March 2014 Clinical Advisor by The Clinical Advisor

THE CLINICAL ADVISOR • MARCH 2014

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■■Quality of life after stroke ■■The hazards of sitting ■■NSAIDs and miscarriage

ADVISOR FORUM

■■Too old for ultrasound? ■■Stubborn ear fungus ■■How to stop oral bleeding

MARCH 2014

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DECODING RHEUMATOLOGY

SEROLOGIES

Serologic testing is important in the early detection of rheumatoid arthritis (shown).

LEGAL ADVISOR

Brain damage after surgery to remove an ear tumor

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n Dermatology Clinic

THICKENED, YELLOW THUMBNAIL PAGE 75

n Dermatologic Look-Alikes VOLUME 17, NUMBER 3

PIGMENTATION IN THE ORAL CAVITY PAGE 79 Take the Scavenger Hunt Challenge and win an iPad! Turn to p. 46 for details

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Editor Joe Kopcha, editor@clinicaladvisor.com Managing editor Marina Galanakis Senior editor Delicia Yard Web editor Nicole Blazek Contributing editors Bruce D. Askey, MSN, CRNP; Rebecca H. Bryan, APRN, CNP; Eileen F. Campbell, MSN, CRNP; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP-BC; Sharon Dudley-Brown, PhD, FNP-BC; Maria Kidner, DNP, FNP-C; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Claire B. O’Connell, MPH, PA-C; Kathy Pereira, MSN, FNP-BC; Sherril Sego, FNP, DNP; Julee B. Waldrop, MS, PNP; Kim Zuber, PA-C Art director Andrew Bass Group art director, Haymarket Medical Jennifer Dvoretz Production director Kathleen Millea Circulation manager Paul Silver Audience development director John Crewe National accounts manager Alison McCauley, 646.638.6098 alison.mccauley @ haymarketmedical.com Group publisher Thomas P. Hennessy, 646.638.6085 tom.hennessy @ haymarketmedia.com Editorial director Jeff Forster Vice president, medical magazines and digital products Jim Burke CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 114 West 26th Street, 4th Floor, New York, NY 10001 For advertising sales, call 646.638.6085. For reprints, contact Wright’s Reprints at 877.652.5295. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Clinical Challenge” are not the actual individuals mentioned in the articles.They appear for illustrative purposes only. The Clinical Advisor® (USPS 017-546, ISSN 1524-7317), Volume 17, Number 3, is published 12 times a year, monthly, for $75.00 per year in the United States; $85.00 in Canada; $110.00 for all other foreign, in U.S. dollars, by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Single copy: $20 U.S.; $30 foreign. www.ClinicalAdvisor.com. To order or update your paid subscription, call 800.436.9269. Periodicals postage rate paid at New York, NY, and additional mailing offices. POSTMASTER: Send address change to DMD Data Inc. 10255 W. Higgins Rd, Suite 280, Rosemont, IL 60018. Call 800.430.5450 to change your address or make other subscription inquiries. Requests for subscriptions from outside the United States must be accompanied by payment. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2014.

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LEVEL

CONTENTS MARCH 2014

NEWS AND COMMENT

57 CME/CE An understanding of substance use disorder Effective treatment requires the recognition of addiction as a brain disease and an understanding of its underlying physiology and pathophysiology.

19 Newsline ■■Life after stroke worse for women ■■HPV tied to more oropharyngeal cancers ■■Big weight gain not a prerequisite for diabetes ■■Recurrent UTI therapies assessed ■■Too much sitting is hazardous ■■Diagnostic criteria for jaw problems issued ■■Hepatitis C advice posted on new website ■■Dense coronary calcium may help, not hurt ■■Help for kids with new Crohn disease ■■NSAIDs do not raise the risk of miscarriage

DEPARTMENTS Jump in oral cancers attributed to HPV 25

72 Derm Dx Read the clinical descriptions, view the images, and make your diagnosis at ClinicalAdvisor.com.

34 Drug Update ■■Breakthrough therapy for HCV infection ■■Improved control of seizures Screening for substance use disorder 57

88 Commentary

and hypertension presented with a thick and yellow right thumbnail that caused pain intermittently.

47 Solving the mystery of rheumatic disease Selecting appropriate lab tests when evaluating patients with symptoms suggesting a rheumatic condition often calls for a bit of detective work.

Continues on page 12

Ear surgery leads to intracranial bleeding 68

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75 CME/CE Dermatology Clinic n More than 20 years earlier, a man developed skin-colored nodules on the proximal and lateral nail folds of several toes and fingers. n A woman with a history of glaucoma

FEATURES

MAKING CONTACT

68 Legal Advisor Bleeding and pressure after surgery to remove a slow-growing tumor from the vestibular nerve cause permanent brain damage.

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CONTENTS 79 CME/CE Dermatologic Look-Alikes Two patients presented with dark pigmentation in the oral cavity. 83 CME/CE Posttest 84 Alternative Meds Update Mushroom extract has been used to boost the immune system and limit or reverse the growth of cancerous tumors.

ADVISOR FORUM Dark pigmentation on the gingiva years after dental implant placement 79

64 Consultations ■■Infant immunization after a blood transfusion ■■Cardiac workup for patients with diabetes ■■And more 66 Clinical Pearls ■■Tick-removal advice ■■Stop the bleeding ■■And more 66 Your Comments ■■Improved performance at the expense of patient care ■■The patient comes first

Mushroom extract shown to improve side effects of chemotherapy 84

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Anemia may raise stroke risk for some Iron deficiency may increase ischemic stroke risk in individuals with defective pulmonary capillary filtration. Multiple-provider opioid prescriptions common in Medicare More than three-quarters of Medicare beneficiaries with four or more providers have concurrent opioid prescriptions, suggesting fragmented care. Even incomplete HPV vaccination cuts risk of genital warts Research indicates that three doses of quadrivalent HPV vaccine, rather than the recommended four, are still protective.

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BP changes in middle age may predict heart disease When clinicians measure BP, they do not usually consider how changes over long periods of time might affect a person’s health. A new study examined whether BP changes between early adulthood and middle age are associated with risk for developing heart disease. Mental-exercise benefits persist 10 years after training Older adults who received as few as 10 sessions of mental training show long-lasting improvements in reasoning and speed-of-processing skills 10 years after the intervention, according to University of Florida Health researchers.

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Derm Dx Interact with your peers by viewing the images and offering your diagnosis and comments. CliniAd.com/1jKZcuG

Robyn Carlisle, MSN, CNM, WHNP The meaningful use paradox “Quality indicators” and “benchmarking” have become buzzwords in many practices, but are such efforts truly benefiting patients? Jim Anderson, MPAS, PA-C, ATC A new vision for the American Academy of Physician Assistants Bad feelings towards the AAPA run deep, but mending bridges is still possible. My goal is to find ways to build connections between disparate PAs who care deeply about the profession but differ greatly regarding organizational directions.

Clubbed fingers A 48-year-old patient with a history of Graves disease presents with clubbing of his fingers.

MAKING CONTACT

Leigh Montejo, MSN, FNP-BC Sacrificing the white coat for infection control? The standard clinic attire may be working against the “Do no harm” mantra by which health-care providers abide.

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Newsline

Rise in oral cancers linked to HPV page 25

M A R C H 2 014

Antibiotics most effective for recurrent UTIs page 26

Biologics for kids with new Crohn disease page 30

Life after stroke worse for women

WOMEN have worse quality of life than do men up to 12 months after suffering a stroke, researchers found even after adjusting for important sociodemographic variables, stroke severity, and disability. In the study, reported in Neurology, quality of life was assessed three and 12 months postdischarge in 1,370 patients (53.7% male; median age 65 years) who had been treated for ischemic stroke or transient ischemic attack (TIA). Women were found to have significantly lower quality of life at both points, faring worse in the dimensions of mobility, pain/ discomfort, and anxiety/depression. Quality of life remained lower for women than for men after multivariable adjustment for sociodemographic, clinical, and stroke-related factors. “As more people survive strokes, physicians and other health-care

Women had less mobility and more pain and anxiety than did men.

providers should pay attention to quality-of-life issues and work to develop better interventions, even gender-specific screening tools, to improve these patients’ lives,” noted Cheryl Bushnell, MD, associate professor of neurology at Wake Forest Baptist Medical Center in Winston-Salem, N.C., and senior author of the study, in a statement issued by Wake Forest Baptist. Bushnell also authored the newly released Guidelines for the Prevention of Stroke in Women: a Statement for Healthcare Professionals from the American Heart Association/ American Stroke Association, (available from the journal Stroke at stroke.ahajournals.org/content/ea rly/2 014/02/0 6/01. str.0000442009.06663.48.full. pdf+html; accessed February 15, 2014). This scientific statement also calls for the development of a female-specific stroke risk score.

High BP, migraine with aura, atrial fibrillation, diabetes, depression, and emotional stress tend to be stronger risk factors for stroke in women than in men. For example, according to the guidelines: • Women should be screened for high BP before initiating oral contraceptive use, as the combination raises the risk of stroke. • Women with a history of high BP before pregnancy should be considered for low-dose aspirin and/or calcium supplement therapy to lower their risk for preeclampsia. • Women who have migraine headaches with aura should stop smoking to avoid higher stroke risk. • Women aged 75 years and older should be screened for atrial fibrillation risks due to this condition’s association with heightened stroke risk.

Most expensive conditions treated in U.S. hospitals Inpatient costs make up the largest single component of health-care spending. Source: Agency for Healthcare Research and Quality, Healthcare Cost and Utilization Project, Statistical Brief #160

Septicemia ($20.3 billion) Osteoarthritis ($14.8 billion) Complication of device ($12.9 billion) Liveborn (newborn) ($12.4 billion) Acute MI ($11.5 billion) 0

Billions

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Newsline CANCERS of the base of the tongue, the tonsils, the soft palate, and the pharynx have increased by 60% in persons younger than age 45 years, and this jump is thought to be related to human papillomavirus (HPV) transmission and changes in sexual practices, say investigators. The Surveillance Epidemiology End Results 9 database showed that 1,603 patients younger than age 45 years received a diagnosis of oropharyngeal squamous cell carcinoma (OPSCC) from 1973 to 2009, according to a research group led by Farzan Siddiqui, MD, PhD, of the Department of Radiation Oncology at Henry Ford Hospital in Detroit. The tea m repor ted in Otolaryngology–Head and Neck Surgery that during the years

studied, the incidence of OPSCC cancer in patients aged 36 to 44 years (90% of the subjects) rose from 0.79 per 100,000 to 1.39 per 100,000, with the rate increasing in whites (73% of the subjects) by 113%, from 0.20 to 0.42, but falling in blacks by 52%, from 0.67 to 0.32. “The growing incidence in oropharyngeal cancer has been largely attributed to the sexual revolution of the 1960s and 1970s, which led to an increased transmission of high-risk HPV,” commented Siddiqui in a statement. “Not only were we surprised to f ind a substantial increase in young adults with cancer of the tonsils and base of tongue, but also a wide deviation among Caucasians and African Americans with this cancer.”

HPV tied to more oropharyngeal cancers

More than 40 types of HPV (shown) can infect the mouth and throat.

Siddiqui’s statement went on to explain that the predominance of oropharyngeal cancer in the age group studied likely suggests either nonsexual modes of HPV transfer at a younger age or a shortened latency period between infection and the development of cancer.

THE great majority of patients in a recent study had only a modest weight gain prior to receiving a diagnosis of type 2 diabetes, suggesting that strategies focusing on small weight reductions for the entire population may be more beneficial than concentrating on weight loss for high-risk individuals (PLoS Med. 2014;11[2]:e1001602; available at www.ncbi.nlm.nih.gov/pmc/ articles/PMC3921118/, accessed February 15, 2014). Researchers evaluated data from 6,705 white men and women from Whitehall II, an

Focusing on small weight reductions may be more beneficial.

observational prospective cohort study of civil servants based in London. All individuals were free of diabetes at enrollment. Over a median follow-up of 14.1 years, type 2 diabetes developed in 645 of the participants. Three patterns of BMI changes were identified among those with diabetes: Most of these individuals (604, or 94%) fell into the “stable overweight” category, with an overweight but relatively constant BMI level throughout follow-up. The 15 “progressive weight gainers” gained weight consistently prior to diagnosis. The remaining

26 patients were “persistently obese”; they were severely obese for 18 years before diagnosis. The stable-overweight patients experienced slight worsening of beta cell function and insulin sensitivity from five years prediagnosis. In the progressive-weight-gain group, the additional pounds were accompanied by linear increases in BP and an exponential increase in insulin resistance a few years before diagnosis. The persistently obese individuals showed relatively stable insulin sensitivity but an initial beta cell compensation followed by loss of beta cell function.

Big weight gain not a prerequisite for diabetes

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Newsline Recurrent Too much sitting is hazardous UTI therapies assessed

Disability risk may be doubled by each additional hour spent sitting.

“The assumption has been that if you’re fit and physically active, that will protect you, even if you spend a huge amount of time sitting each day,” observed Seguin in a separate statement. “In fact, in doing so you are far less protected from negative health effects of being sedentary than you realize.” Men are vulnerable to the dangers of sitting as well (Circ Heart Fail. 2014;7:21-27). Men who spent five or more hours a day sitting were 34% more likely to develop heart failure than were men who sat for two hours or less, irrespective of how much they exercised. A team led by Dorothy D. Dunlop, PhD, reported in Journal of Physical Activity & Health that among 2,286 adults aged 60 years and older, being sedentary was almost as strong a risk factor for disability as was a lack of moderate vigorous activity, and every additional hour spent sitting was linked with a doubling of disability risk, despite the amount of moderate exercise performed.

Diagnostic criteria for jaw problems issued NEW criteria on the diagnosis of temporomandibular disorders (TMDs) have been developed to help clinicians better identify this group of often-painful jaw conditions that affects an estimated 10% to 15% of Americans ( J Oral Facial Pain Headache. 2014;28[1]:6-27). The evidence-based criteria comprise an improved screening tool to help health professionals more readily differentiate the most common forms of TMD.

“We’ve had diagnostic criteria for years; what is unique here is instead of a panel of experts empirically deciding best practices, we relied on science as a methodology to test our best assumptions,” explained colead author Eric Schiffman, DDS. Most people with chronic temporomandibular problems also suffer from other ailments. The new diagnostic criteria facilitate the physical as well as the psychosocial assessments of patients.

DAILY antibiotic use came out on top when compared with several other strategies for managing recurrent urinary tract infections (UTIs). Researchers developed a model of recurrent UTI for each management strategy for which at least two adequate trials had been published (Clin Infect Dis. 2014;58[2]:147-160). The investigators simulated a cohort that experienced three UTIs per year and a secondary cohort that experienced eight UTIs per year. Five strategies for the prevention and management of recurrent UTIs were analyzed: daily antibiotic (nitrofurantoin [Furadantin, Macrobid, Macrodantin]) prophylaxis, daily estrogen prophylaxis, daily cranberry prophylaxis, acupuncture prophylaxis, and symptomatic self-treatment. The nitrofurantoin option proved to be the most effective as well as the most expensive to the payer in the model of three UTIs per year, reducing the UTI rate to 0.4 per year, at an annual cost to the payer of $821. The acupuncture recurrence rate was 0.7 per year. The use of cranberry pills brought the recurrence rate to 1.1 per year, as did estrogen therapy. Symptomatic self-treatment did not reduce recurrence rates but was associated with the highest quality of life of all management strategies (all regimens improved this measure).

SEVERAL new research findings indicate that the less sitting a person does, the better—regardless of fitness level. Rebecca Seguin, PhD, CSCS, and colleagues analyzed data from 92,234 participants in the Women’s Health Initiative Observational Study, aged 50 to 79 years at baseline (1993–1998). Over a mean 12-year follow-up, women reporting more than 11 hours of sedentary time per day (sitting and resting, excluding sleeping) had a 12% increase in all-cause premature mortality compared with women reporting four hours or less of inactivity, regardless of physical mobility and function, chronic disease status, demographic factors, and overall fitness. The most sedentary women had 13%, 27%, and 21% greater risks of death from cardiovascular disease, coronary heart disease, and cancer, respectively, compared with the most active women (Am J Prev Med. 2014;46[2]:122-135).

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Newsline A WEBSITE that provides guidance for clinicians and patients who are managing hepatitis C infection has been launched by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America in collaboration with the International Antiviral Society–USA. HCVguidelines.org carries new recommendations jointly released by the three groups. Whereas some persons with hepatitis C virus will require specialist care, others will be treated by primarycare providers. The treatment recommendations at HCVguidelines. org will be updated as new drugs become available, to provide clinicians with timely guidance. Other relevant information will also be added regularly.

