhan A, Ibrahimi OA, Eisen DB. (2012). Congenital melanocytic nevi: where are we now? Part I. Clinical presentation, epidemiology, pathogenesis, histology, malignant transformation, and neurocutaneous melanosis. J Am Acad Dermatol. 2012;67(4):495.e1-17. 15. Roh MR, Eliades P, Gupta S, Tsao H. Genetics of melanocytic nevi. Pigment Cell Melanoma Res. 2015;28(6):661-672. 16. Bauer J, Curtin JA, Pinkel D, Bastian BC. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol. 2007;127(1):179-182. 17. Castilla EE, da Graça Dutra M, Orioli-Parreiras IM. Epidemiology of congenital pigmented naevi: II. Risk factors. Br J Dermatol. 1981;104(4):421-427. 18. Tannous ZS, Mihm MC, Sober AJ, Duncan LM. Congenital melanocytic nevi: clinical and histopathologic features, risk of melanoma, and clinical

Sarah K. Friske, BBA, is a medical student at Baylor College of Medicine in Houston, Texas; Tara L. Braun, MD, is a resident in the Department of Dermatology at Baylor College of Medicine; and Christopher Rizk, MD, is a dermatologist affiliated with Baylor College of Medicine.

management. J Am Acad Dermatol. 2005;52(2):197-203. 19. Pattee SD, Hansen RC, Bangert JL, Joganic EF. Giant congenital nevus with progressive sclerodermoid reaction in a newborn. Pediatr Dermatol. 2001;18(4):320-324. 20. Khatami A, Seradj MH, Gorouhi F, Firooz A, Dowlati Y. Giant bilateral Becker nevus: a rare presentation. Pediatr Dermatol. 2008;25(1):47-51.

References

21. Price HN, Schaffer JV. Congenital melanocytic nevi—when to worry and

1. Urteaga O, Pack GT. On the antiquity of melanoma. Cancer.

how to treat: facts and controversies. Clin Dermatol. 2010;28(3):293-302.

1966;19(5):607-610.

22. Ibrahimi OA, Alikhan A, Eisen DB. Congenital melanocytic nevi: where are

2. Roguin A. Rene Theophile Hyacinthe Laënnec (1781-1826): the man

we now? Part II. Treatment options and approach to treatment. J Am Acad

behind the stethoscope. Clin Med Res. 2006;4(3):230-235.

Dermatol. 2012;67(4):515.e1-515.e13.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 47

LEGAL ADVISOR CASE

Patient Demands Ivermectin A patient hospitalized with COVID-19 demands the staff give him treatment with ivermectin. BY ANN W. LATNER, JD

In early September 2021, a 54-year-old patient, Mr D, was diagnosed with COVID-19 and admitted to an intensive care unit. While in the hospital, Mr D remained in isolation, and only hospital staff could see him. His wife communicated with him by phone. The staff treated Mr D in accordance with the hospital’s treatment guidelines for COVID-19. He received heated and humidified high-flow oxygen at the maximum setting, methylprednisolone sodium succinate, remdesivir, benzonatate, and guaifenesin-dextromethorphan. Despite this treatment regimen, the patient’s condition did not improve. Mr D clearly expressed that he did not want to be placed on a mechanical ventilator. It was part of his advanced health care directive, and he repeatedly told this to clinicians. Mrs D also discussed her husband’s wishes with his doctors. After he was admitted to the hospital, Mr D texted his wife, asking her to look into alternative treatments. He asked his wife to request ivermectin — an antiparasitic agent approved by the FDA to treat topical fungal diseases but

In this case, a court was asked to compel a health care provider to give ivermectin to a hospitalized patient with COVID-19.

not approved or recommended for COVID-19. Mrs D discussed ivermectin with hospital staff, including her husband’s team and the patient advocacy department. The staff were consistent with the hospital’s guidelines and refused to treat Mr D with ivermectin. Mrs D searched for a physician to prescribe the drug and eventually found Dr B, a family medicine specialist in another town, who was willing to prescribe ivermectin despite never having treated Mr D and without an examination. Dr B wrote the ivermectin prescription, which Mrs D had filled at a local pharmacy. However, since Mr D was in isolation, his wife had no access to him and could not deliver the medication. The hospital refused to administer or authorize the medication and asserted that Dr B did not have privileges at the hospital. Meanwhile, 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 • NOVEMBER/DECEMBER 2021 49

