April 2020 Clinical Advisor

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■■ Weight Loss and Migraine ■■ Physician-Assisted Suicide ■■ Low Vitamin D Levels LEGAL ADVISOR

Refusal to Draw Blood FEATURE

Unpacking Parkinson Disease Psychosis: Diagnosis and Treatment

FEATURE

Budd-Chiari Syndrome: A Case of Hepatomegaly, Abdominal Pain, and Ascites

DERMATOLOGIC LOOK-ALIKES

Blistering Cutaneous Ulcerations

|

APRIL 2020

| www.ClinicalAdvisor.com

MENTAL HEALTH UPDATE

Recognizing and Treating Depression in Your Primary Care Practice

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Unsure about a diagnosis or treatment?

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

Advisor Forum the color of the affected area was normal, the skin CLINICAL PEARLS felt quite thick and inflexible. These skin changes stopped abruptly at the collar line, below which POISON IVY PREVENTION the skin was entirely normal.

Poison ivy season is starting! I recommend that Abundant evidence of sun damage — includ- people take an old pair of knee-high tube socks ing weathering, telangiectasias, solar lentiginosis, and cut off the foot part above the heel. Pull the and numerous actinic keratoses on prominent socks over the arms up to the start of their sleeve areas of his cheeks and ears — was noted. Similar (assuming they are wearing a T-shirt) and tuck changes were noted on the dorsa of both hands into gloves. Use the socks to protect arms when but were not present on his arms and trunk working in the yard or other high-risk poison because he wore long-sleeved shirts when in the ivy areas. They can be rolled off the arms and sun. Although he had worn a wide-brimmed hat thrown away, or washed and re-used. I remind while in the sun during his adult life, he had never people to always wear gloves, and to remove worn anything, such as a bandana, on his neck. the gloves before touching anything, including Always wear The posterior neck is especially susceptible door handles. This significantly reduces the gloves to to the effects of the sun, evidence of which fre- exposure area of skin to poison ivy. —JUDITH protect the quently manifests as it did in this patient. This MCINTOSH, MSN, Kokomo, Indiana skin from condition is called cutis rhomboidalis nuchae (CRN), which represents thickening and weathweath VERRUCA VULGARIS TREATMENT exposure to ering of the epidermis as well as solar elastosis I always recommend candida albicans skin anti- poison ivy, and of the underlying dermis caused by the sun. gen test injections for patients who are not remove them Although this condition is clear evidence of responding well to liquid nitrogen +/- paring for before touching chronic overexposure to the sun, CRN has no verruca vulgaris. A 0.1-mg injection every month anything. malignant potential, and treatment is neither for about 3 months creates an immune response required nor does it exist. against the warts. I have seen resolution of some Besides being common, CRN is unique in its recalcitrant cases that seemed most impossible! presentation, as well as in the patient population —SARAH LUP, PA-C, Chicago, Illinois it affects (eg, older patients with sun damage confined to the posterior neck), so the differen- RETHINKING PRESCRIBING tial is quite narrow. Punch biopsy would resolve DICLEGIS any confusion.

Diclegis is the only FDA-approved prescription CRN puts this patient at higher risk for the medication for nausea and vomiting of pregdevelopmentThe of skin caused by sun expo- nancy that is classified as Category A (safe for se cancers are lette rssquamous sure, such asand basal cell carcinoma, cell mom and baby). Before writing a prescription, from prac successe titioconsider ners arou carcinoma, melanoma, and s,others. the price tag. Diclegis with a coupon obseThis nd the coun rvatpatient ions, andcosts approximately and others with similar histories require regular $345 try for 60 tablets. The pearls with who their to share their skin checks by a qualified dermatology provider most common dosagecolle is 2 tablets/dwan but tcan agues. We clinical chall at least once a year. Although this patient would be more. Some patients may obtain insurance invite you enges to participa be advised to protect himself from the sun, this coverage for this medication, but it will likely te. will do little to ward off any future skin cancers still cost something. Let’s break down Diclegis that will have been caused by sun overexposure CONSUL into its 2 active ingredients: doxylamine sucTAT occurring decades earlier. Application of sun- cinate IONand S pyridoxine hydrochloride (vitamin screen to his neck would prevent IRO worsening of B 6). Unless you are writing a prescription for N PILL 2.

Cohen SM, Kwo PY, Lim, his CRN. a celebrity, recommend that your patients ON LIVE S AND THEIR JK. ACG clinical of abnorm Send us R ENZ al liver chemis ECT guideline: your purchase over-the-counter doxylamine YMESinsteadEFF Can takin evaluat tries.

Am J Gastroe 3. Iron. ion g iron pills nterol. 2017;1 al Institute Reference letters with succinate and vitamin B 6 to take Nation at night elevate liver —AGNES 12:18-35. of Health nih.gov/Iron.h ques website. https:// enzymes? MURPHY, tm. Access for nausea.

—AMBER PA-C, Bolognia JL, Jorizzo JL,tions Rapini RP. Dermatology. 1st ed. NewDEW, PCA and , Americus, livertox. ed April 3, commen 2019.

Georgia Birmingham, Michigan York: Mosby, 2003;1380-1381. ts to: Liver enzym es Advisor Forum aspartate aminosuch as alanine amino , CASE FILE transfe The Clinica l Advisor, phatase are transferase (AST), and rase (ALT), S www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 45 275 7th Aven markers of alkaline phosfunction, and hepat ue, 10th CUTIS RHO should be referre ic injury, not hepat Floor, New Albumin, MBO ic York, d to as liver bilirubin, and chemistries. Contributed by Joe Monr IDALIS NY 10001 measures of prothrombin .You oe, MPAS, hepatocellu time are direct A 78-year-old may conta PA-C lar appropriately ct us heavily lined man presented characterized synthetic function and with thick e-mail at edito by skin on enzymes may are as “liver functio r@ be abnormal n tests.” Liver been present for an his posterior neck ened, clinicaladvis liver diseas that had even in patien indet or.com.

Although e. The differe ts without the striking erminate period of Letters are ntial for elevat broad with time. skin chang tomatic, edited many be further define potential causative ed enzymes is insiste they were concerning es were asympfor length factors and and d that he be to his relativ d by the patien should risk factors. 1 clarity. The seen es who t’s by a medical histor The Clinical y and the patient had spent dermatology provider.

Almost all Advisor’s policy nearl sun, farmi medications ng, ranching, y his whole life small risk of are associated is to print to his in elevat fishing, and the hepatotoxic 2 ed liver chemistries with at least a a histo property in rural tending author’s name Okla ity. Oral with ry homa or of witho iron skin cance . replacement with the letter r and claim He denied doses has little supplementation at typicaut good health. ed to be . liver or serum or No anony in The skin on enzyme elevati no adverse effects on l mous the patien or overdoses, the ons. However, contributio it in high doses lined and thickened t’s nuchal area was ns will of iron poison can cause acute hepato heavily . The multiple overla toxicity as a ing. be accepted. pping rhom lines joined to form result of ferrous sulfate Toxicity occurs after boidal shape ingestion of (approximat ≥3 g s. toxicity with Altho ely 10 tablets ugh aminotransf ). Severe the upper limit erases greate r overdoses and of normal typically than 25 times occurs with high initial larger serum iron dL). Mild levels to usually self-limmoderate cases of iron (>1000 ug/ whereas severe iting and resolve with poisoning are suppo KUSMIN cases become fatal rapidl 3 rtive care, SKY, PA-C y. —LAURA Referenc es

Advisor F

orum

Write us today.

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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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2020 5

CONTENTS APRIL 2020

NEWS 10

Newsline ■■Weight Loss Reduces Incidence and Severity of Migraines ■■Survey Finds Mixed Views on Physician-Assisted Suicide ■■Loss of Vitamin D Linked to Back Problems in Older Women

FEATURES 10 Weight loss and migraines

3 Mental Health Update: Recognizing and Treating 1 Depression in Primary Care A guide to screening and diagnostic tools for PCPs. 8 Unpacking Parkinson Disease Psychosis: 2 Diagnosis and Treatment Psychosis is a frequent and challenging symptom in PD patients.

2 Budd-Chiari Syndrome: A Case of Hepatomegaly, 3 Abdominal Pain, and Ascites Most common cause of BCS is myeloproliferative syndrome.

28 Psychosis common in Parkinson disease

DEPARTMENTS 8

37

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

Dermatology Clinic ■■Thick,Yellow Skin on Soles of Feet ■■Nail Dystrophy With Roughness

37 Hereditary skin condition

47 Burn patient unable to consent to testing

41

Dermatologic Look-Alikes ■■Blistering Cutaneous Ulcerations

47

Legal Advisor ■■Refusal to Draw Blood in Comatose Patient

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

www.ClinicalAdvisor.com

ClinicalAdvisor.com

NEWS ClinicalAdvisor.com/News

FEATURES ClinicalAdvisor.com/Features

Hand-Hygiene Adherence Varies at Critical Points of Care

COPD: Importance of Educating Patients on Proper Inhalation Technique Practitioners can play a vital role in providing education and training on correct inhalation techniques to enhance therapeutic benefit and optimal medication delivery. Overall, the goal for the provider is to be confident when educating patients on proper use of inhalation technique, emphasize the importance of medication adherence, and maintain follow-up appointments.

Healthcare workers are less likely to perform hand-hygiene protocols before critical tasks than before other tasks but are more likely to disinfect hands after contaminating tasks than after other tasks.

Multiple Sclerosis Outcomes Worsened When Youths Transition to Adult Care Researchers conducted a retrospective chart review study to examine data from patients with pediatric-onset MS who transitioned to adult care before the age of 21 years.

Psoriasis in Adolescents Linked to Cardiometabolic Risk Factors Adolescents with psoriasis had elevated levels of cardiovascular and metabolic risk factors compared with their adolescent counterparts without psoriasis.

Antioxidants Not Found to Improve Semen Parameters in Men With Infertility Change in sperm concentration in men who received the antioxidants was -4.0 million/mL compared with 2.4 million/mL in men in the placebo group.

HIV Therapy Symtuza Approved for Use in Pediatric Patients The FDA approved Symtuza for the treatment of HIV-1 infection in pediatric patients weighing ≥40 kg who are treatment-naive or virologically suppressed on an antiretroviral regimen.

THE WAITING ROOM

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Jim Anderson, MPAS, PA-C, DFAAPA Provider Social Media Pages: Supportive or Perilous?

Although provider social media pages are great for networking and collaboration, they can also threaten patient confidentiality and shine a negative light on the clinical abilities of providers who post.

CASE STUDY ClinicalAdvisor.com/CaseStudy Brady Pregerson, MD Itchy and Painful Lesions on Legs A 32-year-old woman presents for evaluation of a worsening rash that begins at her navel and continues down both of her legs. The rash first appeared approximately 10 days earlier and has gotten progressively worse; initially the rash was itchy but now is painful. The patient is not receiving any medications and denies recent travel, fever, or other complaints.

See the full case at ClinicalAdvisor.com/ CaseStudyApr20

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

© TOP: FATCAMERA / 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

Pruritic, Erythematous Papules and Nodules A 35-year-old man presents for evaluation of multiple erythematous papules and nodules affecting his chest, arms, and upper back. He is receiving institutional therapy for opioid use disorder and adjustment disorder with mixed anxiety and depression. He currently takes olanzapine and sertraline.

CAN YOU DIAGNOSE THIS CONDITION?

• Leishmaniasis • Prurigo nodularis

• Discoid lupus erythematosus • Eruptive keratoacanthomas

● See the full case at ClinicalAdvisor.com/DermDx_Apr20

ORTHO DX

In partnership with

TheJopa.org

Journal of Orthopedics for Physician Assistants

Radiating Pain in Buttocks A 14-year-old girl presents for evaluation of pain in her left posterior buttock after sustaining an injury playing soccer 2 days earlier. She is having trouble walking; the pain originates in her buttock and radiates to her hamstring. Anteroposterior radiograph of the pelvis shows an avulsion fracture of the left ischial tuberosity.

WHAT IS THE BEST TREATMENT OPTION?

• Observation with early return to sports • Protected weight-bearing for 4 to 6 weeks followed by physical therapy • Long leg cast in 60° of flexion for 4 weeks • Operative repair ● See the full case at ClinicalAdvisor.com/OrthoDx_Apr20

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2020 9

Newsline AMONG PATIENTS WITH obesity and migraine, surgical or behavioral weight loss is associated with reduction of migraine frequency, pain severity, attack duration, and disability, according to a new meta-analysis published in Obesity Surgery.

The goal of the current meta-analysis was to assess whether any benefit of weight loss on migraine is correlated with the degree of weight change and if different weight reduction strategies may elicit different effects. Ten primary studies (473 patients) were included in the meta-analysis. The outcomes measured included headache frequency (10 studies), pain severity (6 studies), disability (4 studies), and attack duration (6 studies).

Weight loss was associated with a significant reduction in headache frequency

(effect size [ES] -0.78; 95% CI, -1.13 to -0.43, P <.00001), pain severity (ES -1.04; 95% CI, -1.49 to -0.59, P <.0001), and headache disability (ES -0.68; 95% CI, -0.96 to -0.41, P <.0001), and there was a small but significant reduction in headache duration (ES -0.25, 95% CI, -0.45 to -0.04, P =.017).

Improvement in migraine was not correlated to either the degree of obesity at baseline or the degree of weight reduction.

There was no difference between bariatric and behavioral approaches for weight loss on headache frequency, pain severity, or headache disability. However, the effect of weight loss on headache duration was significant only for surgical weight loss.

The beneficial effects of weight loss on headache frequency and disability were

© TETRA IMAGES / GETTY IMAGES

Weight Loss Lessens Migraine Incidence, Severity, and Length

Benefits of weight loss on migraine frequency were seen in adults and children.

similar in adult and pediatric populations, but the impact on attack duration was limited to the adult population.

“This meta-analysis provides further evidence for the efficacy of weight loss as an important adjunctive treatment for individuals with migraine and obesity,” concluded the study authors.

Survey Finds Mixed Views on Physician-Assisted Suicide THERE IS A lack of consensus regarding the acceptability of physician-assisted suicide (PAS) among members of the American Geriatrics Society (AGS); a total of 47% of members support and 52% of members oppose the practice, according to the results of a survey published in the Journal of the American Geriatrics Society.

PAS is currently legal in 9 states and the District of Columbia but remains controversial.To gauge member opinions, the AGS Ethics Committee developed a survey that was distributed to 1488 randomly selected members. The survey asked about

the relationship of PAS to the availability of palliative care, respondents’ experiences with PAS, and concerns for special populations with regard to PAS. Believed to be the first to assess PAS in clinicians who work with the elderly, the survey was distributed on March 24, 2016, and closed on April 22, 2016.

A total of 369 AGS members responded to the survey (24.8% response rate); 60% of respondents were women and 81% were physicians. Respondents were almost equally divided regarding the acceptability of PAS, with 52% opposed

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

to PAS and 47% believing that physicians should have PAS as an option for their patients with terminal illness.

Survey respondents were also divided about the role of PAS when high-quality palliative care is available, with 54% of respondents reporting that PAS would not be necessary and 40% believing that PAS may be necessary even if highquality care were available. A total of 25% of respondents believed that respecting a patient’s autonomy alone was sufficient to justify PAS. Continues on page 12

Newsline SEVERE VITAMIN D deficiency was found to be associated with lumbar degenerative disease and low back pain in postmenopausal women, according to study results published in Menopause.

Low vitamin D is common in postmenopausal women and may be associated with low back pain. Because limited data are available on the role of vitamin D in spinal degenerative diseases, the goal of the current study was to explore the relationship between low vitamin D levels and lumbar degenerative disease and low back pain in older women.

The retrospective observational study included 232 postmenopausal women (mean age, 65.5 years) with low back pain and lumbar degenerative disease who attended the spinal surgery unit in a single hospital. Most women had deficiency/insufficiency of vitamin D (>10 to <30 ng/mL; 173 women; 74.6%), whereas a small minority had severe deficiency (≤10 ng/mL; 30 women; 12.9%) or normal levels (≥30 ng/mL; 29 women; 12.5%).

There were substantial differences in circulating vitamin D concentrations between patients with normal bone density, osteopenia, or osteoporosis (21.62±9.42 vs 18.01±9.41

Physician-Assisted Suicide Continued from page 10

“While just over one-third of respondents [37%] stated they would fulfill a patient’s request for PAS, a larger percentage [46%] indicated they would support this request. This distinction between willingness to actively vs more passively participate in PAS is consistent with findings from previous surveys of palliative care professionals,” the investigators noted.

vs 17.39±8.17 ng/mL, respectively; P <.05). Bone mineral density T-scores were lower in the group of patients with severe vitamin D deficiency (-1.92±1.55) compared with those with deficiency/ insufficiency (-1.19±1.35) or normal levels (-0.70±1.64; P =.004).

With regard to pain, the mean visual analog scale for low back pain was higher among patients with severe vitamin D deficiency (4.07±1.11) compared with those with vitamin D deficiency/insufficiency (3.54±1.11) or normal vitamin D (3.03±1.15; P =.002).

As for the association between lumbar degenerative disease severity and vitamin D concentrations, the statistical analysis revealed that from L1/L2 to L5/S1, patients with severe vitamin D deficiency had more severe disc degeneration compared with those with insufficiency/deficiency or normal concentrations, with evidence for significant differences at L4/L5 (P =.02), L5/S1 (P =.001), and L1/S1 (P =.04).

Analysis of risk factors for moderate to severe pain revealed that severe vitamin D deficiency was the strongest predictor (odds ratio [OR], 5.791; 95% CI, 1.57-21.38; P =.008). Other risk factors included vitamin D deficiency (OR, 3.03; 95% CI, 1.10-8.31; P =.032), osteoporosis (OR, 3.33; 95% CI, 1.39-7.94; P =.007), body mass index (OR, 1.18; 95% CI, 1.06-1.32; P =.004), smoking (OR, 4.18; 95% CI, 1.12-19.89; P =.035), and lack of vitamin D supplementation (OR, 2.85; 95% CI, 1.29-6.26; P =.009). “[A] serum concentration of vitamin D <10 ng/mL should be considered an indicator of severe disc degeneration and [low back pain],” the researchers concluded. Further research is needed to determine whether vitamin D supplementation is effective for the prevention and treatment of these conditions.

A total of 38% of survey respondents believed the AGS should take a neutral stance on the issue of PAS but advocate for safeguards in states where it is legal, 27% endorsed the notion of the AGS supporting PAS with appropriate safeguards and education, whereas 31% suggested that the AGS should discourage or prohibit the practice of PAS. Approximately 70% of respondents believed that PAS is more complex when the individual who might desire assistance belongs to a special patient

population, including those with “low health literacy, low English proficiency, disability, dependency, or frailty.”