Hepatitis B virus also made recent news when the U.S. Preventive Services Task Force (USPSTF) posted a draft recommendation statement and draft evidence report on screening for the infection (available at www. uspreventiveservicestaskforce. org/bulletins/hepbbulletin.pdf; accessed February 15, 2014). The USPSTF proposes that individuals deemed to be at high risk for hepatitis B virus be screened for the infection, including: people who were born in countries and regions with a prevalence of hepatitis B infection, such as Africa, Southeast Asia, the Middle East, Eastern Europe, and the northern countries of South America; people born in the United States who were not vaccinated against hepatitis B

Hep C advice posted on new website

Hepatitis antigens are detected using an in vitro assay (shown).

virus as infants and whose parents were born in regions with a high prevalence of hepatitis B infection; and people who are HIV-positive or injection drug users, men who have sex with men, people with a weakened immune system, and people currently on dialysis.

ALTHOUGH it is not good to have coronary artery calcium (CAC), the more dense form may pose less of a danger to cardiovascular health. “Current scor ing systems assume that denser heart plaque [CAC] is more hazardous, but we found the opposite,” affirmed lead study author Michael H. Criqui, MD, of the University of California, San Diego School of Medicine, in a statement issued by the facility. The Agatston—the standard CAC score—is based on the amount of calcium found in the coronary arteries, and is

CAC density was inversely associated with CVD events.

weighted upward for greater calcium density. Criqui and his research team set out to determine the independent associations of CAC volume and CAC density with incident CVD events. They followed 3,398 non-Hispanic white, black, Hispanic, and Chinese men and women aged 45 to 84 years. All participants were free of known CVD at baseline, and had CAC greater than zero on their baseline CT exam. A total of 175 coronary heart disease events (such as MI or resuscitated cardiac arrest or death) and

90 additional CVD events (such as stroke) occurred during a median follow-up of 7.6 years. CAC volume was positively and independently associated with coronary heart disease and CVD risks. However, at any level of CAC volume, CAC densit y was inversely and significantly associated with coronary heart disease and CVD risks, leading the researchers to conclude that the role of CAC density, and not just CAC volume, should be considered when evaluating current CAC scoring systems ( JAMA. 2014;311[3]:271-278).

Dense coronary calcium may help, not hurt

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Newsline EARLY monotherapy with such anti–tumor necrosis factor (TNF)-alpha agents as inf liximab (Remicade) or adalimumab (Humira) may produce better overall clinical and growth outcomes than does current standard therapy in children with a new diagnosis of Crohn disease. Standard therapy for children with newly diagnosed Crohn disease includes early administration of immunomodulators after initial treatment with corticosteroids, explained Jeffrey S. Hyams, MD, of Connecticut Children’s Medical Center in Hartford, and fellow investigators in Gastroenterology (2014;146:383391). Such biologic agents as infliximab and adalimumab are generally reserved for people with Crohn disease who have not responded to previous therapy.

The researchers compared the effectiveness of early therapy with an anti-TNF-alpha (treatment administered no more than three months’ postdiagnosis) with that of an immunomodulator in attaining clinical remission and facilitating growth in 204 pediatric patients (younger than age 17 years; median age 11.8 years) with inflammatory (nonpenetrating, nonstricturing) Crohn disease. At one year, 85.3% children on the anti-TNF-alpha therapy had attained remission, compared with 60.3% of those receiving an immunomodulator. Early immunomodulator therapy was similar to no early immunotherapy, with 54.4% of children receiving no early immunotherapy achieving remission at one year. At the one-year mark, none of the anti-TNF-alpha recipients

Help for kids with new Crohn disease

Crohn disease causes ulceration (white) of the colon.

had a pediatric Crohn’s Disease Activity Index greater than 30, compared with 7% in the early immunomodulator group and 10% in the no-early-immunotherapy group. In addition, normal growth velocity was established only in the group of children undergoing early anti-TNF-alpha therapy.

THE RISK for spontaneous abortion is not increased following exposure to nonsteroidal anti-inf lammatory drugs (NSAIDs), aff irmed Amalia Levy, MPH, PhD, and associates in CMAJ (available at www.cmaj. ca/content/early/2014/02/03/ cmaj.130605.long; accessed February 15, 2014). Spontaneous abortion is the most common complication of pregnancy and NSAIDs are widely used by pregnant women, but published data are inconsistent regarding the risk of spontaneous

Spontaneous abortion is the most common pregnancy complication.

abortion following NSAID exposure. Levy and coauthors analyzed data from a cohort of 65,457 women who conceived between January 2003 and December 2009. A total of 6,508 (9.9%) experienced spontaneous abortion, and 4,495 (6.9%) of the pregnant women were exposed to NSAIDs during the study period. NSAID exposure was not an independent risk factor for spontaneous abortion, and the investigators found no increased risk for specific NSAIDs, with the exception of a significantly

increased risk with exposure to indomethacin (Indo-Lemmon, Indocin). Clinicians might need to advise women who are of child-bearing age about even more aspects of pregnancy: A study in Fertility & Sterility by Jessica Illuzzi, MD, and colleagues revealed that in a sample of 1,000 women aged 18 to 40 years across the United States, one-third of the subjects were unaware of the adverse implications of sexually transmitted infections, obesity, or irregular menses for procreative success. n

©THINKSTOCK

NSAIDs do not raise the risk of miscarriage

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DrugUpdate New drug information from the publishers of MPR

Breakthrough therapy for HCV infection Product: Sovaldi Company: Gilead Sciences Pharmacologic class:

Hepatitis C virus (HCV) NS5B polymerase inhibitor. Active ingredient:

Sofosbuvir 400mg; tabs. Indication: As a com-

ponent of a combination antiviral treatment regimen for chronic hepatitis C (CHC) genotype 1, 2, 3, or 4 infection, including persons with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplant), and those with HCV/HIV-1 coinfection. Not for use as monotherapy.

pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. Clinical trials: The safety and efficacy of Sovaldi was evaluated in five phase 3 trials in a total of 1,724 HCV mono-infected subjects with genotypes 1–6 CHC and one phase 3 trial in 223 HCV/HIV-1 co-infected subjects with genotype 1, 2, or 3 CHC. The primary endpoint

was sustained virologic response (SVR), which was defined as HCV RNA less than lower limit of quantification at 12 weeks after the end of treatment. NEUTRINO was an open-label, single-arm trial that evaluated 12 weeks of treatment with Sovaldi in combination with peginterferon (PegIFN) alfa 2a (Pegasys) and ribavirin (RBV) (Copegus, Rebetol, Ribasphere, Virazole) in treatment-naïve subjects with genotype 1, 4, 5, or 6 HCV infection compared with prespecified historical control SVR rate of 60% (P <0.001). The overall SVR rate was 90% (295/327). The SVR rates by specific genotype were: Continued pg. 38

Product: Fycompa Company: Eisai Pharmacologic class: α-amino-3-

hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) glutamate receptor antagonist Active ingredient:

Perampanel 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg; tabs. Indication: Adjunctive

treatment of partial-onset seizures with or without secondarily generalized seizures in patients aged 12 years and older. Pharmacology: Perampanel is a noncompetitive antagonist of the ionotropic AMPA glutamate receptor on postsynaptic neurons. The precise mechanism by which perampanel exerts its antiepileptic effects in humans has not been fully elucidated.

Pharmacology:

Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication. This nucleotide prodrug undergoes intracellular metabolism to form the

Improved control of seizures

Sovaldi blocks a specific protein needed by the hepatitis C virus to replicate.

Continued pg. 38

For more products, visit www.eMPR.com

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DrugUpdate Sovaldi from pg. 34

genotype 1, 89% and genotype 4, 96%. FISSION was an activecontrolled trial that evaluated 12 weeks of treatment with Sovaldi plus RBV vs. 24 weeks with PegIFN plus RBV in treatment-naïve subjects with genotype 2 and 3 HCV.The overall SVR rate for both arms was 67%.The SVR rates for genotype 2 was 95% vs. 78% and genotype 3 was 56% vs. 63% in the Sovaldiplus-RBV arm compared with the PegIFN-plusRBV arm, respectively. Adults: 400 mg once daily. Genotype 1: Treat for 12 weeks (with PegIFN alfa plus RBV) or 24 weeks (with RBV) if interferonbased regimen ineligible.

Genotype 2: Treat for 12 weeks (with RBV). Genotype 3: Treat for 24 weeks (with RBV). Genotype 4: Treat for 12 weeks (with PegIFN alfa plus RBV). Hepatocellular carcinoma: Treat up to 48 weeks (with RBV) or until time of liver transplant, whichever occurs first. Dose reduction of sofosbuvir is not recommended. Other dose modifications: See full labeling. If PegIFN alfa or RBV are discontinued, sofosbuvir should also be discontinued. Children: <18 years: not established. Contraindications: Pregnant women and in men whose partners are

Fycompa from pg. 34

Clinical trials: The

Fycompa treats partial-onset seizures in individuals who have epilepsy.

efficacy of perampanel in partial-onset seizures, with or without secondary generalization, was studied in patients aged 12 years and older who were not adequately controlled with one to three concomitant antiepileptic drugs in three randomized, double-blind, placebo-controlled, multicenter trials (Studies 1, 2, 3).

pregnant. (Note: RBV is Cat. X.) PegIFN and RBV contraindications also apply to combination therapy with sofosbuvir. Warnings/Precautions:

Female patients/partners of male patients must have negative pregnancy test before initiating therapy; use two effective nonhormonal methods of contraception during and for six months after treatment completion; perform routine monthly pregnancy test. Severe renal impairment or end-stage renal disease. Decompensated cirrhosis. Post-liver transplant recipients. Pregnancy (Cat. B). Nursing mothers: not recommended.

concomitant strong P-gp inducers (e.g., rifampin [Rifadin], St. John’s wort). Antagonized by carbamazepine, phenytoin (Dilantin, Phenytek), phenobarbital, oxcarbazepine (Trileptal), rifabutin (Mycobutin), rifapentine (Priftin), tipranavir/ritonavir (Aptivus/Norvir); avoid concomitant use. May be coadministered with P-gp and/or breast cancer resistance protein inhibitors. (See full labeling.) Adverse reactions: Rash

fatigue, headache, nausea, insomnia, anemia, pruritus. How supplied: Tabs—28

Interactions: Avoid

For more information, call 800.445.3235 or visit www.Sovaldi.com.

All trials had an initial six-week baseline period, during which patients were required to have more than five seizures. This was followed by a 19-week treatment period (six-week titration plus 13-week maintenance). Patients received an initial dos of 2 mg/day during the titration period, which was increased weekly by 2 mg/ day to the final target dose. The primary endpoint for all studies was the

percent change in seizure frequency per 28 days during the treatment period as compared with the baseline period. A statistically significant decrease in seizure rate was seen at doses of 4 mg/day to 12 mg/day (P <0.05). Dose response was apparent at 4 mg/day to 8 mg/day, with little additional benefit at 12 mg/day. Further analysis revealed a substantially reduced effect of perampanel with

For more products, visit www.eMPR.com

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DrugUpdate concomitant antiepileptic drug inducers (e.g., carbamazepine, oxcarbazepine [Trileptal], or phenytoin [Dilantin, Phenytek]). The percentage of patients with a 40% to <60% reduction in seizure frequency during the maintenance phase were 13.2%, 17.4%, 19.0%, and 15.8% for placebo, 4 mg, 8 mg, and 12 mg, respectively. The percentages of patients with a ≥50% reduction in seizure frequency were 19.3%, 28.5%, 35.3%, and 35.0% for placebo, 4 mg, 8 mg, and 12 mg, respectively. Adults: Initially 2 mg/day at bedtime; may increase by 2 mg/day in weekly increments to 4 mg/day to 12 mg/day; maximum 12 mg/day. Concomitant enzyme-inducing antiepileptic drugs: initially

4 mg/day at bedtime. Elderly or hepatic impairment: Maximum frequency for dose increase is every two weeks; mild: maximum 6 mg/ day; moderate: maximum 4 mg/day. Severe hepatic or renal impairment, hemodialysis: not recommended. Children: Not established. Warnings/Precautions:

Increased risk of serious psychiatric and behavioral reactions (e.g., aggression, hostility, irritability); monitor during treatment (especially initial titration period or at higher doses) and one month after last dose; reduce dose or permanently discontinue if symptoms persist. Increased risk of suicidal thoughts or behavior; monitor for clinical worsening or unusual

changes. Increased risk of neurologic effects (e.g., dizziness, gait disturbance, somnolence, fatigue) or falls and injuries; monitor (especially elderly). Avoid abrupt cessation. Elderly: titrate slowly. Pregnancy (Cat. C). Nursing mothers.

narcotics, barbiturates, sedating antihistamines) and alcohol. Reduces effectiveness of levonorgestrel (Next Choice, Plan B One-Step) (oral or implant contraceptives); use nonhormonal forms. Adverse reactions:

Interactions:

Antagonized by CYP450 inducers (e.g., carbamazepine, phenytoin, oxcarbazepine [Trileptal], topiramate [Topamax]); monitor and may need dose adjustment. Avoid concomitant other strong CYP3A inducers (e.g., rifampin [Rifadin], St. John’s wort). Antagonizes midazolam (Versed). Potentiates oxcarbazepine. Potentiated by ketoconazole (Nizoral). Caution with concomitant central nervous system depressants (e.g., benzodiazepines,

Dizziness, somnolence, fatigue, irritability, falls, nausea, weight gain, vertigo, ataxia, gait disturbance, balance disorder; psychiatric reactions. Note: To enroll in the North American Antiepileptic Drug Pregnancy Registry, call 888.233.2334. How supplied: Tabs— 30, 90 For more information, call 888.274.2378 or visit www.Fycompa.com. n

“When, exactly, did all the stuff you love about me become all the stuff you hate about me?”

Fycompa from pg. 38

For more products, visit www.eMPR.com

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Take the Scavenger Hunt Challenge March edition

Correctly answer the questions below— all of which can be found within this issue of The Clinical Advisor—and you’ll be entered into a random drawing to win an Apple iPad mini. To submit your responses, simply go to CliniAd.com/1egHZ8W. QUESTIONS 1. What is the most common complication of pregnancy? (p. 30) 2. Roughly how many U.S. children have a rheumatic disease? (p. 47) 3. In what year did Waaler and Rose first describe rheumatoid factor? (p. 51) 4. According to the National Center on Addiction and Substance Abuse at Columbia University, how many people in the United States have a substance use disorder? (p. 57) 5. What are the three major structures of the human brain? (p. 58) 6. The presence of erectile dysfunction in patients with type 2 diabetes has been shown to correlate with what disease? (p. 65) 7. According to a 2012 study, approximately what percentage of malpractice claims result in litigation? (p. 70) 8. What is another term for ungual fibromas? (p. 76) 9. Mucosal melanomas account for what percentage of all melanomas? (p. 81) 10. What is the average price of a one-month supply of mushroom extract? (p. 86)

WHO MAY ENTER All nurse practitioners and physician assistants 21 and over who are on The Clinical Advisor’s subscriber list. Employees and families of employees of Haymarket Media Inc., its affiliates, printer, agencies, mailers, and advertisers are not eligible. RULES No purchase necessary. Entries are limited to one per person.Void where prohibited. All entries must be received by April 15, 2014. Entries become the property of The Clinical Advisor and will not be acknowledged or returned. The Clinical Advisor is not responsible for late or misdirected entries, illegible entries, or electronic malfunctions. Entry constitutes acceptance of all rules. PICKING WINNERS Winners will be randomly selected from all accepted entries received by the deadline. Winners will be notified no later than May 1, 2014. Winners will be required to sign an affidavit of eligibility within 14 days of notification, or another winner will be chosen. Where permitted by law, winners agree to the use of their names, likenesses, and photographs for promotional purposes, without additional compensation. Odds of winning depend on the number of entries received. Winners agree to release and hold harmless The Clinical Advisor and Haymarket Media, Inc. from any liability arising from participation in this contest or acceptance and use of a prize. Names of winners will be published in a future issue of The Clinical Advisor. The winners’ names will be available upon written request after May 1, 2014, to individuals who send a stamped, self-addressed, business-sized envelope to Clinical Advisor Contest Winners, 114 W. 26th St., 4th Floor, New York, NY 10001.

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FEATURE: BENJAMIN J. SMITH, PA-C

Solving the mystery of rheumatic disease Selecting appropriate lab tests when evaluating patients with symptoms suggesting a rheumatic condition often calls for a bit of detective work.

