June 2017 Clinical Advisor by The Clinical Advisor

THE CLINICAL ADVISOR • JUNE 2017

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NEWSLINE

■ Pancreatic cancer ■ Breast cancer therapies ■ Colonoscopy timing ALT MEDS UPDATE

Coal tar products can be used topically for psoriasis LEGAL ADVISOR

A nurse is fired for falling asleep at her job

■ Dermatologic Look-Alikes

HYPERPIGMENTED PATCHES PAGE 47

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IMPROVING EPILEPSY OUTCOMES PAGE 24

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GENETIC TESTING IN

PRIMARY CARE A variety of tests can be used to assess the risk of hereditary diseases.

Editor Colby Stong editor@clinicaladvisor.com Senior editor Sandhya George Associate editor Lauren Grygotis Assistant editor Madeline Morr Contributing editors Mark P. Brady, PA-C; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP; Sharon Dudley-Brown, PhD, FNP; Abimbola Farinde, PharmD; Laura A. Foster, CRNP, FNP; Abby A. Jacobson, PA; Maria Kidner, DNP, FNP; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Mary Newberry, CNM, MSN; Claire Babcock O’Connell, MPH, PA; Kathy Pereira, DNP, FNP; Sherril Sego, DNP, FNP; Ann Walsh, PA-C, SCT(ASCP); Kim Zuber, PA-C

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CONTENTS JUNE 2017

NEWS AND COMMENT 9

24 CME Paving the way to better epilepsy outcomes Tailoring treatment using new antiepileptic drugs helps improve patient adherence to therapy by improving seizure control and minimizing side effects. Clinicians managing epilepsy have a great opportunity to improve communication with patients and their families.

Newsline ■■Metastatic pancreatic cancer: a new

clinical practice guideline ■■Integrative therapies during and after

breast cancer treatment: a clinical practice guideline ■■Colonoscopy timing after positive fecal test linked to risk for colorectal cancer ■■Short-term oral corticosteroid use associated with increased risk for sepsis, venous thromboembolism ■■Screening for preeclampsia throughout pregnancy recommended by USPSTF ■■Corticosteroids for sore throat: a mixed bag of results

Metastatic pancreatic cancer guideline 9

DEPARTMENTS

FEATURES 12 Genetic testing: an overview for clinicians Genetic tests can now be used to assess risk for, screen for, diagnose, determine the prognosis of, and manage many hereditary diseases. Providing patients with information about genetic testing will become more commonplace as our understanding of genetics continues to grow. Patients may seek information from other resources, such as the Internet. Thus, clinicians must be knowledgeable about genetic testing because many patients will present with a rudimentary understanding of the subject.

MAKING CONTACT

38 CME Feature posttest

Pink and brown nodule after a mosquito bite 43

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

Dermatology Clinic n Groin rash, profuse bleeding, and a large, eroded plaque n A pink and brown nodule years after a mosquito bite

47 Dermatologic Look-Alikes Hyperpigmented patches Continues on page 6

Legal Advisor: Falling asleep on the job 51

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CONTENTS 51

Legal Advisor Fired for falling asleep on the job. A nurse claims that her firing was in retaliation for taking time off under the FMLA.

Alternative Meds Update Coal tar products are most often used topically for a variety of skin conditions. Coal tar is one of the oldest known treatments for psoriasis, as it reduces scaling, itching, and inflammation.

“Yes?”

ADVISOR FORUM 40

Your Comments ■ Working with multiple attending physicians in the emergency department

Consultations ■ Treatment for cutaneous abscesses

“I wish you warned me first about your razor-sharp wit.”

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TESTING

PRIMARY

C ARE A variety of test can be used s assess the to risk of heredita ry diseases.

DEPARTMENTS cont’d

EXCLUSIVE TO THE WEB AT

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Preventing Lyme disease and tick bites: tips from the CDC Individuals have a higher risk of tick bites and tickborne diseases, including Lyme disease, from May through July. Methadone reduces mortality in opioid-dependent patients Patients receiving methadone maintenance treatment have 25 fewer deaths per 1,000 person-years compared with patients who discontinue treatment. Cognitive remediation may improve executive function in bipolar disorder Cognitive remediation may aid the neurocognitive performance, including attention, working memory, and problem solving, of patients with bipolar disorder.