LEGAL ADVISOR Mr D’s condition worsened; he was diagnosed with severe hypoxic respiratory failure and was on the verge of requiring manual ventilation. The following day, Mrs D’s attorney filed a complaint in court seeking an injunction requiring the hospital to administer the ivermectin prescribed by Dr B. The case was expedited and scheduled for a hearing. Awaiting a decision, Mr D decided to check himself out of the hospital against medical advice and sought home hospice care so that he could self-administer the ivermectin. His wife, with the aid of a hospice nurse, attempted to treat Mr D at home, giving him a large dose of the medication. However, while at home, his oxygen mask broke and his condition rapidly deteriorated. Mr D’s wife called 911 and he was readmitted to the hospital ICU.

The court noted that the efficacy of ivermectin is disputed and the medication is not part of the standard of care. This time, Mr D rescinded his “do not resuscitate” order and agreed to be intubated. At the time of the court decision, Mr D was gravely ill, intubated, and on ventilator support. The Legal Arguments

During the injunction hearing, the plaintiff (Mrs D) claimed that the hospital’s refusal to permit administration of ivermectin breached “the patient/physician contract and the Hippocratic Oath” as well as Mr D’s statutory right to selfdetermination. Mrs D sought an injunction to force the hospital to provide the medication.The hospital argued that the plaintiff did not establish a duty or right that would be enforceable by an injunction because, under its standard of care, ivermectin is not used as a treatment for COVID-19. The hospital argued that it would be harmed if it was forced to act against established medical standards. The Court Decides

The court ruled in favor of the defendant. The court noted that a mandatory injunction can be granted only if the plaintiff can show: 1) entitlement to judgment as a matter of law on the merits of the claim; 2) the failure to issue the injunction will result in immediate and irreparable injury; and 3) the balance of hardships weighs in the plaintiff ’s favor. Explaining how the plaintiff had failed to meet the criteria, the court wrote: “Plaintiff must meet all 3 factors to prevail,

but she falls short on them all. Defendant does not have an enforceable duty to treat Mr D with ivermectin, and Mr D does not have an enforceable legal right to that treatment. Plaintiff has failed to demonstrate irreparable harm: the material fact of whether Mr D will be harmed if deprived of ivermectin is hotly disputed, and the weight of the record favors the defendant.” The court noted that the efficacy of ivermectin is disputed and the medication is not part of the standard of care for treating COVID-19. In fact, “treating COVID-19 with ivermectin is undisputedly contrary to generally accepted health care standards. Pre-eminent institutions representing numerous facets of the national medical establishment, including the FDA, CDC, AMA,World Health Organization, and Infectious Disease Society of America have criticized the use of ivermectin as a treatment for COVID-19.” The court went on to state that Mr D’s statutory right of self-determination in the health care setting only applies to the right to refuse medical or surgical treatment. It doesn’t create a right to a specific treatment. “Even the terminally ill do not have a constitutional right to obtain a particular type of treatment or to obtain treatment from a particular provider,” noted the court. In denying the injunction, the court noted the following: “The evidentiary proceedings before this Court focused on ivermectin’s safety and efficacy, with the hospital explaining why ivermectin is not part of the standard of care and the plaintiff arguing why it should be. But this opinion denies the injunction based on 2 more fundamental, and reciprocal, precepts. Patients, even gravely ill ones, do not have a right to a particular treatment and medical providers’ duty to treat is coterminous with their standard of care. This court will wield its equitable powers only to enforce a right or duty; in their absence, relief is not available. The patient has this Court’s sincerest sympathies and best wishes, but not an injunction.” The court noted that earlier in September an Ohio court denied a similar request to mandate treatment of COVID with ivermectin.That court found that granting the injunction would adversely impact “the safe and effective development of medications and medical practices … a hospital’s standard of care decisions, mandating doctors and nurses to provide care they believe unnecessary, ethical concerns of all doctors involved, patient autonomy, fiduciary duty, accreditation standards for patient protections, obliging one doctor to carry out the treatment regimen of another doctor… and whether a court should medicate or legislate from the bench.” ■ Ann W. Latner, JD, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.

50 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2021 • www.ClinicalAdvisor.com