Abnormal levels of rheumatoid factor do not necessarily indicate rheumatoid arthritis (shown here).

ne in 12 women and one in 20 men will develop a rheumatic disease at some point.1,2 Approximately 300,000 U.S. children have a rheumatic disease.3 Regardless of the specialty or setting in which a health-care provider practices, an opportunity to care for a person with a rheumatic disease will likely occur during his or her career. Many clinicians approach rheumatic disease with uncertainty. This trepidation is partly caused by the complex nature of the conditions encountered. Diagnosing and caring for persons with rheumatic disease requires superb detective work. Hearing what a patient says when obtaining a thorough history, observing telltale signs during a physical examination, and evaluating results of appropriately selected laboratory, radiographic, and other ancillary tests is similar to the work that a detective must do to solve a mystery. Knowing which details are most relevant is essential to providing the highest quality of care. Comprehending the utility of rheumatologyspecific laboratory tests can increase a clinician's confidence in his or her knowledge of the rheumatic diseases. After a brief overview of system review labs, this article will focus primarily on three of the most commonly ordered rheumatology labs: antinuclear antibody (ANA), rheumatoid factor (RF), and anti-citrullinated peptide antibody (ACPA), providing answers to frequently posed questions regarding these common rheumatology serologies. Continues on page 48

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System review laboratory tests

Lab work serves a number of purposes (Table 1). Given the demands for quality and efficiency in the current health-care environment, it is vital that providers have specific purposes when ordering lab work. Many rheumatic conditions are systemic diseases that can affect multiple organs. For this reason, system review laboratory tests, including complete blood counts, blood chemistries (with renal and hepatic function), and urinalysis, play an important role in the diagnosis and monitoring of persons with rheumatic conditions. The ability to interpret these common laboratory studies and describe the results in layman’s terms is a vital part of making appropriate and informed treatment recommendations. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level are also helpful in diagnosing and monitoring those with rheumatic disease. Factors that may TABLE 1.The benefits of lab work Establishes a diagnosis Determines prognosis Monitors disease activity, prognosis, or damage Monitors drug or therapeutic toxicities

POLL POSITION

Which lab test are you most likely to order in a patient with symptoms of rheumatic disease? n=573 18% 34%

n Rheumatoid factor n Antinuclear antibody n Anti-citrullinated peptide antibody

48%

For more polls, visit CliniAd.com/10TDwDb.

cause these acute-phase reactants to be elevated include autoimmune disease, infection, malignancy, pregnancy, anemia, and obesity. Although nonspecific, ESR and the CRP level provide useful information. Several tools that measure disease activity incorporate either the ESR or the CRP level as variables in their formulas.

Establishes complications of the underlying disease process Excludes alternative diagnoses or complications Adapted from Bartlett SJ, ed. Clinical Care in the Rheumatic Diseases. 3rd ed. Atlanta, Ga.: Association of Rheumatology Health Professionals; 2006.

TABLE 2. Conditions associated with a positive ANA Mixed connective tissue disease Polymyositis/dermatomyositis Rheumatoid arthritis Sjögren syndrome Drug-induced lupus Discoid lupus Pauciarticular juvenile chronic arthritis Hashimoto thyroiditis Graves disease Autoimmune hepatitis Primary sclerosing cholangitis Idiopathic pulmonary arterial hypertension Infection (mononucleosis, hepatitis C, subacute bacterial endocarditis,TB, HIV) Malignancy (rarely) Certain drugs (with or without drug-induced lupus) Adapted from UpToDate. Measurement and clinical significance of antinuclear antibodies. Available at www.uptodate.com/contents/measurement-and-clinical-significance-ofantinuclear-antibodies, accessed February 15, 2014.

Antinuclear antibody

In 1948, Hargraves first described lupus erythematosus (LE) cells in sera of patients with systemic lupus erythematosus (SLE).4 LE cells, phagocytes with ingested nuclear contents, were found in various body fluids, including pleural, pericardial, and peritoneal. Various techniques for determining the presence of ANA in a patient’s sera have evolved, but the value of ANA in diagnosing SLE and other autoimmune conditions remains unchanged. Although multiple subtypes of ANA exist (i.e., dsDNA, SS-A, SS-B, ENA, Scl-70), only the more general ANA will be discussed to remain within the scope of this article. An ANA should be ordered whenever the practitioner has a strong clinical suspicion of autoimmune disease. In other words, a high pretest probability of the ANA being positive based on the clinician’s suspicion and differential diagnosis leads to quality utilization of the ANA. It is inappropriate to randomly order an ANA for a patient whose symptoms are not suggestive of autoimmune disease. A false-positive ANA result in such an individual can cause anxiety for both the patient and the provider. Although a positive ANA is one component in the diagnosis of SLE, a positive ANA in and of itself is not diagnostic of SLE. As with all rheumatology serologies, established

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RHEUMATOLOGY SEROLOGIES

sensitivities (true positive rate) and specificities (true negative rate) for ANA exist. It is important for providers to recognize that false-positive ANA results occur. In fact, healthy individuals may have a positive ANA and never develop clinical manifestations suggestive of an autoimmune condition.5 A positive ANA can be associated with other rheumatic and non-rheumatic diseases in addition to SLE (Table 2). Along with a thorough history and physical examination, a helpful determinant as to whether an ANA is a true-positive representing autoimmune disease is the strength of the titer. In general, low titers (≤1:160) are more likely to be falsepositive results. Rheumatoid factor

Waaler and Rose first described RF in 1940.6 RFs are immunoglobulin (Ig) antibodies directed against the Fc portion of IgG. There are various types immunoglobulin antibodies, but IgM is the type most commonly measured today. As with ANAs, positive RFs can be associated with other rheumatic and nonrheumatic conditions besides rheumatoid arthritis (Table 3). Not every positive RF is absolutely diagnostic of rheumatoid arthritis. False-negative RFs also occur, occasionally leading to a diagnosis of seronegative rheumatoid arthritis when the history and the physical examination are supportive after other diagnostic considerations are appropriately ruled out. RFs should not be ordered for every person who presents with joint pain. Obtaining an appropriate history of the location of joints involved in a patient’s symptoms is vital. (Rheumatoid arthritis generally does not affect the low back or the distal interphalangeal joints.) A high pretest probability should exist before a diagnosis of inflammatory polyarthritis is suspected (Table 4). False-positive RFs do occur. Higher RF titers are less likely to be false-positive. Additionally, higher RF titers can be associated with greater disease severity, erosions, extra-articular manifestations, and disability.7,8 Positive RFs are noted in healthy individuals and become more common with age.

TABLE 3. Conditions associated with a positive RF Sjögren syndrome Mixed connective tissue disease Mixed cryoglobulinemia (type II and III) Systemic lupus erythematosus Polymyositis/dermatomyositis Infection (subacute bacterial endocarditis, hepatitis B, hepatitis C) Sarcoidosis Malignancy Primary biliary cirrhosis Adapted from UpToDate. Origin and utility of measurement of rheumatoid factors. Available at www.uptodate.com/contents/origin-and-utility-of-measurement-of-rheumatoidfactors, accessed February 15, 2014.)

TABLE 4. Distinguishing between inflammatory and noninflammatory arthritis History

Inflammatory arthritis

Noninflammatory arthritis

Swelling, warmth, erythema, tenderness

+++

Morning stiffness

+++

Aggravating symptoms

Rest

Activity

Alleviating symptoms

Activity

Rest

Extra-articular manifestations

+++

Swelling, warmth, erythema, tenderness

+++

Limited range of motion

Extra-articular manifestations

+++

Examination

ACPA can be used in combination with RF when confirming a diagnosis of rheumatoid arthritis. ACPA has a higher specificity for rheumatoid arthritis (95%) than does RF.9,10 As with ANA and RF, anti-CCP can be seen in other conditions. Notably, anti-CCP has been noted in 7% to 39% of patients with active TB,11-13 but less commonly in hepatitis C infection.14

Anti-citrullinated peptide antibody

Common questions regarding rheumatology serologies

ACPA is the newest of the three antibodies discussed in this article, having been used in clinical practice for just over a decade. The most commonly used ACPA assay measures antibodies against cyclic citrullinated peptides (CCPs). Some clinicians also measure ACPA antibodies against mutated citrullinated vimentin (MCV), but this test is not as widely ordered as the CCP tests. ACPAs are determined by enzymelinked immunosorbent assay (ELISA) in the lab.

1. I refer patients to labs that offer several techniques for obtaining ANAs. The results of these varying techniques are reported in different ways. Which technique should I choose? There are various methods by which ANAs are tested in a laboratory, including the following: immunofluorescent microscopy (rodent liver or kidney, Hep-2 cell lines), immunodiffusion, hemagglutination, complement fixation, solid-phase immunoassay (ELISA or immunoblotting), and

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RHEUMATOLOGY SEROLOGIES

radioimmunoassay. In its updated position statement of 2011, The American College of Rheumatology, recommended the immunofluorescent ANA assay as the gold standard based on a thorough review of the literature.15 A positive immunofluorescent ANA assay results in the reporting of a titer and pattern. Other methods may yield either a positive or negative result or may numerically quantify the result obtained without a pattern reported. Many laboratories rely on other techniques for detecting ANAs that are less costly and less labor-intensive to perform. The immunofluorescent ANA method is felt to be more sensitive for diagnosing SLE and other autoimmune conditions.15 2. Is the pattern of a positive ANA diagnostic of an autoimmune condition? ANA patterns are provided when an ANA is ordered using the immunofluorescent method and the result is positive. Various staining patterns may be described (i.e., speckled, nucleolar, diffuse, centromere). Except for centromere, the pattern is generally not helpful in the diagnosis. A centromere pattern can be associated with limited scleroderma, referred to as CREST syndrome (Calcinosis, Raynaud phenomenon, Esophageal dysfunction, Sclerodactyly, and Telangiectasias). Occasionally a health-care provider may receive a report stating that the ANA result shows two patterns. Although not diagnostic, this should raise clinical suspicion for autoimmune disease and is felt to be less, likely a false-positive result. 3. Should ANAs, RFs, or CCPs be ordered routinely once a diagnosis has been established? ANAs, RFs, and CCPs are diagnostic laboratory tests and do not measure disease activity. Generally, once a level of certainty is obtained for a given diagnosis, these serologies do not need to be repeated serially, as the results would not be expected to change the course of treatment. If there is uncertainty regarding a diagnosis or if new signs or symptoms suggest an additional or alternative diagnosis, repeat serologies may be indicated. Together with a comprehensive history and physical exam, other lab tests may be helpful when evaluating for disease activity. These include acute phase reactants (ESR, CRP) and system review labs to monitor organ function. When monitoring lupus patients for lupus nephritis, dsDNA, a specific antinuclear antibody, may be used. 4. I follow several patients who have a high titer ANA (or RF/ CCP) but no signs of SLE or other autoimmune condition. This has been verified by a previous rheumatology referral. What should I do? It is not uncommon to incidentally uncover a patient with positive serologies but no clinical suggestion of autoimmune

CLINICAL SLIDESHOW For more information on recognizing systemic lupus erythematosus, view the slideshow at CliniAd.com/1enIbyc.

disease or other explanation for the positive results. The development of autoantibodies may precede the development of clinically recognizable disease by a number of years.16-18 Patients who have positive serologies but no clinical disease should be monitored regularly (every six to 12 months) and instructed to contact a clinician between scheduled appointments if any additional symptoms develop. Conclusion

It is vital for health-care professionals to be able to obtain and interpret data when diagnosing and monitoring patients. Knowing which data are pertinent to a clinical investigation is a useful skill when caring for those with rheumatic disease. Early diagnosis of disease can lead to better outcomes. When used appropriately, rheumatology serologies assist in making early diagnosis and improve patient care. n Mr. Smith is a rheumatology physician assistant at the McIntosh Clinic in Thomasville, Ga. He would like to thank Victor M. McMillan, MD, and James M. Hunt, DO, for their expert review in the preparation of this article. References 1. Crowson CS, Matteson EL, Myasoedova E, et al. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum. 2011;63:633-639. Available at www. ncbi.nlm.nih.gov/pmc/articles/PMC3078757/. 2. American College of Rheumatology. Rheumatic diseases in America. Available at www.simpletasks.org/resources/ACR_Whitepaper_SinglePg.pdf. 3. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58:15-25. 4. Hargraves MM. Discovery of the LE cell and its morphology. Mayo Clin Proc. 1969;44:579-599. 5. Tan EM, Feltkamp TE, Smolen JS, et al. Range of antinuclear antibodies in “healthy” individuals. Arthritis Rheum. 1997;40:1601-1611. 6. Waaler E. On the occurrence of a factor in human serum activating the specific agglutination of sheep blood corpuscles. APMIS. 2007;115:422-438.

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7. van der Heijde DM, van Riel PL, van Rijswijk MH, van de Putte LB.

13. Mori S, Naito H, Ohtani S, et al. Diagnostic utility of anti-cyclic citrul-

Influence of prognostic features on the final outcome in rheumatoid

linated peptide antibodies for rheumatoid arthritis in patients with active

arthritis: a review of the literature. Semin Arthritis Rheum. 1988;17:284-292.

lung tuberculosis. Clin Rheumatol. 2009;28:277-283.

8. Cats A, Hazevoet HM. Significance of positive tests for rheumatoid factor

14. Liu FC, Chao YC, Hou TY, et al. Usefulness of anti-CCP antibodies in

in the prognosis of rheumatoid arthritis. A follow-up study. Ann Rheum Dis.

patients with hepatitis C virus infection with or without arthritis, rheuma-

1970;29:254-260. Available at ard.bmj.com/content/29/3/254.long.

toid factor, or cryoglobulinemia. Clin Rheumatol. 2008;27:463-467.

9. Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: diagnostic accu-

15. American College of Rheumatology. Methodology of testing for anti-

racy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for

nuclear antibodies. Available at www.rheumatology.org/ACR/Practice/

rheumatoid arthritis. Ann Intern Med. 2007;146:797-808.

Clinical/Position/ana_position_stmt.pdf.

10. Avouac J, Gossec L, Dougados M. Diagnostic and predictive value of

16. Arbuckle MR, McClain MT, Rubertone MV, et al. Development of

anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a sys-

autoantibodies before the clinical onset of systemic lupus erythemato-

tematic literature review. Ann Rheum Dis. 2006;65:845-851. Available at

sus. N Engl J Med. 2003;349:1526-1533. Available at www.nejm.org/doi/

www.ncbi.nlm.nih.gov/pmc/articles/PMC1798205/.

full/10.1056/NEJMoa021933.

11. Elkayam O, Segal R, Lidgi M, Caspi D. Positive anti-cyclic citrullinated

17. Heinlen LD, McClain MT, Merrill J, et al. Clinical criteria for systemic

proteins and rheumatoid factor during active lung tuberculosis. Ann Rheum

lupus erythematosus precede diagnosis, and associated autoantibodies

Dis. 2006;65:1110-1112. Available at www.ncbi.nlm.nih.gov/pmc/articles/

are present before clinical symptoms. Arthritis Rheum. 2007;56:2344-2351.

PMC1798246/.

Available at onlinelibrary.wiley.com/doi/10.1002/art.22665/full.

12. Kakumanu P, Yamagata H, Sobel ES, et al. Patients with pulmonary

18. Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific

tuberculosis are frequently positive for anti-cyclic citrullinated peptide

autoantibodies precede the symptoms of rheumatoid arthritis: a study

antibodies, but their sera also react with unmodified arginine-containing

of serial measurements in blood donors. Arthritis Rheum. 2004;50:380-386.

peptide. Arthritis Rheum. 2008;58:1576-1581. Available at www.ncbi.nlm. All electronic documents accessed February 15, 2014.

“It’s the best thing since bread torn into little pieces.”

“Paper cut?”

nih.gov/pmc/articles/PMC3621955/.

WHAT DO YOU THINK? Add your comments to this article —or any article — by going to www.ClinicalAdvisor.com. You will also see what your colleagues are saying.