“Given the recent increase in the number of states permitting PAS and the likely increase in providers receiving requests for PAS, ethical, legal, and policy discussions regarding this practice should ensure that especially careful consideration is given to terminally ill older adults who possess one or more of the aforementioned vulnerabilities,” the authors concluded. ■

Vitamin D supplements may be warranted in postmenopausal women to prevent low back pain and disc degeneration.

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

© ZEPHYR / SCIENCE SOURCE

Loss of Vitamin D Linked to Back Problems in Older Women

FEATURE: SIMONE HOWE, DNP, APRN, FNP-C

Mental Health Update: Recognizing and Treating Depression in Primary Care Time constraints and a lack of established screening and diagnostic protocols can prevent identification of depression in primary care settings.

D

epression is a multifaceted disease that affects the physical, mental, and emotional health of more than 300 million people worldwide and is the leading cause of global disability.1 Individuals of all ages are affected by depression, and it is associated with higher rates of chronic disease, substance use, and suicide.2,3 In approximately 65% of cases, individuals with depression first present for evaluation in the primary care setting.3 However, a meta-analysis found that primary care providers (PCPs) failed to diagnose depression in nearly 50% of individuals who met the criteria for major depressive disorder (MDD).4

© MICHELE GRAHAM

Barriers to Diagnosis

Signs and symptoms of depression are often missed in young adults.

Identification of depression in the primary care setting can be challenging due to a number of barriers, including time constraints of providers, a lack of established screening and diagnostic protocols, increased patient acuity and comorbidities, and variation in the presenting features of depression.3 The United States Preventive Services Task Force (USPSTF) recommends annual screening to identify depression in primary care settings.

However, screening alone has not been shown to improve outcomes. Screening must occur in a clinical setting in which providers can confirm the diagnosis through a clinical interview, treat and/or refer for treatment, and provide adequate follow-up care.2,4

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

MENTAL HEALTH UPDATE: DEPRESSION

One possible solution to overcome time constraints that prevent screening for depression is to change workflow.

Busy clinicians care for increasingly complex patients in brief appointment slots. Time-intensive charting associated with best practices, meaningful use, and Medicare Core Quality Measures, and progress notes can be overwhelming for providers and support staff.

Solutions

Change in Workflow One possible solution to overcome time constraints that prevent screening for depression is to change workflow. In a randomized controlled trial, Mertens et al showed that workflow redesign improved provider adherence to screening and treatment protocols.5 Screening rates improved when medical assistants (MAs) were tasked with baseline screenings and PCPs addressed positive screens with a follow-up diagnostic interview and treatment, if indicated. MAs screened more patients (50.9%) than PCPs (9.2%), and only 3.5% of patients in the control group, with no established screening protocol, were screened.

Providing printed copies of a brief depression screening tool, such as the 2-item Patient Health Questionnaire (PHQ-2), to patients in the waiting area facilitates self-administration of depression screening, further reducing time required by staff for administration. MAs can enter the PHQ-2 (and PHQ-9, if indicated) score into the electronic medical record while with the patient.5 Establish Screening Protocols Use of a depression screening and treatment protocol in primary care practices has been shown to increase screening and evidence-based treatment of depression and improve patient outcomes by decreasing time to remission.6 Gallo et al examined the effects of implementing an evidence-based depression care protocol on depression scores and mortality rates among chronically ill patients in 20 primary care practices.6 Patients with comorbid depression were treated “per protocol” or “per usual care.” Patients treated per protocol had a greater rate of remission at 2 years than did patients treated per usual care. Patients’ risk for mortality rose over time in the usual care group (odds ratio [OR], 3.02; 95% CI, 1.32-8.72) and declined in the treatment group (OR, 1.73; 95% CI, 0.86-3.96).

Recognizing Symptoms Variation in the symptoms of depression throughout the life­span may complicate recognition and treatment of

depression.3 Adolescents are more likely to present with chronic somatic complaints (headache, stomachache, and general pain symptoms), which may explain why approximately 50% of adolescents with depression are not diagnosed until adulthood, when they typically present with complaints of mood alteration.7 Likewise, elderly patients present with somatic symptoms more often than mood alteration or anhedonia.8 Strategies for identification of depression in individuals presenting with chronic somatic symptoms include administering valid and reliable depression screening tools and allowing time for effective provider-patient communication.7,8 Recognizing At-Risk Groups An additional barrier to effective depression screening practices is the lack of knowledge about at-risk groups. Understanding which populations are most at risk for depression helps providers identify individuals who need evaluation more frequently than the minimum recommendation for annual screening in individuals aged 12 years and older.7 Some groups, such as postpartum women, adolescents, adults experiencing high levels of stress, individuals who struggle with substance abuse, or individuals with serious or multiple comorbidities, are at high risk of developing depression and should be evaluated at each primary care visit (Table 1).3,6-9 The American College of Obstetrics and Gynecology (ACOG) recommends screening women for depression at least once during the perinatal period.10 Women should be screened frequently for depression during the postpartum period; 10% to 20% of mothers will develop postpartum TABLE 1. Risk Factors for Depression3,6-9 Family history of depression

Medical comorbidities

Female sex

Poor support system

History of abuse

Prior depressive episode

History of foster care or adoption

Recent childbirth

Low socioeconomic status

Substance abuse

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

Several validated tools have been created to screen for depression; picking the right one depends on individual practice and patient profiles. depression during the first 12 months after childbirth.9 The USPSTF and ACOG recommend screening for postpartum depression during the postpartum visit and the American Academy of Pediatrics (AAP) recommends frequent screening the first year after childbirth.11 Since a new mother has only 1 to 2 postpartum visits with an obstetrician, the AAP recommends that pediatric or family medicine providers screen women for postpartum depression during newborn, first-week, 1-month, 2-month, 4-month, and 6-month visits.12 As providers learn to recognize individuals at high risk for depression, vulnerable groups will receive appropriate screening and treatment to reduce morbidity and mortality.

Screening Tools

Several validated tools have been created to screen for depression; picking the right one depends on individual practice and patient profiles (Table 2).4,13-23 The most validated and widely used depression screening tool is the PHQ-9.4 This 9-item screening tool is available in more than 50 languages and includes a modified version for adolescents, making it a versatile tool for diverse patient populations.7 The PHQ2, a short version consisting of the first 2 questions from the PHQ-9, can be used as a brief initial screening tool.4 Administration of the PHQ-9 is indicated for individuals scoring ≥3 on the PHQ-2.4

TABLE 2. Screening Tools Used to Diagnose Depression4,13-25 Screening Tool

No. of Languages Time to Sensitivity / Number of Items Administration Available Complete, min Specificity, %

Population

Patient Health Questionnaire (PHQ-2)

2

Self

>40

1

89.3/75.9 (cutoff score ≥2)

Adults; modified version for teens

Patient Health Questionnaire (PHQ-9)

9

Self

>50

5

81.3/85.3 (cutoff score ≥10)

Adults; modified version for teens

Beck Depression Inventory (BDI)

21 (BDI-II) 7 (BDI-FS)

Self

Multiple; >10

10 (BDI-II) 5 (BDI-FS)

83.0/73.0 (cutoff score ≥10; cardiac outpatients)

Ages 13-80 y

Hamilton Depression Scale (HAM-D or HRDS)

17 (HAM-D, HRDS) 7 (HRDS-7)

Clinician

Multiple

15-20 (HAM-D, HRDS) 5-10 (HRDS-7)

76/91 Adults (cutoff score >12.6/13.5)

Geriatric Depression Scale (GDS)

30 (long); 15 (short); other versions 10, 8, or 4

Self or caregiver

Multiple

5-7

71.8/78.2 (cutoff score ≥5)

Adults ≥65 y

Pediatric Symptom Checklist (PSC)

35 (PSC or Y-PSC); 17 (PSC-17 or Y-PSC-17)

Parent or self

Multiple; >20 including pictorial versions

5-10

• 58/91 (ADHD) • 52/74 (Anxiety) • 73/74 (Depression) • 62/89 (External) • 42/86 (Total) (cutoff score >15 – total)

PSC – children ≥4 y; Y-PSC – children ≥11 y

Edinburgh Postnatal Depression Scale (EPDS)

10

Self

Multiple

5

80/90 (cutoff ≥13)

Postpartum women

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2020 15

MENTAL HEALTH UPDATE: DEPRESSION

First-line treatment for adults with depression is cognitive behavioral therapy, selective serotonin reuptake inhibitors, or both.

Additional widely validated and reliable screening instruments are available as initial depression screening tools. The Hamilton Depression Rating Scale (HAM-D or HDRS) is a clinicianadministered instrument that addresses the presence and severity of depressed mood, anxiety, somatic symptoms, weight loss, hypochondriasis, insomnia, suicidal ideation, and psychomotor retardation as evaluated by the provider during patient history and initial examination.13-15 The 17-item HAM-D requires 15 to 20 minutes to complete; however, there is a 7-item subscale (HRDS-7) that may be used during shorter patient encounters.13 The Beck Depression Inventory (BDI-II) is a 21-item, selfadministered tool for adolescents and adults to assess symptoms of depression that have been present during the previous 2 weeks.16,17 The tool requires approximately 10 minutes to complete; if greater brevity is desired, patients may complete the Beck Depression Inventory Fast Screen (BDI-FS), a 7-item instrument designed for use in primary care.18 The BDI-FS, which consists of items 1 to 4 and 7 to 9 of the BDI-II, removes screening items related to somatic symptoms.18 The Edinburgh Postnatal Depression Scale (EPDS), designed specifically for postpartum women, omits questions about somatic complaints that are common during the postpartum period, such as sleep disturbance.19 Additionally, the EPDS introduces questions about anxiety because depression and anxiety are more likely to occur together during the postpartum period.13 The EPDS is well validated and widely used to screen for depression in pregnant and postpartum women.19 The Geriatric Depression Scale (GDS) is a 30-item screening tool designed to identify depression in the geriatric population.20-22 Elderly individuals more often experience fatigue, sleep disturbance, or weight loss due to chronic comorbidities or the normal aging process; therefore, questions related to these symptoms are omitted from the tool.21 Shorter versions of the GDS with 15, 10, 8, or 4 items have been developed to reduce test fatigue in elderly patients with frailty or cognitive impairment.20 An additional benefit of the GDS is its dichotomous format.20 The GDS-30 has been shown to be reliable in patients with mild cognitive impairment and those who scored >10 on the Mini Mental Status Exam (MMSE).20 For patients who are unable to complete the self-administered GDS due to cognitive limitations, cognitively intact caregivers may complete the Collateral Source version of the GDS.20 The Collateral Source GDS has been shown to be diagnostically accurate and provides a method of screening for those with dementia or other cognitive impairments.20

The Pediatric Symptom Checklist (PSC) is a depression screening tool designed for administration by a parent or selfadministration by an older child.The PSC initially contained 35 items, but the more recent PSC-17 has been used widely in pediatrics for the past 15 years.23,24 Both the PSC and PSC-17 are designed to be completed by parents, while theY-PSC and Y-PSC-17 are designed to be completed by children aged 11 years and older, when appropriate.23 A recent study found that the PSC-17 demonstrated high reliability in a large outpatient pediatric sample, yielding higher rates of detection than clinical judgment alone.25 The authors found that the instrument’s reliability was comparable to reliability reported in original studies of the PSC-17 conducted 15 years earlier.25 Diagnosis

Depression screening instruments have been shown to have clinical utility as initial assessment tools to identify depression in the primary care setting. However, the most commonly used instruments, including the PHQ-2 and PHQ-9, have not been shown to be effective as case-finding instruments.4 Therefore, providers should conduct clinical interviews using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria to establish a diagnosis of depression in individuals with positive screening scores (Table 3).4,26 In individuals who meet DSM-5 criteria for Continues on page 22

TABLE 3. DSM-5 Criteria for MDD4,26 Answer positive for ≥5 of the following 9 symptoms (≥1 must be either depressed mood or loss of interest or pleasure) in the same 2-week perioda: 1.

2.

3.

4.

5.

6.

7.

8.

9.

Depressed mood (subjective or objective) Loss of interest or pleasure Change in weight or appetite Insomnia or hypersomnia Psychomotor retardation (observed) Loss of energy or fatigue Worthlessness or guilt Impaired concentration or indecisiveness Thoughts of death, suicidal ideation, or suicide attempt

a

Must be a change from previous functioning not attributable to a substance or to another valid medical condition.

DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; MDD, major depressive disorder

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

Start your insulin-naïve patients

ON THE ROAD TO TREATING TYPE 2 DIABETES WITH TRESIBA®

Indications and Usage

Warnings and Precautions

Tresiba® (insulin degludec injection) is indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus.

• Never Share a Tresiba® FlexTouch® Pen, Needle, or Syringe Between Patients, even if the needle is changed. Patients using Tresiba® vials should never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens

Limitations of Use Tresiba® is not recommended for treating diabetic ketoacidosis.

Important Safety Information Contraindications • Tresiba® is contraindicated during episodes of hypoglycemia and in patients with hypersensitivity to Tresiba® or one of its excipients

•H yperglycemia or Hypoglycemia with Changes in Insulin Regimen: Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, or injection site or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia.

Adjustments in concomitant anti-diabetic treatment may be needed.

Please see additional Important Safety Information and Brief Summary of Prescribing Information on the following pages.

FlexTouch® and Tresiba® are registered trademarks of Novo Nordisk A/S. Novo Nordisk is a registered trademark of Novo Nordisk A/S. All other trademarks, registered or unregistered, are the property of their respective owners. © 2020 Novo Nordisk Printed in the U.S.A. US20TSM00079 March 2020

A R E Y O U H AV IN G TH E C O N V ERSATION ABOUT HYPOGLYCEM IA? Common risk factorsa • Diabetes treatment (both secretagogues and insulin)1 • Older age2 • Long duration of diabetes3 • Impaired awareness of hypoglycemia3 • Impaired renal function1 Does not include all factors that may increase a patient with diabetes’ risk for hypoglycemia. a

Medications for cardiovascular conditions may impact hypoglycemia May increase the risk of hypoglycemia1 • ACE inhibitors • Angiotension II receptor blocking agents May mask the signs and symptoms of hypoglycemia1 • Beta blockers • Clonidine

H Y P O G LY C EMIA MAY B E H A PPENING M ORE OFTEN THAN YOU THINK Many patients with hypoglycemic events are asymptomatic 4 TYPE 2 DIABETES (T2D)

TYPE 1 DIABETES (T1D)

In a study of patients with T2D (n=30)

In a study of patients with T1D (n=40)

had unrecognized hypoglycemia, as measured by CGMS

had unrecognized hypoglycemia, as measured by CGMS

47%

63%

See study design (Chico et al) on opposite page.

CGMS=continuous glucose monitoring system.

“A F T E R D I V I N G M O R E I N T O T H E E F F I C A C Y A N D S A F E T Y P R O F I L E D ATA , TRESIBA® BECAME MY GO-TO CHOICE F O R I N S U L I N - N A Ï V E PAT I E N T S . ” –Philip G. Woodham, Endocrinologist Hackensack, NJ

Important Safety Information (cont’d) Warnings and Precautions (cont'd) • Hypoglycemia is the most common adverse reaction of insulin, including Tresiba®, and may be life-threatening. Increase monitoring with changes to: insulin dose, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with hypoglycemia unawareness or renal or hepatic impairment • Accidental mix-ups between basal insulin products and other insulins, particularly rapid-acting insulins, have been reported. To avoid medication errors, always instruct patients to check the insulin label before each injection • Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Tresiba® • As with all insulins, Tresiba® use can lead to life-threatening hypokalemia, which then may cause respiratory paralysis, ventricular arrhythmia, and death. Closely monitor potassium levels in patients at risk of hypokalemia and treat if indicated • Fluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin, including Tresiba®. Patients should be observed for signs and symptoms of heart failure.

If heart failure occurs, dosage reduction or discontinuation of the TZD must be considered Adverse Reactions • Adverse reactions commonly associated with Tresiba® are hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema, and weight gain

Drug Interactions • There are certain drugs that may cause clinically significant drug interactions with Tresiba®. ◦ Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), sulfonamide antibiotics, GLP1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors ◦ Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones ◦ Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine ◦ Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine Please see additional Important Safety Information and Brief Summary of Prescribing Information on the following pages.

DEVOTE—a landmark safety outcomes trial in adults with T2D and ASCVD

T R E S I B A ® U -10 0 A C H IEV E D THE PRIM ARY COM POSITE ENDPOINT (NONINFERIORITY)1

No increased risk of major adverse cardiovascular events (MACE) vs insulin glargine U-100 Percentage of patients experiencing MACE

8.5%

9.3%

in the Tresiba® U-100 group

in the insulin glargine U-100 group

P<0.001 for noninferiority in a 1-sided test.5 Hazard ratio: 0.91 (95% CI, 0.78 to 1.06).1 ASCVD=atherosclerotic cardiovascular disease; MACE=cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

THE ONLY BASAL INSULIN THAT HAS DEMONSTRATED SIGNIFICANTLY LOWER RATES OF SEVERE b HYPOGLYCEMIA VS INSULIN GLARGINE U-100 1,6-9 (SECONDARY CONFIRMATORY ENDPOINT) 1

TRESIBA® U-100

3.70 EVENTS per 100 patient-yearsc

4.9% of patients experienced ≥1 severe hypoglycemic eventsd

40

%

INSULIN GLARGINE U-100

6.25 EVENTS per 100 patient-yearsc

LOWER RATE vs insulin glargine U-100 P<0.001

6.6% of patients experienced ≥1 severe hypoglycemic eventsd

Glycemic control between the 2 groups was similar at baseline and throughout the trial 1 Severe hypoglycemia was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions and during which plasma glucose concentrations may not have been available, but where neurological recovery following the return of plasma glucose to normal was considered sufficient evidence that the event was induced by a low plasma glucose concentration.1 Estimated rate ratio: 0.60 (95% CI, 0.48 to 0.76); P<0.001 for superiority.1,5 d Absolute difference: 1.7%. Estimated odds ratio: 0.73 (95% CI, 0.60 to 0.89); P<0.001 for superiority.1,5 b

c

Chico et al study design: Population: Patients with type 1 and type 2 diabetes.

Study design: 105 patients with diabetes were included: 75 with T1D and 30 with T2D. Patients with inadequately controlled T1D were randomly assigned to 1 of 2 glucose monitoring systems: 1) a group monitored with a CGMS, or 2) a group that used frequent capillary glucose measurements (the control group).

