January/February 2020 Clinical Advisor by The Clinical Advisor

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EVIDENCE-BASED MEDICINE

■■ MMR Vaccine Safety ■■ Diabetic Macular Edema ■■ Thiazides and Skin CA ■■ Rx for Fragility Fractures LEGAL ADVISOR

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Review of Current Screening and Diagnostic Tools for Atrial Fibrillation

DERMATOLOGY CLINIC

Painful Rash on Right Flank

DERMATOLOGIC LOOK-ALIKES

Violaceous Plaque on the Eyelid

JAN/ FEB 2020

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HASHIMOTO THYROIDITIS

Hypothyroidism: A Case of Fatigue, Weight Gain, and Constipation Hypothyroidism is estimated to occur in approximately 5% of the US population.

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If a patient has you stumped, write us and we’ll forward your query to one of our consultants and publish the response in Advisor Forum.You can also use this space to contribute a clinical pearl of your own or comment on another letter.

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

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

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CONTENTS JANUARY/FEBRUARY 2020

NEWS 10

Evidence-Based Medicine ■■MMR Vaccination Not Linked to Increased Risk for Autism ■■Aflibercept for Diabetic Macular Edema: Seeing Dollar Signs ■■Thiazides and Skin Cancer? Don’t Get Burned by the Hype ■■Zoledronate Infusion Every 1.5 Years Reduces Fractures

23 Conference Roundup: 2019 SABCS 11 Cost considerations in therapy for DME

FEATURES 6 Review of Current Screening and Diagnostic Tools 1 for Atrial Fibrillation Early cardiac rhythm monitoring is more accessible, with many options now available on smartphones.

16 Holter monitors for arrhythmia detection

7 Hypothyroidism: A Case of Fatigue, Weight Gain, 2 and Constipation Hashimoto thyroiditis is the most common autoimmune presentation of hypothyroidism.

DEPARTMENTS 8

Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com. Dermatology Clinic ■■Painful Rash on Right Flank ■■Itchy Rash on Hands and Feet

23 Cannabis popular among cancer patients

49 Consequences of a delayed diagnosis

Dermatologic Look-Alikes Violaceous Plaque on the Eyelid

Legal Advisor A Case of Altered Documents

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ClinicalAdvisor.com

NEWS ClinicalAdvisor.com/News

High Concentration of Psych Nurses in Northeast The highest ratio of psychiatric nurses per 100,000 population was found in the Northeast: Maine, Massachusetts, Rhode Island, Connecticut, and Vermont.

ADA 2020 Standards of Care Incorporate CVD Risk Stratification, New Medications Major updates to the 2020 iteration involve recommendations for cardiovascular disease risk reduction, pharmacologic treatments, glycemic targets, and recommendations for individualized patient care.

Study Supports Perioperative Nicotine Replacement Rx In the primary study outcomes, there was no association between receipt of nicotine replacement therapy and in-hospital complications, mortality, all-cause 30-day readmission, or 30-day readmission for wound complications.

Blood Biomarkers Do Not Hasten Diagnosis of Transient Ischemic Attacks The sudden onset of symptoms and the onset in full intensity are still the most important clinical predictors of transient ischemic attacks.

Patients Report Negative, Nonexistent Discussions About Weight Loss With Physicians An review of the literature found that interactions between patients and primary care physicians about being overweight and weight loss were rare.

FEATURES ClinicalAdvisor.com/Features How to Recognize Chronic Kidney Disease in Primary Care Unchecked, CKD will progress to end-stage renal disease, an advanced form of CKD that necessitates renal replacement therapy. Management Strategies for Peripheral Artery Disease Peripheral artery disease is one of the most underdiagnosed entities in vascular medicine, and clinicians should look for specific patient risk factors such as smoking, diabetes, hypertension, and hyperlipidemia when screening for this disease.

CASE STUDY ClinicalAdvisor.com/CaseStudy Brady Pregerson, MD Fever, Cough, and Shortness of Breath A 24-year-old man presents to the ED with a tactile fever, cough, and shortness of breath that have persisted for approximately 7 days. The patient notes that his symptoms have worsened in the past 2 days and denies any signs of bleeding, chest pain, or other complaints. He has no significant medical history. See the full case at ClinicalAdvisor.com/ CaseFeverCough Sara Pethel, PA-S Battle of the Bloat: What Is the Right Rx for IBS? A 56-year-old woman with a history of fibromyalgia and anxiety presents to her clinician to review abnormal laboratory findings. During her visit she mentions worsening digestive problems including bloating and frequent diarrhea, which began approximately 3 years ago and have waxed and waned in severity. See the full case at ClinicalAdvisor.com/CaseBloating

8 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 • www.ClinicalAdvisor.com

TOP: © 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

Firm Nodule on the Nose A 72-year-old woman is transported from an extended care facility for evaluation of a growth on her nose, which she describes as a “growing mass.” Examination reveals a 1.5-cm, firm, flesh-colored nodule that is fixed to underlying tissue. Scattered keratoses are noted on her trunk and arms. CAN YOU DIAGNOSE THIS CONDITION?

• Basal cell carcinoma • Merkel cell carcinoma

• Neurofibroma • Schwannoma

● See the full case at ClinicalAdvisor.com/DermDx_Feb20

In partnership with

ORTHO DX

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Journal of Orthopedics for Physician Assistants

Knee Pain Following a Basketball Game A 14-year-old presents with pain in his left knee after playing basket ball 2 days earlier. Examination reveals a grade I medial collateral ligament (MCL) sprain, and a large 1.6-cm osteochondral lesion on the medial femoral condyle is incidentally noted on radiograph. MRI of the knee shows intact articular cartilage with no reactive edema around the osteochondral lesion. WHICH IS THE BEST TREATMENT OPTION?

• Observation • Partial weight bearing for 8 weeks • Arthroscopic subchondral drilling • Autograft osteochondral plug ● See the full case at ClinicalAdvisor.com/OrthoDx_Feb20

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 9

Evidence-Based Medicine This department uses the best available scientific findings to offer practice guidance on a wide range of conditions seen in primary care.The author, Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Massachusetts, and assistant clinical professor in family medicine, University of Massachusetts Medical School in Worcester. DynaMed (www.ebscohost.com/dynamed/) is a database that provides evidence-based information on more than 3000 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.The most important evidence identified is summarized here.

ONCE AGAIN, MMR VACCINATION NOT LINKED TO INCREASED RISK FOR AUTISM, EVEN AMONG HIGH-RISK CHILDREN Level 2 [mid-level] evidence

Measles outbreaks continue throughout the world, resulting in more than 100,000 deaths each year and millions of dollars spent to treat and prevent the spread of the disease. In 2019, more than 1270 new cases of measles were reported in the United States, the largest report of new cases since 1992. According to the Centers for Disease Control and Prevention, more than 73% of the cases were linked to outbreaks in New York

Numerous studies have demonstrated no link between the MMR vaccine and autism.

State and were concentrated in communities where children were unvaccinated.1 Parents who choose not to vaccinate their children with the highly effective measles, mumps, and rubella (MMR) vaccine provoke a variety of responses from clinicians, ranging from gentle frustration to outright anger. The vaccine prevents upward of 95% of clinical measles cases, yet rates of vaccination have declined precipitously since a fraudulent report published in The Lancet in 1998 associated the vaccine with the onset of autism; the report has since been retracted.2 There are numerous reports demonstrating time and again that there is no association between MMR vaccination and autism. Now we have another study that clinicians can use as they engage parents in an effective conversation about vaccination. A Danish cohort study examined the association of MMR vaccination with the risk of developing autism spectrum disorder among more than 650,000 children born between 1999 and 2010.3 Children with a diagnosis of autism before 1 year of age and those with conditions tightly linked to autism (such as DiGeorge syndrome) were excluded from the analysis. The authors used data from the Danish national registration system to generate an autism risk score, which included advanced maternal and paternal age, method of delivery, 5-minute APGAR score, preterm birth, head circumference, birth weight, and smoking during pregnancy.3 More than 95% of

10 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 • www.ClinicalAdvisor.com

all children received the MMR vaccine. During the study period, 6517 children were diagnosed with autism spectrum disorder as defined by the Danish Psychiatric Central Research Register, which contains diagnoses assigned by child psychiatrists. Regression analysis was used to produce hazard ratios according to vaccine status and adjusted by birth year, sex, other vaccines received, sibling history of autism, and the risk score. The adjusted hazard ratio for the development of autism showed lower risk in the MMR-vaccinated group compared with the unvaccinated group, although the difference was not statistically significant (hazard ratio, 0.93; 95% CI, 0.85-1.02). In addition, receipt of the MMR vaccine did not increase the risk for autism among high-risk groups, including those with a sibling with autism or high autism risk score. This study adds to robust data demonstrating that MMR vaccination is not associated with autism. This large real-world data set demonstrates that even among children at the highest risk for autism spectrum disorder, MMR vaccination does not increase their risk of developing autism. For parents who are hesitant about having their child The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).

vaccinated, bringing fresh data to the table and discussing the facts may help temper the emotions in the room. Although scientists and researchers may wonder why we need yet another publication to further debunk the myth linking MMR vaccination to autism, for some parents, seeing new data may help them move a bit closer to seeing the truth. References 1. Centers for Disease Control and Prevention. Measles cases and outbreaks. CDC website. https:// www.cdc.gov/measles/cases-outbreaks.html. Updated January 6, 2020. Accessed January 7, 2020. 2. Wakefield AJ, Murch SH, Anthony A. Ileallymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children.

Patients with macular edema and preserved visual acuity did not benefit from treatment.

Lancet. 1998;351(9103):637-641. Retracted. 3. Hviid A, Hansen JV, Frisch M, Melbye M. Measles, mumps, rubella vaccination and autism: a nationwide cohort study. Ann Intern Med. 2019;170(8):513-520.

AFLIBERCEPT FOR DIABETIC MACULAR EDEMA: SEEING DOLLAR SIGNS Level 3 [lacking direct] evidence Aflibercept is a vascular endothelial growth factor (VEGF) inhibitor first approved for treatment of diabetic macular edema (DME) in July 2014 after several large trials showed it was superior to laser photocoagulation in patients with reduced visual acuity.Aflibercept is given as an intravitreal injection administered every 4 weeks for the first 5 injections, and then every 8 weeks for at least 20 weeks. Before the introduction of VEGF inhibitors, laser photocoagulation was the standard of care for treatment of DME with or without preserved visual acuity. In a randomized clinical trial, aflibercept was compared with either laser photocoagulation or observation to determine whether aflibercept has

the same benefit in patients with DME and preserved visual acuity as in patients with reduced visual acuity.1 The study included 702 adults with type 1 or type 2 diabetes, who had one eye with center-involved macular edema. There were 3 treatment groups: laser photocoagulation, aflibercept injections, and observation. However, some patients in each group received aflibercept injections. Sixteen percent of patients in the aflibercept group had a decrease in visual acuity of 1 line or more at 2 years compared with 17% of patients receiving laser photocoagulation and 19% of those in the observation group. At the end of the trial period, all 3 groups had a mean vision of 20/20, and the mean changes in visual acuity were not statistically significant. Aflibercept was associated with a higher frequency of increased intraocular pressure compared with observation, while laser photocoagulation was not.The clinical significance of this is unclear. Cost is a critical consideration when deciding among therapies with similar efficacy. Each aflibercept injection costs around $1850, with total

baseline treatment cost in the United States of $416,250 compared with $120,000 for patients having laser photocoagulation. In addition, 80 of the 236 eyes in the observation group received at least 1 aflibercept injection, with a median of 9 injections over 2 years ($16,650). The bottom line is that for patients with preserved visual acuity, the benefit of receiving aflibercept or photocoagulation, even in patients with diabetic macular edema, is limited. Given the cost associated with this therapy, most patients will just see their money slipping away, rather than experience benefit from the expensive and invasive treatment. More data are needed to determine whether aflibercept makes a difference in the preservation of vision in patients with DME. Reference 1. Baker CW, Glassman AR, Beaulieu WT, et al. Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial. JAMA. 2019;321(19):1880-1894.

THIAZIDES AND SKIN CANCER? DON’T GET BURNED BY THE HYPE Level 2 [mid-level] evidence Thiazide-type diuretics reduce the risk for mortality, stroke, and cardiovascular disease among patients with hypertension.1 Given the reasonable adverse effect profile and high-quality evidence for efficacy, thiazide-type diuretics are one of the most commonly prescribed antihypertensive agents worldwide. It has been postulated that thiazide-type diuretics can result in increased photosensitivity and may increase the risk for skin cancer. As clinicians, it is our job to carefully analyze the available evidence and weigh the risks and benefits with our patients.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 11

A recent meta-analysis of observational studies examined the association between thiazide-type diuretic use and the development of skin cancer.2 The authors identified 7 case-control and 2 cohort studies investigating this association. Three of the 9 studies included data from a single Danish registry; 1 of the studies overlapped in time with the other two. Most study samples included a high percentage of non-Hispanic white men, and just 3 of 9 included data about prior sun exposure and sunburns. The analysis found an increased risk for squamous cell carcinoma of the skin among thiazide users compared with nonusers (adjusted odds ratio [aOR], 1.86; 95% CI, 1.23-2.80), a finding that is limited by significant heterogeneity among the studies. There was also a small increased risk for basal cell carcinoma (aOR, 1.19; 95% CI, 1.02-1.38) and malignant melanoma (aOR, 1.14; 95% CI, 1.01-1.29). Subgroup analysis examining hydrochlorothiazide or hydrochlorothiazide combination medications found an increased risk for squamous cell carcinoma (aOR, 2.04; 95% CI, 1.79-2.33) but no association with basal cell carcinoma or malignant melanoma. Use of a thiazide diuretic for more than 4.5 years also appeared to increase the risk for squamous cell carcinoma, although this association was also heterogeneous among included studies. It is important to keep in mind the demonstrated mortality benefit of thiazide diuretics for treatment of hypertension (risk ratio 0.89; 95% CI, 0.82-0.97; NNT 51-303) as we assess the possibility that they may also increase the risk for nonfatal skin cancer.1 Although it might seem easy for clinicians to more heavily weight the high-quality data suggesting improved overall survival against weaker data from observational studies, easing patients’ fears around the term “cancer” can be challenging. Although this study is unlikely to change our choice of antihypertensive

medications, clinicians can use questions about this association as an opportunity to highlight the long-term benefit of thiazide diuretic therapy and encourage all patients to protect themselves from sun damage in the coming summer months. References 1. Wright JM, Musini VM, Gill R. First-line drugs for hypertension. Cochrane Database Syst Rev. 2018;4:CD001841. 2. Shin D, Lee ES, Kim J, Guerra L, Naik D, Prida X. Association between the use of thiazide diuretics and the risk of skin cancers: a metaanalysis of observational studies. J Clin Med Res. 2019;11(4):247-255.