54 THE CLINICAL ADVISOR • MARCH 2014 • www.ClinicalAdvisor.com

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CME CE FEATURED COURSE

n LEARNING OBJECTIVES • Name the major structures of the brain’s reward pathway. • Describe the role that dopamine plays in the process of addiction. • Demonstrate how substance use disorders are diagnosed using DSM-5 criteria. • List the common signs and symptoms of opioid and alcohol withdrawal. • Review the evidence-based screening tools used to determine the presence of a substance use disorder. n COMPLETE THE POSTTEST: Page 83 n ADDITIONAL CME/CE CREDIT: Pages 75, 79

This activity is jointly sponsored by Medical Education Resources (MER) and Haymarket Medical Education (HME). Release Date: March 2014 Expiration Date: March 2015 Estimated time to complete the educational activity: 30 minutes Statement of Need: Substance use disorder has become a growing concern in the United States, and the number of accidental-overdose deaths attributable to prescription drugs continues to rise. To effectively address substance use disorder, clinicians must recognize the condition as a brain disease. To that end, the physiology and pathophysiology of addiction must be fully understood. Finally, clinicians must be able to assess for risky behavior through the use of appropriate screening tools. Target Audience: This activity has been designed to meet the educational needs of primary-care physicians, physician assistants, and nurse practitioners who treat patients with substance use disorder. Faculty Mary Atkinson Smith, DNP, FNP-BC Starkville Orthopedic Clinic Starkville, Miss. Scott Hambleton, MD, FASAM Mississippi Professionals Health Program Ridgeland, Miss. Accreditation Statements Physician Credit: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of MER and HME. MER is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation: MER designates this educational activity for a maximum of 0.5 AMA PRA Category 1 creditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nursing Credit: MER is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. Credit Designation: This CE activity provides 0.5 contact hour of continuing nursing education. MER is a provider of continuing nursing education by the California Board of Nursing Registered Nursing, Provider #CEP 12299, for 0.5 contact hours. American Academy of Physician Assistants AAPA accepts certificates of participation for educational activities certified for Category I credit from AOACCME, Prescribed credit from AAFP, and AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 1 hour of Category I credit for completing this program. Accreditor Disclosure of Conflicts-of-Interest Policy MER ensures balance, independence, objectivity, and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure all scientific research referred to, reported, or used in a CME/CE activity conforms to the generally accepted standards

CA0314_CME.FeatureDisc.indd 56

of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME/CE activities that promote improvements or quality in health care and not a commercial interest. Faculty Disclosures The faculty reported the following financial relationships or relationships to products or devices that they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity: Mary Atkinson Smith, DNP, FNP-BC, and Scott Hambleton, MD, FASAM, have no relevant financial relationships to disclose. Staff/Planners’ Disclosures The planners and managers reported the following financial relationships or relationships to products or devices that they or their spouse/life partner have with commercial interests related to the content of this CME activity: The following HME planners and managers hereby state the following financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months: Joseph Kopcha, Editor; Marina Galanakis, Executive Editor; and Nicole Blazek, Web Editor have no real or apparent conflicts of interest to report. The MER planners and managers, and Veronda Smith, BC-FNP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Method of Participation: There are no fees for participating in and receiving CME/CE credit for this activity. During the period of March 2014 through March 2015, participants must: 1) read the learning objectives and faculty disclosures; 2) study the educational activity; 3) complete the posttest and submit it online (physicians may register at www.myCME.com); and 4) complete the evaluation form online. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better. Disclaimer: The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of MER or HME. The authors have disclosed if there is any discussion of published and/or investigational uses of agents that are not indicated by the FDA in their presentations. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of MER or HME. Before prescribing any medicine, primary references and full prescribing information should be consulted. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management.

2/26/14 3:24 PM

MARY ATKINSON SMITH, DNP, FNP-BC, AND SCOTT HAMBLETON, MD, FASAM

An understanding of substance use disorder Effective treatment requires the recognition of addiction as a brain disease and an understanding of its underlying physiology and pathophysiology.

Negative consequences are minimized in an individual with substance use disorder.

ccording to the National Center on Addiction and Substance Abuse at Columbia University (CASAColumbia), 40 million people in the United States have a substance use disorder.1 Another 80 million (32% of the U.S. population) exhibit behaviors that put them at risk for becoming a substance abuser. For perspective, 19 million Americans have cancer, and 26 million have diabetes. The National Survey on Drug Use and Health (NSDUH), conducted by the Substance Abuse and Mental Health Services Administration (SAMHSA), revealed that 22.6 million Americans (8.9% of the U.S. population) older than age 12 years currently use illicit drugs.2 The NSDUH also showed that the use of illicit drugs among persons aged 18 to 25 years increased from 19.6% in 2008 to 21.5% in 2010.2 Annual expenses related to substance abuse exceed $600 billion in the United States.3 One-third of all inpatient hospital costs are related to addiction, and in 2010, $28 billion was spent to treat 40 million individuals with this disease.1 Deaths caused by accidental overdose of prescription drugs are a growing problem. In 2009, more than 475,000 emergency department (ED) visits were related to abuse of prescription opioids, and this number has almost doubled in the intervening years.4 According to the CDC, for every death caused by accidental overdose of opioids in 2010, there were 35 ED visits for nonfatal overdoses.5 To illustrate the magnitude of the rise in accidental overdose deaths since 1970, consider that the U.S. population increased by approximately 50% to 306 million during that period.6 By contrast, the number of accidental overdose deaths increased more than www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2014 57

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CME CE

SUBSTANCE USE DISORDER

A number of psychoactive drugs exhibit their effects through the alteration of the expression of neurotransmitters in the brain. tenfold during the same interval.5,7 A study in 2012 showed that almost half of the accidental deaths in four counties in southern California were caused by prescription drugs.8 The first of a two-part series, this article will explain the importance of recognizing addiction as a brain disease, understanding the underlying physiology and pathophysiology of addiction, and diagnosing substance use disorders. Addiction as a brain disease

There is a lack of understanding about addiction as a brain disease and a subsequent minimization of the consequences of addiction among health-care providers. This is particularly noticeable in the realm of pain management. In general, clinicians receive minimal training in the area of addiction. Because addiction is a disease of the brain, health-care providers must have a basic understanding of the areas of the brain involved. Research using functional MRI and positron emission tomography (PET) scans has demonstrated that the brain’s survival and pleasure centers are the same areas affected by addiction.9 This part of the brain inspires such primitive and instinctive responses as hunger and thirst and is virtually identical in humans and other animals. A review of the underlying anatomy and physiology of the brain and how this organ normally functions will help the clinician understand addiction as a brain disease. Brain anatomy

The human brain consists of three major structures: the cerebrum, the cerebellum, and the brainstem. The cerebrum is the largest structure and is divided into right and left hemispheres. Each hemisphere consists of a frontal lobe, a parietal lobe, a temporal lobe, and an occipital lobe. The frontal lobe controls problem-solving, judgment, mood, emotions, and skilled muscle movements. The parietal lobe contains the sensory cortex and receives and processes information pertaining to temperature, pain, touch, and taste. The temporal lobe contains the hippocampus and is involved in memory, language comprehension, and hearing. The main function of the occipital lobe is vision and discerning color and movement. The cerebrum’s outer covering is referred to as the cerebral cortex, which contains gray matter and unmyelinated neurons. The cerebellum governs coordination, voluntary movement, balance, and muscle tone. The brainstem connects the brain to the spinal cord and consists of three structures (the

midbrain, pons, and medulla oblongata). The brainstem controls autonomic functions that are necessary for survival (e.g., breathing, heart rate, sleep, digestion). Situated between the cerebral cortex and the midbrain, the thalamus is considered the major relay center of the brain and transmits information between the senses and the cortex. It is important to understand the limbic system of the brain as well when treating addiction. The limbic system regulates emotion and memory and is a complex set of structures located on both sides of the thalamus underneath the cerebrum. The hypothalamus, hippocampus, and amygdala are the three major structures of the limbic system. The physiology of addiction To function properly, the brain depends on neurons to transmit electrochemical signals effectively between brain cells. The electrical properties of neurons are controlled by biochemical and metabolic processes that take place among neurotransmitters and receptors. Neurotransmitters in the brain are chemicals that enable the transport of information from one neuron to another across synapses in the synaptic cleft. Neurotransmitters are used in specific areas of the brain and have specialized functions. Some of the most common neurotransmitters of the brain are glutamate, gamma-aminobutyric acid (GABA), serotonin, acetylcholine, norepinephrine, and dopamine. Neurotransmitters are commonly classified as excitatory or inhibitory. Glutamate, epinephrine, and norepinephrine are typically considered excitatory neurotransmitters, and serotonin and GABA are considered inhibitory neurotransmitters. Some neurotransmitters, such as acetylcholine and dopamine, may have both excitatory and inhibitory effects. A number of psychoactive drugs including antidepressants, nicotine, alcohol, marijuana, heroin, and cocaine exhibit their effects through the alteration of the expression of these neurotransmitters. The effect of the neurotransmitter serotonin is the primary target for some antidepressant medications. Acetylcholine and dopamine are involved in several areas of the brain; however, they are not as widely distributed as glutamate and GABA. Addictive substances and the reward pathway

The 1990s were often referred to as the decade of the brain. Research led to a better understanding of the reward circuitry of the brain, with increased insight into the nature

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of addiction as it related to specific parts of this organ. The neurotransmitter dopamine was noted to have an integral role in the process of addiction, specifically in the activation of the brain’s reward pathway. The reward pathway is made up of brain structures that regulate behavior by producing pleasurable responses. The major structures of the reward pathway are the ventral tegmental area (VTA), the nucleus accumbens, and the prefrontal cortex (Figure 1). The neurons of the VTA trigger the release of dopamine in the nucleus accumbens and the prefrontal cortex. When dopamine is released, a person feels pleasure. In 1954, Olds and Milner demonstrated that rats would press a lever to stimulate electrodes placed directly into the nucleus accumbens.10 Similar experiments in the 1960s demonstrated that rats would press a lever to self-administer injections of heroin.11–13 The rats kept pressing the bar to get more heroin because it is pleasurable. The heroin is positively reinforcing and serves as a reward. When the injection needle was placed in an area outside the nucleus accumbens, the rats would not self-administer the heroin. PET scans have revealed that dopamine release is increased within the reward pathway of rats self-administering heroin, resulting in activation of the reward pathway.14 In many cases, the rats would ignore hunger or thirst to stimulate their nucleus accumbens by electrode or by self-administration of heroin. These experiments demonstrate that powerful instinctive survival behaviors can be overcome by activating the brain’s reward pathway through the release of dopamine. Since rats do not have well-developed dorsolateral prefrontal cortices, the results of these tests also refute the idea that addiction is a behavioral problem originating in this area of the brain. Other than the cortex and size, the rat brain is nearly identical to the human brain. Both use the same neurotransmitters and receptors, the same proteins for synaptic vesicle release and recycling, and similar signaling mechanisms. The reward circuitry is virtually identical as well, and both use dopamine as the principle neurotransmitter responsible for the sensation of pleasure. The midbrain area is the brain’s survival and pleasure center and is sometimes referred to as “the lizard brain” because it generates such primitive behaviors as eating, drinking, and the fight-or-flight reaction. These behaviors are necessary for survival and are linked to the sensation of pleasure and the release of dopamine. In the addicted patient, drug use becomes the most important behavior, which partially explains why

Courtesy of the National Institute on Drug Abuse

Dopamine was noted to play an integral role in the process of addiction, specifically in the activation of the brain’s reward pathway.

Figure 1. Major structures of the brain’s reward pathway

addicted persons continue to take drugs despite such consequences as jail or divorce. To understand drug cravings, think about situations in which survival is threatened, like dying of thirst or starvation. In these situations, such as brain is preoccupied with getting food or water, and the mood becomes dysphoric, marked by depression, anxiety, hopelessness, and fear. These symptoms are relieved instantly as soon as food or water is obtained. The role of dopamine in addiction

Produced in the substantia nigra and VTA, dopamine is a catecholamine neurotransmitter and the biosynthetic precursor to norepinephrine and epinephrine. Additional functions of dopamine include motivational stimuli, sexual arousal, thought, and the learning of new behaviors. Dopamine also inhibits release of the hormone prolactin, which is involved in the sensation of sexual gratification. Dopamine administered in IV or oral form cannot cross the blood-brain barrier and has no direct effect on the central nervous system. Opioids travel to the brain through the bloodstream and bind to opioid receptors in the cortex, VTA, thalamus, nucleus accumbens, brainstem, and spinal cord. Opioids bind to areas involved in the pain pathway (including the thalamus, brainstem, and spinal cord), which leads to analgesia. When opioids bind to opioid receptors in the reward pathway, dopamine is released, and the reward pathway is activated. Supernormal concentrations of dopamine are released with drugs of abuse. To illustrate, consider the effect of cocaine on the release of dopamine from brain cells. Cocaine acts by blocking the removal of dopamine from the synapse, which results in an

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CME CE

SUBSTANCE USE DISORDER

Addiction is a treatable but permanent primary disease and not merely a symptom of some other underlying disorder. accumulation of dopamine and an amplified signal to the receiving neurons. This is what causes the initial euphoria commonly reported by cocaine users. However, although cocaine will increase the dopamine level of anyone who ingests the drug, the majority of users do not become addicted. The reason for this is only partially understood. According to the National Institute on Drug Abuse (NIDA), the increase in dopamine release in the brains of addicted patients is often variable and is actually lower than in those who are not addicted. This comparatively smaller increase in dopamine levels in the addicted patient leads to drug-seeking and drug-craving behavior and helps to explain why people who become addicted can often remember their first experience of substance-induced euphoria in great detail. Data show that people with novelty-seeking personality traits (thrill-seekers) have decreased numbers of dopamine autoreceptors.15 Dopamine autoreceptors reside on the presynaptic neuron and regulate the release of dopamine. The density of dopamine autoreceptors is inversely proportional to an individual’s desire for novel experiences and thrill-seeking behaviors. The fewer available dopamine autoreceptors an individual has, the less his or her brain is able to regulate how much dopamine is released. Because of this, novelty and other potentially rewarding experiences will produce greater dopamine release in individuals with decreased dopamine autoreceptors. Hence, thrill-seekers are chemically wired to take chances. Not surprisingly, patients with addictive disorders are likely to have fewer dopamine autoreceptors. The disease of addiction

Addiction is a primary disease and not merely a symptom of some other underlying disorder. Although addiction is treatable, it is also permanent. Addiction is progressive, can be fatal, and typically causes tremendous suffering in the addicted person as well as among his or her family and friends. Clinicians should be aware of the abnormal yet predictable patterns of behavior that are displayed among individuals with substance use disorders. Cognitive distortion and poor judgment related to continued use of the substance and denial of negative consequences of addiction should be expected in such patients. Substance use disorders

According to criteria from The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), substance use

disorders represent a maladaptive pattern of substance use leading to clinically significant impairment or distress. This impairment or distress is manifested by the presence of at least two of the following symptoms during a 12-month period:16 1. The substance is often taken in larger amounts or over a longer period than was intended. 2. There is a persistent desire or unsuccessful efforts to reduce or control substance use. 3. A great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover from the substance’s effects. 4. Craving, or a strong desire or urge to use the substance 5. Recurrent substance use resulting in a failure to fulfill major obligations at work, school, or home 6. Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance 7. Important social, occupational, or recreational activities are given up or reduced because of substance use. 8. Recurrent substance use in situations in which it is physically hazardous 9. Substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance. 10. Tolerance, as defined by either a need for markedly increased amounts of the substance to achieve intoxication or desired effect or a markedly diminished effect with continued use of the same amount of substance 11. Withdrawal, as manifested by either the characteristic withdrawal syndrome for the substance or when the substance (or a closely related substance) is taken to relieve or avoid withdrawal symptoms. The severity of substance use disorders is classified as mild (presence of two to three of the symptoms described in this list), moderate (presence of four to five symptoms), or severe (presence of six or more symptoms). Opioid and alcohol withdrawal

Clinicians must be aware of the most common signs and symptoms related to opioid and alcohol withdrawal (Table 1). The signs and symptoms of opioid withdrawal typically include three or more of the following: dysphoric mood; nausea or vomiting; muscle aches; lacrimation or rhinorrhea; pupillary dilation, piloerection, or sweating; diarrhea; yawning; fever;

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Cognitive distortion in the addicted patient is manifested as denial of negative consequences, poor judgment, and ineffective impulse control. and insomnia. Alcohol withdrawal includes two or more of the following signs and symptoms: autonomic hyperactivity (e.g., sweating or pulse >100 beats per minute); increased hand tremor; insomnia; nausea or vomiting; transient visual, tactile, or auditory hallucinations or illusions; psychomotor agitation; anxiety; and generalized tonic-clonic seizures. Cognitive distortion

Cognitive distortion refers to the impaired executive functioning that occurs in every addict. The dorsolateral prefrontal cortex primarily directs executive function. Examples of executive function include planning complex activities, moderating social behavior, differentiating conf licting thoughts, and evaluating risk versus reward. Impaired executive function in the addicted patient is manifested as denial of negative consequences, poor judgment, and ineffective impulse control related to use of the substance. The addict becomes unable to adequately process information that is related to the addictive behavior or substance. Negative consequences and harmful behaviors are minimized. It is common to hear an addict rationalize that “things are not that bad yet.” An addicted individual may explain a suspended driver’s license as bad luck or the loss of a job as the result of a difference of opinion. NIDA classifies cognitive distortion as impaired response inhibition and salience attribution (iRISA) and describes an integrated model of drug addiction that encompasses intoxication, craving, binge use, and withdrawal (Figure 2).17 The relationship between inhibitory control and reward processing becomes dysfunctional in a drug-addicted individual. Addiction features ineffective willed-control over automatic processes combined with attribution of high relative reward value to the experience of pleasure. Inhibitory control would be especially disturbed under conditions of high drug salience. For example, a cocaine addict would likely be unable to avoid using cocaine if he or she were in a crack house; the motivation to procure drugs would overpower every other goal.