Study objective: To evaluate the incidence of unrecognized hypoglycemia (glucose value <60 mg/dL) in patients with T1D and T2D, using CGMS.4 DEVOTE study design: Population: Adult patients with T2D and ASCVD. Study design: Treat-to-target, randomized, double-blind, active comparator-controlled, event-driven cardiovascular outcomes trial assessing the noninferiority of once-daily Tresiba® U-100 (n=3818) and once-daily insulin glargine U-100 (n=3819) in terms of the incidence of cardiovascular events.

Primary composite endpoint: Time from randomization to first occurrence of an adjudicated major cardiovascular event (MACE): cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

Secondary confirmatory endpoints: The number and incidence of adjudicated events of severe hypoglycemia, as defined in 2013 by the American Diabetes Association.5 References: 1. Tresiba [package insert]. Plainsboro, NJ: Novo Nordisk Inc; November 2019. 2. American Diabetes Association. Diabetes Care. 2019;42(Suppl 1):S90-S102.

3. Ahrén B. Vasc Health Risk Manag. 2013;9:155-163. 4. Chico A, Vidal-Rios P, Subirà M, Novials A. Diabetes Care. 2003;26(4):1153-1157. 5. Marso SP, McGuire DK, Zinman B, et al. N Engl J Med. 2017;377(8):723-732. 6. Levemir [package insert]. Plainsboro, NJ: Novo Nordisk Inc; December 2019. 7. Lantus [package insert].

Bridgewater, NJ: sanofi-aventis US LLC; November 2019. 8. Toujeo [package insert]. Bridgewater, NJ: sanofi-aventis US LLC; November 2019. 9. Basaglar [package insert].

Indianapolis, IN: Lilly USA LLC; November 2019.

TRESIBA® (insulin degludec injection) Rx Only BRIEF SUMMARY. Please consult package insert for full prescribing information.

INDICATIONS AND USAGE: TRESIBA® is indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus. Limitations of Use: Not recommended for the treatment of diabetic ketoacidosis.

CONTRAINDICATIONS: TRESIBA® is contraindicated: During episodes of hypoglycemia; In patients with hypersensitivity to TRESIBA® or one of its excipients.

WARNINGS AND PRECAUTIONS: Never Share a TRESIBA® FlexTouch® Pen, Needle, or Syringe Between Patients. TRESIBA® FlexTouch® disposable prefilled pens should never be shared between patients, even if the needle is changed. Patients using TRESIBA® vials should never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens. Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, adjustments in concomitant anti-diabetic treatment may be needed. When converting from other insulin therapies to TRESIBA® follow dosing recommendations Hypoglycemia: Hypoglycemia is the most common adverse reaction of insulin, including TRESIBA®. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). TRESIBA®, or any insulin, should not be used during episodes of hypoglycemia.

Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers), or in patients who experience recurrent hypoglycemia. Risk Factors for Hypoglycemia: The risk of hypoglycemia generally increases with intensity of glycemic control. The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of TRESIBA® may vary among different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia. Risk Mitigation Strategies for Hypoglycemia: Patients and caregivers must be educated to recognize and manage hypoglycemia. Selfmonitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia.

In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. Hypoglycemia Due to Medication Errors: Accidental mix-ups between basal insulin products and other insulins, particularly rapid-acting insulins, have been reported. To avoid medication errors between TRESIBA® and other insulins, instruct patients to always check the insulin label before each injection. To avoid dosing errors and potential overdose, never use a syringe to remove TRESIBA® from the TRESIBA® FlexTouch® disposable insulin prefilled pen. Hypersensitivity and Allergic Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including TRESIBA®. If hypersensitivity reactions occur, discontinue TRESIBA®; treat per standard of care and monitor until symptoms and signs resolve. TRESIBA® is contraindicated in patients who have had hypersensitivity reactions to insulin degludec or one of the excipients. Hypokalemia: All insulin products, including TRESIBA®, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death.

Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassiumlowering medications, patients taking medications sensitive to serum potassium concentrations). Fluid Retention and Congestive Heart Failure with Concomitant Use of a PPAR Gamma Agonist: Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists can cause dose related fluid retention, particularly when used in combination with insulin.

Fluid retention may lead to or exacerbate congestive heart failure. Patients treated with insulin, including TRESIBA® and a PPAR-gamma agonist should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.

ADVERSE REACTIONS: The following adverse reactions are also discussed elsewhere: Hypoglycemia [see Warnings and Precautions]; Medication errors [see Warnings and Precautions]; Hypersensitivity and allergic reactions [see Warnings and Precautions)]; Hypokalemia [see Warnings and Precautions]; Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of TRESIBA® in subjects with type 1 diabetes or type 2 diabetes was evaluated in nine trials of 6-12 month duration in adults and in one trial of 12-month duration in pediatric patients 1 year of age and older with type 1 diabetes. The cardiovascular safety of TRESIBA® was evaluated in one double-blinded, event-driven trial of 2-year median duration in patients with type 2 diabetes at high risk of cardiovascular events.

The data in Table 1 reflect the exposure of 1102 adults with type 1 diabetes to TRESIBA® with a mean exposure duration to TRESIBA® of 34 weeks in three open-label trials. The mean age was 43 years and 1% were older than 75 years. Fifty-seven percent were male, 81% were White, 2% were Black or African American and 4% were Hispanic. The mean body mass index (BMI) was 26 kg/m2. The mean duration of diabetes was 18 years and the mean HbA1c at baseline was 7.8%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported in 11%, 16%, 7% and 0.5% respectively. The mean eGFR at baseline was 87 mL/min/1.73 m2 and 7% of the patients had an eGFR less than 60 mL/min/1.73 m2. The data in Table 2 reflect the exposure of 2713 adults with type 2 diabetes to TRESIBA® with a mean exposure duration to TRESIBA® of 36 weeks in six open-label trials. The mean age was 58 years and 3% were older than 75 years. Fifty-eight percent were male, 71% were White, 7% were Black or African American and 13% were Hispanic. The mean BMI was 30 kg/ m2. The mean duration of diabetes was 11 years and the mean HbA1c at baseline was 8.3%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported for 14%,

10%, 6% and 0.6% of participants respectively. At baseline, the mean eGFR was 83 mL/min/1.73 m2 and 9% had an eGFR less than 60 mL/min/1.73 m2. Common adverse reactions (excluding hypoglycemia) occurring in TRESIBA® treated subjects during clinical trials in adult patients with type 1 diabetes mellitus and adults with type 2 diabetes mellitus are listed in Table 1 and Table 2, respectively. Common adverse reactions were defined as reactions occurring in ≥5% of the population studied. Hypoglycemia is not shown in these tables but discussed in a dedicated subsection below. 174 pediatric patients 1 year of age and older with type 1 diabetes were exposed to TRESIBA® with a mean exposure to TRESIBA® of 48 weeks. The mean age was 10 years: 25% were ages 1-5 years, 40% were ages 6-11 years, and 35% were ages 12-17 years. 55.2% were male, 78.2% were White, 2.9% were Black or African American and 4% were Hispanic. The mean body mass index (BMI) was 18.7 kg/m2. The mean duration of diabetes was 3.9 years and the mean HbA1c at baseline was 8.2%. Common adverse reactions in TRESIBA® treated pediatric patients with type 1 diabetes mellitus were similar to the adverse reactions listed in Table 1.

Table 1: Adverse Reactions Occurring in ≥5% of TRESIBA®-Treated Adult Patients with Type 1 Diabetes Mellitus Adverse Reaction TRESIBA® (n=1102) Nasopharyngitis 23.9 % Upper respiratory tract infection 11.9 % Headache 11.8 % Sinusitis 5.1 % Gastroenteritis 5.1 % Table 2: Adverse Reactions Occurring in ≥5% of TRESIBA®-Treated Adult Patients with Type 2 Diabetes Mellitus Adverse Reaction TRESIBA® (n=2713) Nasopharyngitis 12.9 % Headache 8.8 % Upper respiratory tract infection 8.4 % Diarrhea 6.3 % Hypoglycemia: Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including TRESIBA®. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for TRESIBA® with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice. In the open-label adult clinical trials of patients with type 1 and type 2 diabetes, and in the open-label pediatric clinical trial of patients with type 1 diabetes, percentages of adult and pediatric patients with type 1 diabetes randomized to TRESIBA® who experienced at least one episode of hypoglycemia in clinical trials and adults with type 2 diabetes are shown in Tables 3 and 4, respectively. Severe hypoglycemia in the open-label trials with adult patients was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Severe hypoglycemia in the pediatric trial was defined as an altered mental status where the child could not assist in his own care, was semiconscious or unconscious, or in a coma ± convulsions and may require parenteral therapy (glucagon or intravenous glucose). A Novo Nordisk hypoglycemia episode was defined as a severe hypoglycemia episode or an episode where a laboratory or a self-measured glucose calibrated to plasma was less than 56 mg/dL or where a whole blood glucose was less than 50 mg/dL (i.e., with or without the presence of hypoglycemic symptoms).

Table 3: Percent (%) of Type 1 Diabetes Patients Experiencing at Least One Episode of Severe Hypoglycemia or Novo Nordisk Hypoglycemia§ on TRESIBA® in Open-Label Adult and Pediatric Clinical Trials Study A Study B Study J Adults Adults Study C Pediatrics + insulin + insulin Adults + insulin aspart aspart + insulin aspart aspart 52 weeks 26 weeks 26 weeks 52 weeks ® ® TRESIBA TRESIBA at at the same alternating ® ® time each times TRESIBA® TRESIBA TRESIBA (N=472) (N=301) day (N=165) (N=164) (N=174) Severe hypoglycemia* Percent of patients 12.3% 10.6% 12.7% 10.4% 17.8% Novo Nordisk hypoglycemia§ Percent of patients 95.6% 93.0% 99.4% 93.9% 98.3% *Severe hypoglycemia in pediatric patients: an episode with altered mental status, where the child could not assist in his own care, was semiconscious or unconscious, or in a coma ± convulsions and may require parenteral therapy (glucagon or intravenous glucose). § Novo Nordisk hypoglycemia: a severe hypoglycemia episode or an episode where a laboratory or a self-measured glucose calibrated to plasma was less than 56 mg/dL or where a whole blood glucose was less than 50 mg/dL (i.e., with or without the presence of hypoglycemic symptoms).

Table 4: Percent (%) of Patients with Type 2 Diabetes Experiencing at Least One Episode of Severe Hypoglycemia or Novo Nordisk Hypoglycemia§ on TRESIBA® in Open-Label Adult Clinical Trials Study H Study I Study D Study E Study F T2DM ± T2DM ± + 1-2 + 1-2 ± 1-3 0-2 1-2 OADs* OADs* OADs* OADs* + OADs* insulin insulin insulin Study G insulin insulin naïve naïve naïve T2DM ± 0-3 OADs* aspart naïve 52 weeks 26 weeks 26 weeks 26 weeks 52 weeks 26 weeks TRESIBA® (alternating TRESIBA® TRESIBA® TRESIBA® TRESIBA® time) TRESIBA® TRESIBA® (N=766) (N=228) (N=284) (N=226) (N=230) (N=753) (N=226)

Severe Hypoglycemia Percent of 0.3% 0 0 0.9% 0.4% 4.5% 0.4% patients Novo Nordisk Hypoglycemia§ Percent of 46.5% 28.5% 50% 43.8% 50.9% 80.9% 42.5% patients § *OAD: oral antidiabetic agent, Novo Nordisk hypoglycemia: a severe hypoglycemia episode or an episode where a laboratory or a self-measured glucose calibrated to plasma was less than 56 mg/ dL or where a whole blood glucose was less than 50 mg/dL (i.e., with or without the presence of hypoglycemic symptoms).

Allergic Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including TRESIBA® and may be life threatening. Hypersensitivity (manifested with swelling of tongue and lips, diarrhea, nausea, tiredness, and itching) and urticaria were reported in 0.9% of patients treated with TRESIBA®. Lipodystrophy: Long-term use of insulin, including TRESIBA®, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue) and may affect insulin absorption. In the clinical program, lipodystrophy, lipohypertrophy, or lipoatrophy was reported in 0.3% of patients treated with TRESIBA®. Injection Site Reactions: Patients taking TRESIBA® may experience injection site reactions, including injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass. In the clinical program, injection site reactions occurred in 3.8% of patients treated with TRESIBA®. Weight Gain: Weight gain can occur with insulin therapy, including TRESIBA®, and has been attributed to the anabolic effects of insulin. In the clinical program after 52 weeks of treatment, patients with type 1 diabetes treated with TRESIBA® gained an average of 1.8 kg and patients with type 2 diabetes treated with TRESIBA® gained an average of 3.0 kg. Peripheral Edema: Insulin, including TRESIBA®, may cause sodium retention and edema. In the clinical program, peripheral edema occurred in 0.9% of patients with type 1 diabetes mellitus and 3.0% of patients with type 2 diabetes mellitus treated with TRESIBA®. Immunogenicity: As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to TRESIBA® with the incidence of antibodies in other studies or to other products may be misleading. In a 52-week study of adult insulin-experienced type 1 diabetes patients, 68.9% of patients who received TRESIBA® were positive at baseline for anti-insulin degludec antibodies and 12.3% of the patients developed anti-insulin degludec antibodies at least once during the study. In a 52-week study of pediatric insulin-experienced type 1 diabetes patients, 84.1% of patients who received TRESIBA® were positive at baseline for anti-insulin degludec antibodies and 5.8% of patients developed anti-insulin degludec antibodies at least once during the study. In a 52-week study of adult insulin-naïve type 2 diabetes patients, 1.7% of patients who received TRESIBA® were positive at baseline for anti-insulin degludec antibodies and 6.2% of patients developed anti-insulin degludec antibodies at least once during the study. In these trials, between 96.7% and 99.7% of patients who were positive for anti-insulin degludec antibodies were also positive for anti-human insulin antibodies. Postmarketing Experience: The following additional adverse reactions have been identified during post-approval use of TRESIBA®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

DRUG INTERACTIONS: Table 5 includes clinically significant drug interactions with TRESIBA®.

Table 5: Clinically Significant Drug Interactions with TRESIBA® Drugs That May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors.

Intervention: Dose reductions and increased frequency of glucose monitoring may be required when TRESIBA® is co-administered with these drugs.

Drugs That May Decrease the Blood Glucose Lowering Effect of TRESIBA® Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.

Intervention: Dose increases and increased frequency of glucose monitoring may be required when TRESIBA® is co-administered with these drugs.

Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of TRESIBA® Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.

Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when TRESIBA® is co-administered with these drugs.

Drugs That May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine Intervention: Increased frequency of glucose monitoring may be required when TRESIBA® is co-administered with these drugs.

USE IN SPECIFIC POPULATIONS: Pregnancy: Risk Summary: There are no available data with TRESIBA® or insulin degludec in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy. Rats and rabbits were exposed to insulin degludec in animal reproduction studies during organogenesis. Pre-and post-implantation losses and visceral/skeletal abnormalities were observed in rats at doses 5 times (rat) and at 10 times (rabbit) the human exposure at a dose of 0.75 U/kg/day.

These effects were similar to those observed in rats administered human insulin (NPH) [see Data]. The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes

with an HbA1c >7 and has been reported to be as high as 20-25% in women with an HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations: Disease-associated maternal and/or embryo/fetal risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications.

Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data: Animal Data: Insulin degludec was investigated in studies covering fertility, embryo-fetal development and pre- and post-natal development in rats and during the period of embryofetal development in rabbits. Human insulin (NPH insulin) was included as comparator. In these studies insulin degludec caused pre- and post-implantation losses and visceral/skeletal abnormalities when given subcutaneously at up to 21 U/kg/day in rats and 3.3 U/kg/day in rabbits, resulting in 5 times (rat) and 10 times (rabbit) the human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day.

Overall, the effects of insulin degludec were similar to those observed with human insulin, which were probably secondary to maternal hypoglycemia. Lactation: Risk Summary: There are no data on the presence of insulin degludec in human milk, the effects on the breastfed infant, or the effects on milk production. Insulin degludec is present in rat milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TRESIBA® and any potential adverse effects on the breastfed infant from TRESIBA® or from the underlying maternal condition. Data: In lactating rats, insulin degludec was present in milk at a concentration lower than that in plasma.

Pediatric Use: The safety and effectiveness of TRESIBA® to improve glycemic control in type 1 and type 2 diabetes mellitus have been established in pediatric patients 1 year of age and older. The safety and effectiveness of TRESIBA® have not been established in pediatric patients less than 1 year old. The use of TRESIBA® in pediatric patients 1 year of age and older with type 1 and type 2 diabetes mellitus is supported by evidence from an adequate and well-controlled study and a pharmacokinetic study (studies included pediatric patients 1 year of age and older with type 1 diabetes mellitus) . The use of TRESIBA® in pediatric patients 1 year of age and older with type 2 diabetes mellitus is also supported by evidence from adequate and well-controlled studies in adults with type 2 diabetes mellitus. In pediatric patients 1 year of age and older already on insulin therapy, start TRESIBA® at a reduced dose to minimize the risk of hypoglycemia. Geriatric Use: In controlled clinical studies a total of 77 (7%) of the 1102 TRESIBA®-treated patients with type 1 diabetes were 65 years or older and 9 (1%) were 75 years or older. A total of 670 (25%) of the 2713 TRESIBA®-treated patients with type 2 diabetes were 65 years or older and 80 (3%) were 75 years or older. Differences in safety or effectiveness were not suggested in subgroup analyses comparing subjects older than 65 years to younger subjects. In the safety outcomes trial (DEVOTE), a total of 1983 (52%) of the 3818 TRESIBA®-treated patients with type 2 diabetes were 65 years or older and 381 (10%) were 75 years or older. Differences in safety or effectiveness were not observed in these subgroup analyses. Nevertheless, greater caution should be exercised when TRESIBA® is administered to geriatric patients since greater sensitivity of some older individuals to the effects of TRESIBA® cannot be ruled out. The initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be more difficult to recognize in the elderly. Renal Impairment: In clinical studies [see Clinical Studies (14)] a total of 75 (7%) of the 1102 TRESIBA®-treated patients with type 1 diabetes had an eGFR less than 60 mL/min/1.73 m2 and 1 (0.1%) had an eGFR less than 30 mL/min/1.73 m2. A total of 250 (9%) of the 2713 TRESIBA®-treated patients with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m2 and no subjects had an eGFR less than 30 mL/min/1.73 m2. In the safety outcomes trial (DEVOTE), a total of 1429 (37.4%) of the 3818 TRESIBA®treated patients with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m2, and 108 (2.8%) subjects had an eGFR less than 30 mL/min/1.73 m2. Differences in safety or effectiveness were not observed in the subgroup analyses. No clinically relevant difference in the pharmacokinetics of TRESIBA® was identified in a study comparing healthy subjects and subjects with renal impairment including subjects with end stage renal disease. However, as with all insulin products, glucose monitoring should be intensified and the TRESIBA® dosage adjusted on an individual basis in patients with renal impairment. Hepatic Impairment: No difference in the pharmacokinetics of TRESIBA® was identified in a study comparing healthy subjects and subjects with hepatic impairment (mild, moderate, and severe hepatic impairment).