ZOLEDRONATE INFUSION EVERY 1.5 YEARS REDUCES FRACTURES Level 1 [likely reliable] evidence Osteopenia places postmenopausal women at a higher risk for fragility fracture, which can increase morbidity and mortality. To date, no randomized trial has demonstrated therapeutic benefit

of bisphosphonate therapy for fracture prevention in women with osteopenia. New Zealand investigators conducted a randomized trial comparing zoledronate 5 mg infusion every 18 months with placebo infusion to assess the effectiveness for preventing fragility fracture among women with osteopenia.1 Postmenopausal women aged ≥65 years with a total hip or femoral neck T-score between -1 and -2.5 were included in the trial. Women with a hip T-score <-2.5 on one side but between -1 and -2.5 on the contralateral side were also included in the trial. Patients were followed for 6 years for the primary endpoint, which was time to first occurrence of a fragility fracture. Symptomatic fractures was one of several secondary endpoints. In an intention-to-treat analysis, there was a statistically significant reduction in the cumulative incidence of first fragility fracture in the zoledronate group compared with placebo (NNT 15).There was also a statistically significant reduction in symptomatic fractures (hazard ratio 0.73, NNT 22 over 6 years). When women with an osteoporotic hip on one side were excluded from the analysis, there was still a statistically significant reduction in fragility fractures. Nearly twice as many women in the zoledronate group declined any additional infusion due to an acute reaction during the first infusion. The rate of adverse events was similar in the 2 groups, with no documented osteonecrosis of the jaw or atypical femur fractures.The zoledronate group experienced a significantly lower rate of cancers, although the clinical significance of this secondary outcome is uncertain. Short-term adverse events were not reported. ■ Reference 1. Reid IR, Horne AM, Mihov B, et al. Fracture

Postmenopausal women with osteopenia are at increased risk for fracture.

12 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 • www.ClinicalAdvisor.com

prevention with zoledronate in older women with osteopenia. N Engl J Med. 2018;379(25):2407-2416.

Evidence-Based Medicine

FEATURE: JAMES ZAPATA, PA-C; DREW ZIMMER, PA-C; BENJAMIN RINARD, PA-C; AMIR ABDOU, PA-C; ARIELLE PAAMONI, PA-C; CATHERINE CHANG LETHERER, PA-C

Review of Current Screening and Diagnostic Tools for Atrial Fibrillation The goal of new screening criteria has been to detect atrial fibrillation in asymptomatic patients before cardiovascular complications occur.

trial fibrillation (AF) is the most common sustained arrhythmia and is associated with cardiovascular complications, thrombosis, and stroke.1 An estimated 5 million Americans 65 years of age and older experience atrial fibrillation, with the number predicted to double in 25 years.1,2 One in 5 patients diagnosed with AF initially presents with a cerebrovascular accident, and approximately 20% of AF cases are undiagnosed.1 With the projected increase in prevalence, it is important that clinicians have access to the most current screening and diagnostic tools for AF to prevent thromboembolic complications.

Clinical Presentation

Holter monitors, worn 24/7, allow for early diagnosis of arrhythmias.

AF has a wide range of clinical presentations. The most common symptoms reported include fatigue (80% of women; 70% of men), dyspnea (70% of women; 62% of men), and palpitations (70% of women; 58% of men).3 Chest pain, dizziness, and anxiety are less commonly reported in individuals with AF.3 Infrequent chest pain, dizziness, and anxiety were reported in <40% of those presenting with AF, whereas <10% reported frequent chest pain, dizziness, and anxiety.3 The presentation of AF also varies between the sexes, with 10% of men having no symptoms compared with 5% of women.3,4 Differences between the sexes may reflect symptom severity or cultural norms. Men typically have less frequent or milder symptoms, whereas women may be more apt to seek treatment.3,5

16 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 • www.ClinicalAdvisor.com

An irregularly irregular rhythm, an inconsistent first heart sound (S1), and palpitations make up the triad of AF findings.6,7 Some patients may present with abnormal variants of AF, such as decreased heart rate and chest pain.7 However, a decreased heart rate is rare in AF because the arrhythmia originates above the atrioventricular node of the heart. Screening Techniques

Screening for AF may be difficult, as it may be asymptomatic in the earlier stages. The goal of new screening criteria has been to detect AF in asymptomatic people.8 Screening for AF is recommended for patients determined to be at increased stroke risk as determined by CHA2DS2-VASc score.9 (Figure) Physical Examination Screening for cardiac arrhythmias begins with the physical examination. Clinicians ought to routinely assess patients’ pulse rate, rhythm, and heart sounds on each visit. An irregularly irregular rate and rhythm can be routinely screened for with pulse palpation in the primary care setting.8 Inspection of jugular venous pulsations can also indicate previously undetected AF.6 Detection of these abnormalities may also indicate a more life-threatening pathology, in addition to AF.

CHA2DS2-VASc Score Further work-up is indicated for patients presenting with abnormal physical findings and major risk factors for AF. 9,10 Current data suggest the CHA2DS2-VASc criteria may be beneficial for screening undetected AF. A retrospective study has demonstrated a direct correlation between the CHA2DS2VASc score criteria and new onset of AF.10 The CHA2DS2-VASc score assesses the risk of developing AF and experiencing a stroke. Patients who are older than 65 years, female, or who have a history of congestive heart failure, hypertension, transient ischemic attacks, vascular disease, or previous stroke are at increased risk for stroke according to the CHA2DS2-VASc criteria.9,10 Additional risk factors associated with stroke in patients with AF include excessive alcohol use, European ancestry, and left atrial enlargement.6 The CHADS2 and CHA2DS2-VASc scores have historically been used to guide anticoagulation therapy. 9 Although both are helpful tools, the CHA2DS2-VASc is considered superior and is more widely recognized.11 The recognized highest risk factors (older age, history of congestive heart failure, and hypertension) contribute to the self-propagating nature of AF development by inflammation, and structural and electrical remodeling.

Screening indicated if patient positive for any of following: • History of stroke or TIA • CHA2DS2-VASc score ≥2 (Men) or ≥3 (Women) • Symptomatic

Evidence of AF

• Assess CHA2DS2-VASc score • Assess duration of symptoms • Perform TTE or TEE • Perform CBC, CMP, TSH

Follow indicated treatment protocols

12-lead ECG

Evidence of AF

Patch monitor (14 days)

Cardiac event monitors (1 month)

No evidence of AF or nonspecific

Stable patient

Unstable patient

Holter monitor (24 hours)

Consider other diagnosis

No evidence of AF or nonspecific

High clinical suspicion Consider further cardiac monitoring

Implantable loop recorders (3 years) AF, atrial fibrillation; CBC, complete blood count; CMP, comprehensive metabolic panel; ECG, electrocardiogram; TEE, transesophageal echocardiography; TIA, transient ischemic attack; TTE, transthoracic echocardiogram; TSH, thyroid-stimulating hormone

FIGURE. Algorithm for atrial fibrillation screening and workup. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 17

ATRIAL FIBRILLATION SCREENING AND DIAGNOSIS

Atrial fibrillation presentation varies between the sexes, with 10% of men and 5% of women presenting with no symptoms. Biomarkers Biomarkers are not currently sanctioned as predictors of AF in clinical guidelines but are being studied as a possible additional tool for screening and diagnosis of AF.1 Three types of biomarkers are associated with AF: electrophysiologic, molecular, and morphologic. Electrophysiologic biomarkers include abnormal P wave and J wave electrocardiographic (ECG) findings. Prolonged P-wave duration >110 ms on any lead indicates erratic atrial firing. The presence of a J wave in the QTc interval has been associated with AF development.1 Molecular biomarkers such as brain natriuretic peptide, troponin T, C-reactive protein, von Willebrand factor, fibrinogen, and various collagen peptides are associated with newly diagnosed paroxysmal AF. Structural factors such as size and function of the left atrium may serve as predictors of undetected AF. Smartphone Cardiac Monitoring Advances in technology have allowed cardiac rhythm monitoring to be accessed on personal smartphones. In 2017,AliveCor made its debut into the smartphone market with its single-lead ECG, coined KardiaMobile. The device is used by placing the middle and index fingers of each hand simultaneously on 2 electrodes.The application records a single-lead ECG tracing for 30 seconds up to 5 minutes.12 The KardiaMobile device was approved by the US Food and Drug Administration (FDA) for medical-grade ECG recordings.13,14 As it is not covered by insurance, KardiaMobile is currently an out-of-pocket expense, and the device can be purchased online. For patients unable to afford the KardiaMobile device, the Cardiio heart rate monitor application (app) is free for use on the iPhone and iPad, and the Accurate Heart Rate Monitor is free for use on Android smartphones. Both apps use photoplethysmography. Patients place their index finger over the camera and light of the smartphone and follow the prompts. Photoplethysmography technology uses the camera light to record blood flowing in the fingertip. A recent study suggests the Cardiio app can detect patients with AF with greater sensitivity and comparable specificity to KardioMobile. In the study, the Cardiio app had a 92.9% sensitivity and 97.7% specificity in detecting AF, compared with KardioMobile that demonstrated a 71.4% sensitivity and 99.4% specificity.15 Smartphone apps demonstrate adequate sensitivity and specificity as screening tools for AF in the primary care setting.8,16 Being able to monitor rate and rhythm and screen for potential arrhythmia development with smartphone technology

empowers patients to better partner with their clinicians in monitoring their health. Diagnosis

The 12-lead ECG remains the gold standard test for diagnosing AF.8 A positive ECG reading will show a lack of a P wave, an oscillatory baseline wave with varying amplitudes, an irregular rhythm, and the classic irregularly irregular ventricular waves. Sensitivity and specificity of AF detection with a 12-lead ECG when interpreted by general practitioners are 80% and 92%, respectively.17 Additional work-up may be required if clinical suspicion of AF is high and the 12-lead ECG is nonspecific. Holter Monitors The 24-hour Holter monitor allows for early detection of arrhythmias in patients with a high clinical suspicion for AF but whose initial 12-lead ECG finding are inconclusive.18 A Holter monitor is a 5- to 7-lead, battery-powered cardiac device hung around the neck or secured on the waist. Continuous monitoring for 24 hours is performed and recorded. Use of a Holter monitor is often covered by insurance and is recognized as being effective in detecting arrhythmias before complications occur. Use of the 24-hour Holter monitor in a clinical study has demonstrated a 96.3% sensitivity and 96.8% specificity for detecting AF.19 Despite its high sensitivity and specificity, the Holter monitor may still be insufficient in the detection of asymptomatic or paroxysmal AF, as they are less likely to be detected within a 24-hour period.14,18 Patch Monitors Technology has contributed to the development of more convenient methods of outpatient continuous cardiac recording. The Zio patch, manufactured by iRhythm Technologies, Inc, is an FDA-approved, 14-day continuous monitoring system. The device is a low-profile, self-adhesive, water-resistant patch that adheres to the left chest wall; no leads or wires are required. This simple design allows for use without interfering with daily activities. Compared with the Holter monitor, patients preferred the patch monitor: 93.7% of users found the patch comfortable to wear compared with 51.7% who wore the Holter monitor.20 The Holter monitor still outperforms the Zio patch in detecting arrhythmias within a 24-hour window, but the Zio patch has demonstrated benefits in detecting arrhythmias outside the 24- to 48-hour window.20 With a mean wear time of