Screening, Brief Intervention, and Referral to Treatment (SBIRT).18 SBIRT is a model of practice that allows for the identification, reduction, and prevention of the harmful use, abuse, and dependence related to alcohol and illicit drugs and can be used in any community setting. As is evident by its name, the model is made up of three major components: • Screening. The clinician assesses the individual for risky substance use behaviors using standardized screening tools. • Brief intervention. The clinician describes risky substance use behaviors in a brief conversation, providing feedback and advice. • Referral to treatment. The clinician provides patients who screen positively with a referral to therapy or additional treatment. A second useful screening tool is the World Health Organization (WHO) Alcohol Use Disorders Identification Test (AUDIT), which is a questionnaire comprised of 10 items that screens for the presence of harmful alcohol consumption.19 The questionnaire has the ability to correctly classify 95% of patients as alcoholic or nonalcoholic. The AUDIT is easy to administer in the primary-care setting and may be utilized in a wide variety of patient populations TABLE 1. Signs and symptoms of opioid and alcohol withdrawal Opioid withdrawal

Alcohol withdrawal

• Yawning

• Autonomic hyperactivity (e.g., sweating or pulse >100 beats per minute

• Sweating

• Increased hand tremor

• Lacrimation

• Insomnia

• Rhinorrhea

• Psychomotor agitation

• Dysphoric mood

• Anxiety

• Fever

• Nausea/vomiting

• Insomnia

• Tonic-clonic seizures

• Dilated pupils

• Transient visual, tactile, or auditory hallucinations and/or illusions

• Piloerection • Chills

Screening tools

Primary-care clinicians need to be knowledgeable about the various evidence-based screening tools and practices that are available to determine the presence of a substance use disorder. If a substance use disorder is suspected, screening allows for early detection and intervention. An extremely valuable practice model for the primary-care setting is

• Tachycardia • Hypertension • Nausea/vomiting • Crampy abdominal pains • Diarrhea • Muscle aches and pains

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Craving Drug expectation and attention bias

Intoxication Impaired self-awareness

Addiction Withdrawal Amotivation and anhedonia

Bingeing Loss of control

Figure 2. Impaired response inhibition and salience attribution (iRISA) syndrome of drug abuse Adapted from Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry. 2002;159:1642-1652; available at ajp.psychiatryonline.org/article.aspx?articleid=175797, accessed February 15, 2014.

and cultural groups. A copy of the questionnaire is available from the WHO (whqlibdoc.who.int/hq/2001/who_msd_ msb_01.6a.pdf, accessed February 15, 2014). The CAGE questionnaire is a quick and easy screening tool that primary-care clinicians can use when they suspect a potential substance use disorder.20 CAGE consists of four questions designed to help the clinician determine whether a further assessment for alcohol abuse is warranted. • Have you ever felt you should Cut down on your drinking? • Have people Annoyed you by criticizing your drinking? • Have you ever felt bad or Guilty about your drinking? • Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover (Eye-opener)? Responses are scored 0 or 1, and a higher score should be seen as an indication of alcohol problems. A total score of 2 or greater is considered clinically significant. A variation on the CAGE questionnaire, the CAGE AID (Adapted to Include Drug use) screening tool consists of the same four questions but with slight modifications to include illegal-drug use and the use of prescription drugs other than as prescribed. The advantage of the CAGE AID is that it allows clinicians to screen for potential alcohol and drug abuse simultaneously. The Drug Abuse Screen Test (DAST) is a self-reporting questionnaire for patients that consists of 28 yes-or-no questions. 21 A condensed 10-question version (DAST10) is also available and may be more appropriate for the primary-care setting. Patients can complete the DAST-10 in less than eight minutes.

A list of additional screening tools can be found on the SAMHSA website (available at www.integration.samhsa. gov/clinical-practice/screening-tools, accessed February 15, 2014). The list includes a description of each tool and printable copies that can be used immediately in the clinical setting. Recovery works

Recovery from substance use disorders involves brain “healing” and recalibration of the hedonic set point so that such natural pleasures as food, music, or art are once again perceived as enjoyable. People successful in recovery are able to develop effective impulse control to enable the realization of long-term abstinence and stability. A study involving PET-scan imaging showed that the brain can recover after total abstinence, even in methamphetamine abusers.22 In this study, the concentration of dopamine transporters actually increased after 24 months of abstinence. Up next

The next installment of this two-part series will focus on the potential for abuse among the various classes of controlled substances and will include evidence-based recommendations regarding the prescription of opioids for the treatment of pain. n Dr. Atkinson Smith is a nurse practitioner at Starkville Orthopedic Clinic in Starkville, Miss., and an adjunct faculty at Capstone College of Nursing, University of Alabama, in Tuscaloosa. Dr. Hambleton is the medical director of the Mississippi Professionals Health Program in Ridgeland.

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12.Thompson T, Schuster CR. Morphine self-administration, food-rein-

1. CASAColumbia. Addiction medicine: Closing the gap between science

forced, and avoidance behaviors in rhesus monkeys. Psychopharmacologia.

and practice. Available at www.casacolumbia.org/addiction-research/

1964;5:87-94.

reports/addiction-medicine.

13. Bozarth MA, Wise RA. Toxicity associated with long-term intravenous

2. Substance Abuse and Mental Health Services Administration. Results from

heroin and cocaine self-administration in the rat. JAMA. 1985;254:81-83.

the 2010 National Survey on Drug Use and Health: Summary of National Findings,

14. R&D Magazine. Tiny “wearable” PET scanner ready for use. Available at

NSDUH Series H-41, HHS Publication No. (SMA) 11-4658. Rockville, Md.:

www.rdmag.com/news/2011/03/tiny-wearable-pet-scanner-ready-use.

Substance Abuse and Mental Health Services Administration, 2011.

15. Zald DH, Cowan RL, Riccardi P, et al. Midbrain dopamine receptor

3. National Drug Intelligence Center. The Economic Impact of Illicit Drug

availability is inversely associated with novelty-seeking traits in humans.

Use on American Society. Available at www.justice.gov/archive/ndic/

J Neurosci. 2008;28:14372-14378. Available at www.jneurosci.org/con-

pubs44/44731/44731p.pdf.

tent/28/53/14372.long.

4. Substance Abuse and Mental Health Services Administration. Drug

16. Hasin DS, O’Brien CP, Auriacombe M, et al. DSM-5 criteria for sub-

abuse warning network, 2010: National estimates of drug-related

stance use disorders: recommendations and rationale. Am J Psychiatry.

emergency department visits. Available at www.samhsa.gov/data/2k13/

2013;170:834-851.

DAWN2k10ED/DAWN2k10ED.htm.

17. Goldstein RZ, Volkow ND. Drug addiction and its underlying neuro-

5. Centers for Disease Control and Prevention. CDC grand rounds: pre-

biological basis: neuroimaging evidence for the involvement of the frontal

scription drug overdoses—a U.S. epidemic. MMWR Morb Mortal Wkly

cortex. Am J Psychiatry. 2002;159:1642-1652; available at ajp.psychiatryon-

Rep. 2012;61:10-13. Available at www.cdc.gov/mmwr/preview/mmwrhtml/

line.org/article.aspx?articleid=175797.

mm6101a3.htm.

18. SAMHSA-HRSA Center for Integrated Health Solutions. SBIRT:

6. U.S. Census Bureau. Historical national population estimates: July 1,

Screening, Brief Intervention, and Referral to Treatment. Available at

1900 to July 1, 1999. Available at www.census.gov/population/estimates/

www.integration.samhsa.gov/clinical-practice/sbirt.

nation/popclockest.txt.

19. Saunders JB, Aasland OG, Babor TF, et al. Development of the Alcohol

7. Kochanek KD, Xu J, Murphy SL, et al . Deaths: preliminary data for 2009.

Use Disorders Identification Test (AUDIT): WHO collaborative project

Natl Vital Stat Rep. 2011;59:1-51.

on early detection of persons with harmful alcohol consumption. Addiction.

8. Glover S, Girion L. Legal drugs, deadly outcomes. Los Angeles Times.

1993;88:791-804.

November 11, 2012. Available at www.latimes.com/news/science/

20. Mayfield D, McLeod G, Hall P. The CAGE questionnaire: validation of a

prescription/la-me-prescription-deaths-20121111-html.

new alcoholism screening instrument. Am J Psychiatry. 1974;131:1121-1123.

9. Nestler EJ, Malenka RC. The addicted brain. Sci Am. 2004;290:78-85.

21. Skinner HA. The drug abuse screening test. Addict Behav. 1982;7:363-371.

10. Olds J, Milner P. Positive reinforcement produced by electrical stimula-

22. Volkow ND, Chang L, Wang GJ, et al. Loss of dopamine transport-

tion of septal area and other regions of rat brain. J Comp Physiol Psychol.

ers in methamphetamine abusers recovers with protracted abstinence.

1954;47:419-427.

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involved in a laboratory method of detecting the addictiveness of drugs. J Am Pharm Assoc Am Pharm Assoc (Baltim.). 1955;44:229-231.

“Get a tomb!”

All electronic documents accessed February 15, 2014.

“I lost the hand to a shark, the leg to a barracuda, and the gallbladder to Dr. Steven Erlich.”

References

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Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

Inside the Forum MARCH 2014

Consultations Infant immunization after a blood transfusion. . . . . . . . . . . . . . . 64 Cardiac workup for patients with diabetes. . . . . . . . . . . . . . . . . . 64 How old is too old for ultrasound?. . . 65 Antifungal-resistant ear infection. . . . .65

Clinical Pearls Tick-removal advice . . . . . . . . . . . . . 66 Stop the bleeding. . . . . . . . . . . . . . . . 66 And more. . . . . . . . . . . . . . . . . . . . . 66

Your Comments Improved performance at the expense of patient care. . . . . . . . . . . 66 The patient comes first. . . . . . . . . . . .66

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. You may also fax (646) 638-6117, or contact us by e-mail at letters@ clinicaladvisor.com. If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter. No anonymous contributions will be accepted.

CONSULTATIONS INFANT IMMUNIZATION AFTER A BLOOD TRANSFUSION A full-term infant requires a blood transfusion at age 3 days. How would this affect the routine immunization schedule? —WANDA BRADSHAW, MSN, NNP-BC, Durham, N.C. According to the CDC, a blood transfusion at age 3 days should not impact the routine immunization schedule (MMWR Recomm Rep. 2011;60:1-64; available at www.cdc.gov/mmwr/preview/mmwrhtml/ rr6002a1.htm, accessed February 15, 2014). The varicella vaccine and the measles, mumps, and rubella (MMR) vaccine would not be due for one year, and precautions related to blood transfusion are for the previous 11 months only. For whole blood, the wait to administer MMR (measles component) or varicella-containing vaccine would be six months. No other routinely recommended immunizations have precautions.—Julee B. Waldrop, DNP (185-1)

CARDIAC WORKUP FOR PATIENTS WITH DIABETES It is well known that patients with diabetes are at increased risk for cardiac events, but I am unclear as to what warrants a workup for cardiac disease in this population (e.g., a cardiac stress test) except in instances where patients report such symptoms as angina or dyspnea. Given that people with

OUR CONSULTANTS

Rebecca H. Bryan, APRN, CNP,

Philip R. Cohen, MD,

is a lecturer in the Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is clinical associate professor of dermatology, University of Texas Medical Center, Houston.

Deborah L. Cross, MPH, CRNP, ANP-BC, is associate program

director, Gerontology NP Program, University of Pennsylvania School of Nursing, Philadelphia.

Abby A. Jacobson, PA-C,

Maria Kidner, DNP, FNP-C,

is a physician assistant at Delaware Valley Dermatology Group in Wilmington, Del.

is a nurse practitioner with Cheyenne Cardiology Associates in Cheyenne, Wyo.

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diabetes have different symptoms or may have no symptoms at all, would a more aggressive approach in working up this population be advisable?—MARY HORST, ANP, Goodview, Va. Concerns about the high rate of cardiovascular disease in the diabetes population are well warranted since the risks for MI and stroke are two to four times greater among these patients. However, a large observational randomized clinical trial noted no differences in cardiac events over 4.8 years in those screened with adenosine-stress radionuclide myocardial perfusion imaging (MPI) over those randomized to routine care (JAMA. 2009;301:1547-1555; available at jama. jamanetwork.com/article.aspx?articleid=183751, accessed February 15, 2014). Earlier trials had also verified the lack of benefit to screening asymptomatic patients. This evidence has led the American Diabetes Association to advise against routine screening in favor of aggressive risk modification, including antiplatelet therapy as indicated, smoking cessation, and aggressive BP and lipid management. It is important to assess for such other subtle clues as unusual fatigue or shortness of breath or for other signs of vascular disease. For instance, the presence of erectile dysfunction in patients with type 2 diabetes has been shown to correlate with coronary heart disease (J Am Coll Cardiol. 2008;51:2045-2050). Other complications of diabetes, including retinopathy and nephropathy, share the same pathophysiologic mechanism for peripheral vascular disease, so a careful review of history is warranted when assessing risk.—Katherine Pereira, DNP, RN, FNP-BC, ADM-BC, coordinator, FNP specialty, Duke University School of Nursing, Durham, N.C. (185-2)

HOW OLD IS TOO OLD FOR ULTRASOUND? What is the maximum patient age at which an interventional radiologist should attempt to use ultrasound to complete a

Debra August King, PhD, PA,

is senior physician assistant at New York-Presbyterian Hospital, New York City.

Mary Newberry, CNM, MSN

provides well-woman gynecologic care as a midwife with Prima Medical Group, Greenbrae, Calif.

lumbar puncture in a child after other modalities have not been successful?—KIRBY MEYER, PA-C, Seattle I spoke with two neurointerventionalists, and neither knew of a maximum age for the use of ultrasound in the event of unsuccessful lumbar puncture. Although primarily used in neonates, in capable hands ultrasound can be used in patients older than age 18 years. The clinician is simply looking for the interlaminar space, and bone can easily be seen on ultrasound. Fluoroscopy is often the imaging modality of choice for difficult cases.—Deborah Semmel, FNPBC, Duke University Medical Center, Division of Interventional Radiology, Durham, N.C. (185-3)

ANTIFUNGAL-RESISTANT EAR INFECTION What is the best way to treat ear fungus that is resistant to ketoconazole (Extina, Ketozole, Nizoral, Xologel)?—JILL DUNN, MSN, RN, NP-C, Elba, Ala. To clarify, “resistant” could mean one of three things. First, it could mean that the clinician performed a culture and ran a susceptibility report indicating that the fungal causative agent was truly resistant to ketoconazole. In such a case, the report should identify the causative agent, and the susceptibility report should indicate the antifungals to which the causative agent responds. Second, “resistant” could mean that the clinician used ketoconazole in the past with success but the patient now says it is no longer effective. (This is a good time to culture the infection.) If this is the case, consider topical oxiconazole (Oxistat) b.i.d. or topical naftifine (Naftin) gel once a day. Finally, “resistant” could refer to a case in which the clinician used ketoconazole and it did not work or did not work well enough to control the symptoms. In the situation described by Ms. Dunn, the issue may an incorrect diagnosis (determine whether the infection is more inflammatory than infective) or a diagnosis that is only partially correct. For example, the infection

Claire O’Connell, MPH, PA-C,

teaches in the PA Program at the New Jersey Medical School and Rutgers University, Piscataway, N.J.

Sherril Sego, FNP-C, DNP,

is a primary-care nurse practitioner at the Department of Veterans Affairs Medical Center in Kansas City, Mo.

Julee B.Waldrop, DNP,

is associate professor at the University of Central Florida (UCF), and practices pediatrics at the UCF Health Center.