However, as with all insulin products, glucose monitoring should be intensified and the TRESIBA® dosage adjusted on an individual basis in patients with hepatic impairment.

OVERDOSAGE: An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid reoccurrence of hypoglycemia. Hypokalemia must be corrected appropriately.

More detailed information is available upon request.

Version: 8 Novo Nordisk ®, TRESIBA ®, FlexTouch ®, LEVEMIR ®, NOVOLOG ®, NovoFine ® and NovoTwist ® are registered trademarks of Novo Nordisk A/S. PATENT Information: http://novonordisk-us.com/patients/products/product-patents.html Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd, Denmark For information about TRESIBA® contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 1-800-727-6500 www.novonordisk-us.com © 2015-2020 Novo Nordisk US19TSM00765 1/2020

MENTAL HEALTH UPDATE: DEPRESSION

When pharmacotherapy is indicated in geriatric patients, monotherapy should be prescribed to mini­mize the potential for side effects.

MDD, it is important to assess for symptoms of mania, such as pressured speech, grandiosity, and sleeplessness, to avoid incorrectly diagnosing MDD in individuals with bipolar disorder.27 Treatment

The task of choosing a treatment option for a patient with depression may seem overwhelming to new PCPs or providers with limited mental health experience. First-line treatment for adults with depression is cognitive behavioral therapy (CBT), pharmacotherapy with selective serotonin reuptake inhibitors (SSRIs), or both.28 In 2 randomized controlled trials, researchers found that pharmacotherapy with an SSRI, referral for CBT, or a combination of these treatments showed similar positive outcomes for individuals with MDD.29,30 Mergl et al found that the SSRI sertraline and CBT showed similar long-term clinical effects in MDD treatment.31 The most important consideration when choosing an evidencebased treatment for MDD is shared decision-making with the patient to increase adherence to the chosen treatment.

Matching evidence-based treatments to patient preferences has been shown to increase adherence to treatment regimens and, therefore, reduce time to remission.29 Children and Adolescents Providers treating children and adolescents should receive specific training related to screening, diagnosing, and treating pediatric depression.7 Clinicians are urged to monitor patients for emergence or worsening of suicidal thoughts and behaviors.32 Less than half of children and adolescents with depression are identified, and a small fraction of those identified receive treatment.7,23 Pediatric patients who screen positively for depression should be diagnosed according to DSM-5 criteria and treated with CBT and/or pharmacotherapy.7 Fluoxetine is the first-line pharmacologic therapy for children and adolescents aged <18 years.7,32 Pediatric patients with depression should be re-evaluated frequently using a reliable screening tool to monitor progress toward remission and recovery.7,23 The package insert for fluoxetine includes a black-box warning related to an increased risk for suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants.32 Older Adults First-line treatment of depression in older adults should include CBT and/or pharmacotherapy.28 Geriatric patients aged ≥75 years may exhibit reluctance to participate in shared

decision-making. A recent study showed that patients aged ≥75 years with depression expressed difficulty making decisions when a provider presented them with treatment options.33 The researchers also noted that although CBT is prescribed less often for elderly patients, study participants either showed equal preference for CBT and pharmacotherapy or exhibited a preference for CBT over pharmacotherapy.33 Treatment decisions also should be guided by age-related considerations, such as decreased renal and hepatic clearance, polypharmacy, and cognitive or physical limitations.34 When pharmacotherapy is indicated in geriatric patients with depression, monotherapy should be prescribed to minimize the potential for side effects.28,34 SSRIs generally are safe in geriatric patients and are first-line treatment for geriatric depression; however, providers should initiate therapy at 50% of the recommended adult dose and titrate slowly to a therapeutic dose.28 The American Geriatrics Society Beers Criteria® for inappropriate prescribing in the elderly recommend avoiding tricyclic antidepressants and the SSRI paroxetine (Table 4).35 Pregnant and Postpartum Women In a systematic review of depression during pregnancy and the postpartum period, CBT was associated with an increased likelihood of remission compared with usual care.19 Continues on page 26

TABLE 4. 2019 American Geriatrics Society Beers Criteria®: Inappropriate Antidepressants for Geriatric Prescribinga,35 Amitriptyline

Imipramine

Amoxapine

Nortriptyline

Clomipramine

Paroxetine

Desipramine

Protriptyline

Doxepin (>6 mg/d)

Trimipramine

a

First- and second-generation antipsychotics are not recommended for major depressive disorder.

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

MENTAL HEALTH UPDATE: DEPRESSION

POLL POSITION Which of the following treatments is not recommended for patients aged ≥65 years with depression?

■ Cognitive behavioral therapy ■ Selective serotonin reuptake inhibitor (except paroxetine) ■ Serotonin and norepinephrine reuptake inhibitors

7.25%

4.35% 3.62%

84.78%

■ Tricyclic antidepressant

For more polls, visit ClinicalAdvisor.com/Polls.

Second-generation antidepressants, particularly SSRIs and venlafaxine, were associated with increased risks for preeclampsia, postpartum hemorrhage, and miscarriage.19 In addition, SSRIs and venlafaxine were associated with adverse infant outcomes including neonatal seizures, preterm birth, congenital malformations, pulmonary hypertension, and other serious conditions.19 Although SSRIs and venlafaxine were associated with risks to mother and infant, adverse events were rare. Absolute risk for infants exposed to ≥3 months of maternal therapy was 0.66% compared with 0.28% for unexposed infants (OR, 2.39).19 Untreated mothers, however, may experience serious adverse events related to depression including psychologic and physiologic morbidity, psychosis, and suicidality.19 Infants and children of mothers with depression are at greater risk for emotional and behavioral problems, poor bonding, and, in severe cases, infanticide.19 When treating pregnant or postpartum women, providers should critically evaluate the risks of treatment modalities vs the risks of failing to treat.When appropriate, shared decisionmaking should be used to plan treatment for women experiencing depression during pregnancy or the postpartum period.

validated symptom measurement tool, such as the PHQ-9.4,9 A PHQ-9 score ≤5 is an indicator that a patient may have achieved remission.4 After a patient achieves remission, providers should use clinical judgment based on the patient’s previous history of depressive episodes, severity of symptoms, and risk factors to determine the need for continued maintenance treatment with CBT, medications, or both.28 Conclusion

The use of depression screening tools in primary care has been shown to increase identification of individuals with depression. Although screening in isolation has not been shown to improve depression outcomes, screening is necessary to identify those who will benefit from treatment. Depression screening — coupled with provider confirmation of diagnosis, evidence-based treatment, and follow-up care — has been shown to increase identification of cases, improve depression outcomes, and improve outcomes of comorbid illnesses.

Workflow redesign and education can help overcome barriers to screening and treating depression in primary care to facilitate achievement of these goals. ■ Simone Howe, DNP, APRN, FNP-C, is a family nurse practitioner at OCH Jay Family Medicine in Jay, Oklahoma.

References 1. World Health Organization. Depression and other common mental disorders. Global health estimates. World Health Organization website. http://apps.who.int/iris/bitstream/10665/254610/1/WHO-MSD-MER-2017.2eng.pdf. Published 2017. Accessed March 5, 2020.

2. Siu AL; US Preventive Services Task Force (USPSTF). Screening for depression in adults: US Preventive Services Task Force recommendation statement. JAMA. 2016;315(4):380-387.

3. Deneke DE, Schulz HE, Fluent TE. Screening for depression in the primary care population. Psychiatr Clin North Am. 2015;38(1):23-43.

4. Mitchell AJ, Yadegarfar M, Gill J, Stubbs B. Case finding and screening clinical utility of the Patient Health Questionnaire (PHQ-9 and PHQ-2) for depression in primary care: a diagnostic meta-analysis of 40 studies.

BJPsych Open. 2016;2(2):127-138.

5. Mertens JR, Chi FW, Weisner CM, et al. Physician versus non-physician delivery of alcohol screening, brief intervention and referral to treatment in adult primary care: the ADVISe cluster randomized controlled implementation trial. Addict Sci Clin Pract. 2015;10:26.

Follow-up Care

After treatment is initiated, therapy should be continued for 4 to 8 weeks before the provider and patient make a decision about efficacy.28 Following this acute treatment phase, patients should continue treatment for 4 to 9 months to prevent relapse.28 Individuals with depression should be treated until they achieve remission, as verified by the provider and a

6. Gallo JJ, Hwang S, Joo JH, et al. Multimorbidity, depression, and mortality in primary care: randomized clinical trial of an evidence-based depression care management program on mortality risk. J Gen Intern Med. 2015;31(4):380-386.

7. Zuckerbrot RA, Cheung A, Jensen PS, Stein REK, Laraque D; GLAD-PC Steering Group. Guidelines for Adolescent Depression in Primary Care (GLAD-PC): part I. Practice preparation, identification, assessment, and initial management. Pediatrics. 2018;141(3):e20174081.

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

8. Hegeman JM, de Waal MW, Comijs HC, Kok RM, van der Mast RC. Depression

24. Gardner W, Lucas A, Kolko DJ, Campo JV. Comparison of the PSC-17 and

in later life: a more somatic presentation? J Affect Disord. 2015;170:196-202.

alternative mental health screens in an at-risk primary care sample. J Am Acad

9. Waldrop J, Ledford A, Perry LC, Beeber LS. Developing a postpartum

Child Adolesc Psychiatry. 2007;46(5):611-618.

depression screening and referral procedure in pediatric primary care.

25. Ardic E, Barlas GU, Bulduk S. Validation and sensitivity of pictorial Pediatric

J Pediatr Health Care. 2018;32(3):e67-e73.

Symptom Checklist. Sigma Repository website. https://sigma.nursingrepository.org/

10. American College of Obstetricians and Gynecologists. ACOG Committee

handle/10755/335141. Published November 17, 2014. Accessed March 6, 2020.

Opinion No. 757: screening for perinatal depression. Obstet Gynecol.

26. American Psychiatric Association. Diagnostic and Statistical Manual of

2018;132(5):e208-e212.

Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.

11. American Academy of Pediatrics. Managing maternal depression

27. Smithson S, Pignone MP. Screening adults for depression in primary care.

before and after birth. AAP website. https://www.aap.org/en-us/about-the-

Med Clin North Am. 2017;101(4):807-821.

aap/aap-press-room/pages/Managing-Maternal-Depression-Before-and-After-

28. Gelenberg AJ, Freeman MP, Markowitz JC, et al. American Psychiatric

Birth.aspx. Published Oct 25, 2010. Accessed March 5, 2020.

Association. Practice Guidelines for the Treatment of Patients With Major Depressive

12. Hagan JF, Shaw JS, Duncan PM, eds. Bright Futures. Guidelines for Health

Disorder. 3rd ed. Washington, DC: American Psychiatric Association; 2010.

Supervision of Infants, Children, and Adolescents. 4th ed. Elk Grove Village, IL:

29. Dunlop BW, Kelley ME, Aponte-Rivera V, et al. Effects of patient preferenc-

American Academy of Pediatrics; 2017.

es on outcomes in the predictors of remission in depression to individual and

13. Bobo WV, Angleró GC, Jenkins G, Hall-Flavin DK, Weinshilboum R, Biernacka

combined treatments (PREDICT) study. Am J Psychiatry. 2017;174(6):546-556.

JM. Validation of the 17-item Hamilton Depression Rating Scale definition of

30. Meyers MA, Groh CJ, Binienda J. Depression screening and treatment in

response for adults with major depressive disorder using equipercentile link-

uninsured urban patients. J Am Board Fam Med. 2014;27(4):520-529.

ing to Clinical Global Impression scale ratings: analysis of Pharmacogenomic

31. Mergl R, Allgaier AK, Hautzinger M, Coyne JC, Hegerl U, Henkel V. One-

Research Network Antidepressant Medication Pharmacogenomic Study

year follow-up of a randomized controlled trial of sertraline and cognitive

(PGRN-AMPS) data. Hum Psychopharmacol. 2016;31(3):185-192.

behavior group therapy in depressed primary care patients (MIND study).

14. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry.

J Affect Disord. 2018;230:15-21.

1960;23(1):56-62.

32. Prozac (fluoxetine) [package insert]. Indianapolis, IN: Eli Lilly and

15. Bagby RM, Ryder AG, Schuller DR, Marshall MB. The Hamilton Depression

Company; 2017.

Rating Scale: has the gold standard become a lead weight? Am J Psychiatry.

33. Luck-Sikorski C, Stein J, Heilmann K, et al. Treatment preferences for

2004;161(12):2163-2177.

depression in the elderly. Int Psychogeriatr. 2017;29(3):389-398.

16. Beck AT, Steer RA, Brown GK. Beck Depression Inventory. 2nd ed. New

34. Bradley B, Backus D, Gray E. Depression in the older adult: what should

York, NY: Psychological Corp; 1996.

be considered? Ment Health Clin. 2016;6(5):222-228.

17. Moullec G, Plourde A, Lavoie KL, Suarthana E, Bacon SL. Beck Depression

35. American Geriatrics Society. American Geriatrics Society 2019 updated

Inventory II: determination and comparison of its diagnostic accuracy in

AGS Beers Criteria® for potentially inappropriate medication use in older

cardiac outpatients. Eur J Prev Cardiol. 2015;22(5):665-672.

adults. J Am Geriatr Soc. 2019;67(4):674-694.

18. Wang YP, Gorenstein C. Assessment of depression in medical patients: a systematic review of the utility of the Beck Depression Inventory-II. Clinics (Sao Paulo). 2013;68(9):1274-1287.

19. O’Connor E, Rossom RC, Henninger M, Groom HC, Burda BU. Primary care screening for and treatment of depression in pregnant and postpartum women: evidence report and systematic review for the US Preventive Service Task Force. JAMA. 2016;315(4):388-406 20. Li Z, Jeon YH, Low LF, et al. Validity of the Geriatric Depression Scale and the collateral source version of the Geriatric Depression Scale in nursing homes. Int Psychogeriatr. 2015;27(9):1495-1504.

21. Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res. 1982-1983;17(1):37-49.

Geriatric Depression Scale in a diverse elderly home care population. Am J Geriatr Psychiatry. 2008;16(11):914-921.

23. Murphy JM, Bergmann P, Chiang C, et al. The PSC-17: subscale scores, reliability, and factor structure in a new national sample. Pediatrics. 2016; 138(3):e20160038.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2020 27

© Harley Schwadron 2020

22. Marc LG, Raue PJ, Bruce ML. Screening performance of the 15-item

FEATURE: S. HAYDEN NEWMAN, MPAS, PA-C; LISA DAITCH, MPAS, PA-C

Unpacking Parkinson Disease Psychosis: Diagnosis and Treatment Severe neuropsychiatric dysfunction, including psychosis and dementia, is associated with more advanced Parkinson disease.

© KATERYNA KON / SCIENCE SOURCE

Parkinson disease psychosis is associated with more advanced disease.

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

P

arkinson disease (PD) is a chronic, progressive neurodegenerative disorder that affects approximately 10 million people worldwide, making it the second most common neurologic disorder after Alzheimer disease.1 The primary pathologies of PD involve neuronal cell inclusions (Lewy bodies) and accumulation of the protein α-synuclein within the basal ganglia.1 These pathologies lead to degradation of dopaminergic neurons and dopamine depletion in the basal ganglia.2 Further depletion of dopamine, serotonin, and acetylcholine leads to both motor and nonmotor disturbances in PD.1,2 The traditional clinical assessment of PD is focused on the symptoms of motor dysfunction.

The 4 cardinal motor symptoms (resting tremor, bradykinesia, rigidity, and postural instability) have been used for decades to support a clinical diagnosis of PD.3 However, PD now is recognized as a complex, diverse neurologic disorder, involving both motor and nonmotor manifestations.3,4 In fact, the nonmotor symptoms of PD often are more disabling and difficult to diagnose and treat in both primary and specialty care settings.3 Nonmotor symptoms of PD include neuropsychiatric dysfunction (depression, anxiety, psychosis, dementia), autonomic dysfunction (orthostatic hypotension, gastrointestinal disorders, sexual dysfunction), sleep disorders, and sensory disturbances of pain and olfaction.3 Nearly all patients with PD will develop nonmotor symptoms, with sensory, sleep, and neuropsychiatric dysfunction being the most frequent and disabling symptoms.3

Severe neuropsychiatric dysfunction, including psychosis and dementia, is associated with more advanced PD. Neuropsychiatric disorders are associated with more extensive deposition of Lewy bodies and resulting pathologic changes in cortical processing pathways.5 Parkinson Disease Psychosis

Unlike the prototypical motor symptoms of PD, Parkinson disease psychosis (PDP) can be diagnostically challenging and underreported.3,4,6 However, psychosis has been identified in up to 50% of patients with PD with or without dementia.7 PDP affects both the patient and those involved in the patient’s care; it is correlated with diminished quality of life, high caregiver burden, nursing home placement, and increased patient mortality.8,9 Although PDP can occur in patients with PD at any age, generally it develops in patients with advanced-stage disease.9 Other risk factors for the development of PDP include older age, older age at PD onset, longer duration of PD, higher doses of antiparkinson drugs, comorbid nonmotor symptoms, and severe motor symptoms.5,6 Patients with PDP report hallucinations or delusions as the primary manifestations of psychosis, with visual hallucinations accounting for nearly 40% of these manifestations.10 Nonvisual hallucinations, such as auditory, tactile, or olfactory hallucinations, also may occur, either alone or in conjunction with visual hallucinations.6,10 Visual hallucinations in patients with PDP are complex and commonly include animals, people, objects,“sensations of presence,” or “sensations of movement in the periphery.”10 Delusions usually are persecutory or paranoid in nature, often involving infidelity of a spouse or plots to harm the patient.5,10 Unlike patients with other psychotic disorders, patients with PDP initially maintain insight that their hallucinations or delusions are false, only losing this insight with considerable disease progression.5,10 Nonetheless, even in patients with insight, these hallucinations and delusions negatively affect the ability to perform activities of daily living, distressing both the patient and caregiver.3,8 Differential Diagnosis

PDP is a clinical diagnosis; no laboratory test or imaging method can definitively diagnose PDP or its symptoms.1 Diagnostic criteria, described by the National Institute of Neurological Disorders and Stroke and National Institute of Mental Health work group, have helped categorize the clinical symptoms of PDP (Table 1).11 PDP was originally thought to be an adverse effect of chronic use of antiparkinson drugs. While these agents are still posited to exacerbate PDP, the condition is now considered to be a complication of the underlying disease process separate from the effects of the patient’s drug regimen.9 However, given that hallucinations and confusion are listed as potential adverse effects for most treatment options for PD (Table 2, page 30),12

thorough communication among all providers involved in a patient’s care is needed to accurately diagnose and treat PDP. A patient cannot be diagnosed with PDP if the patient has an infection, is intoxicated, or is experiencing delirium or substance-induced psychosis.11 Thus, these conditions must be ruled out or treated before proceeding with the diagnosis of PDP. Other neurodegenerative disorders also must be excluded in the workup for PDP, including dementia with Lewy bodies (DLB), progressive supranuclear palsy, and corticobasal ganglionic degeneration.11 The chronologic course of disease progression distinguishes these disorders from PDP. For example, DLB is one of the primary imitators of PDP when it occurs with dementia, with the main difference being the temporal course of the disease.11 DLB is defined as dementia occurring before the onset of motor symptoms, whereas PDP with dementia is defined as motor symptoms occurring before the onset of dementia.11 However, discerning a timeline for neurodegenerative disorders can prove difficult due to their subjective and often obscure origins.