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Continues on page 20

ATRIAL FIBRILLATION SCREENING AND DIAGNOSIS

Advances in technology have allowed cardiac rhythm monitoring to be more accessible, with many options now available on smartphones. 10.9 days and a median wear time of 13.0 days, the Zio patch is a convenient option for detecting intermittent arrhythmias within a 14-day period.21 Cardiac Event Monitors Cardiac event monitors are capable of monitoring heart activity from a couple of weeks to just over a month. This device is useful when patients report AF symptoms that occur more than 1 week apart from each other. Cardiac event monitors come in 2 forms: external loop memory recorders and handheld event recorders. The looping memory recorder begins recording and stores information from a few minutes before and after abnormal input from the chest leads. The handheld event recorder allows a patient to manually capture a recording when symptoms occur.22 Because of the design of the cardiac event monitors, which rely on symptomatic stimuli or manual activation by the patient, the sensitivity of these devices ranges from 31.3% to 71.0%.23 For those individuals with more intermittent symptomatic arrhythmias, however, these devices are a good option. Implantable Loop Recorders Implantable loop recorders (ILRs) are small devices that are implanted subcutaneously in the chest. Continuous heart monitoring can be performed with an IRL for up to 3 years. It is a powerful tool used to discover undetected paroxysmal AF. 24 An IRL is indicated when short-term monitors fail to identify an arrhythmia and there remains a high suspicion of AF. New generations of ILRs incorporate P-wave detection algorithms, raising the sensitivity and specificity for AF detection to 97% each.25 The ILR may also be used to monitor the long-term efficacy of radiofrequency ablation, cryoballoon ablation, and anticoagulation therapy.26 An advantage of the ILR is its self-sufficiency; it requires no maintenance and patients do not need to carry a device around with them. Transthoracic and Transesophageal Echocardiograms A transthoracic echocardiogram is indicated in the initial evaluation in all patients with AF and detects heart size, chamber size, and valvular function, as well as directs further work-up and treatment modalities. A transesophageal echocardiogram (TEE) more accurately determines pressures and flow of the heart chambers and wall motion abnormalities, and detects thrombus formation in the left atrium.27,28 Indications for the use of TEE are to guide treatment of direct current cardioversion for AF. Direct current cardioversion may pose a risk for a

thromboembolic event if thrombus formation was present in the left atrium or left atrial appendage, and may require prior anticoagulation.29 The use of TEE is beneficial in detecting 5% to 15% of thrombus before direct current cardioversion.6 After the indicated AF work-up, TEE helps identify risks associated with AF, in addition to other possible conditions. Additional Workup When making a diagnosis of AF, additional studies are indicated to identify underlying causes, rule out other pathologies, and assess baseline disease severity. In addition to the diagnostic workup, initial studies include a complete blood count, complete metabolic panel, and thyroid-stimulating hormone. Initial studies help to identify comorbid or exacerbating conditions — such as infection, anemia, and hyperthyroidism — as well as abnormalities in renal function, hepatic function, electrolytes, and glucose levels. A chest radiograph should be performed and is useful in recognizing potential pulmonary disease or comorbid heart failure. Detecting Subtypes of Atrial Fibrillation

Establishing the AF subtype helps tailor treatment and better understand the condition. Classification of AF is based on TABLE. Categories of Atrial Fibrillation Classification

Duration of Symptoms/Concurrent Conditions

Paroxysmal

AF <7 days

Persistent

AF >7 days

Longstanding Persistent

AF >12 months

Permanent

No treatment to return patient to sinus rhythm

Valvular

AF with underlying rheumatic mitral stenosis, prosthetic valve, or any mitral valve repair

Nonvalvular

AF with none of the characteristics that make up valvular AF

AF, atrial fibrillation Note: The criteria for determining the AF subtype depends on its duration and underlying heart conditions. Categorizing AF subtypes helps tailor treatment.

20 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 • www.ClinicalAdvisor.com

A number of conditions can mimic AF and need to be ruled out, including atrial flutter, premature atrial contractions, and multifocal atrial tachycardia. the duration of symptoms and concurrent cardiac conditions (Table).6,30 AF is considered symptomatic in the presence of an irregular pulse, jugular venous flutter, palpitations, fatigue, dizziness, dyspnea, tachycardia, murmurs, or neurologic deficits, in addition to positive risk factors for AF.

2. Link MS, Giugliano RP, Ruff CT. Stroke and mortality risk in patients with various patterns of atrial fibrillation: results from the ENGAGE AF-TIMI 48 Trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48). Circ Arrhythm Electrophysiol. 2017;10(1):e004267. 3. Schnabel RB, Pecen L, Ojeda FM. Gender differences in clinical presentation

Differential Diagnosis

and 1-year outcomes in atrial fibrillation. Heart. 2017;103(13):1024-1030.

A number of conditions can mimic AF and need to be ruled out, including atrial flutter, premature atrial contractions (PACs), and multifocal atrial tachycardia.31 Atrial flutter should be considered alongside AF when ECG findings are consistent with absence of P waves and atrial tachycardia.32 Atrial flutter is characterized by a regular ventricular rhythm and a “sawtooth” pattern seen in the atrial leads II, III, and augmented limb lead aVF. PACs are caused by ectopic foci that fire before the next sinus impulse. ECG findings indicative of PAC include isolated interruptions of P-wave morphology with a regular rhythm. Patients with PACs can be differentiated from those with AF, as the PAC usually disappears when the heart rate is accelerated and is generally asymptomatic. Multifocal atrial tachycardia needs to be ruled out in patients presenting with AF, as palpitations are present in both arrhythmias. In patients with multifocal atrial tachycardia, the ECG displays 3 or more varying P-wave morphologies with an irregular P-P interval and increased rate of 100 to 140 beats per minute, which is not characteristic of AF.33 Differentiation of AF from other cardiac abnormalities may be obscure, which is why close attention to clinical symptoms, proper diagnostic workup, and use of the 12-lead ECG and indicated monitors are necessary for accurate distinction. ■

4. Ko D, Rahman F, Schnabel RB, Yin X, Benjamin EJ, Christophersen IE. Atrial fibrillation in women: epidemiology, pathophysiology, presentation, and prognosis. Nat Rev Cardiol. 2016;13(6):321. 5. Ball J, Carrington MJ, Wood KA, Stewart S; SAFETY Investigators. Women versus men with chronic atrial fibrillation: insights from the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY). PLoS One. 2012; 8(5):e65795. 6. January CT, Wann LS, Alpert JS; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64(21):e1-e76. 7. Bickley LS, Szilagyi PG. Bates’ Guide to Physical Examination and History Taking. 12th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams;2017. 8. Freedman B, Camm J, Calkins H; AF-Screen Collaborators. Screening for atrial fibrillation: a report of the AF-SCREEN international collaboration. Circulation, 2017;135(19):1851-1867. 9. Tischer TS, Schneider R, Lauschke J, et al. Prevalence of atrial fibrillation in patients with high CHADS2- and CHA2DS2VASc-scores: anticoagulate or monitor high-risk patients? Pacing Clin Electrophysiol. 2014;37(12): 1651-1657. 10. Saliba W, Gronich N, Barnett-Griness O, Rennert G. Usefulness of

James Zapata, PA-C, is an emergency medicine physican assistant (EMPA) fellow at Arrowhead Regional Medical Center, in Colton, CA; Drew Zimmer, PA-C, is an EMPA at JFK Memorial Hospital, Indio, CA; Benjamin Rinard, PA-C, is an EMPA intern at St. Bernardine Medical Center in San Bernardino, CA; Amir Abdou, PA-C, is a PA at Western University of Health Sciences, Pomona, CA; Arielle Paamoni, PA-C, is a cardiology PA at Sherev Heart and Vascular Clinic, La Mesa, CA; and Catherine Chang Letherer, PA-C, is an assistant professor of Physician Assistant Education, Western University of Health Sciences, Pomona, CA.

CHADS2 and CHA2DS2-VASc scores in the prediction of new-onset atrial fibrillation: a population based study. Am J Med. 2016;129(8):843-849. 11. Chen JY, Zhang AD, Lu HY, Guo J, Wang FF, Li ZC. CHADS2 versus CHA2DS2-VASc score in assessing the stroke and thromboembolism risk stratification in patients with atrial fibrillation: a systematic review and metaanalysis. J Geriatr Cardiol. 2013;10(3):258-266. 12. Haberman ZC, Jahn RT, Bose R, et al. Wireless smartphone ECG enables large-scale screening in diverse populations. J Cardiovasc Electrophysiol. 2015;26(5):520-526. 13. KardiaMobile. Alivecor website. https://www.alivecor.com/kardiamobile. Accessed December 17, 2019.

References

14. Treskes RW, Gielen W, Wermer MJ, et al. Mobile phones in cryptogenic

1. Howlett PJ, Hatch FS, Alexeenko V, Jabr RI, Leatham EW, Fry CH.

strOke patients Bringing sIngle Lead ECGs for Atrial Fibrillation detec-

Diagnosing paroxysmal atrial fibrillation: are biomarkers the solution to

tion (MOBILE-AF): study protocol for a randomised controlled trial. Trials.

this elusive arrhythmia? Biomed Res Int. 2015;2016:910267.

2017;18(1):402.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 21

ATRIAL FIBRILLATION SCREENING AND DIAGNOSIS

15. Chan PH, Wong CK, Poh YC, et al. Diagnostic performance of a smart-

24. Frontera A, Carpenter A, Ahmed N, et al. Demographic and clinical char-

phone-based photoplethysmographic application for atrial fibrillation screen-

acteristics to predict paroxysmal atrial fibrillation: insights from an implantable

ing in a primary care setting. J Am Heart Assoc. 2016;5(7):e003428.

loop recorder population. Pacing Clin Electrophysiol. 2015;38(10):1217-1222.

16. Freedman B. Screening for atrial fibrillation using a smartphone: is there an

25. Galli A, Ambrosini F, Lombardi F. Holter monitoring and loop recorders:

app for that? J Am Heart Assoc. 2016;5(7):e004000.

from research to clinical practice. Arrhythm Electrophysiol Rev. 2016;5(2):

17. Mant J1, Fitzmaurice DA, Hobbs FD. Accuracy of diagnosing atrial fibrilla-

136-143.

tion on electrocardiogram by primary care practitioners and interpretative

26. Davtyan K, Shatakhtsyan V, Poghosyan H, et al. Radiofrequency versus

diagnostic software: analysis of data from screening for atrial fibrillation in the

cryoballoon ablation of atrial fibrillation: an evaluation using ECG, Holter

elderly (SAFE) trial. BMJ. 2007;335(7616):380.

monitoring, and implantable loop recorders to monitor absolute and clinical

18. Chiang LK, Ng L. Holter monitoring (ambulatory electrocardiography)

effectiveness. Biomed Res Int. 2018;2018:3629384.

defined cardiac arrhythmia among patients presented with palpitation in the

27. Suriya S, Taqi M, Adl F, Quardi S, Sodhi A, Mortazavi M. Transthoracic

primary care setting. J Fam Med Health Care. 2017;3(1):12-16

echocardiogram versus transesophageal echocardiogram in identification of

19. Jiang K, Huang C, Ye SM, Chen H. High accuracy in automatic detection of

intracardiac thrombus in acute ischemic stroke patients (P6.239). Neurology.

atrial fibrillation for Holter monitoring. J Zhejiang Univ Sci B. 2012;13(9):

2018;90(15 Supplement):P6.239.

751-756.

28. Gutierrez C, Blanchard DG. Diagnosis and treatment of atrial fibrillation.

20. Barrett PM, Komatireddy R, Haaser S, et al. Comparison of 24-hour Holter

Am Fam Phys. 2016;94(6):442-52.

monitoring with 14-day novel adhesive patch electrocardiographic monitor-

29. Jaakkola S, Kiviniemi TO, Airaksinen KEJ. Cardioversion for atrial fibrillation —

ing. Am J Med. 2014;127(1):95:e11-e17.

how to prevent thromboembolic complications? Ann Med. 2018;50(7):549-555.

21. Tung CE, Su D, Turakhia MP, Lansberg MG. Diagnostic yield of extended

30. Fauchier L, Philippart R, Clementy N, et al. How to define valvular atrial

cardiac patch monitoring in patients with stroke or TIA. Front Neurol.

fibrillation? Arch Cardiovasc Dis. 2015;108(10):530-539.

2015;5:266

31. Thakkar S, Bagarhatta R. Detection of paroxysmal atrial fibrillation or

22. Patten M, Maas R, Karim A, Müller HW, Simonovsky R, Meinertz T.

flutter in patients with acute ischemic stroke or transient ischemic attack by

Event-recorder monitoring in the diagnosis of atrial fibrillation in symp-

Holter monitoring. Indian Heart J. 2014;66(2):188-192.

tomatic patients: subanalysis of the SOPAT trial. J Cardiovasc Electrophysiol.

32. Huang HK, Chang SL, Lin YJ, et al. Atrial fibrillation originating from

2006;17(11):1216-1220.

superior vena cava with atrial flutter‐electrocardiogram pattern. Pacing Clin

23. Hindricks G, Pokushalov E, Urban L, et al. Performance of a new leadless

Electrophysiol. 2017;40(7):754-761.

implantable cardiac monitor in detecting and quantifying atrial fibrillation

33. Huh J. Clinical implication of multifocal atrial tachycardia in children for

results of the XPECT trial. Circ Arrhythm Electrophysiol. 2010;3(2):141-147.

pediatric cardiologist. Korean Circ J. 2018;48(2):173-175.

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

22 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 • www.ClinicalAdvisor.com

Conference Roundup 2019 SABCS

San Antonio Breast Cancer Symposium 2019 San Antonio, Texas

BREAST CANCER RISK IDENTIFIED FOR GENES IN GENERAL POPULATION Breast cancer risks associated with common germline mutations were identified for the general population using a set of studies that make up the CARRIERS consortium.As hereditary “cancer genetic testing is already provided to many women at increased risk; populationbased risk estimates associated with predisposition gene mutations will be needed for appropriate clinical management of these patients,” the authors of a poster presentation reported at SABCS. The current analysis was based on data from 32,247 patients with breast cancer and 32,544 matched individuals who were cancer-free, all of whom supplied germline DNA for sequencing. Among the 24 genes evaluated for mutations, 12 were for breast cancer predisposition genes: ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, and TP53. A higher percentage of cases had a predisposition-gene mutation in the germline compared with the matched controls (5% vs 1.7%, respectively). An adjusted case-control association analysis revealed that for the general population, BRCA1 (overall response [OR], 7.35; 95% CI, 5.17-10.81), BRCA2 (OR, 5.28; 95% CI, 4.13-6.85), PALB2 (OR, 3.66; 95% CI, 2.58-5.33), and ATM mutations (OR, 1.82; 95% CI, 1.46-2.27) were linked to a significant increased risk of breast cancer.

“We anticipate that the results from this study will inform on cancer screening and other risk-management strategies for women in the general population with mutations in predisposition genes,” the authors wrote.