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Advisor Forum the laceration for a good 20 minutes. This numbs the area and avoids a scary needle and painful injection.—MELISSA SULLIVAN, CPNP, Charlotte, N.C. (185-7)

WHAT DOES A PLEURAL RUB SOUND LIKE? When teaching a colleague about a pleural rub, explain that the sound is similar to that of a finger rubbing over a balloon.—DONNA BERTHOFF, FNP, PA-C, Syracuse, N.Y. (185-8)

YOUR COMMENTS Otitis externa (shown) can be caused by fungal or bacterial infection.

may be a process that has fungal and inflammatory aspects—like seborrheic dermatitis—in which case the addition of a low-dose topical steroid or anti-inflammatory cream may help make the ketoconazole more effective. Consider hydrocortisone 2% or desonide (Desonate, DesOwen, Verdeso) for one week. To avoid steroids completely, consider off-label pimecrolimus (Elidel), which is approved to treat atopic dermatitis. If none of these suggestions work, consider referring the patient to a specialist.—Abby A. Jacobson, PA-C (185-4)

CLINICAL PEARLS TICK-REMOVAL ADVICE A squirt of ethyl chloride will cause an embedded tick to let go and will facilitate removal.—GREGORY HOBBS, FNP, Greenville, S.C. (185-5) STOP THE BLEEDING Rinsing with ice water will often stop difficult oral bleeding. Alternatively, place pressure on the area of bleeding with a wet teabag (nonherbal). This method can even be used in a patient taking warfarin (Coumadin, Jantoven) or aspirin.—VICTORIA ROGERS, PA-C, Boise (185-6) USE A PARENT TO FACILITATE SUTURING A CHILD I rarely use an injectable anesthetic to suture a laceration on a child. Instead, I give the parent cotton swabs and topical XAP (xylocaine/adrenaline/pontocaine) and ask him or her to continually apply the anesthesia around and inside

Editor’s note: These comments were written in response to a post in The Waiting Room, our collection of expert blogs. To read more, visit the website at CliniAd.com/VwgfCl.

IMPROVED PERFORMANCE AT THE EXPENSE OF PATIENT CARE I echo the frustrations Robyn Carlisle expressed in her blog post, “The meaningful use paradox” (available at CliniAd. com/LUITgd). Electronic health records do not seem to be designed to improve communication and certainly do not increase efficiency. In a 20-minute patient visit, nearly half of my time is spent on the computer. My performance evaluations are based on the numbers generated from “clicks” rather than any extra information that I might add to a chart. The actual patient diagnosis and treatment is rarely discussed.—SANDRA HOYMAN, PA-C, Denver (185-9) THE PATIENT COMES FIRST I agree that measuring patient care has not led to improved patient care. However, electronic charting has streamlined medical records, especially in intensive care. As a predominately inpatient nurse for the past 40 years, I have adapted to many changes in health care. The only time I might type in front of a patient is during an admission. I cannot stand it when my own clinician’s eyes are glued to a computer screen. As far as clicking all the boxes, are staff nurses fully assessing their patients for these items or simply copying what the previous nurse had checked? Is this information improving communication? If I have something important to communicate, I write it by hand on the progress note. My younger colleagues have commented that I am always running late, but taking care of the patient comes first in my book.—SUSAN BOHDAN, RN, Berwyn, Ill. (185-10) n

66 THE CLINICAL ADVISOR • MARCH 2014 • www.ClinicalAdvisor.com

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LEGAL ADVISOR CASE

Brain injury casused by ear surgery

BY ANN W. LATNER, JD

Sometimes doing everything right is still not enough. As the following case shows, lawsuits can happen even to those who do nothing to deserve them. While litigation may be inevitable, liability can be avoided. Ms. P, aged 36 years, was a nurse working on the surgical floor of a mid-size hospital. She had been working at the same hospital for her entire career and had received stellar reviews from her supervisors. However, she had recently begun to feel unfulfilled professionally and decided to go back to school part-time to pursue an advanced-practice degree. Ms. P wished that she had the savings to be able to quit work and focus completely on school, but that was not possible at this time, so she remained on staff at the hospital. Ms. P hoped that once she had the degree she would work for a private practice so that she could experience another type of work setting. Ms. P’s performance at the hospital was impeccable. In the 10 years she had been there, she had never once been reprimanded or received anything other than praise from her supervisors.

Intracranial bleeding and pressure after removal of an acoustic neuroma leads to permanent damage.

Ms. P decided to do another neurology check and found that the patient was exhibiting left-side weakness.

She took her work and the health of her patients very seriously. One of Ms. P’s patients was Mrs. A, a 62-yearold woman who had been suffering from hearing loss and ringing in her right ear. An MRI revealed that Mrs. A had an acoustic neuroma, a benign and usually slow-growing tumor of the vestibular nerve. After a comprehensive examination, the patient was given three choices by her neuro-otologist: observation with further testing to monitor the tumor growth, surgery to remove the tumor, or radiotherapy. Upon learning that the tumor appeared to be growing faster than expected, Mrs. A opted for surgery. The surgery went as planned, and Mrs. A was transferred to the intensive care unit for monitoring overnight. Everything remained normal, and Mrs. A was transferred to the main floor of the hospital the next day, at which point Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

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Download the new app for the iPhone, iPad,and Android— created specifically for nurse practitioners and physician assistants from the publishers of the highest rated journal for these health-care professionals. With the Clinical Advisor app you can: • Take Derm Dx quizzes to learn about difficultto-identify dermatology conditions, and then see how you performed against your peers. • Use medical calculators to do things like assess liver function, convert HbA1C to mean plasma glucose, evaluate BP, determine BMI and more. • Read the latest news about breakthrough treatments, disease outbreaks, drug approvals and recalls, and clinical research.

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Scaling on the vermilion border of the lower lip A white man, aged 65 years, presents to the dermatology clinic with complaints of scaling on the vermilion border of the lower lip. The patient has a history of basal cell carcinoma of the temple, which was treated with Mohs surgery two years ago. WHAT IS YOUR DIAGNOSIS?

• Actinic cheilitis • Contact cheilitis • Cheilitis granulomatosa • Fordyce spots ● See the full case at CliniAd.com/1inaGkH

Pain and swelling around the fingernail A man had experienced severe pain and swelling around the fourth fingernail for several days. The proximal nail fold is tender to palpation, and fluctuance and a small, yellowish abscess is noted on examination. WHAT IS YOUR DIAGNOSIS?

• Chronic paronychia • Acute paronychia • Onychorrhexis • Onycholysis ● See the full case at CliniAd.com/1bF7ewW

Have you missed any recent Derm Dx cases? Go to CliniAd.com/10KIbCF for a complete archive of past quizzes as well as additional images of last month’s other cases.

“Twisted” hands

Clubbed fingers

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CME CE

n LEARNING OBJECTIVES

For Dermatology Clinic • Identify and diagnose dermatologic conditions and review up-to-date treatment.

For Dermatologic Look-Alikes • Distinguish and properly treat dermatologic conditions with similar presentations. n COMPLETE THE POST TEST: Page 83

DERMATOLOGY COURSES

n ADDITIONAL CME/CE CREDIT: Pages 57

This activity is jointly sponsored by Medical Education Resources (MER) and Haymarket Medical Education (HME). Release Date: March 2014 Expiration Date: March 2015 Estimated time to complete the educational activity: 30 minutes Statement of Need: Undertraining in dermatology for primary-care providers is a common phenomenon. Thus, primary-care providers need additional educational outlets devoted to identifying and treating dermatologic conditions. For clinicians out of training, CME/CE becomes the most accessible route. Target Audience: This activity has been designed to meet the educational needs of primary-care clinicians who treat patients with various dermatologic conditions. Faculty Sara Braswell; Julia R. Nunley, MD Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond, Va. Esther Stern, NP-C Advanced Dermatology & Skin Surgery, P.C., Lakewood, N.J. Kerri Robbins, MD Baylor College of Medicine, Houston Damjan Jutric The University of Texas School of Dentistry, Houston Accreditation Statements Physician Credit: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of MER and HME. MER is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation: MER designates this educational activity for a maximum of 0.5 AMA PRA Category 1 creditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nursing Credit: MER is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. Credit Designation: This CE activity provides 0.5 contact hour of continuing nursing education. MER is a provider of continuing nursing education by the California Board of Nursing Registered Nursing, Provider #CEP 12299, for 0.5 contact hour. American Academy of Physician Assistants AAPA accepts certificates of participation for educational activities certified for Category I credit from AOACCME, Prescribed credit from AAFP and AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 1 hour of Category I credit for completing this program. Accreditor Disclosure of Conflicts of Interest Policy MER ensures balance, independence, objectivity, and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts

CA0314_CME_DermDis.indd 74

are resolved by MER to ensure all scientific research referred to, reported, or used in a CME/CE activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME/CE activities that promote improvements or quality in health care and not a commercial interest. Faculty Disclosures The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity: Sara Braswell; Julia R. Nunley, MD; Esther Stern, NP-C; Kerri Robbins, MD; and Damjan Jutric have no relevant financial relationships to disclose. Staff/Planners’ Disclosures The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity: The following HME planners and managers hereby state the following financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months: Joe Kopcha, Editor; Marina Galanakis Executive Editor; and Nicole Blazek, Web Editor have no real or apparent conflicts of interest to report. The MER planners and managers, and Veronda Smith, BC-FNP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Method of Participation: There are no fees for participating in and receiving CME/CE credit for this activity. During the period of March 2014 through March 2015, participants must: 1) read the learning objectives and faculty disclosures; 2) study the educational activity; 3) complete the posttest and submit it online (physicians may register at www.myCME.com); and 4) complete the evaluation form online. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better. Disclaimer: The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of MER or HME. The authors have disclosed if there is any discussion of published and/or investigational uses of agents that are not indicated by the FDA in their presentations. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of MER or HME. Before prescribing any medicine, primary references and full prescribing information should be consulted. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management.

2/27/14 10:53 AM

CME CE

Dermatology Clinic n LEARNING OBJECTIVES: To identify and diagnose dermatologic conditions and review up-to-date treatment. n COMPLETE THE POSTTEST: Page 83

n ADDITIONAL CME/CE: Pages 57, 79

Turn to page 56 for additional information on this month’s CME/CE courses.

CASE #1

Pink papules on the fingers and toes SARA BRASWELL AND JULIA R. NUNLEY, MD

A black man, aged 40 years, came to the clinic for the treatment of growths on his toes that were making his shoes uncomfortable to wear. First noticed when he was a teenager, these growths had increased in size and number and affected his fingers as well. Skin-colored nodules were present along the proximal and lateral nail folds of several toes and fingers. Numerous other cutaneous lesions were discovered on full skin examination, including multiple small red-to-pink papules on the face, a finger-sized hypopigmented patch on the torso, and multiple small white patches and a large pink textured plaque on the torso. What is your diagnosis? Turn to page 76

CASE #2

Thickened, painful, and yellow thumbnail ESTHER STERN, NP-C

Approximately six months ago, a woman, aged 65 years, noticed a yellow discoloration of her right thumbnail. Since then, the nail became thicker and would intermittently cause pain in the affected digit. The woman noted that her toenails appeared to be similarly affected, but all other fingernails appeared normal. No other dermatologic medical condition was noted. Medical history was notable for hypertension and glaucoma. No surgical history or recent trauma to the affected finger was noted. Physical exam revealed yellow subungual hyperkeratosis as well as onycholysis of the nail plate. Yellow streaking observed throughout the nail plate was also observed. What is your diagnosis? Turn to page 77 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MARCH 2014 75

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CME CE

CASE #1

Dermatology Clinic

Tuberous sclerosis complex

The diagnosis of tuberous sclerosis complex (TSC) can be readily made in the patient described in this case based simply on his cutaneous findings. TSC is a genetic neurocutaneous syndrome that is manifested by the development of hamartomas in multiple organs, particularly the skin, brain, retina, lungs, kidneys, and heart.1,2 The diagnostic criteria for TSC were revised at the 2012 TSC Consensus Conference.2 The clinical criteria are divided into two categories: major features and minor features.2 The major clinical criteria include hypomelanotic macules, facial angiofibromas or fibrous cephalic plaque, ungual fibromas, shagreen patch, retinal nodular hamartomas, cortical dysplasias, subependymal nodules, subependymal giant cell astrocytoma, cardiac rhabdomyoma, lymphangiomyomatosis, and renal angiomyolipoma. Minor features include confetti skin lesions, dental enamel pits, intraoral fibromas, retinal achromic patch, renal cysts, and nonrenal hamartomas.2 A definitive diagnosis of TSC can be made when a patient has two major features, or has one major and two minor features, or has an identified genetic mutation, regardless of clinical features.2 The man in this case exhibited several of the major cutaneous features of TSC: The digital lesions he complained about were ungual fibromas; the papules on his face were angiofibromas; the textured plaque was a shagreen patch; and of the hypopigmented patches, the larger finger-shaped lesion was identified as an “ash leaf macule.” This ash leaf macule, often present at birth, occurs in more than 90% of patients with TSC and is best visualized with a Wood’s lamp. Angiofibromas, also referred to as adenoma sebaceum, affect approximately 75% of patients with TSC but typically do not develop until after age 2 years. The shagreen patch is a connective-tissue hamartoma with an orange-peel-like texture and usually develops in the first decade of life. Although present in 50% of patients with TSC, the shagreen patch can be seen alone or in other syndromes as well.1,2 Ungual fibromas are also referred to as Koenen tumors.1 Present in approximately 20% of all patients with TSC, these fibromas typically begin around puberty, grow in number and size throughout life,1,2 and can be found in up to 80% of older adult patients.2 Lesions are more common

on toes than on fingers,1 and women more commonly affected than men.3 Although characteristic skin lesions of TSC were reported as early as 1835, the facial lesions were not called adenoma sebaceum until 1890.4 Von Recklinghausen was first to note brain involvement in 1862,1,2 yet, Bourneville is credited with naming the syndrome in 1880 by describing the pathology of the cortex as “sclérose tubéreuse des circonvolutions cérébrales.”1,4 At the beginning of the 20th century, a relationship between the cutaneous and cerebral manifestations was realized when Vogt described the triad of epilepsy, developmental delay, and angiofibroma.1,4 Epidemiologic data have subsequently revealed that this triad occurs in only 29% of patients and that 6% of individuals have none of these entities.1 A complete description of the clinical findings of TSC was not published until 1979.4 The genetic abnormalities were eventually discovered in the 1990s.1 A mutation in one of two genes—TSC1 on chromosome 9 or TSC2 on chromosome 16—can result in the development of TSC. 1 TSC1 and TSC2 encode for hamartin and tuberin, respectively, which interact to form a tumor suppressor heterodimer that inhibits the mammalian target of rapamycin (mTOR), an important regulator of cell proliferation.1 A defect in either protein prevents the inhibition of mTOR, allowing unregulated cellular proliferation. TSC occurs in approximately 1 in 10,000 live births. Although the condition has an autosomal dominant inheritance, two-thirds of cases are sporadic.1 Sporadic cases are more likely to be associated with a TSC2 defect and have more severe disease.1 Multiple alleles of TSC1 and TSC2 exist, possibly explaining the widely variable clinical presentations of TSC.1 Before genetic testing was commercially available, the definitive diagnosis of TSC was delayed until an average age of 5 years because of the paucity of clinical criteria.1 The differential diagnosis of a Koenen tumor comprises a variety of subungual or periungual growths, including a pyogenic granuloma, verruca vulgaris, keratoacanthoma, subungal exostosis, and acquired periungual fibrokeratoma. In contrast to Koenen tumors, acquired periungual fibrokeratomas more commonly appear on the fingers than on the toes and frequently develop following trauma.5,6 Interestingly, the authors from one study suggested the non-random distribution of ungual fibromas in TSC is evidence that trauma may have a role in their development as well.7 However, when a multitude of lesions are present, the diagnosis is more likely TSC; two or more lesions must be present in order to qualify as a major diagnostic feature for TSC.2

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Histology can further help distinguish an acquired periungual fibrokeratoma from a Koenen tumor.6 Whereas both conditions can be characterized by abundant dermal collagen with capillaries and an acanthotic and hyerkeratotic epidermis, the presence of atypical stellate fibroblasts distinguishes Koenen tumors from acquired periungual fibrokeratomas.3,5-7 Treatment of TSC is site-specific and symptom-specific. Surgical excision is currently the therapeutic mainstay for ungual fibromas, but there is a high recurrence rate.5,8 Other modes of removal and destruction have been tried. Berlin et al. reported a successful cosmetic and therapeutic outcome in one patient treated with a continuous CO2 laser, with no recurrence at 11 months.8 Another study showed superior conservation of the proximal nail fold and nail plate integrity through shave excision of multiple lesions with subsequent phenolization, reporting no recurrence at six months.9 A new agent may have promise for patients with TSC. Sirolimus (Rapamune), also known as rapamycin, is a medication commonly used in the solid-organ transplant recipient. An inhibitor of mTOR, sirolumus is being investigated as a treatment option for various hamartomas of TSC.1,10 Initial reports suggest that topical sirolimus may be effective for facial angiofibromas.10 The use of sirolimus was discussed with the patient in this case. Unfortunately the man’s insurance would not cover the cost, and he opted for surgical removal of the most symptomatic lesions instead. The man was also referred to a primarycare clinician for evaluation for other stigmata of TSC. Ms. Braswell is a third-year student at Medical College of Virginia Hospitals, Virginia Commonwealth University, in Richmond, where Dr. Nunley is a professor of dermatology. References 1. Schwartz RA, Fernández G, Kotulska K, Jó´z wiak S. Tuberous sclerosis complex: advances in diagnosis, genetics, and management. J Am Acad Dermatol. 2007;57:189-202. 2. Northrup H, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49:243-254. 3. Ma D, Darling T, Moss J, Lee CC. Histologic variants of periungual fibromas in tuberous sclerosis complex. J Am Acad Dermatol. 2011;64:442-444. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3026635/. 4. Jansen FE, van Nieuwenhuizen O, van Huffelen AC. Tuberous sclerosis complex and its founders. J Neurol Neurosurg Psychiatry. 2004;75:770. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC1763558/pdf/ v075p00770.pdf.