About 1 in 3 drugs has a safety concern after FDA approval Almost one third of the new therapeutics approved by the FDA between 2001 and 2010 were affected by a postmarket safety event, according to a recent study published in JAMA. Watch the video here: ClinicalAdvisor.com/FDAApprovalVideo

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Sharon M. O’Brien, MPAS, PA-C Sleep paralysis: A world between wakefulness and sleep Patients who experience sleep paralysis may find themselves unable to move or speak and may have a difficulty taking a deep breath.

Cartoon Archive The Clinical Advisor’s monthly cartoons are also available online.

ClinicalAdvisor.com/cartoons

Jim Anderson, MPAS, PA-C, DFAAPA Could “safe consumption sites” help the heroin epidemic in the US? “Safe consumption sites” are medically supervised venues where heroin users can inject heroin in clean, safe, and medicallysupervised facilities. Pierre Manzo, MD Managing new technology in medical practice Incorporating new technology in medical practices to manage outpatient records can sometimes be a challenge.

“I’d like to have him deprogrammed from basketball season.”

Sharon M. O’Brien, MPAS, PA-C The characteristics of nightmares vs sleep terrors Many patients experience ongoing issues with nightmares or night terrors. See more on page 8

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Advisor Dx

EXCLUSIVE TO THE WEB

INTERACT WITH YOUR PEERS by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/AdvisorDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

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A fibula fracture with ankle swelling A 29-year-old man presents to the emergency department with pain in his left leg and ankle after slipping on ice. On examination, the patient has pain over the proximal fibula and over the ankle at the deltoid ligament and anterior tibiofibular ligament. He has diffuse swelling over both the medial and lateral ankle as well. WHAT IS THE BEST TREATMENT OPTION?

• Open reduction, internal fixation of proximal fibula • Non-weight-bearing boot for 4 to 6 weeks • Weight bearing as tolerated in a walking boot for 6 to 8 weeks ● See the full case at ClinicalAdvisor.com/OrthoDx_Jun17

Derm Dx A firm nodule with a positive skin crease sign A 10-year-old boy presents with an asymptomatic firm nodule on his right cheek; it has enlarged slowly in size over the past year. The boy is in good health. On squeezing the lesion, a longitudinal crease is noted traversing the center of the growth. CAN YOU DIAGNOSE THIS CONDITION?

• Dermatofibroma • Epidermoid cyst • Pilomatricoma • Pilar cyst ● See the full case at ClinicalAdvisor.com/DermDx_Jun17

8 THE CLINICAL ADVISOR • JUNE 2017 • www.ClinicalAdvisor.com

Journal of Orthopedics for Physician Assistants

Newsline J U N E 2 017

Integrative therapies in breast cancer page 10

Colonoscopy timing and risk of colorectal cancer page 10

Corticosteroids for sore throat: mixed results page 11

THE AMERICAN Society of Clinical Oncology has released a clinical practice guideline to help clinicians determine the appropriate treatment of patients who have metastatic pancreatic cancer and to help them advise patients and their families about how to access and use palliative care services. An expert panel developed the clinical practice guideline recommendations, published in the Journal of Oncology Practice, using a systematic review of the medical literature. The researchers note that the clinical course of pancreatic cancer is generally aggressive with potential for substantial deterioration in quality of life. “Therefore,” the authors wrote, “palliative care to focus on distressing symptoms and quality of life is an important adjunct in the management of this condition.” A summary of the key recommendations includes the following: • A mu lt ipha se computed tomography scan of the chest, abdomen, and pelvis should be performed to assess the extent of the disease, and other staging studies should be performed as dictated by symptoms (intermediate quality of evidence, strong recommendation).

• Clinicians should carefully evaluate baseline per formance status, symptom burden, and comorbidity profile of patients with metastatic pancreatic cancer (intermediate quality of evidence, strong recommendation). • Clinicians should discuss the goals of care, patient preferences, and support systems with patients diagnosed with metastatic pancreatic cancer and his or her caregivers (intermediate quality of evidence, strong recommendation). • Multidisciplinary collaboration to formulate treatment plans and disease management for patients with metastatic pancreatic cancer should be the standard of care (intermediate quality of evidence, strong recommendation). • Patients with pancreatic cancer should be offered information about clinical trials, including therapeutic trials in all lines of treatment as well as palliative care, biorepository/biomarker, and observational studies (intermediate quality of evidence, strong recommendation). • Leucovorin, fluorouracil, irinotecan, and oxaliplatin are recommended for patients who meet the following criteria:

Metastatic pancreatic cancer: a new clinical practice guideline

Microscopic image of mitochondrial stained pancreatic cancer cells. Chemotherapy is a common treatment.

Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, favorable comorbidity profile, patient preference and support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services (intermediate quality of evidence, strong recommendation). • Gemcitabine plus NA B paclitaxel is recommended for patients with an ECOG performance status 0 or 1, a relatively favorable comorbidity prof ile, and patient preference and support system for relatively aggressive medical therapy (intermediate quality of evidence, strong recommendation). • Patients with metastatic pancreatic cancer should undergo a full assessment of symptom burden, psychological status, and social supports as early as possible, preferable at the first visit. In most cases the assessment will indicate a need for formal palliative care consult and services (intermediate quality of evidence, strong recommendation).

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2017 9

Newsline Integrative therapies in breast cancer treatment THE SOCIETY for Integrative Oncology (SIO) has issued an updated clinical practice guideline regarding the use of integrative therapies for specific clinical indications during and after breast cancer treatment, as published in CA: A Cancer Journal for Clinicians. The recommendations should be considered as a viable but not singular option for managing a specific symptom or side effect. Chemotherapy-induced nausea and vomiting

• Acupressure can be considered in addition to antiemetics drugs to control nausea and vomiting during chemotherapy. Grade B • Electroacupuncture can be considered as an addition to antiemetics drugs to control vomiting during chemotherapy. Grade B

Lymphedema

• Low-level laser therapy, manual lymphatic drainage, and compression bandaging can be considered for improving lymphedema. Grade C Pain

• Acupuncture, healing touch, hypnosis, and music therapy can be considered for the management of pain. Grade C Quality of life Guidelines focus on therapies before and after breast cancer treatment.

Depression/mood disturbance

• Meditation, particularly mindfulness-based stress reduction, is recommended for treating mood disturbance and depressive symptoms. Grade A • Relaxation is recommended for improving mood disturbance and depression. Grade A

• Meditation is recommended. Grade A Vasomotor/hot flashes

• Acupuncture can be considered. Grade C • Soy is not recommended for hot flashes in patients with breast cancer due to lack of effect. Grade D

IN PATIENTS WITH a positive fecal immunochemical test (FIT) result, a follow-up colonoscopy after 10 months was associated with a higher risk of colorectal cancer and more advanced-stage disease at the time of diagnosis compared with a follow-up colonoscopy at 8 to 30 days, researchers reported in JAMA. Researchers conducted a retrospective cohort study in which 70,124 patients between 50 and 70 years of age (median age, 61; men, 52.7%) were eligible for colorectal cancer screening with a positive FIT result who had a follow-up colonoscopy.

The main outcome was the risk of any colorectal cancer and advanced-stage disease, which was defined as stage III and IV cancer. A total of 2,191 cases of any colorectal cancer and 601 cases of advanced-stage disease were diagnosed. Compared with colonoscopy follow-up within 8 to 30 days (n = 27,176), no significant differences were observed between follow-up at 2 months (n = 24,644), 3 months (n = 8,666), 4 to 6 months (n = 5,251), or 7 to 9 months (n = 1,335) for risk of any colorectal cancer (cases per 1,000 patients: 8 to 30 days, 30; 2 months, 28; 3 months, 31; 4 to

10 THE CLINICAL ADVISOR • JUNE 2017 • www.ClinicalAdvisor.com

Timing of a colonoscopy in patients who have had a positive FIT result is associated with the risk of colorectal cancer.

6 months, 31; and 7 to 9 months, 43) or advanced-stage disease (cases per 1,000 patients: 8 to 30 days, 8; 2 months, 7; 3 months, 7; 4 to 6 months, 9; and 7 to 9 months, 13), according to the investigators. The risks were significantly higher for examinations conducted at 10 to 12 months (n = 748) for any colorectal cancer (OR, 1.48; 49 cases per 1,000 patients) and advanced-stage disease (OR, 1.97; 19 cases per 1,000 patients) and more than 12 months (n = 747) for any colorectal cancer (OR, 2.25; 76 cases per 1,000 patients) and advanced-stage disease (OR, 3.22; 31 cases per 1,000 patients).