CANCER PATIENTS TURN TO MEDICAL CANNABIS TO MANAGE SYMPTOMS Women with breast cancer sought medical cannabis for management of pain, anxiety, insomnia, nausea, and anorexia, according to the results of a new study. The researchers reviewed Pennsylvania’s new medical marijuana program and found that patients with breast cancer

Cancer patients are turning to medical cannabis to manage pain, nausea, and anxiety.

sought medical cannabis to manage an average of 3 symptoms. To study what symptoms cancer patients were hoping to treat with medical cannabis, the researchers included 54 cancer patients and 31 breast cancer patients (22 had nonmetastatic disease and 9 had metastatic disease). There were significant age differences among the patients, ranging from 26 years to 86 years (median age, 64). The study found 16 of the 22 (73%) women with nonmetastatic breast cancer chose cannabis for pain. Among these 16 women, 25% (4 patients) developed chemotherapy-induced peripheral neuropathy and 19% (3 patients) experienced exacerbation of pre-existing muscle/joint pain from hormonal therapy. Among the 22 patients with nonmetastatic breast cancer, 11 (50%) had insomnia and 10 (45%) had anxiety; 8 women reported experiencing both insomnia and anxiety. One of the 22 women reported nausea, and 3 women reported they were recreational users who wanted to upgrade to medical-grade products. Among the 9 patients with metastatic breast cancer, 8 (89%) sought medical cannabis for cancer pain and 8 (89%) sought it for anxiety. Three women (33%) wanted the medical cannabis for insomnia; the same number of women wanted it for anorexia (33%) and nausea (33%). Overall, the researchers found that patients had an average of 3 symptoms, and approximately 50% of patients with pain expressed concern over opioid use and wanted to avoid its use.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 23

YOU CAN SAVE LIVES.

Treating tobacco use is an important part of mental health treatment. Double your patients’ chances of quitting with counseling and medication.

TalkToYourPatients.health.ny.gov U.S. Dept. of Health and Human Services, Public Health Service, Treating Tobacco Use and Dependence Clinical Practice Guideline 2008 Update

PAID EDUCATIONAL ADVERTISEMENT

Treating Tobacco use is an Important Part of Mental Health Treatment Six Things Every Health Care Provider Should Know Providers who treat people with mental health conditions have an important role to play in their patients’ ability to quit using tobacco products. Here are six things that every provider should know: 1. Providing smoking cessation treatment is an important part of mental health treatment. Providers who treat people with mental health conditions are well positioned to help patients successfully quit tobacco use and enjoy the mental, emotional, and physical benefits of a tobaccofree life. Smoking cessation treatments work.

2. Medicaid reimburses for counseling and covers FDA-approved smoking cessation medications, including over-the-counter therapies with a fiscal order. Medicaid will cover repeated treatment and prescriptions because it can take multiple attempts before patients quit successfully. Medicaid covers nicotine replacement therapies (NRT) – patch, gum, lozenge, inhaler and nasal spray; and two non-nicotine oral medications (pills) – bupropion SR (brand names Zyban or Wellbutrin) and varenicline (brand name Chantix).

3. People with mental health conditions smoke at rates that are at least two times higher than the general population.¹ They may also smoke more heavily and frequently, compared to those without mental health conditions. The Centers for Disease Control and Prevention estimates that nearly one third (31%) of all cigarettes consumed in the United States are smoked by people with mental health conditions.1

4. The high rates of smoking among people with mental health conditions have devastating health consequences. Smoking-related diseases such as cardiovascular disease, lung disease, and cancer are among the most common causes of death among adults with mental health conditions.² Despite the heavy disease burden, a US national survey of mental health treatment facilities found that only about one-quarter provided services to help patients quit smoking.³

5. Many smokers with mental health conditions want to and are able to quit smoking.⁴ Research has shown that adult smokers with mental health conditions—like other smokers—want to quit, can quit, and benefit from proven smoking cessation treatments.⁵

6. Quitting smoking will not interfere with mental health recovery and may have mental health benefits. Smoking is not an effective mental health treatment strategy. On the contrary, smoking is associated with poor clinical outcomes, such as greater depressive symptoms, greater likelihood of psychiatric hospitalization, and increased suicidal behavior.⁴

References 1. Centers for Disease Control and Prevention. (2013). Vital signs: Current cigarette smoking among adults aged ≥ 18 years with mental illness— United States, 2009–2011. Morbidity and Mortality Weekly Report, 62(5), 81–7. 2. Druss, B. G., Zhao, L., Von Esenwein, S., Morrato, E. H., & Marcus, S. C. (2011). Understanding excess mortality in persons with mental illness: 17-Year follow up of a nationally representative US survey. Medical Care, 49(6), 599-604. 3. Substance Abuse and Mental Health Services Administration. (2014). The National Mental Health Services Survey (N-MHSS) data spotlight report, November 25, 2014. http://www. samhsa.gov/data/sites/default/files/Spot148_NMHSS_Smoking_Cessation/ NMHSS-Spot148-QuitSmoking-2014.pdf. Accessed January 15, 2016. 4. Prochaska, J. J. (2011). Smoking and mental illness — Breaking the link. New England Journal of Medicine, 365(3), 196-198. 5. Siru, R., Hulse, G. K., & Tait, R. J. (2009). Assessing motivation to quit smoking in people with mental illness: a review. Addiction, 104(5), 719-733.

YOU CAN SAVE LIVES.

Treating tobacco use is an important part of mental health treatment. Double your patients’ chances of quitting with counseling and medication.

TalkToYourPatients.health.ny.gov U.S. Dept. of Health and Human Services, Public Health Service, Treating Tobacco Use and Dependence Clinical Practice Guideline 2008 Update

PAID EDUCATIONAL ADVERTISEMENT

Conference Roundup

Fixed combination of netupitant and palonosetron helped prevent CINV.

COMBO THERAPY IMPROVES CHEMO-INDUCED NAUSEA, VOMITING IN CA PATIENTS A fixed combination of netupitant/palonosetron (NEPA) was effective in preventing chemotherapy-induced nausea and vomiting (CINV), according to a real-life study conducted in Germany. The findings showed that an oral fixeddose of NEPA (netupitant 300 mg/ palonosetron 500 mg) may help improve adherence to antiemetic guidelines to improve CINV in patients with breast cancer receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). The researchers sought to examine QoL in adults receiving NEPA as primary prophylaxis for CINV associated with MEC or HEC.To determine this, they conducted an interim analysis of a subgroup of patients with breast cancer, representing the largest subpopulation (66%) enrolled in the AkyPRO study. The study began in September 2015 and has enrolled 2427 patients (986 patients with breast cancer). Among the 986 patients with breast cancer, 80% of patients received HEC.

The study found that 84% of patients reported no effect on daily life due to vomiting in all analyzed cycles. When it came to nausea, 51% to 56% of the patients reported no effect on daily life due to nausea, and 93% of patients reported no emesis. During the 5 days postchemotherapy during all 3 treatment cycles, 81% of patients reported a complete response (no vomiting, no rescue medication). This treatment was not as effective in combating nausea, with 37% of patients reporting nausea one or more times during the 5 days following chemotherapy. The physicians’ assessments rated NEPA as very good/good for 89% to 91% of the patients in cycle 1, cycle 2, and cycle 3. These percentages were similar to the patients’ assessments.This study also confirmed previous findings that NEPA is well tolerated. The most frequent treatment-related adverse events were low-grade constipation (2.2%) and insomnia (1.4%).

MANY PALLIATIVE CA DRUGS LACK EVIDENCE OF CLINICAL BENEFIT Breast cancer drugs approved in the United States may lack substantial clinical benefit, particularly those used in the palliative setting, an analysis of clinical trials that support these drug approvals found. Using the Drugs@FDA website, study researchers identified 18 breast cancer drugs that were approved between January 1, 2006, and June 30, 2019.The approved drugs spanned 24 indications and were supported by 28 pivotal clinical trials. Most of the trials (79%) were for the palliative setting and the rest (21%) were for the curative setting. The following validated tools were used to quantify the clinical benefit of cancer drugs: the American Society of Clinical Oncology (ASCO) Cancer Research

26 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 • www.ClinicalAdvisor.com

Committee (ASCO-CRC), the ASCO Value Framework Net Health Benefit score version 2 (ASCO-NHB v2), and the European Society for Medical OncologyMagnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1). Substantial clinical benefit was defined according to criteria for each validated tool. The researchers found a varying proportion of trials that achieved the established threshold of substantial clinical benefit. For trials in the palliative setting, the proportion of trials that showed substantial clinical benefit ranged from 23% with ESMO-MCBS v1.1 to 79% with ASCO-CRC; according to ASCO-NHB v2, 45% of trials showed a substantial clinical benefit. For trials in the curative setting, the proportion of trials that showed substantial clinical benefit ranged from 25% with ASCO-NHB v2 to 80% with ESMO-MCBS v1.1. In addition, only 9% of trials in the palliative setting showed a considerable overall survival (OS) benefit, whereas no trials in the curative setting showed an extensive OS benefit. Also, among the trials that reported quality of life (QoL) measures, 60% in the palliative setting and none in the curative setting showed a QoL benefit. “Perhaps these findings weren’t terribly surprising,” said study discussant Michael Hassett, MD, MPH, Dana-Farber Cancer Institute, Boston, Massachusetts. One reason is that initial drug evaluations often focus on patients with advanced disease, he said. In metastatic disease, the analysis found that “most FDA approval trials do not meet the ASCO-NHB v2 and ESMO-MCBS v1.1 thresholds for substantial clinical benefit.” He noted that “in patients with early breast cancer, low agreement observed between the ASCO-NHB v2 and ESMO-MCBS v1.1 suggest that the respective frameworks may require additional refinement to accurately capture substantial clinical benefit in the curative setting.” ■

FEATURE: VALERIE WEST, PA-C; MICHAEL W. FELZ, MD

Hypothyroidism: A Case of Fatigue, Weight Gain, and Constipation Approximately 4.6% of the US population has hypothyroidism, and Hashimoto thyroiditis is the most common autoimmune presentation.

53-year-old woman presents to her primary care provider with complaints of fatigue, weight gain, and constipation. She states that her weight has gradually increased over the last year despite no change in her activity level or eating habits. She works roughly 8 hours a day as a nutrition assistant, but she falls asleep as soon as she gets home in the afternoon. She lacks motivation to do anything during the weekend, and notes that she does not feel like herself. Upon questioning, the patient reports the following changes: thinning of her scalp hair, brittle nails, dry skin, and cold intolerance. Physical examination confirms dry skin, brittle nails, coarse and dry hair, and abdominal distension.The only medication she takes is a multivitamin daily. She has a positive family history for autoimmune disorders and stroke. Normal Thyroid Anatomy and Physiology

Thyroid scintigram with iodine 131 of patient with Hashimoto disease.

The thyroid gland is a small, butterfly-shaped gland located in the neck, under the trachea.1 The thyroid functions as an endocrine gland and produces thyroid hormones and calcitonin, which are responsible for controlling metabolism, growth, and serum electrolyte concentrations.1 Similar to other endocrine glands, the thyroid has a regulatory feedback system that starts in the hypothalamus, where thyrotropin-releasing Continues on page 33

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HYPOTHYROIDISM: A CASE STUDY

A negative feedback loop regulates the release of thyroid hormones; when levels in the bloodstream fall, more hormones are released. hormone is released into the hypothalamic-hypophyseal portal system and transported to the anterior pituitary gland.2 Thyrotropin-releasing hormone then stimulates the pituitary gland to release thyroid-stimulating hormone (TSH).2 TSH travels to the thyroid and binds to receptors located on the follicular cells of the thyroid gland, where it activates a cascade of events inside the follicular cells that ultimately cause the release of thyroxine (T4) and triiodothyronine (T3), the thyroid hormones.2,3 It is important to note that although the thyroid does produce and release both T4 and T3, most of T3 is made in the periphery via the deiodination of T4.3 This cascade of hormones is regulated by a negative feedback system: when the levels of T4 and T3 increase in the bloodstream, they travel back to the hypothalamus and pituitary to signal them to stop releasing their respective hormones.2 When the levels of T4 and T3 decrease, the hypothalamus and pituitary return to secreting thyrotropinreleasing hormone and TSH, respectively.2 Epidemiology of Hypothyroidism

Hypothyroidism, the condition in which the thyroid gland does not produce enough hormone, occurs in approximately 4.6% of the population in the United States.4 The vast majority of cases involve women (85%).1,3 Thyroid deficiency compromises almost all body functions, and if left undiagnosed or untreated, it can lead to infertility, Hashimoto encephalopathy, and myxedema coma.3,5-7 Autoimmune dysfunction is one of the major causes of thyroid disease.8 In the case of hypothyroidism, Hashimoto thyroiditis is the most common autoimmune presentation. It is characterized by infiltration of the thyroid by T and B lymphocytes.8 This leads to thyroiditis, an inflammatory reaction of the thyroid gland that leads to the production of antibodies to thyroid antigens, thyroid peroxidase, and thyroglobulin. Ultimately, the follicular cells of the thyroid are destroyed, thereby interfering with thyroid hormone synthesis.8 Risk factors for developing Hashimoto thyroiditis include iodine consumption, smoking, radiation exposure, female sex, aging, and genetics.8 Those with autoimmune thyroid disease are more likely to have other autoimmune disorders (polyautoimmunity). Polyautoimmunity is so common that guidelines now recommend searching for other autoimmune disorders in patients with autoimmune thyroid disease, as well as poor treatment outcomes, before initiating combination therapy for hypothyroidism.8

Signs and Symptoms

The manifestation of hypothyroidism can vary markedly from patient to patient. At this time, no clear guidelines exist for screening for hypothyroidism. The US Preventive Services Task Force does not recommend screening patients for thyroid dysfunction.9 Other associations, including the American Academy of Family Physicians and the American College of Physicians, suggest screening for thyroid dysfunction only in women older than 60 years.10 Some clinicians may find it reasonable to screen all patients at risk for hypothyroidism.10 Those at risk include patients with other autoimmune disorders, history of radiation exposure, or family history of thyroid disease; women; and those 60 years of age or older.3 Symptoms of hypothyroidism are nonspecific and reflect the generalized slowing of the metabolic processes and TABLE 1: Manifestations of Hypothyroidism by Body System3,11,12 System

Clinical and Physical Signs

General

Fatigue, weight gain, lethargy, cold intolerance

Dermatologic

Cold, pale, dry skin; thin and brittle nails; thinning and coarse hair; puffy eyelids and face; lateral eyebrow thinning

Ear, nose, throat

Dysphagia, hoarseness

Pulmonary

Dyspnea on exertion, hypoventilation, sleep apnea

Cardiovascular

Bradycardia

Gastrointestinal

Constipation

Reproductive

Oligomenorrhea

Neurologic

Decreased relaxation phase of deep tendon reflexes, headache

Psychiatric

Depression, difficulty concentrating, memory impairment

Orthopedic

Carpal tunnel syndrome, arthralgia, myalgia

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and underwent a full laboratory workup.