5. Baran R, Richert B. Common nail tumors. Dermatol Clin. 2006;24:297-311. 6. Carlson RM, Lloyd KM, Campbell TE. Acquired periungual fibrokeratoma: a case report. Cutis. 2007;80:137-140. 7. Aldrich CS, Hong CH, Groves L, et al. Acral lesions in tuberous sclerosis complex: insights into pathogenesis. J Am Acad Dermatol. 2010;63:244-251. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2947366/. 8. Berlin AL, Billick RC. Use of CO2 laser in the treatment of periungual fibromas associated with tuberous sclerosis. Dermatol Surg. 2002;28:434-436. 9. Mazaira M, del Pozo Losada J, Fernández-Jorge B, et al. Shave and phenolization of periungual fibromas, Koenen’s tumors, in a patient with tuberous sclerosis. Dermatol Surg. 2008;34:111-113. 10. Koenig MK, Hebert AA, Roberson J, et al. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex: a double-blind, randomized, controlled trial to evaluate the safety and efficacy of topically applied rapamycin. Drugs R D. 2012;12:121-126. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3585992/. All electronic documents accessed February 15, 2014.

CASE #2

Onychomycosis

Onychomycosis, also known as tinea unguium, refers to a fungal infection of the nail. This very common condition accounts for 30% of all superficial fungal infections, and may involve the nail plate, nail bed, or nail matrix.1 The organism Trichophyton rubrum accounts for approximately 70% of cases and Trichophyton mentagrophytes accounts for approximately 20% of all cases; yeasts and nondermatophyte molds account for the remainder.2 Overall, the toenails are affected at a significantly higher rate than are the fingernails. There are four basic subtypes of onychomycosis. Distal subungual onychomycosis, the most common form, presents with yellow or white subungual hyperkeratosis, onycholysis, and yellow streaking starting at the distal edge of the nail and progressing proximally. White superficial onychomycosis almost always affects the toenails only and presents with superficial white or milky patches and speckling on the nail plate. Caution should be taken not to mistake this condition for keratin granulations, which has a similar appearance but is caused by frequent use of nail polish remover. Proximal subungual onychomycosis occurs when the fungus invades the newly forming nail plate, causing leukonychia that starts at the

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CME CE

Dermatology Clinic

proximal nail plate and advances distally as the nail grows. This condition is most common in patients with immunosuppression. Finally, candidal onychomycosis presents with marked periungual inflammation and is caused by a candida infection that is almost always secondary to a preexisting onycholysis. The prevalence of onychomycosis in the adult population is between 6% and 8%.1 Risk factors include immunosuppression, advancing age, humid environment, diabetes, peripheral vascular disease, communal bathing, and occlusive footwear. Although onychomycosis is largely a cosmetic issue, a significant number of patients report intermittent pain and discomfort. Some develop periodic episodes of paronychia. In addition, there may be an increased risk of bacterial infection, particularly in persons with diabetes or a suppressed immune system. Such other conditions as lichen planus, psoriasis, alopecia, Darier disease, allergic/irritant contact dermatitis, traumatic onycholysis, and yellow nail syndrome can also affect the nails and mimic onychomycosis. When only one nail is affected, extreme caution must be used to rule out squamous cell carcinoma, malignant melanoma, or other tumors of the nail bed. Therefore, it is important to always confirm the diagnosis, using either direct microscopy with potassium hydroxide smear or fungal culture. Treatment options for onychomycosis depend on the clinical subtype, the number of nails affected, and the patient’s health status. Some patients are asymptomatic and may not seek treatment, whereas others may request treatment largely for cosmetic purposes. Topical therapy usually requires long-term administration, and the results are often disappointing. Systemic treatment is challenging because of the associated side effects and safety profiles. Surgical therapy is often painful and is therefore not well accepted. Topical treatments include antifungals in cream form and in a nail-lacquer preparation. These options are typically only moderately effective, and often require months of consistent treatment. One study showed a cure rate of 29% to 36% after 48 weeks of treatment with ciclopirox 8% topical solution (Penlac Nail Lacquer).3 Although topical ciclopirox has an excellent safety profile and the cost is reasonable, a 48-week treatment period is unrealistic for most patients. Oral terbinafine (Lamisil), itraconazole (Onmel, Sporanox), and fluconazole (Diflucan) have all been used for systemic treatment of onychomycosis. Terbinafine 250 mg/day for six weeks is indicated for treatment of the fingernails, and a 12-week course is indicated for treatment of the toenails. Terbinafine is the most recent drug of choice for onychomycosis. Itraconazole is given as pulse dosing, 200 mg b.i.d. for

one week out of every month for two to four months. In 2001, however, the FDA advised against prescribing itraconazole for treatment of onychomycosis in patients who have congestive heart failure (CHF) or a history of CHF.4 Prescribed less commonly, fluconazole is given once a week for six to 12 months. Prior to the start of treatment, patients should be told that these medications have a success rate of approximately 80%.5 Patients should be screened to ensure they have no contraindications or potential for medication interactions. The FDA issued a warning regarding the potential for serious liver problems resulting from use of terbinafine and itraconazole.4 Clinicians must discuss with patients the risks and benefits of treatment. Although there do not appear to be any strong recommendations, some providers monitor liver function prior to and during treatment with these medications. Laser treatment has recently emerged as another option for onychomycosis treatment. Because so little information is available regarding cure rates and recurrence rates, patients should be encouraged to consider the risks, benefits, and side effects prior to initiating this costly option. The patient in this case was counseled regarding the treatment options for onychomycosis. Topical treatment would require a significant time investment, whereas systemic treatments carried the potential for significant side effects. Surgical and laser treatment were ruled out. The patient decided to hold off on any treatment and elected to cover up the condition with nail polish. n Ms. Stern is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. References 1. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa.: Saunders Elsevier; 2011:295-296. 2. Derby R, Rohal P, Jackson C, et al. Novel treatment of onychomycosis using over-the-counter mentholated ointment: a clinical case series. J Am Board Fam Med. 2011;24:69-74. Available at www.jabfm.org/content/24/1/69.long. 3. Gupta AK, Fleckman P, Baran R. Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis. J Am Acad Dermatol. 2000;43:S70-S80. 4. U.S. Food and Drug Administration. Sporanox and Lamisil for the treatment of onychomycosis. Available at www.fda.gov/drugs/drugsafety/ postmarketdrugsafetyinformationforpatientsandproviders/drugsafetyinformationforheathcareprofessionals/publichealthadvisories/ucm052094.htm. 5. Elewski BE. Onychomycosis: pathogenesis, diagnosis, and management. Clin Microbiol Rev. 1998;11:415-429. Available at cmr.asm.org/content/11/3/415.long. All electronic documents accessed February 15, 2014.

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CME CE

Dermatologic Look-Alikes n LEARNING OBJECTIVE: To distinguish and properly treat dermatologic conditions with similar presentations. n COMPLETE THE POSTTEST: Page 83

n ADDITIONAL CME/CE: Pages 57, 75

Turn to page 56 for additional information on this month’s CME/CE courses.

Dark pigmentation in the oral cavity KERRI ROBBINS, MD, AND DAMJAN JUTRIC

CASE #1

CASE #2

A woman, aged 53 years, presented complaining of a dark spot of unknown duration inside her mouth. Examination of the right posterior gingiva and buccal mucosa revealed a darkly pigmented macule. A large amalgam restoration was also noted on her first upper-right molar. A large fracture was noted within the amalgam restoration. The patient reported that the amalgam had been placed more than 35 years ago. She was also experiencing hypersensitivity involving that tooth and had made an appointment with her dentist to have it checked.

A man, aged 67 years, presented with pigmentation in his oral cavity of unknown duration. He had recently seen an oral surgeon for implant placement in his upper left quadrant to restore an edentulous area, and the lesion was discovered at that time. X-ray revealed an irregular, moth-eaten appearance of the bone and showed no evidence of any radiopaque material. A cone beam scan revealed a large subgingival growth. Subsequent clinical examination showed a diffuse dark-pigmented area on the left maxillary gingiva.

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CME CE

CASE #1

Dermatologic Look-Alikes

Amalgam tattoo

Amalgam tattoos often present as a solitary area of discoloration caused by dental amalgam becoming embedded under the mucosal surface within the oral cavity. These lesions arose concurrently with the use of amalgam as a restorative dental material. Analysis of cadaver teeth from the T’ang dynasty in China estimates dental amalgam was used around 618 a.d.-907 a.d. for restorations. Amalgam’s first documented use was presented by Strockerus in Germany in approximately 1528. It was not until 1830 that use of amalgam as a dental material became widespread.1 In its earliest form, amalgam was made out of a mixture of mercury and silver derived from commonly used coins. Today, amalgam alloy is a powder comprised primarily of silver, zinc, tin, and copper.2 Dental amalgam consists of the amalgam alloy (50%) mixed with mercury (50%). The mercury is needed for a surface reaction to take place within the alloy powder, leading to the formation of a crystallized structure. Amalgam materials are not bonded

The areas most commonly affected by amalgam tattoos are the buccal mucosa, the alveolar mucosa, and the gingiva. to the tooth structure but are retained mechanically using various features in tooth preparation and design. Amalgam tattoos appear to affect all races, sexes, and ages equally and occur when dental amalgam becomes embedded in the oral mucosa. Amalgam may become embedded due to rubber-dam perforation during restorative procedures, through amalgam dust created by high-speed turbines used during polishing and occlusal adjustments, and even as a result of flossing newly placed interproximal amalgam restorations. Larger particles of amalgam may become implanted into an open wound during a concomitant surgical procedure. Amalgam is also used for endodontic treatments in apical retrofill procedures, which may cause apical discoloration of the mucosa. Intentional intraoral tattooing is also prevalent in various cultures around the world.

Clinically, an individual with an amalgam tattoo will present with persistent multiple or single gray, black, or blue lesions in the oral cavity. The border may be well defined or irregular. Overall, amalgam tattoos remain stable in size, but they may grow laterally in the initial few months. The lesions are generally painless, but local inflammation and peripheral nerve injury may cause some pain in rare instances in which large particles have been implanted. The most commonly affected areas are the buccal mucosa, the alveolar mucosa, and the gingiva. However, lesions can be found on any area on the mucosa that is in close proximity to an amalgam restoration. Histologically, brown and/or black granules of varying sizes are seen within the connective tissue. Silver salts, which are found as a corrosion component of amalgam, preferentially stain the reticulin fibers that surround nerves and vascular channels. Smaller particles often cause a more significant inflammatory response, which may consist of lymphocytes and plasma cells, or a granulomatous reaction with macrophages and foreign-body giant cells. Larger particles often become surrounded by dense fibrous connective tissue with minimal inflammation. The differential diagnosis of an amalgam tattoo includes malignant oral melanoma, melanocytic nevus, melanotic macule, Kaposi sarcoma, hyperestrogenemia, smoker’s melanosis, and physiologic pigmentation. An easy way to distinguish amalgam tattoo from other entities is to obtain a radiograph of the discolored region with a high-resolution film. If amalgam is present, it will easily be identified as a radiopaque anomaly. Clinicians must also obtain a dental history, including any previous amalgam restorations. If the patient has had an amalgam restoration present for years or has recently had a long standing amalgam restoration removed, it is highly probably that the lesion is an amalgam tattoo. If needed, a biopsy can be done for a definitive diagnosis. Amalgam tattoos are often asymptomatic and thus require no treatment. However, some lesions may occur in aesthetic areas and patients may prefer elective removal. Removal may be accomplished by conservative surgical excision or by laser therapy utilizing the Q-switched ruby or alexandrite laser. The goal of laser surgery is to break up the pigmented particles into small enough pieces to be removed via phagocytes. The number of treatments needed is highly dependent on the density and composition of the amalgam.3 A radiograph performed on the woman in this case revealed a radiopaque anomaly in the area of the discoloration. A biopsy confirmed the diagnosis of amalgam tattoo, and no treatment was sought.

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CASE #2

Oral melanoma

Melanoma is a malignant tumor derived from melanocytes, cells that are responsible for skin complexion. The tumor may arise from a benign melanocytic lesion or from melanocytes of normally healthy skin or mucosa. Although most melanomas arise on the skin, they may develop anywhere on the body that contains melanocytes (e.g., the oral cavity, eyes, nails). Melanoma was originally discovered in the 1780s by an English surgeon named John Hunter. Malignant melanoma of the oral mucosa was first described by Weber in 1859.4 Today, oral melanoma falls under a rare subtype of melanoma called mucosal lentiginous melanoma. Only 1 of every 2 million persons in the United States will develop mucosal lentiginous melanoma. In fact, mucosal melanomas account for only 1.4% of all melanomas, and 25% to 50% occur in the head-and-neck region.5 The exact etiology of oral melanoma remains unknown. Melanoma arises from melanocytes, which originate from our neural crest cells. These cells migrate through cellular spaces (during the early fetal period) to the basal cell layer. It is clear that melanocytes within the oral cavity are metabolically inactive and do not produce any melanin; hence, there is no pigmentation in the mouth. Because most mucosal melanomas are located in highly vascularized and hidden areas, they are often not found until they are in advanced stages. This unfortunately accounts for the high mortality rate associated with these cancers. New advances have been made with gene expression models. The proto-oncogene c-kit is known to be a key regulator of proliferation, migration, growth, and differentiation of melanocytes. One study noted that c-kit expression was found in 88% of oral melanomas, and 22% of those tumors actually harbored activating mutations.6 Two out of every three patients with oral melanoma are males, and affected persons typically are in their sixth or seventh decade of life. It should be noted that 50% of all oral melanomas are found on the hard palate, and 20% on the maxillary gingiva.7 It is very rare for oral melanomas to be found on the buccal mucosa, floor of the mouth, or tongue. Most lesions are soft to palpation. Radiograph examinations may show underlying bone or adjacent bone with an irregular appearance or moth-eaten destruction.