Comorbid psychotic disorders, including schizophrenia, schizoaffective disorder, brief psychotic disorder, delusional disorder, and mood disorders with psychotic features, also must be considered in the workup of PDP.11 Primary psychotic disorders generally can be distinguished from PDP by their clinical features, including early psychosis (before or within 3 months of PD diagnosis), prominent nonvisual hallucinations, prominent fearful and paranoid delusions, and lack of diurnal fluctuation of symptoms.11 Additional clinical symptoms of PDP used to delineate it from other psychotic disorders include a time frame of >1 month, older age at symptom onset, and lack of affective symptoms.11 If these alternate disorders and external causes are ruled out and psychotic symptoms persist, then a diagnosis of PDP should be considered.

TABLE 1. NINDS and NIMH Work Group Diagnostic Criteria for Parkinson Disease Psychosis11 1. The presence of at least 1 of the following symptoms of psychosis: illusions, false sense of presence, hallucinations, or delusions 2. A primary diagnosis of Parkinson disease 3. Symptoms of psychosis occur after onset of Parkinson disease 4. The duration of symptoms of psychosis are recurrent or continuous for at least 1 month 5. Symptoms of psychosis are not accounted for by another cause of parkinsonism, including dementia with Lewy bodies, psychiatric disorders (such as schizophrenia, schizoaffective disorder, delusional disorder, or mood disorder with psychotic features), or a general medical condition, such as delirium NINDS, National Institute of Neurological Disorders and Stroke; NIMH, National Institute of Mental Health

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

UNPACKING PARKINSON DISEASE PSYCHOSIS

Management

Medical management of PDP attempts to decrease psychotic symptoms without impeding motor symptom control. The first step in treatment involves reducing the dose of antiparkinson drugs, starting with those with the least clinical effect on motor symptoms.5 Dose reductions of anticholinergic agents, amantadine, and monoamine oxidase type B inhibitors should be considered first, with changes in doses of the more effective catechol-Omethyltransferase inhibitors, dopamine agonists, and carbidopalevodopa being reserved for the most recalcitrant cases.5,13

If adjusting antiparkinson drugs fails to improve psychotic symptoms, additional treatment with atypical antipsychotics is warranted (Table 3).13 Treatment must be individualized for each patient, considering adverse effect profiles, overall cost to the patient, and the ultimate effectiveness of each drug.

Low doses of atypical antipsychotic agents have long been used off-label for PDP treatment because their typical antipsychotic counterparts were associated with significant risk for extrapyramidal side effects.5 The 2 most commonly used atypical antipsychotics are clozapine and quetiapine, both of

TABLE 2. Selected Treatment Options for Parkinson Disease12 Agent

Available Doses

Adverse Effects

Carbidopa/levodopa

10 mg/100 mg, 25 mg/100 mg, and 25 mg/ Motor fluctuations: “wearing off ” effect, “on-off ” effect, dyskinesia 250 mg tablets and orally disintegrating tablets Drowsiness, dizziness, nausea, hallucinations, headache, agitation, and psychosis

DOPAMINE AGONISTS Ropinirole

0.25 to 5 mg tablets

Pramipexole

0.125 to 1.5 mg tablets

Bromocriptine

• 2.5 mg tablets • 5 mg capsules

Sleepiness, nausea, vomiting, orthostatic hypotension, confusion, hallucinations, and lower extremity edema Drowsiness, dizziness, confusion, delirium, hallucinations, dyskinesia, vasospasm, pulmonary fibrosis

CATECHOL-O-METHYLTRANSFERASE INHIBITORS Entacapone

200 mg tablets

Nausea, anorexia, diarrhea, confusion, orthostatic hypotension, dyskinesia, hallucinations

Tolcapone

100 mg tablets

Elevated liver enzymes (tolcapone only)

MONOAMINE OXIDASE TYPE B INHIBITORS Rasagiline

0.5 to 1 mg tablets

Selegiline

5 mg tablets, capsules

Drowsiness, dizziness, nausea, confusion, insomnia, mood changes, suicidal ideation, headache, hypertension in conjunction with tyramine-containing foods

OTHER Benztropine mesylate

• 0.5 to 2 mg tablets • 2 mg/2 mL ampules, vials

Anticholinergic adverse effects: mood changes, xerostomia, blurred vision, constipation, urinary retention, nausea, tachycardia, hallucinations

Amantadine

• 100 mg tablets, capsules • 50 mg/5 mL oral solution

Confusion, hallucinations, livedo reticularis, peripheral edema

TABLE 3. Current Treatment Options for Parkinson Disease Psychosis13 Agent

Available Dosages

Adverse Effects

Clozapine

Initial: 6.25 mg/d Maintenance: 10-50 mg/d

Drowsiness, dizziness, headache, tremor, salivation, sweating, dry mouth, visual disturbances, tachycardia, hypotension, syncope, constipation, nausea, fever

Quetiapine

Initial: 12.5 mg/d Maintenance: 12.5-150 mg/d

Drowsiness, dizziness, weight gain, xerostomia, constipation, elevated ALT, dyspepsia

Pimavanserin

34 mg/d

Confusion, constipation, nausea, peripheral edema, QT prolongation, somnolence, gait disturbance, hallucinations

ALT, alanine aminotransferase

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

which have been shown to improve psychosis with minimal disruption of motor symptom control.5,9 Clozapine is used less often due to increased risks for agranulocytosis, myocarditis, and fatal arrhythmias and the strict monitoring protocol that these risks necessitate.13,14 Although quetiapine and clozapine rarely cause extrapyramidal symptoms, studies have shown that these antipsychotics can block the therapeutic effects of antiparkinson drugs on motor symptoms.9 This effect is thought to be attributed to the affinity of these agents for dopaminergic D2 receptors.9,13,14 The newest treatment for PDP is pimavanserin, which was approved by the US Food and Drug Administration in 2016 and is the only drug specifically indicated for the treatment of hallucinations and delusions in PD.13 Pimavanserin is a selective serotonin 5-HT2A receptor inverse agonist that does not affect dopaminergic receptors and, thus, preserves motor function.9,14 Pimavanserin initially was promoted as a safer treatment option for PDP for this reason, but multiple adverse reactions to pimavanserin have since been documented, including prolongation of the QT interval, peripheral edema, somnolence, and confusion.14,15 Although pimavanserin also carries the atypical antipsychotic black box warning of increased mortality in elderly patients with dementia-related psychosis, it is not approved for treatment of psychosis unrelated to PD.15 Following up on multiple patient reports suggesting that pimavanserin may increase the risk for death, in 2018 the FDA reviewed postmarketing reports of patient mortality and found no new safety risks associated with pimavanserin use in patients with PDP.15

2. Papadakis MA, McPhee SJ, Rabow MW, eds. Current Medical Diagnosis & Treatment 2017. 56th ed. New York, NY: McGraw-Hill Education; 2017.

3. Chaudhuri KR, Martinez-Martin P, Schapira AH, et al. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson’s disease: the NMSQuest study.

Mov Disord. 2006;21(7):916-923.

4. Barone P, Antonini A, Colosimo C, et al. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease. Movement Dis. 2009;24(11):1641-1649.

5. Martinez-Ramirez D, Okun MS, Jaffee MS. Parkinson’s disease psychosis: therapy tips and the importance of communication between neurologists and psychiatrists. Neurodegen Dis Manage. 2016;6(4):319-330.

6. Sanchez-Ramos JR, Ortoll R, Paulson GW. Visual hallucinations associated with Parkinson disease. Arch Neurol. 1996;53(12):1265-1268.

7. Williams DR, Lees AJ. Visual hallucinations in the diagnosis of idiopathic Parkinson’s disease: a retrospective autopsy study. Lancet Neurol. 2005; 4(10):605-610.

8. Aarsland D, Larsen JP, Tandberg E, Laake K. Predictors of nursing home placement in Parkinson’s disease: a population-based, prospective study.

J Am Geriatr Soc. 2000;48(8):938-942.

9. Fredericks D, Norton JC, Atchison C, Schoenhaus R, Pill MW. Parkinson’s disease and Parkinson’s disease psychosis: a perspective on the challenges, treatments, and economic burden. Am J Manag Care.

2017;23(5):83-92.

10. Fenelon G, Mahieux F, Huon R, Ziegler M. Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain.

2000;123(4):733-745.

11. Ravina B, Marder K, Fernandez HH, et al. Diagnostic criteria for

Prognosis

psychosis in Parkinson’s disease: report of an NINDS, NIMH work group.

Psychosis is a frequent and challenging symptom of PD. Due to its tremendous effect on caregiver burden, psychosis surpasses motor dysfunction as the greatest risk factor for nursing home admission in patients with PD.8 The course of PDP is progressive, eventually advancing from hallucinations or delusions with insight to psychosis without insight.5 These psychotic symptoms herald a decline in patient function — as these symptoms progress, rates of patient morbidity and mortality significantly increase.6,16,17 Even with appropriate recognition of symptoms and subsequent treatment, PDP poses a clinical challenge; no single agent has proven effective for all patients with PDP.9,16,17 ■

Movement Disorders. 2007;22(8):1061-1068.

12. Goldenberg MM. Medical management of Parkinson’s disease. P T. 2008;33(10):590-606.

13. Schleisman A, Spangler M, Knezevich E. Treatment of Parkinson’s disease psychosis. US Pharmacist. 2016;41(11). https://www.uspharmacist.com/article/ treatment-of-parkinsons-disease-psychosis. Accessed February 24, 2020.

14. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial.

Lancet. 2014;383(9916):533-540.

15. Center for Drug Evaluation and Research. FDA analysis finds no new or unexpected safety risks associated with Nuplazid (pimavanserin), a medication to treat the hallucinations and delusions of Parkinson’s disease

S. Hayden Newman, MPAS, PA-C, is a physician assistant who graduated from the Physician Assistant Department of Augusta University in Augusta, Georgia. Lisa Daitch, MPAS, PA-C, is an associate professor in the Physician Assistant Department at the Augusta University, Augusta, Georgia.

psychosis. US Food and Drug Administration Home Page. https://www. fda.gov/Drugs/DrugSafety/ucm621160.htm. Published September 20, 2018.

Accessed January 23, 2019.

16. Forsaa EB, Larsen JP, Wentzel-Larsen T, Alves G. What predicts mortality in Parkinson disease? A prospective population-based long-term study.

Neurology. 2010;75(14):1270-1276.

References

17. Factor SA, Feustel PJ, Friedman JH, et al; Parkinson Study Group.

1. Elbaz A, Carcaillon L, Kab S, Moisan F. Epidemiology of Parkinson’s disease.

Longitudinal outcome of Parkinson’s disease patients with psychosis. Neurology.

Rev Neurol (Paris). 2016;172(1):14-26.

2003;60(11):1756-1761.

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

FEATURE: MARY-KATE HUNNICUTT, PA-C; ALICIA ELAM, PHARMD; MICHAEL FELZ, MD

Budd-Chiari Syndrome: A Case of Hepatomegaly, Abdominal Pain, and Ascites Causes of Budd-Chiari syndrome include myeloproliferative syndromes, malignancy, infection, and Behçet syndrome.

© CNRI/SCIENCE SOURCE

A

Malignant tumors are implicated in the etiology of Budd-Chiari syndrome in nearly 10% of cases.

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

45-year-old woman presents to the emergency department complaining of nausea and extreme abdominal pain on her right side. She notes that symptoms came on suddenly 2 days before. The patient works as a personal fitness trainer and exercises daily. She drinks an occasional glass of red wine and takes hydrochlorothiazide 25 mg/d for hypertension.

On physical examination, the patient has a low-grade fever and slight chill (Table). Her abdomen is soft, with shifting dullness consistent with an enlarged liver and moderate ascites.

Tenderness and guarding over the right lower quadrant are noted. The spleen is palpable in the left upper quadrant, and bowel sounds are hyperactive. Costovertebral angle tenderness is absent. Neurologic and extremity examinations are normal.

Computed tomographic (CT) imaging of the abdomen shows hepatomegaly (16 cm) and moderate ascites suggestive of cirrhosis and end-stage liver disease. During the course of her visit, the patient’s symptoms worsen to include vomiting, right lower quadrant abdominal pain, dizziness, and diaphoresis.

The patient is immediately admitted to the intensive care unit and treated for sepsis. The following day, she develops fulminant liver failure.

After transfer to a specialist center, the patient’s symptoms progress to shock, ascites, jaundice, acute kidney injury, acute respiratory failure, and metabolic acidosis.

Two days later, she undergoes further studies that include Doppler ultrasound, CT of the abdomen with contrast, CT-guided paracentesis, and echocardiogram. The diagnosis of Budd-Chiari syndrome (BCS) is made based on a combination of physical findings and ultrasound and CT evidence of hepatic vein occlusion. Liver biopsy reveals that the patient’s liver is 60% necrotic, with no evidence of inflammation or chronic liver disease.

Budd-Chiari Syndrome

Although most clinicians may not recognize BCS, understanding the trio of symptoms — abdominal pain, hepatomegaly, and ascites — can improve the likelihood of an accurate diagnosis and facilitate optimal treatment.

George Budd first described the clinical picture of BCS in 1845 and Hans Chiari described the underlying histopathology half a century later.1 A multifactorial disease process characterized by hepatic venous outflow obstruction, BCS occurs in approximately 1.4 million people in the United States.2,3 An underlying disorder can be identified in more than 80% of these patients.2 Causes of BCS include myeloproliferative syndromes (MPS), malignancy, infection, Behçet syndrome, and miscellaneous other conditions and idiopathic causes. The American Association for the Study of Liver Diseases, therefore, recommends evaluating individuals with BCS for lesions or malignant tumors, thrombosis, and systemic diseases.4 BCS often is the initial presentation of an MPS, and approximately 50% of BCS cases may be due to an underlying MPS, such as essential thrombocytopenia, primary myelofibrosis, agnogenic myeloid metaplasia, and the most common MPS, polycythemia vera.2 In one study, bone marrow biopsy showed that 78% of patients diagnosed with idiopathic BCS had a primary MPS.5 Malignancies are implicated in the etiology of BCS in nearly 10% of cases.6 Hepatocellular carcinoma is the most frequent malignancy, followed by malignancies of the adrenal gland, kidney, lung, pancreas, and stomach, as well as sarcomas of the right atrium, inferior vena cava, or hepatic veins.7 Invasion of vascular structures coupled with the hypercoagulable state associated with malignancy can result in venous thrombosis and/or obstruction.

Systemic diseases associated with BCS include autoimmune diseases (such as systemic lupus erythematosus), mixed connective tissue disease, and Sjögren syndrome.

Inflammatory bowel disease, sarcoidosis, minimal change nephrotic syndrome, neurofibromatosis, trauma, torsion of the liver, and rare familial clusters also have been identified as being associated with BCS. Infections and benign lesions account for another 10% of BCS cases.6 Women who are pregnant, use oral contraceptives, or are postpartum account for nearly 20% of BCS cases. Welldefined risk factors for thrombosis include factor V Leiden

mutation, factor II gene mutation, antiphospholipid syndrome, antithrombin deficiency, protein C and S deficiencies, and paroxysmal nocturnal hemoglobinuria.7 There is no known underlying cause of BCS in up to 20% of cases.2 Myeloproliferative Syndromes

A pivotal discovery related to MPS involves a somatic mutation (V617F) within the Janus tyrosine kinsase-2 (JAK2) gene in myeloid cells. This mutation has been detected in 37% to 45% of patients with primary BCS and approximately 80% of BCS patients with an MPS.3 In the presence of BCS, the peripheral blood cell count tends to remain within normal limits in patients with an MPS, which curtails recognition of an underlying syndrome.

Hypersplenism, hemodilution, occult gastrointestinal bleeding, and iron deficiency all mask peripheral blood abnormalities.

TABLE. Summary of Patient’s Vital Signs and Laboratory Results Vital Signs

Results

Weight, kg

58.5

Temperature, °C

37

Blood pressure, mm Hg

103/51

Heart rate, beats/min

58

Respiratory rate, breaths/min

16

O2 saturation rate, %

98 (on room air)

Mean arterial pressure, mm Hg

66

Laboratory Test

Results

CBC: • WBC, x 109/L • Hb, g/dL • HCT, % • Platelet, mm3

• 13.9 • 13.9 • 45.2 • 227

Lactate level, mg/dL

2.68

Prothrombin time, sec

13.2

International normalized ratio

1.2

Glomerular filtration rate, mL/min

43

Hb, hemoglobin; HCT, hematocrit; WBC, white blood cell count

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2020 33

BUDD-CHIARI SYNDROME

Approximately 50% of Budd-Chiari cases may be due to an underlying myeloproliferative syndrome, such as polycythemia vera.