HYPOTHYROIDISM: A CASE STUDY

FIGURE. Close-up of swollen thyroid glands caused by Hashimoto disease.

include fatigue, lethargy, cold intolerance, and weakness.3 Signs and symptoms secondary to matrix glycosaminoglycan accumulation include coarse and dry hair, puffy eyelids and face, enlargement of the tongue, and hoarseness (Table 1).3,11,12 Of note, older patients often present with symptoms that could be attributed to other conditions, whereas younger patients usually display signs and symptoms more typical of hypothyroidism.12 Physical signs include an enlarged thyroid (Figure), bradycardia, hypertension, and slow relaxation phase of deep tendon reflexes.3 Thinning of the outer halves of the eyebrows, also known as Queen Anne sign, and galactorrhea are rare additional findings.3 Clinicians must exclude a multitude of other disorders that mimic hypothyroidism, especially in older patients.The differential diagnosis includes anemia, other autoimmune disorders, chronic fatigue syndrome, constipation, depression, early menopause, adrenal dysfunction, normal aging processes, and pituitary dysfunction.9,13 Our patient presented early in the course of her condition and had many of the typical symptoms of hypothyroidism. Her family history of other autoimmune disorders was an additional clue. Her presentation led her provider to order a series of tests to help in diagnosis.

normal ranges for thyroid laboratory values14; however, what is considered within the upper limit of normal is still widely debated.16 According to the 2012 American Association of Clinical Endocrinologists and American Thyroid Association cosponsored guidelines, “if the upper and lower limits of normal for a third-generation TSH assay are not available, an upper limit of 4.12 mIU/L and a lower limit of 0.45 mIU/L should be considered in iodine-sufficient areas.”4 Additional findings include hyponatremia, hypoglycemia, anemia, increased low-density lipoprotein cholesterol, increased liver enzymes, and increased creatine kinase, all reflecting hypofunctioning of many body systems.3 Measurement of free T3 (f T3) and thyroid peroxidase antibody titers is typically not necessary but affirm the etiology of hypothyroidism and determine whether autoimmunity plays a role.3,17 Normal TSH values vary widely depending on age, and the ranges of normal values are typically higher in older adults.This is important, as a select number of patients manifest recurrent symptoms despite normal-appearing thyroid values.Assessment of f T3 may be useful in these cases. Although TSH and f T4 may be within normal limits, f T3 may be lower and could account for recurrent symptoms (see box).18 Experts agree that a TSH on the higher range of normal predicts symptomatic hypothyroid deficiency. Typical symptoms with TSH in the lower range of normal probably indicates decreased peripheral conversion from T4 to T3.19 In the case presented, a complete blood count, complete metabolic panel, and lipid and thyroid panels were ordered. All were within normal limits except TSH and f T4, which were 6.71 mIU/L and 0.6 ng/dL, respectively. These results were diagnostic for mild hypothyroidism. At this time the patient’s primary care provider initiated therapy. Treatment

Treatment for hypothyroidism is aimed at slowly stabilizing TSH and f T4 by administering synthetic thyroxine, or levothyroxine.20 The starting dosage of levothyroxine is TABLE 2: Normal Thyroid Laboratory Ranges16 Test

Optimum Values

TSH

0.4-4.0 mIU/L

f T4

0.7-1.9 ng/dL

f T3

230-619 pg/dL

Diagnostic Tests

Definitive diagnosis of hypothyroidism requires laboratory evaluation of TSH and free thyroxine (f T4). Once the diagnosis is suspected, complete blood count, complete metabolic panel,TSH, f T4, vitamin D, and lipid panels should be ordered.14 Serum TSH is by far the most sensitive and specific test in the diagnosis of hypothyroidism, and symptom severity is associated with higher levels of TSH.15 Table 2 lists the

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1.6 μg/kg/d, or about 25 μg/d.18 Doses can be adjusted according to to patient symptoms and the dose at which TSH normalizes.3 In severe hypothyroidism, initiation of T4 therapy may exacerbate adrenal hypofunction.19 To avoid adrenal insufficiency, patients should also receive supplemental prednisone for the first week of T4 therapy.19 Once initial treatment has begun, monitoring of serum TSH and serum f T4 should be performed every 4 to 6 weeks until TSH is reduced to normal limits and the patient is in a euthyroid state.3 Some patients still have symptoms despite normal thyroid laboratory

values; these patients may benefit from slight increases in their levothyroxine dose.3 The patient was started on 50 μg/d of levothyroxine initially. Since that time, the levothyroxine has been titrated up to a dosage of 75 μg/d and the patient has been maintained in a euthyroid state. Patient Education

It is important to instruct patients on how to properly ingest the medication and what, if any, adverse effects to anticipate. Levothyroxine has a half-life of 14 days and should be taken

Management of Conversion Disorder and Subclinical Hypothyroidism Conversion Disorder Some patients with hypothyroidism may be symptomatic and have a normal TSH and fT4, but their fT3 may be slightly low. This indicates a potential problem with the conversion of T4 to T3 in the peripheral tissues.1 This is known as conversion disorder, euthyroid sick syndrome, or nonthyroidal illness syndrome.1 Typical therapy for hypothyroidism is levothyroxine, but not all patients normalize T3 with this therapy because of conversion issues. Multiple studies have been performed to determine the usefulness of combination therapy with levothyroxine and liothyronine for this patient population. Results of some of these studies determined that patients preferred combination therapy.2,3 A meta-analysis of other studies found no significant difference between the 2 therapy groups.4 It has been suggested that there may be a certain patient population that benefits from combination therapy, but because of the short half-life and rapid absorption of liothyronine, multiple doses per day need to be taken to create a stable level of T3.1 Newer studies need to be performed with a longeracting form of liothyronine to determine the true significance of combination therapy vs monotherapy. Subclinical Hypothyroidism Subclinical hypothyroidism (SCH) is described as an elevated TSH and normal fT4 and fT3.2 This is much more common with autoimmune thyroid disease, and about 2% to 5% of patients with SCH progress to overt hypothyroidism every year.5 Undiagnosed and untreated SCH can lead to increased risk for cardiovascular disease, dyslipidemia, liver disease, neuropsychiatric symptoms, and potentially infertility.5 For this reason, early diagnosis is important. In general, SCH is detected clinically through laboratory testing, and much less by patient symptoms. If present, symptoms are generally nonspecific, similar to those of hypothyroidism. The most frequently reported symptoms include memory impairment, slowness of thinking, muscle cramps, muscle

weakness, tiredness, dry skin, feeling colder, hoarseness of voice, puffy eyes, and constipation.5 Diagnosis can be made with typical thyroid testing, but often thyroid peroxidase antibody testing can help determine an autoimmune etiology, as well as serve as an indicator for likelihood of progression to hypothyroidism.6 If tested early on in the disease process, antibodies may not be at a detectable level. In this case, a thyroid ultrasound may be helpful.3 There are 2 classes of SCH: the first with TSH between 4.0 and 10.0 mIU/L, and the second with TSH >10.0 mIU/L.2 There has been debate over whether to treat patients with mildly elevated TSH (4.0-10.0 mIU/L). If SCH is indicated on initial testing, it is wise to repeat testing 2 to 3 months before diagnosing and potentially treating.6 This is in part because of the variations of TSH levels, which can change throughout the day and peak in the evening.6 Ranges also increase with increasing age and are unpredictable in individuals with irregular sleep patterns.6 Individuals who exercise vigorously or have severe depression may also have altered TSH ranges.6 Once SCH is diagnosed, patients are sorted by age,TSH levels, and presence of symptoms to determine whether to treat or not to treat.6 Current guidelines recommend that patients <70 years old with TSH <10 mIU/L but with symptoms, may start a 3-month trial of levothyroxine and be assessed thereafter.6 REFERENCES 1. Abdalla SM, Bianco AC. Defending plasma T3 is a biological priority. Clin Endocrinol (Oxf). 2014;81(5):633-641. 2. Appelhof BC, Fliers E, Wekking EM, et al. Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double‐blind, randomized, controlled clinical trial. J Clin Endocrinol Metab. 2005;90(5):2666-2674. 3. Nygaard B, Jensen EW, Kvetny J, Jarløv A, Faber J. Effect of combination therapy with thyroxine (T4) and 3,5,3’-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study. Eur J Endocrinol. 2009;161(6):895-902. 4. Grozinsky-Glasberg S, Fraser A, Nahshoni E,Weizman A, Leibovici L.Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2006;91(7):2592-2599. 5. Khan MA, Ahsan T, Rehman UL, Jabeen R, Farouq S. Subclinical hypothyroidism: frequency, clinical presentations, and treatment indications. Pak J Med Sci. 2017;33(4):818-822. 6. Pearce SH, Brabant G, Duntas LH, et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013;2(4):215-228.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 35

right-hand column like this one does at the top

HYPOTHYROIDISM: A CASE STUDY

of Clinical Endocrinologists and the American Thyroid Association. Thyroid.

POLL POSITION

2012;22:1200-1235 5. Huang HK, Wang JH, Kao SL. Association of hypothyroidism with all-cause

Which of the following symptoms is not associated with hypothyroidism?

mortality: a cohort study in an older adult population. J Clin Endocrinol Metab. 2018;103(9):3310-3318. 6. Lillevang-Johansen M1, Abrahamsen B, Jørgensen HL, Brix TH, Hegedüs L. Over- and under-treatment of hypothyroidism is associated with excess

9.64%

mortality: a register-based cohort study. Thyroid. 2018;28(5):566-557.

■ Bradycardia ■ Dysphagia ■ Chronic fatigue syndrome

7. Laulund AS, Nybo M, Brix TH, Abrahamsen B, Jørgensen HL, Hegedüs

12.56%

L. Duration of thyroid dysfunction correlates with all-cause mortality. the 53.14%

24.66%

■ Carpel tunnel syndrome

OPENTHYRO Register Cohort. PLoS One. 2014;9(10):e110437. 8. Bliddal S, Nielsen CH, Feldt-Rasmussen U. Recent advances in understanding autoimmune thyroid disease: the tallest tree in the forest of polyautoimmunity. F1000Res. 2017;6:1776. 9. US Preventive Services Taskforce. Final recommendation statement. Thyroid

For more polls, visit ClinicalAdvisor.com/Polls.

dysfunction: screening. Available at: https://www.uspreventiveservicestaskforce. org/Page/Document/RecommendationStatementFinal/thyroid-dysfunctionscreening. Accessed January 10, 2020. 10. Fallahi P, Ferrari SM, Ruffilli I, et al. The association of other autoimmune diseases in patients with autoimmune thyroiditis: review of the literature and

at the same time every day on an empty stomach with a full glass of plain water.19 Because of the longer half-life, patients who may not be adherent to treatment still receive some benefit from taking levothyroxine. In addition, it is important to inform the patient to take medication 1 hour before breakfast and to avoid medications that interfere with levothyroxine’s metabolism, such as cholestyramine, colestipol, colesevelam, aluminum hydroxide, calcium carbonate, sucralfate, iron sulfate, raloxifene, omeprazole, and lansoprazole.19 Other medications that impair acid secretion, such as sevelamer, lanthanum carbonate, and chromium, may also interfere with levothyroxine therapy.19 If the provider has difficulty titrating the correct dose of levothyroxine to normalize TSH, or if the patient has significant coronary artery disease, the patient should be referred for consultation with an endocrinologist.3 ■

report of a large series of patients. Autoimmun Rev. 2016;15(12):1125-1128. 11. Surks MI. Clinical manifestations of hypothyroidism. https://www.uptodate. com/contents/clinical-manifestations-of-hypothyroidism. Updated July 16, 2019. Accessed December 16, 2019. 12. El-Shafie KT. Clinical presentation of hypothyroidism. J Family Community Med. 2003;10(1):55-58. 13. Orlander PR. Hypothyroidism differential diagnoses. https://emedicine. medscape.com/article/122393-differential. Updated November 5, 2019. Accessed March 14, 2019. 14. Ross DS. Diagnosis of and screening for hypothyroidism in nonpregnant adults. https://www.uptodate.com/contents/diagnosis-of-and-screeningfor-hypothyroidism-in-nonpregnant-adults. Updated September 16, 2019. Accessed March 12, 2019. 15. Canaris GJ, Steiner JF, Ridgway EC. Do traditional symptoms of hypothyroidism correlate with biochemical disease? J Gen Intern Med. 1997;12(9):544-550.