Oral melanoma lesions typically begin as brown to black macules with irregular borders. The macule extends laterally and can vary in size from millimeters to centimeters. As the lesion progresses, vertical growth is initiated and a lobulated exophytic mass develops. It is at this stage that the cancer is typically diagnosed. Early ulceration and pain may develop but is uncommon. Lesions are usually painless, which partially explains why patients are oblivious to the growing cancer. Another feature that adds to the cancer’s elusiveness is that more than 20% of oral melanomas contain so little pigment that they have an essentially normal mucosal tint.8 Histologically, atypical melanocytes are seen at the dermalepidermal junction. Early lesions will show either nests or single scattered melanocytes among the basal epithelial cells. Atypical cells tend to be larger and have varying degrees of hyperchromatism and nuclear pleomorphism. As the cancer progresses, it will undergo a radial-growth phase that includes a lateral spread of the atypical melanocytes along the basal cell layer. Advanced oral melanoma shows atypical melanocytes advancing into the dermis; this is considered the vertical-growth phase. The invading cells are either spindle-shaped or epithelioid. As they infiltrate the connective tissue, the invading cells are loosely aggregated in cords or sheets of pleomorphic cells. Oral melanomas also tend to invade the lymphatic and blood vessels more frequently than do their cutaneous counterparts. The oral cavity may pose diagnostic challenges for the clinician, as many lesions appear similar. The differential diagnosis of oral melanoma includes amalgam tattoo, melanotic macule, Kaposi sarcoma, hyperestrogenemia, smoker’s melanosis, physiologic pigmentation, and melanocytic nevus. Because all have similar clinical features, histopathologic confirmation is often necessary to differentiate between the disorders. Surgical resection with or without sentinel lymph node biopsy (depending on depth at presentation) remains the treatment of choice for primary oral melanoma. Prognosis is typically poor if the depth is greater than 0.5 mm. Lymph node dissection is usually performed on patients with clinically evident regional metastasis in the absence of distant metastasis. If distant metastasis is confirmed, systemic chemotherapy is usually initiated. Historically, dacarbazine (DTIC-Dome) has been the mainstay of treatment. Temozolomide (Temodar), a cytotoxic alkylating agent, has demonstrated results similar to those of dacarbazine. More recent advances and understanding of genetic mutations in melanomas have opened new doors for targeted

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CME CE

Dermatologic Look-Alikes

therapy. For example, imatinib (Gleevec), a new tyrosine kinase inhibitor, is more specific for the c-kit domain that is often found in mucosal melanomas.9 Unfortunately, the prognosis for many patients with oral melanoma is extremely poor, with five-year survival studies ranging between 13% and 22%.10 Early metastasis and late detection are to blame for the high mortality rate. The patient in this case was diagnosed with a mucosal melanoma with a depth of 0.9 mm and palpable lymph nodes on clinical examination. He was referred for surgical excision and oncology consultation. n Dr. Robbins is an instructor in the Department of Dermatology at Baylor College of Medicine in Houston. Mr. Jutric is a third-year dental student at The University of Texas School of Dentistry, also in Houston.

“I found this stuck in the sand right next to some sleeping people.”

References 1. Bjørklund G. [The history of dental amalgam]. Tidsskr Nor Laegeforen. 1989;109:3582-3585. 2. Lundin K, Schmidt G, Bonde C. Amalgam tattoo mimicking mucosal melanoma: a diagnostic dilemma revisited. Case Rep Dent. 2013;2013:787294. Available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC3606745/. 3. Gojkov-Vukelic M, Hadzic S, Pasic E. Laser treatment of oral mucosa tattoo. Acta Inform Med. 2011;19:244-246. Available at www.ncbi.nlm.nih.gov/ pmc/articles/PMC3564178/. 4. Nehse G, Mensing H, Maerker R. [Differential diagnosis and therapy of malignant melanomas of the oral cavity]. Fortschr Kiefer Gesichtschir. 1988;33:127-129. 5. Seetharamu N, Ott PA, Pavlick AC. Mucosal melanomas: a case-based

review of the literature. Oncologist. 2010;15:772-781. Available at www. ncbi.nlm.nih.gov/pmc/articles/PMC3228004/. 6. Rivera RS, Nagatsuka H, Gunduz M, et al. C-kit protein expression correlated with activating mutations in KIT gene in oral mucosal melanoma. Virchows Arch. 2008;452:27-32. 7. Tucci R, Aburad De Carvalhosa A, Anunciação G, et al. Late diagnosis of a primary oral malignant melanoma: a case report. Minerva Stomatol. 2010;59:55-59. 8. Neville BW, Damm DD, Allen CM, Bouquot J. Oral and Maxillofacial Pathology, 3rd ed. St. Louis, Mo.: Saunders/Elsevier; 2009:435. 9. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305:2327-2334. 10. Gorsky M, Epstein JB. Melanoma arising from the mucosal surfaces of the head and neck. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;86:715-719. All electronic documents accessed February 15, 2014.

“I dreamed I got eight hours of sleep.”

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POSTTEST Expiration date: March 2015

Physician Credit This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Medical Education Resources (MER) and Haymarket Medical. MER is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Medical Education Resources designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. American Academy of Physician Assistants AAPA accepts cer tificates of par ticipation for educational activities cer tified for

Category I credit from AOACCME, Prescribed credit from AAFP and AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician Assistants may receive a maximum of 1 hour of Category I credit for completing this program. Nursing Credit Medical Education Resources is accredited as a provider of continuing nursing education by the American Nur ses Credentialing Center’s Commission on Accreditation. This CE activity provides 1 contact hour of continuing nursing education. Medical Education Resources is a provider of continuing nursing education by the California Board of Registered Nursing, Provider #CEP 12299, for 1 contact hour.

CREDITS: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 57

page 75

page 79

1. Which neurotransmitter is the primary target for some antidepressants? a. Serotonin b. Dopamine c. Acetylcholine d. Gamma-aminobutyric acid (GABA)

Case #1

1. What is a minor clinical criterion for tuberous sclerosis complex? a. Fibrous cephalic plaque b. Intraoral fibroma c. Cortical dysplasia d. Hypomelanotic macule

1. What is included in the differential diagnosis of amalgam tattoo? a. Physiologic pigmentation b. Kaposi sarcoma c. Smoker’s melanosis d. All of the above

2. What is currently the therapeutic mainstay for ungual fibromas? a. Continuous CO2 laser b. Phenolization c. Surgical excision d. Topical sirolimus (Rapamune)

2. What is used to distinguish amalgam tattoo from other entities? a. Autofluorescence imaging b. Radiograph with high-resolution film c. Digital microscopy d. MRI

2. According to DSM-5 criteria, what symptom associated with substance use disorders is needed to establish the diagnosis? a. The substance is often taken in larger amounts than was intended. b. A strong urge to use the substance c. Recurrent substance use in situations in which it is physically hazardous d. All of the above 3. Which of the following is a sign or symptom of alcohol withdrawal? a. Yawning b. Dilated pupils c. Transient hallucinations d. Rhinorrhea 4. Which questionnaire classifies patients as alcoholic or nonalcoholic? a. Screening, Brief Intervention and Referral to Treatment (SBIRT) b. Alcohol Use Disorders Identification Test (AUDIT) c. CAGE Questionnaire d. Drug Abuse Screen Test (DAST) TO TAKE THE POSTTEST please go to CliniAd.com/1mDdLCp

Case #2 3. Where are 50% of all oral 3. What is the presentation of melanomas found? the most common subtype of a. Tongue onychomycosis? b. Buccal mucosa a. Yellow or white subungual c. Hard palate hyperkeratosis d. Maxillary gingiva b. Superficial white or milky patches c. Leukonychia starting at the 4. What is the treatment of choice proximal nail plate for primary oral melanoma? d. Marked periungual inflammation a. Surgical resection b. Systemic chemotherapy 4. The FDA advises against itrac. UVB phototherapy conazole (Onmel, Sporanox) in d. Topical fluorouracil (Carac, Efudex, patients with Fluoroplex) a. Congestive heart failure Case #2

b. Renal impairment c. Osteoporosis d. Seizure disorder TO TAKE THE POSTTEST please go to CliniAd.com/1k5zykt

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ALTERNATIVE MEDS UPDATE

What you should know about the herbs and supplements patients use

By Sherril Sego, FNP-C, DNP. Ms. Sego is a staff clinician at the VA Hospital in Kansas City, Mo., where she practices adult medicine and women’s health. She also teaches at the nursing schools of the University of Missouri and the University of Kansas.

Mushrooms

Mushrooms are not typically thought of as medicinal, but in ancient times, this food source was highly prized for its healing properties. A significant number of modern prescription medications have been derived from mushrooms. Multiple bioactive compounds have been identified in mushrooms, and researchers continue to refine and use these compounds—which range from complex polysaccharides to proteins with a wide variety of actions in human physiology—to fight numerous diseases.

Background The term “mushroom” describes a variety of gilled fungi that fall into two general categories: Ascomycota and Basidiomycota.1 The use of medicinal mushrooms is documented to have occurred as early as the 29th century b.c. in the Chinese catalog known as the Shennong Bencao Jing, which contained an official list of some 365 medicinal plant substances.2 A review of the literature yields hundreds of studies describing the medicinal uses of a wide range of mushroom subspecies. One of the more prominent and clinically significant uses studied was the effect of mushroom extracts on cancer.The breadth of the data and specific subspecies makes individual reporting in this forum impractical, so general study data will be reported.

Science The ravages of cancer are known to be largely attributable to blockage of the normal immune-system protection,

altered cell-signaling (inducing abnormal cell proliferation), and accelerated oxidative damage impacting normal DNA. Multiple trials using both animal and human cell models have shown promising effects of mushroom extracts on these areas of vulnerability.3 Researchers studying mushroom extracts from Cordyceps sinensis and C. militaris verified immune system up-regulation and significant induction of cellular apoptosis in human cancer cells.3 Another observed phenomenon was a unique “Trojan horse” activity in which the extract molecule mimics the cancerous RNA and causes cell death by preventing replication.3 A laboratory trial tested the action of Tricholoma matsutake in human cells to determine metabolic effects in nondiseased cell lines.4 The results showed strong increased production of nitric oxide and tumor necrosis factor (TNF)-alpha. A human trial studying the effect of dietary supplementation with the mushroom extract Agaricus blazei Murill Kyowa on patients with cervical, ovarian, or endometrial cancer showed statistically significant increases in natural killer cell

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Nurse Practitioner Associates for Continuing Education

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ALTERNATIVE MEDS UPDATE activity and a marked improvement in typical chemotherapy-associated side effects.5 Chronic myeloid leukemia is known for causing abnormally high levels of a specific enzyme (BCR-ABL kinase). A recent trial examined the effect of the mushroom Daedalea gibbosa on mouse cells implanted with BCR-ABL kinase cells.6 The extract showed statistically significant in vivo antitumor activity by blocking the kinase activity. When tested against an active control of the FDA-approved drug imatinib (Gleevec), the mushroom extract’s tumor-inhibitory effect was stronger. Another mechanism of cancer-cell proliferation is the increase in healthy-cell injury and death. A study of the effect of extract from the fungus Cyathus stercoreus examined its protective action on the cell by blocking the attacks of highly reactive oxidative processes.7 The cell lines studied showed a dramatic reduction in oxidative damage and death and preservation of the normal DNA when compared with the untreated cells. Extracts of the Reishi mushroom (Ganoderma lucidum) have also been shown to be hepato-protective against both oxidative damage and multiple chemical insults.8,9

Safety, interactions Allergic reactions to any alternative medication are always a concern, and the area of drug and herb interactions has yet to be sufficiently researched. However, multiple specific substances derived from mushrooms have been approved for placement on the FDA’s GRAS (Generally Regarded as Safe) list.

Summary A number of mushroom-based compounds are recommended for increasing energy, reducing levels of blood glucose, losing weight, and boosting the immune system. However, reliable data from actual human clinical trials is still relatively lacking. n References 1. Encyclopedia Britannica. Mushroom. Available at www.britannica.com/EBchecked/topic/398886/mushroom.

Mushroom extracts aid induction of apoptosis (shown) in cancer cells.

Mushroom extracts have been shown to protect the liver from oxidative damage and multiple chemical insults.

How supplied, dose, cost

2. Wong HS, Chen N, Leong PK, Ko KM. β-sitosterol enhances cellular glutathione redox cycling by reactive oxygen species generated from mitochondrial respiration: protection against oxidant injury in H9c2 cells and rat hearts. Phytother Res. 2013 Nov 26. [Epub ahead of print.] 3. Patel S, Goyal A. Recent developments in mushrooms as anti-cancer therapeutics: a review. 3 Biotech. 2012;2:115. Available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC3339609. 4. Byeon SE, Lee J, Lee E, et al. Functional activation of macrophages, monocytes and splenic lymphocytes by polysaccharide fraction from Tricholoma matsutake. Arch Pharm Res. 2009;32:1565-1572. 5. Ahn WS, Kim DJ, Chae GT, et al. Natural killer cell activity and quality of life were improved by consumption of mushroom extract, Agaricus blazei Murill Kyowa, in gynecological cancer patients undergoing chemotherapy. Int J Gynecol Cancer. 2004;14: 589-594. 6. Khamaisie H, Sussan S, Tal M, et al. Oleic acid is the active component in the mushroom Daedalea gibbosa inhibiting Bcr-Abl kinase autophosphorylation activity. Anticancer Res. 2011;31:177-183. Available at ar.iiarjournals. org/content/31/1/177.long. 7. Kang HS, Kim KR, Jun EM, et al. Cyathuscavins A, B, and C, new free radical scavengers with DNA protection activity from the Basidiomycete Cyathus stercoreus. Bioorg Med Chem Lett. 2008;18:4047-4050. 8. Shi Y, Sun J, He H, et al. Hepatoprotective effects of Ganoderma lucidum peptides against D-galactosamineinduced liver injury in mice. J Ethnopharmacol. 2008;117:415-419. 9. Kim DH, Shim SB, Kim NJ, Jang IS. Beta-glucuronidaseinhibitory activity and hepatoprotective effect of Ganoderma lucidum. Biol Pharm Bull. 1999;22:162-164 All electronic documents accessed February 15, 2014.

Most commercially available mushroombased formulations are powder-filled capsules. Depending on the vendor, these formulations are often part of a multi-ingredient product. The actual dose of mushroom extracts is difficult to determine, but most product labels recommend one or two capsules daily. The price varies widely by brand but averages around $30 for a one-month supply. 86 THE CLINICAL ADVISOR • MARCH 2014 • www.ClinicalAdvisor.com

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makes all the difference

With CancerCare, the difference comes from: • Professional oncology social workers • Free counseling • Education and practical help • Up-to-date information • CancerCare for Kids® For needs that go beyond medical care, refer your patients and their loved ones to CancerCare. CancerCare’s free services help people cope with the emotional and practical concerns arising from a cancer diagnosis and are integral to the standard of care for all cancer patients, as recommended by the Institute of Medicine.

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COMMENTARY Rachael Buitrago, DNP, CPNP, is an ANCC board-certified pediatric nurse practitioner in a private office in South Florida, and has taught as adjunct nursing faculty at local universities.

My patient, myself ? Not always! “What would you do if you were me?”A loaded question with a multitude of variables that can affect the decision and the answer. If your patient is asking this question of you, remind him or her that in health care, the clinician strives to guide the person toward optimum health and disease prevention with the best quality of life. I believe what one may decide for oneself and what one may feel someone else should do are affected not just by the best course of treatment at the time but by one’s personal morals as well. One cannot completely escape the beliefs that have been instilled in one’s life.Therefore, it may be tricky for you as the provider to separate best medical advice from personal opinion.

Sometimes I can easily tell the patient what I would do if it were me, and other times the answer is very convoluted.

Isn’t it true that clinicians do not make for good patients, often not taking the advice that they so frequently give to others? With this being said, I can honestly say that sometimes I can easily tell the patient what I would do if it were me, and other times the answer is very convoluted. Consider this example: A mother is worried about giving her child an antibiotic for a streptococcal pharyngitis infection because the child has never taken antibiotics before. If this were my child I would, without a doubt, use the antibiotic. The risks of not treating with an antibiotic are too severe for me to chance with my child. So, in that scenario, stating what I would do is a no-brainer. However, this is a relatively bland application of the question, “What would you do if you were me?’’ If my patient asked me this question because he or she had been given a diagnosis of a debilitating or terminal illness, my answer would not come so quickly or easily. Many factors come into play for the patient who is confronting a lifetime of illness or the possibility of death in the near future: • Would the disease have an impact on my physical or psychological well-being? • Do I have a support system? • Are my children grown? • Do I have the financial means for the best treatment options?

The place where a person is in life upon receiving critical health news plays a great role in deciding how to move forward. I’m sure there have been cases in which the health-care provider has looked into radical treatment options for a patient who has been told he or she has little time left, only for the patient to decide to accept whatever the future holds without enlisting any extreme measures. Such radical treatments may be what that particular health-care provider would choose for himself or herself; other clinicians might decide to live out what time is left with a focus on quality rather than on quantity. Some health-care issues may be simple or cutand-dried, whereas others may require both the provider and the patient to do research, think over the options, and discuss the possibilities with others. Whatever decision the patient makes, the clinician should remain neutral and unbiased. Providing the necessary information regarding all possible treatments and outcomes available while allowing the patient to come to his or her own decision about the most appropriate course of action is the best care a clinician can offer to someone who is facing a significant medical issue. Although it may be difficult to keep your personal feelings out if it, be sure to remember that when your patient asks you the question, “What would you do?” n

88 THE CLINICAL ADVISOR • MARCH 2014 • www.ClinicalAdvisor.com

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Ron Culberson, MSW, CSP Speaker, Author, Humorist

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