Colonoscopy timing is linked to colorectal cancer risk

Corticosteroid Screening for preeclampsia in pregnancy are small. The USPSTF concluded PREGNANT WOMEN should use linked to that there is substantial net benefit receive screening for preeclamprisk for sepsis sia with blood pressure measureof preeclampsia screenings. ments throughout pregnancy, according to a recommendation statement from the US Preventive Services Task Force (USPSTF) published in JAMA. The USPSTF reviewed evidence on the accuracy of screening and diagnostic tests for preeclampsia, the benefits and harms of screening for preeclampsia, the effectiveness of risk prediction tools, and the benefits and harms of treatment of screen-detected preeclampsia. The task force found adequate evidence that screening for preeclampsia provides substantial benefit for the mother and infant. There is also adequate evidence that suggests the harms of preeclampsia screenings and treatment

Blood pressure measurements are routinely used to screen for preeclampsia, and these measurements should be obtained during each prenatal care visit during pregnancy. If the patient has an elevated blood pressure reading, clinicians should confirm the readBlood ing with repeated measurements. pressure The USPSTF notes that manmonitoring agement strategies for diagnosed is used to preeclampsia may include close fetal and maternal monitoring, screen for preeclampsia. antihypertension medications, and magnesium sulfate. The task force also recommends the use of low-dose aspirin (81 mg/d) as preventive medication after 12 weeks of gestation in women with a high risk of preeclampsia.

Corticosteroids for sore throat yield mixed results A SINGLE DOSE of oral dexamethasone in adults with an acute sore throat did not increase the proportion of patients who had resolution of symptoms at 24 hours but did have a significant difference at 48 hours compared with placebo, according to a study in JAMA. Researchers conducted a double-blind, placebo-controlled, randomized trial in which they administered a single oral dose of 10 mg of dexamethasone (n=293) or identical placebo (n=283). The primary outcome measure was the proportion of study participants who had complete resolution of their symptoms at 24 hours. Among the 565 eligible participants who were randomized (median age, 34; 75.2% women), 288 received dexamethasone

and 277 received placebo. At 24 hours, 65 patients (22.6%) in the dexamethasone group and 49 (17.7%) in the placebo group achieved complete resolution of symptoms (risk difference, 4.7%; relative risk, 1.28). At 24 hours, participants who received dexamethasone were not more likely than those who received placebo to have complete symptom resolution. However, at 48 hours, 102 participants (35.4%) in the dexamethasone group compared with 75 (27.1%) in the placebo group achieved complete resolution of symptoms (risk difference, 8.7%; relative risk, 1.31). This difference was also observed in patients who were not offered a delayed antibiotic prescription (risk difference, 10.3%; relative risk, 1.37). n

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2017 11

SHORT-TERM USE of oral corticosteroids is associated with an increased risk of sepsis, venous thromboembolism, and fracture, even at low doses, according to a study published in the BMJ. Researchers conducted a retrospective cohort study and selfcontrolled case series to determine the frequency of prescriptions for short-term use of oral corticosteroids, as well as adverse events (sepsis, venous thromboembolism, and fractures) associated with their use. Of 1,548,945 adults (aged 18 to 64) included, 327,452 (21.1%) received at least one outpatient prescription for short-term use of oral corticosteroids during the 3-year period. Use was more frequent among older patients, women, and white adults, with significant regional variation. The most common indications for use were upper respiratory tract infections, spinal conditions, and allergies. Within 30 days of drug initiation, sepsis rates increased (incidence rate 5.30), venous thromboembolism (3.33), and fracture (1.87), which diminished over the subsequent 31 to 90 days. “Over a 3-year period, approximately 1 in 5 American adults in a commercially insured plan used oral corticosteroids for less than 30 days,” the authors said. “The short term use of these drugs was associated with increased rates of sepsis, venous thromboembolism, and fracture; even at relatively low doses.”

FEATURE: GINA R. BROWN, MPAS, PA-C, SETH METZLER, MPA, PA-C, TRISHA DESJARDINS, MPA, PA-C,

AND BRITTANY SEILER, MPA, PA-C

Genetic testing: an overview for clinicians Genetic tests can now be used to assess risk for, screen for, diagnose, determine the prognosis of, and manage many hereditary diseases.

Male XY chromosomes. The white glow may be a genetic mutation.