Valerie West, PA-C, is a physician assistant at the Center for Primary Care in Groverton, Georgia, and MichaelW. Feltz, MD, is an assistant professor at Augusta University in Augusta, Georgia.

16. Lewandowski K. Reference ranges for TSH and thyroid hormones.

References

of Internal Medicine, 20e. New York, NY: McGraw-Hill.

1. Allen E, Fingeret A. Anatomy, head and neck, thyroid. In: StatPearls. Treasure

18. Ceresini G, Marina M, Lauretani F, et al. Physical performance across the

Thyroid Res. 2015;8(suppl1):A17. 17. Jameson JL, Mandel SJ, Weetman AP. Hypothyroidism. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles

Island, FL: StatPearls Publishing; 2019.

thyroid function values within the normal range in adult and older persons.

2. Shahid MA, Sharma S. Physiology, thyroid hormone. In: StatPearls. Treasure

Aging Clin Exp Res. 2019;31(3):385-391.

Island, FL: StatPearls Publishing; 2019.

19. Felz MW, Forren AC. Profound hypothyroidism—a clinical review

3. Fitzgerald PA. Endocrine disorders. In: McPhee SJ, Papadakis MA, eds.

with eight recent cases: is it right before our eyes? South Med J. 2004;97(5):

Current Medical Diagnosis and Treatment 2018. 57th ed. New York:

490-498.

The McGraw-Hill Companies; 2018:1132-1137.

20. Ross DS. Treatment of primary hypothyroidism in adults. https://www.

4. Garber JR , Cobin RH , Gharib H, et al. Clinical practice guidelines

uptodate.com/contents/treatment-of-primary-hypothyroidism-in-adults.

for hypothyroidism in adults: cosponsored by the American Association

Updated May 8, 2019. Accessed March 13, 2019.

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Dermatology Clinic CASE #1

Painful Rash on Right Flank JAY PATEL, BS;YELENA DOKIC, BSA; CHRISTOPHER RIZK, MD

A 65-year-old woman presents to the clinic with a painful rash on her right side. On examination, there is a group of vesicles on an erythematous base on her right flank. The patient reports the rash appeared the day before, but the region around the vesicles “felt like it was on fire” the past week. The patient has never experienced these symptoms before. Medical history confirms the patient had chicken pox when she was 7 years old. What is your diagnosis? Turn to page 38

CASE #2

Itchy Rash on Hands and Feet ELEANOR JOHNSON, BA;YELENA DOKIC, BSA; CHRISTOPHER RIZK, MD

A 3-year-old girl presents to the clinic with a history of “itchy rash on hands and feet” that started 2 days earlier. On examination, the patient displays multiple small, erythematous papules on the palms, sides, and webs of her hands and fingers, and on the soles of her feet. The mother notes that the pruritus became worst the night before, which caused her child not to sleep well. The mother also states that she is also feeling itchy but thought it was “all in her head.” The patient attends daycare while her mother is at work. What is your diagnosis? Turn to page 40 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 37

Dermatology Clinic CASE #1

Herpes Zoster

Herpes zoster (HZ), or shingles, is a painful dermatomal rash caused by reactivation of latent varicella-zoster virus (VZV) that persists in neurons after varicella (chicken pox) infection.1 HZ has been recognized since ancient Greece: its name derives from the Greek herpein zoster, meaning “to creep” and “girdle or zone.”2 It was first associated with peripheral nerves in 1818 by Mehlis, and in 1861, von Bärensprung linked it to sensory neuron cell bodies.3,4 In 1900, Head and Campbell described a viral inflammation in the cell bodies,5 but it was not until the 1950s that it was confirmed that the same VZV caused varicella and herpes zoster.6 HZ has no seasonal prevalence, and the incidence increases with age. Half the yearly cases occur in individuals >60 years of age.1 In the community, HZ has an incidence of 2 to 5 cases per 1000 person-years, which increases to 8 to 12 per 1000 years in adults ≥70 years of age.1,7 The primary risk factor in developing HZ is a prior varicella infection.1 HZ occurs when latent VZV becomes reactivated, which leads to the appearance of painful vesicles in the regions where the sensory neurons project, referred to as a dermatomal pattern.1,8 A depressed immune system is a major risk factor in the reactivation of VZV, accounting for 10% of HZ cases. At-risk, immunocompromised individuals include organ transplant recipients or patients with tumors or immunologic/rheumatologic diseases.1 HZ is also a prominent sign of HIV immune deficiency; therefore, HIV should be considered especially in young patients presenting with HZ.1 Other risk factors include female gender, trauma to a sensory dermatome, family history of HZ, white race, and certain genetic predispositions including interleukin 10 gene polymorphisms.1,9 Histologically, HZ resembles an intraepidermal blister.1 Key features include acantholysis with solitary keratinocytes in the blister cavity.1 Because of the viral infection, keratinocytes will have nuclear changes, including multinucleation and nuclear inclusions, as well as viral inclusions in the nucleus that resemble small pink deposits with a clear halo.1 Tzanck smear can be used to identify multinucleated giant cells.1 Patients with HZ will often have a prodrome of pain and paresthesia in the affected areas.1 The pain can be as severe as pain associated with diseases from visceral organs, such as myocardial infarction or cholecystitis.10 Altered sensations in the areas include itching, tingling, or burning.10 Select patients

can develop the skin eruption without prodromal pain, known as zoster sine herpete.11 The distinctive skin eruption is a unilateral rash limited to a body region innervated by a single sensory ganglion.1 The most common areas affected are the ophthalmic division of the trigeminal nerve and the truncal region between sensory levels of T3-L2.12 On examination, the HZ rash will appear as tightly grouped vesicles on an erythematous base.1 The vesicles begin as macules and papules, with vesicles forming within 24 hours, transitioning to pustules in about 3 days, and then a dry crust in 7 to 10 days, which can persist up to 3 weeks. Other key clinical features of HZ include pain, which is often severe and can lead to decreased physical and social functioning, and pruritus, which can remain until all crusts are gone.

A depressed immune system is a major risk factor in the reactivation of varicellazoster virus, accounting for 10% of cases. In the prodromal phase of HZ, diagnosis can be difficult, as the pain can be confused with other causes of localized pain such as cholecystitis, myocardial infarction, gastritis, and so on. The diagnosis is usually clinical, with a dermatomal eruption along with pain and sensory abnormalities. HZ is most often confused with zosteriform herpes simplex, as both present with a cluster of vesicles, although with zosteriform herpes simplex, the cluster often appears near the mouth or genitals.1 A history of multiple recurrences in the same region often differentiates the 2 diagnoses. In addition to zosteriform herpes simplex, the differential diagnosis includes contact dermatitis, insect bites, and burns, and less likely, drug eruptions, scabies, papular urticaria, erythema multiforme, and molluscum contagiosum.1 For most of these, the unilateral dermatomal patterned painful rash is often sufficient to diagnose HZ; however, a biopsy can be used to confirm HZ. Polymerase chain reaction is the optimal diagnostic test to detect VZV, can distinguish between VZV and herpes simplex virus, and can be performed from vesicular fluid, lesion or crust scrapings, or tissue biopsy.13 Complications of HZ include bacterial superinfection of the lesions, scarring (from excessive scratching), or cutaneous dissemination through nearby neurons or the spinal cord.1,7 Visceral adverse effects can also occur, such as pneumonitis, hepatitis, esophagitis, gastritis, and so on.7 Neurologic complications include nerve palsies, sensory loss, ocular complications

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Dermatology Clinic (especially with ophthalmic HZ), and most important, postherpetic neuralgia (PHN).2,7 PHN is defined as pain that continues after the rash is healed and can last up to 6 months from onset. PHN occurs in 5% to 30% of patients with HZ.2,7 Effective treatment of HZ includes antiviral agents such as acyclovir, famciclovir, and valacyclovir.8 These treatments are most effective at reducing acute pain and preventing PHN if started within 72 hours of rash onset.8 Importantly, for HZ affecting the ophthalmic region of the trigeminal nerve, antiviral treatment is necessary and must be started even if >72 hours have elapsed since rash onset.8 For ophthalmic HZ, topical antiviral cream should also be used along with oral corticosteroids.8 Oral prednisolone with acyclovir reduces pain, increases the healing speed of lesions, and allows for a faster resolution, especially for nonophthalmic HZ.14 Therefore, the addition of oral steroids to antiviral treatment should be considered when there are no contraindications. Other treatment agents include tricyclic antidepressants, which have been shown to reduce the prevalence of PHN at 6 months; however, these agents should be used with caution in older patients because of anticholinergic adverse effects precipitating delirium or tachycardia.8 Opioids and nonsteroidal anti-inflammatory drugs can also be used for pain management: oxycodone has been shown to reduce acute pain, and tramadol has been used to treat PHN.8 The advent of the varicella vaccine and eradication of primary varicella should lead to the eventual eradication of HZ. Although there were concerns that the loss of childhood chicken pox could lead to an increase in HZ, analyses of the prevalence of HZ after varicella vaccination has not supported this claim.15 In addition, in patients who may have had a primary varicella infection as children, administration of the varicella zoster virus vaccine in patients older than 60 years was effective at reducing the number of HZ cases and the incidence of PHN.16 The patient in the case was treated with oral valacyclovir. Her lesions crusted over and disappeared over the course of 2 weeks. Jay Patel, BS, andYelena Dokic, BSA, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is a dermatologist at Elite Dermatology in Houston,Texas. References 1. Levin MJ, Schmader KE, Oxman MN. Varicella and herpes zoster. In: Fitzpatrick’s Dermatology. 9th ed. New York, NY: McGraw-Hill Education; 2019. 2. Roxas M. Herpes zoster and postherpetic neuralgia: diagnosis and therapeutic considerations. Altern Med Rev. 2006;11(2):102-113. 3. von Bärensprung FGH. Die Gürtelkrankheit. Ann d char krankenh zu Berl. 1861;9:40-128. 4. Meyer R, Brown HP, Harrison JH. Herpes zoster involving the urinary bladder. N Engl J Med. 1959;260(21):1062-1065.

5. Head H, Campbell AW, Kennedy PGE. The pathology of herpes zoster and its bearing on sensory localisation. Rev Medical Virol. 1997;7(3):131-143. 6. Weller TH, Witton HM. The etiologic agents of varicella and herpes zoster; serologic studies with the viruses as propagated in vitro. J Exp Med. 1958;108(6):869-890. 7. Kawai K, Gebremeskel BG, Acosta CJ. Systematic review of incidence and complications of herpes zoster: towards a global perspective. BMJ Open. 2014;4(6):e004833. 8. Wareham DW, Breuer J. Herpes zoster. BMJ. 2007;334(7605):1211-1215. 9. Haanpää M, Nurmikko T, Hurme M. Polymorphism of the IL-10 gene is associated with susceptibility to herpes zoster. Scand J Infect Dis. 2002;34(2):112-114. 10. Chen TM, George S, Woodruff CA, Hsu S. Clinical manifestations of varicella-zoster virus infection. Dermatologic Clinics. 2002;20(2):267-282. 11. Lewis GW. Zoster sine herpete. Br Med J. 1958;2(5093):418-421. 12. Ragozzino MW, Melton LJ, Kurland LT, Chu CP, Perry HO. Population-based study of herpes zoster and its sequelae. Medicine (Baltimore). 1982;61(5):310-316. 13. Harbecke R, Oxman MN, Arnold BA, et al. A real-time PCR assay to identify and discriminate among wild-type and vaccine strains of varicella-zoster virus and herpes simplex virus in clinical specimens, and comparison with the clinical diagnoses. J Med Virol. 2009;81(7):1310-1322. 14. Whitley RJ, Weiss H, Gnann JW, et al. Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Ann Intern Med. 1996;125(5):376-383. 15. Jumaan AO, Yu O, Jackson LA, Bohlke K, Galil K, Seward JF. Incidence of herpes zoster, before and after varicella-vaccination-associated decreases in the incidence of varicella, 1992-2002. J Infect Dis. 2005;191(12):2002-2007. 16. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352(22):2271-2284.