The proposed workup for investigating underlying risk factors for individuals with BCS should include testing for V617F JAK2 in peripheral blood granulocytes. If no mutation is detected, bone marrow biopsy should be performed to search for clusters of dystrophic megakaryocytes indicative of an MPS.3 In a study of 163 patients with newly diagnosed BCS, most had identifiable risk factors. An MPS, the most frequent causative factor, was found in 50 (49%) of the 103 patients who underwent bone marrow biopsy, red cell mass measurement, and colony cultures. The V617F JAK2 mutation was identified in 35 (29%) of 121 tested patients. Twenty-eight of the 35 individuals with the mutation had features of an MPS on bone marrow biopsy.8 History and Physical Findings

Because the presentation of BCS is highly variable, providers should consider it in the differential diagnosis of patients presenting with acute or chronic liver failure. Common BCS symptoms include fever, abdominal tenderness, abdominal distension, hepatosplenomegaly, lower extremity edema, and ascites.9 Jaundice, gastrointestinal bleeding, and hepatic encephalopathy may be evident but are less common presenting symptoms.9 More than 60% of patients with BCS will present with sudden-onset abdominal pain, hepatomegaly, and ascites.

Providers also should recognize features of nephrotic syndrome, such as proteinuria, edema, and hypoalbuminemia.2 An absence of symptoms at the time of diagnosis, which occurs in as many as 20% of patients with BCS, correlates with large hepatic venous collaterals.10 Acute, subacute, and chronic forms of BCS are categorized by the duration and severity of acute fulminant liver failure.

Fulminant BCS is rare; approximately 5% of patients will present with acute liver failure demonstrated by elevated transaminase levels, jaundice, hepatic encephalopathy, and an international normalized ratio (INR) >1.5.2 Approximately 20% of patients with BCS present with an acute form, in which accelerated development of manifestations occurs rapidly over the course of a few weeks.11 Such patients present with severe right upper quadrant pain, hepatomegaly, and eventually jaundice and ascites.11 Most causes of BCS are subacute and chronic in nature.2 In subacute or chronic BCS, patients often are symptomatic; the obstruction is gradual and generally discovered incidentally, such as when imaging studies or liver function tests are ordered

for unrelated reasons. In subacute BCS, symptoms develop slowly over the course of 3 to 6 months, and patients may experience vague abdominal or right upper quadrant pain reflective of increasing portal vein pressure. In chronic BCS, symptoms of chronic liver disease, such as spider angiomas, palmar erythema, ascites, and esophageal varices, are delayed until the patient develops cirrhosis.

Differential Diagnosis

A detailed history and physical examination along with imaging studies are essential for accurately diagnosing BCS. Chronic BCS should be considered in the differential diagnosis of idiopathic processes including cirrhosis and portal hypertension in the setting of preserved liver function. Patients with BCS generally are young and in good overall health.12 The fulminant and acute forms of BCS may mimic other causes of acute liver injury, such as ischemic, toxic, or viral hepatitis; malignancy; infiltrative liver diseases; and hepatic veno-occlusive disease. The subacute and chronic forms of BCS share many clinical features with any cause of cirrhosis or portal hypertension. Right-sided heart failure, right atrial myxoma, and constrictive pericarditis may present in a similar fashion but are distinguishable from BCS on physical examination.13 In patients with symptoms suggestive of BCS, several diagnostic modalities can be performed. Noninvasive assessment with Doppler ultrasonography, CT, or magnetic resonance imaging (MRI) is effective for initial evaluation. Evidence for thrombosis is rarely obtained with liver biopsy.10 Biopsy usually provides nonspecific evidence for impaired blood outflow, such as congestion, coagulative necrosis, or fibrosis.3 Although abnormal liver function tests are an important feature of BCS, completely normal tests do not preclude the presence of BCS. In acute and fulminant BCS, levels of serum aspartate aminotransferase and alanine aminotransferase (ALT) may be more than 5 times the upper limit of normal.2 Levels of serum albumin and bilirubin, as well as prothrombin time, can be normal or abnormal.9 Vascular congestion results in ischemic hepatocellular damage, elevating serum ALT.10 ALT concentrations can range from initial values of 100 to 200 U/L to >600 U/L (normal, 10-40 U/L). In acute BCS, serum alkaline phosphatase (ALP) often is in the range of 300 to 400 U/L (normal, 20-140 U/L). Serum bilirubin levels usually are <7 mg/dL at the time of presentation but may increase sharply.10 In subacute or chronic BCS cases, normal or mild to moderate elevations of serum ALT, ALP, and serum

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BUDD-CHIARI SYNDROME

Providers should consider Budd-Chiari syndrome in the differential diagnosis of patients presenting with acute or chronic liver failure. bilirubin are evident.7 Serum creatinine should be included in the initial assessment due to the frequency of coexisting renal impairment in patients with BCS.10 In patients presenting with ascites, diagnostic paracentesis is recommended.2,10 Ascitic fluid in patients with BCS has a high serum-to-ascites protein gradient (>1.1), reflecting elevated portal pressure.6 The protein concentration is variable (ranging from 1.5 to 4.9 g/dL) and is directly related to serum protein and inversely related to portal pressure. Patients with subacute or chronic BCS may have hypoalbuminemia.10 Protein content >3.0 g/dL in ascitic fluid is indicative of BCS or cardiac/pericardial disease.9 Treatment

A step-wise approach has been suggested for managing BCS14 to achieve the following goals: prevent propagation of any clot, restore patency of thrombosed veins, decompress the congested liver, and manage any complications. Initial steps include correction of underlying disorders, initiation of anticoagulation, and treatment of portal hypertension complications.15 Angioplasty or stenting are helpful treatment options that may be advisable to restore venous patency.

If initial treatment options fail, a transjugular intrahepatic portosystemic shunt (TIPS) may be placed to decompress the liver.16 Patients with acute liver failure may need transplantation and should be referred to a liver transplantation center for specialized treatment.16 Patients with chronic BCS should be managed for complications of portal hypertension, hepatocellular carcinoma, and transformation of any underlying MPS. Nutritional status should be evaluated and improved if malnutrition develops.15 The patient in this case underwent successful TIPS placement for portal hypertension. She was listed as status 1A for liver transplantation and underwent orthotopic liver transplant.

Excellent allograft function was observed. Lifelong anticoagulation was started with low-molecular-weight heparin. The patient’s renal function continued to deteriorate, requiring living donor kidney transplantation a few months later. She recovered well from her second organ transplant.

One year after the kidney transplant, hematologic experts diagnosed that patient as having primary myelofibrosis based on a bone marrow biopsy. The patient was found to be positive for the JAK2 mutation at the time of her BCS diagnosis but was able to return to vigorous activity as a personal fitness trainer, exercising several hours each day. Her hepatic and renal function have remained stable for 48 months.

Conclusion

The overall prognosis from treated BCS is favorable, with 5-year survival rates at 90%.2 Asymptomatic cases have a good prognosis,3 but symptomatic patients have a high mortality rate that exceeds 90% if not treated.7 Long-term outcome data show the potential for transformation of underlying hematologic disorders and the risk of hepatocellular carcinoma.9 In a study that included 25 individuals who underwent liver transplantation for BCS, the overall mortality rate after liver transplantation was similar among patients with (n=18) and without (n=7) an MPS (16.7% vs 14.3%, respectively).1 In patients with an MPS, the recurrent thrombosis rate was 22.2% compared with 14.3% in those without a neoplasm. Follow-up over 4.9 years showed no progression of a known MPS into acute leukemia. After 10 years, the risk of myelofibrosis and acute leukemia does increase. The long-term rate of blastic transformation of underlying MPS occurs in 10% at 15 years and 25% at 25 years. Therefore, clinical surveillance by detailed laboratory assessment is mandatory after liver transplantation throughout a patient’s lifetime.1 The long-term effect of immunosuppression on progression of MPS is uncertain, but evidence for rapid progression of MPS after liver transplantation is scant. BCS patients with and without myeloproliferative neoplasms had similar long-term survival after liver transplantation. Patients who developed leukemia or primary myelofibrosis during long-term follow-up have been identified. However, based on these data, immunosuppression has not heightened risk for progression of MPS.16 ■ Mary-Kate Hunnicutt, PA-C, is a physician assistant,Alicia Elam, PharmD, is associate professor, and Michael Felz, MD, is clinical associate professor in the Department of Physician Assistant at Augusta University.

References 1. Oldakowska-Jedynak U, Ziarkiewicz M, Ziarkiewicz-Wróblewska B, et al.

Myeloproliferative neoplasms and recurrent thrombotic events in patients undergoing liver transplantation for Budd-Chiari syndrome: a single-center experience. Ann Transplant. 2014;19:591-597.

2. Goel RM, Johnston EL, Patel KV, Wong T. Budd-Chiari syndrome: investigation, treatment and outcomes. Postgrad Med J. 2015;91(1082):692-697.

3. Valla DC. Primary Budd-Chiari syndrome. J Hepatol. 2009;50(1):195-203.

4. DeLeve LD, Valla DC, Garcia-Tsao G; American Association for the Study of Liver Diseases.Vascular disorders of the liver. Hepatology. 2009;49(5):1729-1764.

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Continues on page 46

Dermatology Clinic CASE #1

Thick,Yellow Skin on Soles of Feet ANGELA HUANG, BA;YELENA DOKIC, BSA; CHRISTOPHER RIZK, MD

A 56-year-old woman presents with thickened, yellow skin on the soles of her feet that has been present since she was a child. On examination, the affected areas appear localized to the weight-bearing pressure areas of her feet, with hypertrophy of her fifth toenail. She has a history of hyperhidrosis, and her mother and grandfather had similar symptoms on their soles. Histologic examination of a skin sample shows a nonepidermolytic pattern, with increased thickness of the stratum corneum (hyperkeratosis) and acanthosis. Molecular testing reveals a mutation in the KRT6C gene, which codes for an isoform of keratin 6.

What is your diagnosis? Turn to page 38

CASE #2

Nail Dystrophy With Roughness PREEYA BHAVSAR, BS; EMILY BURNS, BA; CHRISTOPHER RIZK, MD

An 8-year-old boy presents to the clinic for evaluation of a progressively worsening nail dystrophy that began a few months ago. The patient’s mother denies a family history of skin diseases and reports that her son has no history of medical problems. On physical examination, all of the boy’s fingernails and toenails show hyperkeratosis, longitudinal ridging, loss of luster, and roughness.

His hair, skin, and oral mucosa are unremarkable. Nail biopsy reveals spongiotic changes and exocytosis of inflammatory cells into the nail epithelia. The results of a fungal culture are negative.

What is your diagnosis? Turn to page 39 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2020 37

Dermatology Clinic CASE #1

Palmoplantar Keratoderma

Keratoderma refers to a diverse group of disorders presenting with abnormal thickening of the epidermal layer of skin that most commonly affect the palms and soles (palmoplantar keratoderma [PPK]).1 PPKs are divided into 2 categories: hereditary or acquired. The exact prevalence and incidence of PPK are unknown, but they vary geographically. For example, the estimated prevalence of epidermolytic PPK in Northern Ireland is 4.4 per 100,000,2 whereas the estimated prevalence of the most common type of PPK in Asia, PPK type Nagashima, is 1.2 per 10,000 in Japan and 3.1 per 10,000 in China.3 Hereditary PPK usually is caused by mutations in genes coding for structural proteins of the intracellular cytoskeleton, most commonly keratins, leading to hyperkeratosis. Mutations also may occur in genes coding for desmosomal proteins and proteins involved in cell signaling. Acquired PPK can be caused by medications, malnutrition, toxins, systemic disease, infectious etiologies, and malignancy.4 Autosomal dominance is the most common inheritance pattern of PPK, although autosomal-recessive, X-linked, and mitochondrial transmission also have been found.1 Hereditary PPK tends to present at birth, early childhood, or young adulthood, and in the majority of cases the disorder continues throughout a patient’s life. Hereditary PPK, which exists either in isolation or as syndromic PPK with extracutaneous manifestations, is categorized into subgroups with distinct clinical phenotypes: diffuse, focal, and punctate.

Diffuse PPKs are characterized by symmetric epidermal thickening over the entire surface of the palms and soles.1 There may be a sharp demarcation at the edge of the palms and soles or continuation of patches up to the elbows and/or knees, termed transgrediens hyperkeratosis.Associated hyperhidrosis in the feet can increase the risk for fungal and bacterial infections.1 Diffuse PPKs includeVörner type,Thost-Unna type, DSG1 gene mutation, Mal de Meleda, Gamborg Nielsen type (Norrbotten, Sweden), Nagashima type, Bothnia type, and Greither disease.5 Focal PPKs are characterized by large compact areas of hyperkeratosis that develop at palmoplantar sites exposed to frequent friction or pressure.1 The lesions resemble calluses and may be painful. Focal PPKs include pachyonychia congenita and focal nonepidermolytic PPK.5 Punctate PPKs are characterized by multiple small areas of round lesions scattered around the palmoplantar areas.1 The

lesions may grow larger and increase in number with age or develop on the dorsal aspects of the hands and feet. Punctate PPKs include Buschke-Fischer-Brauer syndrome, punctate porokeratosis palmaris et plantaris, and acrokeratoelastoidosis.5 Syndromic PPKs manifest beyond the palms and soles.

Extracutaneous manifestations in patients with syndromic PPK tend to appear later in life. Symptoms include deafness, periodontitis, cardiomyopathy, woolly hair, alopecia, mucosal abnormalities, nail abnormalities, esophageal cancer, and corneal dystrophies.5 Certain syndromic PPKs, such asVohwinkel syndrome and Olmsted syndrome, may present as mutilating PPK characterized by bands that constrict around fingers and toes, leading to autoamputation.6 The differential diagnosis for PPK includes similar diseases that present with thick or hardened patches of skin, including inflammatory conditions such as psoriasis, lichen planus, and chronic dermatitis.1 The color, scaling quality, and location of patches beyond the palms and soles can help distinguish these conditions. Clinical appearance and laboratory testing can help differentiate PPK from infectious etiologies such as warts, tinea corporis, and scabies.

The differential diagnosis of palmoplantar keratoderma includes psoriasis, lichen planus, and chronic dermatitis.

The diagnosis of PPK is made through comprehensive history, skin examination, histologic analysis, and genetic testing.

To determine treatment options, it is important to categorize PPK. Diffuse, focal, and punctate PPK are differentiated primarily through skin examination. Epidermolytic and nonepidermolytic PPK are differentiated through histologic analysis.

Histopathology findings may show acanthosis and epidermolysis, but the main histologic feature of PPK is hyperkeratosis.7 A patient history supporting a diagnosis of hereditary PPK includes childhood onset of symptoms, positive family history, consanguinity of parents, and extracutaneous manifestations.7 A history supporting acquired PPK includes later onset, occupational hazards, infections, malignancy, medications, and alleviation of symptoms during medication vacation.7 It is important to investigate PPK in patients as a potential first symptom of malignancy. Paraneoplastic PPK often is associated with Sezary syndrome, Bazex syndrome, and Howel-Evans syndrome.7 There are no curative treatments for PPK. Therapies are aimed at cosmetic and symptomatic relief. Keratolysis and mechanical reduction of hyperkeratosis may be achieved

38 THE CLINICAL ADVISOR • APRIL 2020 • www.ClinicalAdvisor.com

through home therapies including regular bathing and foot and hand care.7 Hydration of the skin can be maintained through moisturization, use of emollients such as petroleum jelly, and topical therapy with keratolytic effects, such as urea and salicylic acid. Antifungals and antibiotics should be started as prophylaxis or to treat local infections.7 Systemic treatments including retinoids, specifically acitretin, may improve PPK manifestations. However, retinoids are discouraged for epidermolytic PPK because they can lead to erosions and skin detachment.7 Systemic retinoids also should be avoided in pregnant women because they carry a risk for birth defects; patients of childbearing age must receive contraception before initiating systemic retinoids.8 Hyperhidrosis associated with PPK can be controlled by products containing aluminum chloride. Inflammation from PPK should be targeted with topical corticosteroids.

Customized footwear, analgesics, and topical anesthetics can relieve pain from walking and daily activities. Symptoms of acquired PPK may be improved by treatment of the underlying cause, such as in the case of paraneoplastic PPK.4 Genetic counseling and gene therapy would benefit patients with PPK identified through molecular testing.6 Potential curative therapies in the form of RNA interference are being explored for PPK caused by dominant mutations.9 This therapy involves the introduction of site-specific small interfering RNA into cells to turn off dominant negative alleles; wild-type alleles are spared to allow the creation of functioning keratin intermediate filaments.

The patient in our case was treated with emollients and topical salicylic acid. She had symptomatic improvement after several weeks.

Angela Huang, BA, and Yelena Dokic, BSA, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is a dermatologist affiliated with Elite Dermatology in Houston,Texas.

References 1. Has C, Technau-Hafsi K. Palmoplantar keratodermas: clinical and genetic aspects. J Dtsch Dermatol Ges. 2016;14(2):123-140.

2. Covello SP, Irvine AD, McKenna KE, et al. Mutations in keratin K9 in kindreds with epidermolytic palmoplantar keratoderma and epidemiology in Northern Ireland. J Invest Dermatol. 1998;111(6):1207-1209.

3. Kubo A, Shiohama A, Sasaki T, et al. Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis. Am J Hum Genet. 2013;93(5):945-956.

4. Patel S, Zirwas M, English JC 3rd. Acquired palmoplantar keratoderma. Am J Clin Dermatol. 2007;8(1):1-11.

5. Guerra L, Castori M, Didona B, Castiglia D, Zambruno G. Hereditary palmoplantar keratodermas. Part I. Non-syndromic palmoplantar keratodermas: classification, clinical and genetic features. J Eur Acad Dermatol Venereol. 2018;32(5):704-719.

6. Kelsell DP, Stevens HP. The palmoplantar keratodermas: much more than palms and soles. Mol Med Today. 1999;5(3):107-113.

7. Schiller S, Seebode C, Hennies HC, Giehl K, Emmert S. Palmoplantar keratoderma (PPK): acquired and genetic causes of a not so rare disease.

J Dtsch Dermatol Ges. 2014;12(9):781-788.

8. Guerra L, Castori M, Didona B, Castiglia D, Zambruno G. Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas – diagnostic algorithm and principles of therapy. J Eur Acad Dermatol Venereol. 2018;32(6):899-925.

9. Hickerson RP, Flores MA, Leake D, et al. Use of self-delivery siRNAs to inhibit gene expression in an organotypic pachyonychia congenita model.

J Invest Dermatol. 2011;131(5):1037-1044.

CASE #2

Trachyonychia

The term trachyonychia is derived from trakos, the Greek word for “rough nails.”1 The condition is a nail plate abnormality characterized by roughness, excessive longitudinal ridging, cuticle thickening, and brittleness of the distal nail.