CASE #2

Scabies

Scabies is a highly contagious parasitic infection that has plagued humans throughout history and is described both in the Bible and in Aristotle’s writing.1 The term “scabies” is credited to Roman physician Celcius,1 but the causal relationship between the scabies mite and the skin manifestations was not described until 1687 by Giovan Cosimo Bonomo and Diacinto Cestoni.2 The incidence of scabies is higher in developing counties, especially among those in the lower socioeconomic classes, but scabies can affect anyone regardless of sex, age, or ethnicity.2-7 It

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is estimated to affect 300 million people a year worldwide.3-5 Some areas of the world experience seasonal increases in incidence during the winter, possibly because mites survive away from their host better in cooler environments.2,3 Sarcoptes scabiei is the mite responsible for this condition.2-8 Scabies transmission occurs predominantly via direct contact with an infected individual.3,6-8 Theoretically, scabies can also occur via fomites, but studies have shown that clinically, this mode of transmission is rare.2,3 Because scabies can also infect animals, such as domestic pets, animal-to-human transmission is rare but possible.5 Genital scabies infection occurs via sexual transmission.3 Once in contact with a new host, the pregnant female parasite burrows into the upper stratum of the epidermis and lays eggs.7,8 The larvae will mature and repeat the cycle in about 2 weeks.7 In classic cases of scabies, an individual is host to 10 to 12 mites.2,7 In crusted scabies, a severe infestation that affects immunocompromised individuals, counts can reach into the millions.2 The risk of contracting scabies is higher in environments where people are in close contact with infected individuals. This can occur in healthcare settings such as hospitals and nursing homes, in crowded housing situations, and in prisons.2,3,5,6 Classical scabies presents as pruritic, erythematous papules that symptomatically worsen at night.2,3,7,8 Because of its highly contagious nature, patients with scabies may present with several family members also experiencing similar symptoms.7 The papules may progress to vesicles and bullae.2 These symptoms occur as a hypersensitivity response to the infestation.3 During the primary infection, symptoms are delayed in onset as the adaptive immune response is generated. If an individual is reinfected, symptoms occur within a day.2 The most common locations are the finger webs, wrists, elbows, axillae, buttocks, genitalia, and breasts.3,7 In adults, the head is generally spared, but in infants, the face and scalp are commonly affected.3,7 Because neonates cannot scratch, they present as poorly feeding and irritable, with pinkish-brown nodules.7 The most specific clinical sign for scabies are burrows, which appear as short, wavy lines.2,3,7 Because this is a pruritic condition, excoriations are commonly seen and can lead to eczematization, crusting, and impetiginization.2,3 Superinfection with Streptococcus can lead to acute glomerulonephritis.2,6 Crusted scabies is a hyperkeratotic skin disease that presents with exfoliating scales.2 Predisposing conditions associated with this hyperinfestation are immunocompromising infections (HIV, human T-cell leukemia virus), neurologic conditions, and among elder patients in long-term care facilities.2,5,7 The differential diagnosis includes many of the other pruritic dermatoses. In developed countries, eczema, tinea, and

atopic dermatitis are more common than scabies; whereas in developing countries, pyoderma is more likely. Crusted scabies appears very similar to psoriasis. Scabies can also mimic a variety of systemic diseases such as lupus erythematosus, bullous pemphigoid, Langerhans cell histiocytosis, urticaria pigmentosa, and seborrheic dermatitis.2 When diagnosing skin rashes with pruritus, it is important to include scabies in the differential diagnosis and to perform a thorough physical examination, especially on patients coming to the hospital from a long-term care facility or from resource-poor settings.A recent study performed by Hong et al found that 65% of patients admitted to the hospital through the emergency department with scabies were not diagnosed on admission.4

Permethrin is still considered first-line therapy for scabies, even for pregnant patients, as little is systemically absorbed. Diagnosis can be made clinically, but historically, super ficial skin scrapings have been examined in an attempt to identify mites, eggs, or remnants.3 This method of diagnosis is controversial because of its low sensitivity; thus, less-invasive methods are being studied.2 Epiluminescence microscopy and dermoscopy have been shown to be valuable diagnostic tools.6,8 The adhesive tape test is an alternative to skin scraping in resource-poor settings and when attempting to diagnose uncooperative children.8 Biopsies are rarely performed, but histologic examination typically reveals a nonspecific, delayed hypersensitivity reaction.3 If a mite is visualized, it is surrounded by eosinophils, lymphocytes, and histiocytes.2 In the United States, permethrin cream (5%) is used as firstline therapy.2,7 Benzyl benzoate cream (19% or 25%) is used in developing countries, and studies report high efficacy2,3; it is more affordable, but must be applied more frequently and is associated with skin irritation.2 Lindane cream was historically prescribed but has potential neurotoxic effects, such as numbness, tremor, and convulsions, and is now considered a second-line treatment option.2,5 For pregnant patients, permethrin is still considered first-line therapy, as very little is absorbed systemically, and it is rapidly detoxified.7 If topical treatments cause intolerable adverse effects or a patient is nonadherent, oral ivermectin may be used offlabel.2,3 Oral ivermectin is also used in combination with topical permethrin and a keratolytic to treat crusted scabies.2

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Dermatology Clinic Other alternatives that are still being studied include essential oils (tea tree oil, neem oil, lippie oil, Eupatorium adenophorum oil) and turmeric.2,5 It is crucial that all the people who have been in close contact with the infected person are also treated simultaneously to avoid reinfection.2,3 Although indirect person-to person-transmission is rare, it is still common practice to recommend washing clothes and bed linens used by the infected individual.3 Symptoms should resolve during a 6-week treatment period. If not, adherence should be addressed and reinfestation considered.7 In this case, because of a strong clinical suspicion of scabies, microscopic examination of scrapings was performed. Upon examination, mites were observed. Both the patient and her mother were prescribed permethrin cream, and the mother was instructed to wash all bedding and clothing worn during the last 3 days. ■

References 1. Roncalli RA. The history of scabies in veterinary and human medicine from biblical to modern times. Vet Parasitol. 1987;25(2):193-198. 2. Heukelbach J, Feldmeier H. Scabies. Lancet. 2006;367(9524):1767-1774. 3. Chosidow O. Clinical practices. Scabies. N Engl J Med. 2006;354(16): 1718-1727. 4. Hong MY, Lee CC, Chuang MC, Chao SC, Tsai MC, Chui CH. Factors related to missed diagnosis of incidental scabies infestations in patients admitted through the emergency department to inpatient services. Acad Emerg Med. 2010;17(9):958-964. 5. Mounsey KE, McCarthy JS, Walton SF. Scratching the itch: new tools to advance understanding of scabies. Trends Parasitol. 2013;29(1):35-42. 6. Dupuy A, Dehen L, Bourrat E, et al. Accuracy of standard dermoscopy for diagnosing scabies. J Am Acad Dermatol. 2007;56(1):53-62. 7. Johnston G, Sladden M. Scabies: diagnosis and treatment. BMJ. 2005; 331(7517):619-622. 8. Walter B, Heukelbach J, Fengler G, Worth C, Hengge U, Feldmeier H. Comparison of dermoscopy, skin scraping, and the adhesive tape test for the diagnosis of scabies in a resource-poor setting. Arch Dermatol. 2011; 147(4):468-473.

Eleanor Johnson, BA, andYelena Dokic, BSA, are medical students at Baylor University, and Christopher Rizk, MD, is a certified dermatologist at Elite Dermatology in Houston,Texas.

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Dermatologic Look-Alikes Violaceous Plaque on the Eyelid RONALD SCOTT BUKOSKI, MS; JULIA R. NUNLEY, MD

CASE #1

CASE #2

A 48-year-old black man presents to the clinic with asymptomatic lesions around his right eye that have been present for approximately 1 year. He notes that he started experiencing shortness of breath and a cough over the same time period. Otherwise, his medical history is unremarkable.The patient recalls that his late sister had “some disease of her lungs,” but he was unsure of the diagnosis. Employed as an engineer, he works in an office and denies any high-risk social activities. Physical examination shows several purplish plaques around his right eye; similar lesions are present on his arms, legs, and chest. A skin biopsy and a chest radiograph are performed.

A 35-year-old black woman with HIV comes into the dermatology clinic with an asymptomatic lesion on her right eye that has been present for about a month. Clinical review of symptoms is otherwise unremarkable. However, insurance issues have prevented her from taking her antiretroviral medications for the past 6 months. On physical examination, the patient has an indurated, nontender, violaceous plaque on her right upper eyelid. Similar lesions are present in her mouth and on her trunk and arms. A complete blood count shows a CD4 count of 180 cell/mm3 with an HIV viral load of 10,000 copies/mL. A biopsy is taken of a lesion on her chest.

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Dermatologic Look-Alikes CASE #1

Sarcoidosis

Sarcoidosis is a noninfectious granulomatous disease that can affect any organ system, although it has strong predilection for the lungs, lymph nodes, and skin. Cutaneous lesions, which may be the presenting sign or develop later in the disease, occur in 25% to 30% of patients and are most often red-to-brown to violaceous papules and plaques.1 Cutaneous lesions, however, are rarely the only manifestation of this disease. Of note, sarcoidosis has a unique propensity to develop in areas of trauma, so plaques are common on the knees, elbows, and within tattoos.2 However, sarcoidosis can develop anywhere in and on the skin, and lesion morphology is protean.1 Lesions on the face are often symmetrically distributed affecting periocular and nasal areas.The term lupus pernio is used to describe a characteristic presentation with indurated violaceous papulonodules and/or plaques that develop on the nose, cheeks, and ears. Identifying lupus pernio is important as it strongly suggests lung and upper respiratory tract involvement. The age of onset of sarcoidosis is bimodal, occurring most commonly between the ages of 25 to 35 years and then between 45 and 65 years. Black individuals are at a higher risk of developing the disease, with an estimated incidence of 39 per 100,000 compared with an incidence of 5 per 100,000 in white individuals. In addition, black patients are more severely affected, with an age-adjusted mortality rate 12 times higher than that seen in white patients.3 There is a strong genetic component, with an 80-fold increase in risk demonstrated in monozygotic twins of affected individuals.4 The pathogenesis of sarcoidosis involves a genetic susceptibility to characteristic granuloma formation triggered by exposure to currently unknown antigens. Identification of specific T-cell clones from tissue samples supports the theory of an antigenic trigger; however, it is unclear whether the antigens are of an autoimmune, infectious, or foreign body etiology. Sarcoidal granuloma formation is similar to other granulomatous disorders involving T-helper 1 (Th1) cells that produce various cytokines including interleukin (IL)-2, IL-12, IL-18, and interferon gamma, which act to recruit macrophages. Tumor necrosis factor-alpha (TNF-Îą) production within the granuloma guides the fusion of epithelioid histiocytes, forming the classic multinucleated giant cells.5 Of interest, sarcoidal granulomas also incorporate the innate immune system and Th17 cell subtypes into their pathogenesis.6

Sarcoidosis is the great imitator and may resemble many other types of lesions including annular, psoriasiform, ichthyosiform, ulcerative, hypopigmented, subcutaneous, and erythrodermic lesions.2,7 Sarcoidosis, therefore, is a diagnosis that relies on a combination of clinical and laboratory evidence. Histologic examination will show the classic noncaseating granulomas throughout the dermis with epithelioid cells and fused multinucleated giant cells. These epithelioid tubercles and the paucity of a lymphocytic infiltrate help to differentiate sarcoidal granulomas from other granulomatous disorders.Asteroid and Schaumann bodies are inclusions sometimes found within the giant cells but are not specific for sarcoidosis. It is important that the tissue evaluation include a variety of other studies to exclude other causes of granulomatous disease.

When present, cutaneous sarcoidosis lesions are most often red-to-brown to violaceous papules and plaques. The differential diagnosis of cutaneous sarcoidosis is vast and variable depending upon lesion morphology. Fortunately, the finding of granulomas histologically helps narrow the possibilities. Noninfectious granulomatous disorders to be considered include granuloma annulare, necrobiosis lipoidica, annular elastocytic giant cell granuloma, cutaneous Crohn disease, palisading neutrophilic and granulomatous dermatitis, and rheumatoid nodules. Foreign body reactions from exposure to beryllium, silica, zirconium, and tattoo ink should also be part of the differential diagnosis. Infectious granulomatous disease can be due to mycobacterium or fungal organisms. Because these other disorders must be excluded, special stains, polymerase chain reaction, tissue cultures, and polarization are needed; therefore, sarcoidosis can be considered a diagnosis of exclusion.1 Recognition of both the cutaneous and extracutaneous manifestations is important in the management of patients with sarcoidosis, as any organ system can be affected. Pulmonary involvement is the most common, occurring in 90% of patients, and is associated with symptoms such as cough, dyspnea, and wheezing. In addition, all patients should be screened for signs and symptoms associated with other conditions including uveitis, cardiac abnormalities, cranial neuropathies, hepatic disease, endocrine dysfunction, renal disease, and musculoskeletal disorders. As mentioned, cutaneous disease is highly variable, but identification of skin lesions can readily aid in the diagnosis as a skin biopsy is more easily performed than biopsies of other organ systems.7 Therefore, coordination

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Dermatologic Look-Alikes between specialists is necessary for diagnosis and management. A complete investigation should include chest radiograph, pulmonary function testing, ophthalmologic evaluation, electrocardiogram, tuberculin skin testing, and laboratory tests including thyroid function, complete blood count, and comprehensive metabolic panel including calcium and vitamin D levels.1 Treatment is dictated by the organ(s) involved and disease severity. Since systemic disease is usually present, systemic therapy is usually needed; the most commonly used agents include prednisone, as well as various steroid-sparing immune modulators such as methotrexate and TNF inhibitors.1,8 Cutaneous lesions may respond to systemic therapy. However, skin-directed therapy may be needed either in combination with systemic therapy or as monotherapy if systemic therapy is not indicated. All classes of topical steroids, as well as intralesional injection of triamcinolone, are commonly used for various lesions in different anatomic sites. Antimalarial therapy, most commonly with hydroxychloroquine, can also be useful; beneficial effects are usually not seen for 2 to 3 months. Evaluation of the patient revealed significant pulmonary disease. Skin biopsy showed “naked” epithelioid granulomas in the dermis with only a few surrounding lymphocytes and some peripheral fibrosis. Special stains and tissue cultures were negative for organisms, supporting the diagnosis of sarcoidosis. The chest radiograph showed bilateral hilar lymphadenopathy with some interstitial changes, which is also consistent with a diagnosis of sarcoidosis. His cutaneous lesions improved with the use of prednisone for his pulmonary disease and judiciously applied topical alclometasone cream.