Defective keratinization of the proximal nail matrix causes the disease. Trachyonychia often is called “20 nail dystrophy,” but the phrase is falling out of favor because it does not accurately describe the condition, which may involve 1 or as many as 20 nails.2 The incidence of trachyonychia is not known, and it does not seem to show a predilection for either sex.2 Two types of trachyonychia are recognized: opaque and shiny.2 Opaque trachyonychia is more common and severe, presenting with rough, brittle, and longitudinally ridged nails. This type of trachyonychia often is referred to colloquially as “sandpaper nails” because the nails appear to have been rubbed with sandpaper.

Shiny trachyonychia occurs less frequently and is characterized by uniform, opalescent nails with multiple small geometric pits.2 In both forms, fingernails are affected more commonly than toenails.

Histopathologic examination reveals differences between the 2 types of trachyonychia. The opaque type of trachyonychia shows inflammation that never ceases over the duration of the condition. Shiny-type trachyonychia demonstrates a waxing and waning pattern of abnormality punctuated by periods of normal nail matrix function.3 Trachyonychia occurs more commonly in children but can occur at any age.2 It may be idiopathic or associated with other dermatologic or nondermatologic conditions. The most common dermatologic diseases associated with trachyonychia are

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2020 39

Dermatology Clinic alopecia areata, lichen planus, and psoriasis.2 Alopecia areata, the disease most commonly associated with trachyonychia, is estimated to affect 3.65% of patients.4 Gordon et al describe trachyonychia as alopecia areata of the nails.1 Less commonly associated skin diseases include vitiligo, ichthyosis vulgaris, atopic dermatitis, and pemphigus vulgaris. Nondermatologic conditions associated with trachyonychia include immunoglobulin A deficiency, amyloidosis, and sarcoidosis.2 Histopathologic findings for trachyonychia often but not always match the associated skin disease.4-7 For example, patients with psoriasis and trachyonychia can demonstrate similar pathologic changes in the nails and skin, with findings of acanthosis, focal

It is important to counsel the patient on the benign nature of trachyonychia and its generally good prognosis. parakeratosis, and accumulation of polymorphonuclear cells along the dorsal nail plate.1 The majority of patients with idiopathic trachyonychia or trachyonychia associated with alopecia areata exhibit spongiotic changes and exocytosis of inflammatory cells into the nail epithelia on nail biopsy.4,5 However, there are reports of patients with alopecia areata demonstrating typical features of lichen planus on nail biopsy.4 Nail findings in patients with idiopathic trachyonychia also can include histologic findings common to lichen planus, psoriasis, and even pemphigus vulgaris.4,5 Trachyonychia is a clinical diagnosis, and nail biopsy, which can be invasive and cause scarring, is not indicated.1,7,8 When evaluating a patient with trachyonychia, health care practitioners should consider other causes of nail dystrophy in the differential diagnosis. A thorough personal and family history of skin disorders is recommended as well as careful examination of the skin, mucosa, and hair to evaluate for associated disorders.

Many features of trachyonychia overlap with those of other nail dermatoses. In particular, onychomycosis, brittle nails, and senile nails should be considered in the differential diagnosis of a patient with trachyonychia. Onychomycosis may be eliminated from the differential by confirmatory testing, including histology, fungal culture, or potassium hydroxide prep. Trachyonychia often is misdiagnosed as onychomycosis and, therefore, these tests are recommended before initiation of antifungal therapy.6 In patients with onychomycosis, brittle nails show superficial and longitudinal splitting but not the excess ridging and roughness seen in patients with trachyonychia.8 Senile nails show mild longitudinal ridging and beading, but these abnormalities are not diffuse and do not involve the entire nail plate.8

In most cases, trachyonychia improves spontaneously. The median duration of disease is 32.5 months in children and 77.0 months in adults.9 It is important to counsel patients on the benign nature of the disease and its generally good prognosis.

However, patients may request treatment to improve the appearance of their nails. For patients with shiny trachyonychia, use of clear nail polish is a low-risk treatment option that may improve the appearance of the nails.2 In patients who have trachyonychia associated with an underlying disease, treatment of the associated disease is recommended.2 In patients without an associated disease, the recommended course is a trial period of observation followed by topical or systemic treatments.2 Topical treatments include tazarotene gel, 5-fluorouracil, corticosteroids, and psoralen plus ultraviolet A therapy.

Systemic options include retinoids such as acitretin, corticosteroids, and antimalarial agents. Intralesional injection of triamcinolone into the proximal nail fold also has been shown to be effective.2 There is no standardized, evidence-based method of treatment.8 The age of the patient, the type and severity of trachyonychia, prior treatments, and associated diseases all should be taken into account when determining the best treatment regimen.2 In this case, the mother of the boy was reassured that the lesions may resolve over time and no treatment was prescribed. â&#x2013; Preeya Bhavsar, BS, and Emily Burns, BA, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is dermatologist affiliated with Elite Dermatology in Houston,Texas.

References 1. Gordon KA, Vega JM, Tosti A. Trachyonychia: a comprehensive review. Indian J Dermatol, Venereol Leprol. 2011;77(6):640-645.

2. Haber JS, Chairatchaneeboon M, Rubin AI.Trachyonychia: review and update on clinical aspects, histology, and therapy. Skin Appendage Disord. 2017;2(3-4):109-115.

3. Tosti A, Bardazzi F, Piraccini BM, Fanti PA, Cameli N, Pileri S. Is trachyonychia, a variety of alopecia areata, limited to the nails? J Invest Dermatol.

1995;104(5 suppl):27S-28S. 4.Tosti A, Fanti PA, Morelli R, Bardazzi F. Trachyonychia associated with alopecia areata: a clinical and pathologic study. J Am Acad Dermatol. 1991;25(2 Pt 1):266-270.

5.Tosti A, Bardazzi F, Piraccini BM, Fanti PA. Idiopathic trachyonychia (twenty-nail dystrophy): a pathological study of 23 patients. Br J Dermatol. 1994;131(6):866-872.

6. Chu DH, Rubin AI. Diagnosis and management of nail disorders in children.

Pediatr Clin North Am. 2014;61(2):293-308.

7. Grover C, Khandpur S, Reddy BS, Chaturvedi KU. Longitudinal nail biopsy: utility in 20-nail dystrophy. Dermatol Surg. 2003;29(11):1125-1129.

8. Jacobsen AA, Tosti A. Trachyonychia and twenty-nail dystrophy: a comprehensive review and discussion of diagnostic accuracy. Skin Appendage Disord.

2016;2(1-2):7-13.

9. Lee YB, Cheon MS, Park HJ, Cho BK. Clinical study of twenty-nail dystrophy in Korea. Int J Dermatol. 2012;51(6):677-681.

40 THE CLINICAL ADVISOR â&#x20AC;˘ APRIL 2020 â&#x20AC;˘ www.ClinicalAdvisor.com

Dermatologic Look-Alikes Blistering Cutaneous Ulcerations RIYAD N. H. SEERVAI, BA, BS; ELEANOR JOHNSON, BA; CHRISTOPHER RIZK, MD

CASE #1

CASE #2

A 12-year-old boy presents with a reddish-brown rash.

His mother reports that the rash started as reddish-brown spots and has become very itchy, often keeping her son up at night. She is concerned that it may be varicella zoster virus infection. Physical examination reveals scaly, erythematous macules with areas of ulceration along the anterior trunk, arms, legs, and elbows. Two weeks ago, the boy missed school due to a “sore throat” and mild flu-like symptoms, but his mother reports that she did not take her son to the doctor or seek treatment.

A 40-year-old man presents to the dermatology clinic complaining of extremely painful sores on his back, neck, and chest. Approximately a month ago, the patient visited his dentist for evaluation of painful sores in his mouth. He developed hoarseness and had difficulty swallowing, for which he was evaluated by an otolaryngologist. Physical examination of the patient’s skin reveals numerous painful, flaccid blisters with bloody erosions and a positive Nikolsky sign. The patient denies pruritus and has no lesions on his palms or soles.

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Dermatologic Look-Alikes CASE #1

PLEVA

Pityriasis lichenoides et varioliformis acuta (PLEVA) is the acute form of pityriasis lichenoides (PL), a rare cutaneous inflammatory condition of unknown etiology.1 PLEVA, also known as MuchaHabermann disease, was first characterized by the Austrian dermatologist Viktor Mucha in 1916 and the German dermatologist Rudolf Habermann in 1925.2 PLEVA falls along the continuum of PL conditions that range from the milder pityriasis lichenoides chronica (PLC) to the life-threatening febrile ulceronecrotic Mucha-Habermann disease (FUMHD).1,2 Collectively, these conditions pose a series of diagnostic and managerial challenges for patients and clinicians.3 PLEVA has no clearly defined incidence, prevalence, risk factors, or racial or geographic distribution. It occurs most frequently in children and young adults (aged 10 to 30 years), with a slight predisposition in men.1,2 The etiology and pathogenesis of PLEVA are not well understood. It generally is described as a lymphoproliferative disorder, with 2 prevailing theories classifying it as either a premalignant T-cell dyscrasia or a reactive immune response to infection.3 The former is based on identification of clonal T-cell populations in patients with PLEVA and FUMHD, as well as rare reports of cutaneous T-cell lymphoma following PLEVA and PLC.4,5 The aberrant immune response theory stems from reports of PLEVA arising in the aftermath of infections caused by bacteria (Staphylococcus aureus, Streptococcus pyogenes), viruses (Epstein-Barr virus, parvovirus B19 [fifth disease], hepatitis B virus, adenovirus), or parasites (Toxoplasma gondii). PLEVA even has been described as an early cutaneous manifestation of HIV infection.6 It has been classified as an immune complex-mediated hypersensitivity vasculitis.3 PLEVA presents clinically as a subacute-to-acute eruption of multiple erythematous macules, most prominently along the anterior trunk, flexural surfaces, and proximal extremities.

The macules evolve into vesiculopustules, with hemorrhaging, necrosis, ulceration, and crusting.1-4 These scaly, red-brown papules have an appearance that is more consistent with PLC.2 A characteristic sign of PLEVA is the presence of lesions at multiple stages of development.1,2 As individual lesions resolve over the course of a few weeks, new lesions develop due to

ongoing disease.1,2 The lesions usually are asymptomatic but can be associated with pruritus or burning.1-3 PLEVA typically is a benign, self-limited disease. Following the resolution of lesions, there may be some hypopigmentation or hyperpigmentation.3 There is little mucosal involvement, and systemic symptoms normally are absent.1 General PLEVA resolves faster than localized PLEVA.2 Occasionally, patients with PLEVA will completely transition to PLC.3 Histologically, PLEVA presents as a constellation of features, none of which are pathognomonic. These include1,2: • Parakeratosis, spongiosis, dyskeratosis, acantholysis, vacuolization of the basal layer, and focal epidermal necrolysis; • A moderately dense, wedge-shaped lymphohistiocytic perivascular inflammatory infiltrate, extending from the papillary to the reticular dermis and obscuring the dermoepidermal junction; and • Dilation/engorgement of blood vessels, vascular congestion, dermal hemorrhage, and extravasation of lymphocytes and erythrocytes into the epidermis.

Immunohistochemical staining (hematoxylin and eosin [H&E]) of the inflammatory infiltrate reveals a predominance of CD8+ cytotoxic T lymphocytes.7 There are no specific serologic tests for PLEVA, although some tests can be used to uncover a preceding or coexisting infection.1 Compared with PLEVA, FUMHD is associated with clinical symptoms that are more severe.1-3 It can arise de novo or from preexisting PLEVA, with rapid progression to severe

PLEVA appears as a subacute-to-acute eruption of macules, most prominently along the trunk and extremities. ulceronecrotic disease, painful hemorrhagic bullae, mucosal involvement, and high fevers.2 Systemic manifestations include cardiomyopathy, interstitial pneumonitis, malabsorption, abdominal pain, central nervous system vasculitis, and sepsis due to secondary infection of bullae and pustules.1,2 Resolution of skin lesions results in atrophic scarring.1-3 FUMHD has a poor prognosis (25% mortality rate) and is, thus, considered a dermatologic emergency.2,3 The histologic features of FUMHD are similar to those of PLEVA, with leukocytoclastic vasculitis, denser perivascular infiltrates, and more widespread necrosis.3 Serology commonly shows elevations in erythrocyte sedimentation rate or C-reactive protein levels.1,3 The differential diagnosis for PLEVA is extensive due to its intermediate position in the PL spectrum and its shared

42 THE CLINICAL ADVISOR • APRIL 2020 • www.ClinicalAdvisor.com

clinical features with multiple inflammatory conditions.1,2 Lymphomatoid papulosis (LyP) most closely resembles PLEVA, with eruption of inflammatory papules and small nodules regressing over a few weeks.1,2 Histologically, LyP shows little basal layer vacuolization and is characterized by a dense infiltrate of CD30+ (not CD8+) T lymphocytes.1,8 PLC presents as gradually developing red-brown maculopapules with overlying micaceous (silvery) scale scattered across the trunk and proximal extremities.

Other conditions that mimic PLEVA include varicella (shorter disease course), disseminated herpes simplex, Gianotti Crosti syndrome (lymphadenopathy and hepatomegaly seen), Langerhans cell histiocytosis rash (localized to seborrheic or intertriginous areas), and multiple arthropod bites (vesiculation and necrosis infrequent).1-3 When cutaneous findings raise the suspicion for PLEVA, a biopsy is required to confirm this diagnosis and rule out other conditions.1-3 Since PLEVA is benign and typically self-limited, it is possible for a patient to be followed in clinic without treatment if the disease is limited, nonscarring, and asymptomatic.

However, patients with extensive, persistent, scarring, or symptomatic PLEVA can be treated with systemic antibiotics, phototherapy, topical agents, and systemic immunomodulators.9 Examples of these treatments include the following9: • Antibiotics: doxycycline and minocycline (adults) and erythromycin (children) are used for their anti-inflammatory and immune-response properties.

• Ultraviolet (UV) light treatments: UVB is a first-choice therapy, followed by psoralen plus UVA and broadband/ narrowband UVB phototherapy.

• Topical corticosteroids and antihistamines can be used to manage pruritic symptoms but do not alter the disease course.

• For severe refractory PLEVA and FUMHD, methotrexate has been found to be the most efficacious therapy.

Other treatments used for FUMHD have included acyclovir, dapsone, cyclosporine, and intravenous immunoglobulin (IVIG). There also is a report showing that infliximab therapy may be beneficial for FUMHD, given the elevated tumor necrosis factor-α levels seen in patients with FUMHD.10 Due to clinical suspicion for PLEVA, the patient in this case underwent a 4-mm punch biopsy of his largest lesion.

Because of his recent infection, he also was tested for Group A Streptococcus and Epstein-Barr viral infections. The histologic results of the biopsy supported the diagnosis of PLEVA, although serology testing was negative. The patient was prescribed a topical corticosteroid for symptomatic relief and told to follow up in 3 months. At his follow-up visit, most of his lesions had cleared and there was no evidence of scarring.

CASE #2

Pemphigus Vulgaris

Pemphigus vulgaris (PV) is a life-threatening immunobullous disorder affecting the mucous membranes and skin.

PV together with pemphigus foliaceus (PF), immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus (PNP) make up the pemphigus group of autoimmune blistering diseases characterized by intraepidermal acantholysis and antidesmosomal antibodies.11 This is in contrast to the pemphigoid autoimmune blistering diseases, in which the body creates subepidermal blisters and antibodies against the basement membrane zone.12 The term pemphigus (pemphix, the Greek term for pustule) originally encompassed all mucocutaneous blistering diseases until the discovery of autoantibodies in patients with pemphigus in the 1960s and 1970s.13,14

The mechanisms of pemphigus vulgaris are rooted in the formation of IgG autoantibodies against desmoglein.

Although rare, PV is the most common of the pemphigus variants, with an incidence of 1 to 5 per million people per year.15 It occurs most commonly in adults, with disease onset at 40 to 60 years of age, and affects men and women equally.

A higher prevalence is seen in patients of Ashkenazi Jewish, Indian, and Mediterranean descent.15,16 The genetic component of PV is strengthened further by higher susceptibility in patients with specific human leukocyte antigen allele variants (DR4, DR14, DRB1).17 The pathophysiology of PV is rooted in the formation of IgG autoantibodies against desmoglein, a transmembrane glycoprotein of desmosomes.11,18 Binding of these antibodies to the apical surface of keratinocytes leads to disruption of acantholysis, resulting in intraepithelial blistering.17 The type of antibody helps to differentiate mucosal PV (antidesmoglein 3), mucocutaneous PV (antidesmoglein 1 and 3), and PF (antidesmoglein 1).17,18 In contrast, IgA pemphigus (subcorneal pustular dermatosis) is characterized by IgA antibodies against the desmosomal protein desmocollin 1.17 Severity of PV has been linked to levels of antidesmoglein antibodies.19

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Dermatologic Look-Alikes PLEVA1-10

Pemphigus Vulgaris11-20

Dermatologic Presentation

• Subacute to acute eruption of multiple erythematous macules at various stages of evolution into vesiculopustules with hemorrhage, necrosis, ulceration, and crusts • No mucosal involvement

• Initial presentation: ulcerations and erosions of the oral mucosa • Later phase: cutaneous erythematous macules evolving into blistering ulcerations and erosions

Associations

• Generally asymptomatic • Can cause pruritus, burning, hypo/hyperpigmentation, scarring • May transition to PLC • Rare association with lymphoma

• Extremely painful, nonpruritic • Positive Nikolsky sign • Dysphagia, hoarseness, malnutrition, weight loss, GU/GYN symptoms

Etiology

• Lymphoproliferative disorder, classified as either a premalignant T-cell dyscrasia or a reactive immune response to infection

• Presence of IgG autoantibodies against desmoglein (transmembrane glycoproteins of desmosomes)

Characteristic Location

• Anterior trunk, flexural areas, and proximal extremities • No mucous membrane involvement • Can affect palms and soles

• Mucosal surfaces, chest and back, scalp, and intertriginous areas • Palms and soles generally are spared

Histology

• Epidermis: parakeratosis, spongiosis, dyskeratosis, acantholysis, vacuolization, focal epidermal necrolysis • Dermis: edema; dense, wedge-shaped lymphohistiocytic perivascular inflammatory infiltrate

• H&E: Intraepithelial cleavage with acantholysis, “tombstone” keratinocytes along the basement membrane zone • Direct IF: IgG antidesmoglein antibodies along the apical surface of epidermal keratinocytes

Diagnosis

• History and physical examination • Biopsy with H&E, immunohistochemistry for CD8

• History and physical examination • Biopsy with H&E, IF • Indirect IF, ELISA

Treatment

• Anti-inflammatory antibiotics • Phototherapy • Topical/systemic corticosteroids, antihistamines • Methotrexate, systemic immunomodulators • Acyclovir, dapsone, cyclosporine, IVIG

• Systemic/topical corticosteroids during remission induction • Adjuvant immunosuppressants during remission maintenance • Rituximab, IVIG, immunoadsorption, CAAR T-cell therapy

CAAR, chimeric autoantigen receptor; CD8, cluster of differentiation 8; ELISA, enzyme-linked immunosorbent assay; GU, genitourinary; GYN, gynecologic; H&E, hemotoxylin and eosin; IF, immunofluorescence; IgG, immunoglobulin G; IVIG, intravenous immunoglobulin; PLC, pityriasis lichenoides chronica

Investigators have theorized that UV radiation, drug exposure (antibiotics, nonsteroidal anti-inflammatory drugs), and diet are precipitating or exacerbating factors for PV.17 Most patients with PV initially present with persistent, quickly eroding mucosal ulcerations followed by cutaneous manifestations. Of the mucosal surfaces, the oral mucosa — notably the buccal mucosa, gingiva, tongue, hard and soft palate — is most commonly involved.11,16-18 PV lesions are extremely painful, and patients experience dysphagia, hoarseness (laryngeal involvement), malnutrition, and weight loss.17,18 Other mucous membranes can be affected,

including conjunctiva, esophagus, nose, anus, vulva, vagina, and cervix.17,18 Weeks to months after the appearance of mucosal PV, patients develop erythematous macules that eventually evolve into flaccid, nonpruritic blisters that easily rupture to form bloody erosions. Commonly affected areas include the chest and back, scalp, and intertriginous areas, such as axillae or skin folds of the breast, with the palms and soles generally spared.11,17,18 The Nikolsky sign (applying tangential pressure adjacent to a lesion induces a blister) is a frequently used, somewhat-specific diagnostic sign.17 PV occasionally can

44 THE CLINICAL ADVISOR • APRIL 2020 • www.ClinicalAdvisor.com

involve the nails, causing discoloration, paronychia, onychorrhexis, hemorrhage, and onycholysis.18 A small but important subset of individuals with PV presents with predominant cutaneous symptoms and little to no mucosal involvement.11 The diagnosis of PV relies heavily on well-sampled lesional and perilesional biopsies.11,17 The histologic hallmark of PV is intraepithelial cleavage with acantholysis. Basal keratinocytes remain attached along the basement membrane zone, producing characteristic “tombstone” morphology on H&E staining. Direct immunofluorescence reveals deposition of IgG antidesmoglein antibodies along the apical surface of epidermal keratinocytes. Circulating antibodies also are detectable through indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA).11,17,18 The differential diagnosis for PV includes several other autoimmune blistering diseases.17,18 PF, a superficial variant of pemphigus, also presents with cutaneous lesions in a seborrheic distribution and also may have a positive Nikolsky sign.