CASE #2

Kaposi Sarcoma

The development of new cutaneous lesions in the setting of HIV is disconcerting. The widespread nature of the lesions and the violaceous morphologic pattern seen in this case suggest the development of AIDSrelated Kaposi sarcoma (KS), which was confirmed by biopsy. KS is considered a malignancy characterized by proliferation of spindle cells of endothelial origin with varying degrees of abnormal vascularity that proliferate in the skin, oral mucosa, lymph nodes, and visceral organs. Originally described in 1872 by a Hungarian dermatologist, Moritz Kaposi,9 KS was of little epidemiologic concern

in America, or other Western countries, until the AIDS epidemic began in the 1980s. For the first several decades of the AIDS epidemic, KS was a well-recognized complication, mostly affecting Haitians and individuals who contracted HIV through sexual contact. At that time, the viral etiology for each condition was not known, so co-infection with these sexually transmitted viruses (HIV and KS) was not recognized. Many years after HIV was identified as the cause of AIDS, the pathogenesis of KS was linked to the human herpes virus 8 (HHV-8) or KS-associated herpesvirus (KSHV). HHV-8 contributes to the development of this typically low-grade neoplasm by stimulating processes of inflammation, proliferation, and angiogenesis within virally infected host endothelial cells.10 Host cell cycle regulatory genes, such as p53 and RB, are inhibited by processes that HHV-8 uses to maintain latency in the human host, allowing for more lenient progression through the cell cycle and decreased apoptosis.10 HHV-8 also confers changes in the transcriptional programming of infected endothelial cells allowing the lineage of the classic spindle cell to develop. It is still controversial whether these spindle cells are of vascular or lymphatic origin; however, their endothelial origin is clearly demonstrated with cell markers including CD31, CD34, and CD36.11 Fortunately, widespread use of highly active antiretroviral therapy (HAART) has greatly reduced the incidence of KS, at least in the HIV-infected population in developed countries. However, it remains an issue in certain parts of the world.We now recognize 4 distinct variants of KS: classic, iatrogenic, AIDS-related epidemic, and African endemic.11,12 Recently, cases of indolent KS resembling classic KS have been discovered in men who have sex with men, without the presence of HIV; this may become a fifth type of KS: nonepidemic KS.12 KS is a relatively rare disease worldwide, with less than 2 cases annually per 100,000 people. It is more common in patients with immunosuppression, with a worldwide annual incidence of 482 per 100,000 in HIV-infected patients and 69 per 100,000 in transplant patients.13 Classic KS occurs in the elderly, especially individuals of Jewish or Eastern European descent, and its onset may be associated with age-related immunosenescence. Iatrogenic KS occurs in patients who are immunosuppressed because of taking systemic medications, often in transplant patients taking cyclosporine.14 AIDS-related epidemic KS is seen predominantly in HIV-infected men who have sex with men. African endemic KS predominantly affects black Africans, most commonly children. The AIDS-related epidemic variant typically occurs when CD4 T-cell numbers are <500 cells/mm³ and is considered an AIDS-defining disease; however, the exact timing of onset is variable. KS may be the initial presenting sign, especially in underserved areas.10

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AIDs-related epidemic KS lesions most commonly arise on the trunk or face with a propensity for regions around the nose, eyes, and ears. Early lesions appear as red-pink oval-shaped macules or papules, which can progress to form larger purpleblack plaques or nodules causing significant disfigurement, with a potential to ulcerate and erode.10 In 10% to 15% of patients, blue or violaceous oral lesions appear. Classic and iatrogenic variants tend to have pink to red-violet macules on the lower extremities, with a more indolent course. It is important to note that KS can affect visceral organs, especially the gastrointestinal tract and lungs, so these systems should also be evaluated.15 The diagnosis of KS is made histologically. Histologic findings depend on the stage of the lesion - patch, plaque, or nodule and diagnostic changes are more readily identified in more mature lesions.The abnormal spindle cell of KS appears as an elongated endothelial cell and increases in number in more advanced lesions; however, these are not pathognomonic for KS. KS-specific changes

cases of KS may require cytotoxic chemotherapy, and topical regimens may be possible for more localized lesions. Overall clinical response depends on the stage and variant of KS, but generally high recurrence rates are common.16 Once our patient was able to resume her HAART medications her CD4 count slowly rose, her viral load became undetectable, and the cutaneous lesions slowly resolved. ■ Ronald Scott Bukoski, MS, is a medical student and Julia R. Nunley, MD, is a professor of dermatology at the Medical College of Virginia Hospitals,Virginia Commonwealth University, Richmond,Virginia. References 1. Wanat KA, Rosenbach M. A practical approach to cutaneous sarcoidosis. Am J Clin Dermatol. 2014;15(4):283-297. 2. Haimovic A, Sanchez M, Judson MA, Prystowsky S. Sarcoidosis: a comprehensive review and update for the dermatologist: part I. Cutaneous disease. J Am Acad Dermatol. 2012;66(5):699.e1-18;quiz 717-718.

AIDS-related Kaposi sarcoma lesions most often arise on the truck or face with a propensity for the nose, eyes, and ears.

3. Mirsaeidi M, Machado RF, Schraufnagel D, Sweiss NJ, Baughman RP. Racial difference in sarcoidosis mortality in the United States. Chest. 2015; 147(2):438-449. 4. Sverrild A, Backer V, Kyvik KO, et al. Heredity in sarcoidosis: a registry-based twin study. Thorax. 2008;63(10):894-896. 5. Patterson KC, Chen ES. The pathogenesis of pulmonary sarcoidosis and implications for treatment. Chest. 2018;153(6):1432-1442. 6. Facco M, Cabrelle A, Teramo A, et al. Sarcoidosis is a Th1/Th17 multisystem

are seen within the vasculature. Early patch stage lesions display subtle jagged-appearing blood vessels that dissect the collagen of the superficial dermis. In plaque stage lesions, these vascular structures have matured and extend deeper into the dermis and subcutis, eventually forming a characteristic sieve-like pattern as the spindled endothelial cells replace the dermal collagen in the final nodular or tumor stage. An immunohistochemical stain for the HHV-8-encoded protein ORF73, called the latency-associated nuclear antigen (LANA), has demonstrated high diagnostic sensitivity and specificity for diagnosing KS.16 The clinical appearance of KS similarly depends upon the stage of the disease. Lesions can resemble vasculitis, lymphatic or vascular malformations, leukemia or lymphoma cutis, lichen planus, sarcoidosis, and other early stage vascular tumors. Histologically, KS must be differentiated from bacillary angiomatosis, acroangiodermatitis, Kaposiform hemangioendothelioma (in children), spindle cell hemangioma, angiosarcoma, and other fibrohistiocytic tumors.15 Treatment for KS varies with the subtype. Patients with the AIDS-related epidemic variant, like our patient, should be treated with HAART. Improving the T-cell count and decreasing the HIV viral load both contribute to KS regression. Iatrogenic KS also responds to immune reconstitution; however, in these cases it is a complex task to decrease immunosuppression without risking organ rejection. More advanced

disorder. Thorax. 2011;66(2):144-150. 7. Haimovic A, Sanchez M, Judson MA, Prystowsky S. Sarcoidosis: a comprehensive review and update for the dermatologist: part II. Extracutaneous disease. J Am Acad Dermatol. 2012;66(5):719.e1-10;quiz 729-730. 8. Heidelberger V, Ingen-Housz-Oro S, Marquet A, et al. Efficacy and tolerance of anti-tumor necrosis factor α agents in cutaneous sarcoidosis: a French study of 46 cases. JAMA Dermatol. 2017;153(7):681-685. 9. Cohn JM, Burgin S. Moritz Kaposi. A notable name in dermatology. JAMA Dermatol. 2015;152(8):867. 10. Bhutani M, Polizzotto MN, Uldrick TS, Yarchoan R. Kaposi sarcomaassociated herpesvirus-associated malignancies: epidemiology, pathogenesis, and advances in treatment. Semin Oncol. 2015;42(2):223-246 11. Radu O, Pantanowitz L. Kaposi sarcoma. Arch Pathol Lab Med. 2013;137(2):289-294. 12. Lanternier F, Lebbé C, Schartz N, et al. Kaposi’s sarcoma in HIV-negative men having sex with men. AIDS. 2008;22(10):1163-1168. 13. Liu Z, Fang Q, Zuo J, Minhas V, Wood C, Zhang T.The world-wide incidence of Kaposi’s sarcoma in the HIV/AIDS era. HIV Med. 2018;19(5):355-364. 14. Ganem D. KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine. J Clin Invest. 2010;120(4):939-949. 15. Grayson W, Pantanowitz L. Histological variants of cutaneous Kaposi sarcoma. Diagn Pathol. 2008;3:31. 16. Schneider JW, Dittmer DP. Diagnosis and treatment of Kaposi sarcoma. Am J Clin Dermatol. 2017;18(4):529-539.

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LEGAL ADVISOR CASE

A Case of Altered Documents Failure to refer to surgeon after CT scan leads to long delay in diagnosis and treatment of cancer. BY ANN W. LATNER, JD

Mr M, a 54-year-old man, had been going to the same internal medicine practice for almost 20 years. The practice was staffed by several physicians, physician assistants, and nurse practitioners. Mr M typically saw Mr P, a 48-year-old physician assistant, for his appointments. Mr M presented to the office for assessment of a lump in his right groin. After an examination conducted by Mr P, the patient underwent a computed tomography (CT) scan, the results of which showed an enlarged inguinal lymph node. Although receipt of the results was documented in the patient’s record, there was no indication in the record that the patient had been notified about the results or what the next steps should be. Two months later, at Mr M’s next appointment, the office’s electronic health record system was down and Mr P could not access the patient’s chart for review. At that appointment, Mr M did not mention the groin lump, and Mr P, who saw many patients each day, did not remember it. During the next 10 months, the patient came in for a few visits with Mr P, but he never mentioned the groin lump.The following year, Mr M

Legal experts were extremely critical of the physician assistant who added documentation to the patient’s file 2 years after the appointment.

returned to the practice and saw a nurse practitioner, Ms N.The clinician noted that the groin mass had increased in size and was now painful. Ms N referred Mr M to a general surgeon who performed a biopsy of the enlarged lymph node. The biopsy revealed stage 3 Hodgkin lymphoma. When Mr P heard about Mr. M’s diagnosis, he looked at the patient’s record and realized he had not documented the follow-up of the original CT scan. Mr P added a note to Mr M’s health record stating that he had told the patient about the CT results 2 years earlier and instructed him to follow up with a surgeon. However, there was no referral form in the record or any indication from the time of the CT scan that the results had been conveyed to the patient. After Mr M was told by an oncologist that his prognosis was worse than it would have been had the cancer been discovered 2 years earlier, Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

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LEGAL ADVISOR he decided to seek the counsel of an attorney. After reviewing the patient’s records, the attorney filed a lawsuit against Mr P, his supervising physician, and the practice. Legal Background

The case alleged numerous lapses in patient care and failures of communication that ultimately led to a delayed diagnosis and poor patient outcome. Mr M told his attorney that Mr P had never advised him about the results of his CT scan and that he assumed the results were negative. He denied being referred to a surgeon by Mr P. His attorney hired experts to look at the records, and the experts agreed that from the notes, it appeared that Mr M was never originally told about the CT scan results and that Mr P’s retroactive note was added solely to protect himself. Mr P and his supervising physician met with a defense attorney provided by their malpractice insurance company. The attorney had her experts review the records, and they were critical of both Mr P and his supervisor. They identified 5 areas of weakness where the plaintiff could allege that the standard of care had been breached: 1. The experts concluded that there was no timely documentation that provided evidence that the CT scan results had been discussed or that the patient was told a follow-up plan. 2. Although Mr. P claimed to have referred the patient to a surgeon after the CT scan, there was no referral documentation, and no formal written referral was made. 3. The computer failure at the appointment after the CT scan prevented Mr P from accessing the patient’s file; however, the patient subsequently came in several times in the next

10 months, but the groin lump was never addressed, and the CT results were not discussed. 4. The experts also found fault with the supervising physician, who had apparently signed off on Mr M’s chart but never saw the patient himself, discussed the CT scan results and treatment plan with Mr P, or questioned why the groin lump had not been discussed with the patient. 5. Finally, the experts were extremely negative about Mr P’s adding documentation 2 years after the appointment. They told the attorney that this would look particularly bad to a jury and would harm Mr P’s credibility. The practice, supervising physician, and Mr P decided to settle the case out of court for an amount within their malpractice limits. Protecting Yourself

The experts identified many of the key issues in this case: poor communication with the patient, no referral given, no results provided to the patient, no oversight by the supervising physician, and a faulty computer system. But on the surface, the mistake that would look the worst to a judge or jury was Mr P’s decision to amend the patient file 2 years later to include what he “thought” he had said at the time. Memory is faulty. It is extremely difficult to remember a conversation with a patient a week later, much less 2 years later. Notes must be taken contemporaneously, preferably at the point of care. Adding them to a patient’s record later can create doubt about the quality of patient care and the integrity of the provider. ■ Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.

LETTER TO THE EDITOR AN ISSUE OF MISDIAGNOSIS— WHO IS LIABLE? In the December 2019 issue, I read an article in the Legal Advisor column titled “An Issue of Missed Diagnosis” (Clinical Advisor. 2019;22[11]:39-40). In the section on protecting yourself, Ann Latner wrote: “A proper nursing assessment of a lower extremity injury should provide the data needed to confirm or to rule out DVT [deep vein thrombosis] or compartment syndrome.The treating physician will need the nurses’ assessment of skin condition, capillary refill, and pulse, as well as the patient’s report of sensation and pain. My question is: shouldn’t the physician assistant (PA), nurse practitioner (NP), and physician do their own assessment?

Why were these practitioners not held legally liable? —KEVIN STROHL, FNP, Merrillville, IN Indeed, you are correct; the other healthcare practitioners in the case — PA, NP, MD — should certainly have done their own assessment of the patient’s injury. Your question is: Why were the nurses the only ones held liable? The answer in this case, as in most cases, is that the plaintiff sued everyone involved in the injury — from the nurses to the doctor to the hospital. Most cases do not make it to trial. The majority are either dismissed along the way or are settled out of court. In this case, the other parties (PA and MD) settled out of court. The nurses were simply the only ones left by the time the case went to trial. — ANN LATNER

50 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2020 • www.ClinicalAdvisor.com