Mucosal involvement typically is absent and antidesmoglein 1 is the predominant antibody.11 In IgA pemphigus, patients present with subacute development of vesicles that evolve into pustules with accompanying erythematous plaques.

Immunofluorescence reveals IgA, rather than IgG, antibodies.18 Bullous pemphigoid is the most common blistering autoimmune disease. Unlike patient with PV, patients with bullous pemphigoid present at an older age (>80 years), with highly pruritic, tense, fluid-filled blisters most commonly appearing on flexural surfaces. Mucosal involvement is rare and Nikolsky sign is negative. Biopsy reveals subepidermal splitting with inflammation of the upper dermis, and IgG antibodies directed against hemidesmosomal proteins bullous pemphigoid antigen 180 (BP180) and BP230 can be visualized at the dermal-epidermal junction by immunofluorescence.12,16 Other conditions in the differential include drug-induced pemphigus, familial benign pemphigus (Hailey-Hailey disease), or PNP.17 The mucocutaneous lesions seen in patients with PV also can occur with several other conditions.17,18 Oral lesions seen early in the disease could suggest erosive lichen planus, herpetic gingivostomatitis, or aphthous ulcers.18 Cervical mucosal lesions can be misinterpreted as cervical dysplasia on Papanicolaou test.17 The cutaneous symptoms can resemble erythema multiforme or Stevens-Johnson syndrome.17,18 A thorough patient history, physical examination, and biopsy with histology and immunofluorescence can help eliminate these items from the differential and provide a definitive diagnosis of PV. However, the overlap in the early symptoms with other conditions commonly results in diagnosis being delayed until there is cutaneous involvement and the patient

already has seen several different specialists, such as dentists, oral surgeons, gynecologists, and otolaryngology-head and neck surgeons.11 First-line treatment for PV has been systemic/topical steroids aimed at inducing remission (suppressing active disease, minimizing formation of new lesions, and allowing existing lesions to heal during a consolidation period).20 The second phase of PV management, remission maintenance, involves keeping the patient on a disease-free course. Oral steroids are tapered during this phase to minimize side effects and replaced with immunosuppressant therapy (azathioprine, mycophenolate, dapsone, methotrexate, or cyclophosphamide).11 Rituximab, a monoclonal anti-CD20 B-cell antibody, has been found to be effective in treating pemphigus by reducing the amount of circulating autoantibodies. Other treatments for PV include newer B-cell therapies, IVIG, immunoadsorption, and a highly promising chimeric autoantigen receptor T-cell therapy.18 Although treatment has helped reduce the high mortality associated with PV (> 70%), these treatments are not benign, and patients risk complications ranging from simple skin infections to life-threatening systemic infection after immunosuppression.20 The patient in this case underwent lesional skin biopsy for H&E staining, perilesional skin biopsy for direct immunofluorescence, and serum collection for ELISA and indirect immunofluorescence. The results of the testing confirmed the diagnosis of PV, and the patient was started on systemic corticosteroids and followed closely. After a week of therapy, the patient had no new lesions and the corticosteroids were tapered slowly. ■ Riyad N. H. Seervai, BA, BS, and Eleanor Johnson, BA, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is a certified dermatologist at Elite Dermatology in Houston,Texas.

References 1. Treat JR. Pityriasis lichenoides et varioliformis acuta (PLEVA). UpToDate website. https://www.uptodate.com/contents/pityriasis-lichenoides-etvarioliformis-acuta-pleva?search=Pityriasis%20lichenoides%20et%20varioliformis %20acuta%20(PLEVA).&source=search_result&selectedTitle=1~15&usage_ type=default&display_rank=1. Updated July 12, 2019. Accessed February 20, 2020.

2. Fernandes NF, Rozdeba PJ, Schwartz RA, Kihiczak G, Lambert WC. Pityriasis lichenoides et varioliformis acuta: a disease spectrum. Int J Dermatol.

2010;49(3):257-261.

3. Khachemoune A, Blyumin ML. Pityriasis lichenoides: pathophysiology, classification, and treatment. Am J Clin Dermatol. 2007;8(1):29-36.

4. Weiss LM, Wood GS, Ellisen LW, Reynolds TC, Sklar J. Clonal T-cell populations in pityriasis lichenoides et varioliformis acuta (Mucha-Habermann disease).

Am J Pathol. 1987;126(3):417-421.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2020 45

Dermatologic Look-Alikes 5. Sibbald C, Pope E. Systematic review of cases of cutaneous T-cell lymphoma

14. Jordon RE, Sams WM Jr, Diaz G, Beutner EH. Negative complement

transformation in pityriasis lichenoides and small plaque parapsoriasis. Br J

immunofluorescence in pemphigus. J Invest Dermatol. 1971;57(6):407-410.

Dermatol. 2016;175(4):807-809.

15. Meyer N, Misery L. Geoepidemiologic considerations of auto-immune

6. Relvas M, Santiago L, Cardoso JC, Oliveira H. Pityriasis lichenoides et

pemphigus. Autoimmun Rev. 2010;9(5):A379-A382.

varioliformis acuta as presenting feature of acute human immunodeficiency

16. Kayani M, Aslam AM. Bullous pemphigoid and pemphigus vulgaris.

virus infection. BMJ Case Rep. 2019;12(8):pii: e231864.

BMJ. 2017;357:j2169.

7. Wenzel J, Gütgemann I, Distelmaier M, et al. The role of cytotoxic skin-

17. Hertl M, Sitaru C. Pathogenesis, clinical manifestations, and diagnosis

homing CD8+ lymphocytes in cutaneous cytotoxic T-cell lymphoma and

of pemphigus. UpToDate website. https://www.uptodate.com/contents/

pityriasis lichenoides. J Am Acad Dermatol. 2005;53(3):422-427.

pathogenesis-clinical-manifestations-and-diagnosis-of-pemphigus?search=

8. LeBoit PE. Lymphomatoid papulosis and cutaneous CD30+ lymphoma.

Pathogenesis,%20clinical%20manifestations,%20and%20diagnosis%20of

Am J Dermatopathol. 1996;18(3):221-235.

%20pemphigus&source=search_result&selectedTitle=1~85&usage_

9. Bellinato F, Maurelli M, Gisondi P, Girolomoni G. A systematic review

type=default&display_rank=1. Updated February 27, 2020. Accessed

of treatments for pityriasis lichenoides. J Eur Acad Dermatol Venereol.

March 2, 2020.

2019;33(11):2039-2049.

18. Didona D, Maglie R, Eming R, Hertl M. Pemphigus: current and future

10. Meziane L, Caudron A, Dhaille F, et al. Febrile ulceronecrotic Mucha-

therapeutic strategies. Front Immunol. 2019;10:1418.

Habermann disease: treatment with infliximab and intravenous immunoglob-

19. Harman KE, Seed PT, Gratian MJ, Bhogal BS, Challacombe SJ, Black MM.

ulins and review of the literature. Dermatology. 2012;225(4):344-348.

The severity of cutaneous and oral pemphigus is related to desmoglein 1 and

11. Melchionda V, Harman KE. Pemphigus vulgaris and pemphigus

3 antibody levels. Br J Dermatol. 2001;144(4):775-780.

foliaceus: an overview of the clinical presentation, investigations and

20. Hertl M, Geller S. Initial management of pemphigus vulgaris and pemphi-

management. Clin Exp Dermatol. 2019;44(7):740-746.

gus foliaceus. UpToDate website. https://www.uptodate.com/contents/

12. Daniel BS, Murrell DF. Review of autoimmune blistering diseases: the

initial-management-of-pemphigus-vulgaris-and-pemphigus-foliaceus?search=

pemphigoid diseases. J Eur Acad Dermatol Venereol. 2019;33(9):1685-1694.

Initial%20management%20of%20pemphigus%20vulgaris%20and%20

13. Beutner EH, Jordon RE. Demonstration of skin antibodies in sera of

pemphigus%20foliaceus&source=search_result&selectedTitle=1~150&u

pemphigus vulgaris patients by indirect immunofluorescent staining. Proc Soc

sage_type=default&display_rank=1. Updated August 17, 2018. Accessed

Exp Biol Med. 1964;117:505-510.

February 20, 2020.

Budd-Chiari Syndrome

diagnosis. https://www.uptodate.com/contents/budd-chiari-syndrome-

Continued from page 36

epidemiology-clinical-manifestations-and-diagnosis?search=budd%20chiari%20syndrome%20etiology&source=search_result&selectedTitle=2~126&usage_type=

5. De Stefano V, Teofili L, Leone G, Michiels JJ. Spontaneous erythroid colony

default&display_rank=2. Updated April 1, 2019. Accessed February 14, 2020.

formation as the clue to an underlying myeloproliferative disorder in patients

11. Darwish Murad S, Valla DC, de Groen PC, et al. Determinants of

with Budd-Chiari syndrome or portal vein thrombosis. Semin Thromb Hemost.

survival and the effect of portosystemic shunting in patients with Budd-Chiari

1997;23(5):411-418.

syndrome. Hepatology 2004;39(2):500-508.

6. Mitchell MC, Boitnott JK, Kaufman S, Cameron JL, Maddrey WC. Budd-

12. Lin M, Zhang F, Wang Y, et al. Liver cirrhosis caused by chronic Budd-Chiari

Chiari syndrome: etiology, diagnosis and management. Medicine (Baltimore).

syndrome. Medicine (Baltimore). 2017;96(34):e7425.

1982;61(4):199-218.

13. Cura M, Haskal Z, Lopera J. Diagnostic and interventional radiology for

7. Lai M. Etiology of the Budd-Chiari syndrome. UpToDate website. https://

Budd-Chiari syndrome. Radiographics. 2009;29(3):669-681.

www.uptodate.com/contents/etiology-of-the-budd-chiari-syndrome?search=

14. Pavri TM, Herbst A, Reddy R, Forde KA. Budd-Chiari syndrome: a single-

budd%20chiari%20syndrome%20etiology&source=search_result&selected

center experience. World J Gastroenterol. 2014;20(43):16236-16244.

Title=1~126&usage_type=default&display_rank=1. October 31, 2018.

15. Lai M. Budd-Chiari syndrome: management. UpToDate website. https://www.

Accessed February 13, 2020.

uptodate.com/contents/budd-chiari-syndrome-management?search=budd%20

8. Darwish Murad S, Plessier A, Hernandez-Guerra M, et al. Etiology,

chiarisyndrome&source=search_result&selectedTitle=2~126&usage_type=default

management, and outcome of the Budd-Chiari syndrome. Ann Intern Med.

&display_rank=2. Updated November 15, 2018. Accessed February 13, 2020.

2009;151(3):167-175.

16. Potthoff A, Attia D, Pischke S, et al. Long-term outcome of liver transplant

9. Plessier A,Valla DC. Budd-Chiari syndrome. Semin Liver Dis. 2008;28(3):259-269.

patients with Budd-Chiari syndrome secondary to myeloproliferative neo-

10. Lai M. Budd-Chiari syndrome: epidemiology, clinical manifestations, and

plasms. Liver Int. 2015;35(8):2042-2049.

46 THE CLINICAL ADVISOR • APRIL 2020 • www.ClinicalAdvisor.com

LEGAL ADVISOR CASE

Refusal to Draw Blood

BY ANN W. LATNER, JD

Mr G, a truck driver, was brought to the burn unit of a university hospital after his semitrailer truck was involved in a head-on collision with a pickup truck. The pickup truck, which was traveling at high speed, was driven by an intoxicated man fleeing the police. The driver of the pickup truck died on impact, and Mr G was severely burned when his truck exploded. He was transported via ambulance to the university hospital in a sedated and comatose state.

Ms A was the staff nurse working in the burn unit when the patient was admitted. She was approached by one of the police officers, Officer J, who had accompanied Mr G in the ambulance.

Officer J requested that Ms A take a blood sample from the unconscious patient. Ms A politely refused, explaining that hospital policy forbade taking blood from a comatose patient. Officer J reassured Ms A that he wasn’t seeking the blood sample because the patient was a suspect; rather, he wanted to establish that the patient had not been driving under the influence as a protective measure.

When Ms A again refused, the officer demanded that she take the blood sample. Ms A told him

© TFOXFOTO / GETTY IMAGES

What happens when a police officer and nurse have a difference of opinion over whether blood can be drawn from an unconscious patient?

A difference of opinion leads to an arrest, a firing, a settlement, and a potential ongoing lawsuit.

that hospital policy required either a warrant or a court order (neither of which the officer had), or the patient’s consent (which wasn’t possible because he was comatose). The officer believed that he had the authority to order a blood draw under the state’s code. The nurse believed that without a warrant or legal document, blood could not be taken from a patient who is unable to consent. The discussion became heated, and the officer told Ms A that he would arrest her if she continued to refuse his order. Ms A showed the officer a printed copy of the hospital’s policy, but he was unmoved.

Ms A then called her supervisor and put him on speakerphone. Officer J told the supervisor he was going to arrest Ms A and hold her criminally liable for not proceeding with the blood draw.

The supervisor began to tell the officer that he was making a mistake, when Officer J cut Cases presented are based on actual occurrences.

Names of participants and details have been changed.

Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2020 47

LEGAL ADVISOR the supervisor off and grabbed hold of Ms A to arrest her.

A struggle ensued and was caught on the hospital’s security cameras and Officer J’s bodycam. Ms A began shouting for help as she was led out of the hospital, put in handcuffs, told she was being arrested, and put into a police car.

Ms A eventually was released, and no charges were filed against her. An investigation was launched against Officer J, and he was eventually fired from his position. Mr G, the burn patient, died from his injuries.

Legal Background

In this case, the police officer mistakenly believed that he had the authority to compel hospital personnel to draw blood from the victim of an accident. However, Ms A was correct when she cited the hospital policy. Officer J wrongly believed that implied consent was applicable in the case or that exigent circumstances of the crash made it necessary; however, the patient was the victim of the accident, not a suspect. A 2016 US Supreme Court decision permits warrantless breath tests but not warrantless blood tests in drunk driving arrests.

Based on the security camera videos, which were released to the public, there was general agreement that Officer J had acted inappropriately in arresting Ms A. She hired an attorney and filed a lawsuit. The city settled with Ms A for $500,000.

A rally against police brutality that called for the firing of Officer J took place and after an internal investigation, he was fired from his job.

department policies. Officer J’s lawsuit claimed that he and Ms A were both following orders from their supervisors. The lawsuit claimed that although Ms A was awarded $500,000, Officer J’s life had been ruined and he has been left “to live in seclusion with scant employment opportunities.” This case is currently pending.

Protecting Yourself

Ms A handled the situation appropriately by explaining the hospital policy to the police officer. She calmly told him that 1 of 3 criteria — warrant, court order, or patient consent — had to be present for a police-ordered blood draw. The footage from the officer’s bodycam showed that until Ms A was physically grabbed and arrested, she had been acting professionally and appropriately.

Although it’s always best to avoid confrontations with the police, health care professionals have a responsibility to protect the rights of patients, particularly those who are unable to speak for themselves. ■ Ann W. Latner, JD, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.

The notoriety of the case led to the state’s Judiciary Committee to unanimously vote to start drafting a bill meant to clarify consent laws regarding police-ordered blood draws.

After the state’s House of Representatives passed the bill, the state Governor signed it into law. The new bill requires officers in the state to present a warrant to obtain a blood draw. The hospital also changed its policy after the incident.

Now police officers are not allowed in patient-care areas and have to speak to supervisors, not nurses, when requesting blood draws.

More than 2 years after the accident, Officer J filed a lawsuit against his former police department, claiming he was wrongfully terminated for following orders and complying with 48 THE CLINICAL ADVISOR • APRIL 2020 • www.ClinicalAdvisor.com

“They now think that kryptonite is actually good for you, in small doses.”

© The New Yorker Collection 2020 from cartoonbank.com. All Rights Reserved.

The police officer believed that he had the authority to compel the nurse to draw blood from the comatose patient.