12 THE CLINICAL ADVISOR • JUNE 2017 • www.ClinicalAdvisor.com

ealthcare providers are constantly adapting to new discoveries about health and medicine. Being aware of the options available for patients is part of their role in everyday practice. Genetics is a complex, everadvancing field that is becoming increasingly utilized in primary care; thus, a variety of genetic tests are now options that can be made available to patients when indicated. As our understanding of and ability to test the human genome advance at a rapid pace, primary care providers (PCPs) have the opportunity to integrate new information into everyday practice.1 A 2013 study of PCP perceptions of genetic testing conducted by the Council of Academic Family Medicine Educational Research Alliance (CERA) found that most of the participants felt that they were not knowledgeable about genetic testing but that genetic testing is of some value at present and will be increasingly valuable in the future.2 Genetic tests can now be used to assess risk for, screen for, diagnose, determine the prognosis of, and manage many hereditary diseases.3 Yet, many providers do not feel competent in the use of these tests.2,4 A recent survey of 315 primary care physicians showed that more than 80% fail to initiate any patient discussions regarding genetic testing even once per month, and that only 19% had ever ordered genetic testing.4 These findings demonstrate the need for continuing education for healthcare providers about genetic tests and their common uses, with the aim of increasing provider confidence and so improve patient care.

The purpose of this article is to present information about five common genetic tests: karyotype, microarray, polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), and whole-exome sequencing (WES). The discussion of each test includes examples of its use in primary care, as well as precautions regarding the interpretation of results and patient education. Karyotype

Karyotype (Figure) is an older genetic test that is still commonly used to evaluate chromosomal abnormalities by sampling blood, amniotic fluid, chorionic villi, umbilical cord blood, products of conception, and bone marrow, among others. By isolating and pairing a patient’s 23 pairs of chromosomes during mitosis, the test identifies largescale chromosomal abnormalities (e.g., aneuploidy) and aberrations. Still commonly used in obstetrics to screen for chromosomal abnormalities in women with high-risk pregnancies, karyotype is also useful in primary care when providers suspect the presence of a hereditary condition like Down syndrome, Klinefelter syndrome, Philadelphia

chromosome, trisomy 18, or Turner syndrome.5 (Some diseases caused by chromosomal abnormalities and others caused by genetic mutations are listed in Table 1.6-9) PCPs may choose to perform chromosomal analysis when a woman has recurrent miscarriages or when an infant exhibits unusual features or developmental delays.5 In a meta-analysis of studies of the prenatal diagnosis of chromosomal aberrations, karyotype was found to have a sensitivity of 67.3% and specificity of 99%.10 PCPs must be aware of mosaicism for chromosomal aberration, in which not all of an individual’s cells are affected by an abnormality. Although karyotype is very useful in diagnosing aneuploidy, it cannot predict outcome or the extent to which an individual will be affected by the diagnosis, so patient education before testing is essential to assist patients in making well-informed decisions. Microarray

Microarray is designed to recognize deletions, insertions, and duplications in DNA by looking for discrepancies in the amount of chromosomal material between a DNA sample and a control. This makes it possible to detect abnormal regions of DNA in

TABLE 1. Genetic mutations and chromosomal abnormalities with associated disease states*6-9 Type of change

Disease states

GENETIC MUTATION Missense mutation: change in a single base pair that results in incorporation of an alternate amino acid into a protein

• Sickle cell disease • Xeroderma pigmentosum • Fanconi anemia • Phenylketonuria (can result from missense mutations or deletions)

Nonsense mutation: change in a single base pair that leads to a premature stop in the protein

• Duchenne muscular dystrophy • Beta-thalassemia

Frameshift mutations (all types may result in changed protein function): • Insertion: placement of an additional base in a gene • Deletion: removal of one or more than one base • Duplication: copying a base abnormally one or more times

• Cystic fibrosis (varied mutations, but deletions most common) • Alpha-thalassemias (deletions) • Crohn disease (insertion) • Tay-Sachs disease (deletion) • Amyotrophic lateral sclerosis (insertions, deletions, and others)

Repeat expansion: multiple repetitions of three or four base pairs in a DNA sequence

• Huntington disease (trinucleotide repeat) • Fragile X syndrome (trinucleotide repeat) • Friedreich ataxia (trinucleotide repeat)

CHROMOSOMAL ABNORMALITY Aneuploidy: change in the number of chromosomes from the normal 23 pairs

• Down syndrome (trisomy 21) • Turner syndrome (monosomy X) • Klinefelter syndrome (47,XXY)

Translocation: breakage of a piece of a chromosome and attachment to another chromosome

• Chronic myelogenous leukemia/Philadelphia chromosome • Cri du chat syndrome

Isochromosome: chromosome with two identical arms, one on each side of the centromere

Pallister-Killian mosaic syndrome

Ring: chromosome breakage in two locations, with free ends joining together and loss of some genetic material

Epilepsy in ring chromosome 14 and ring chromosome 20 syndromes

*This table presents examples and is not a comprehensive list of either genetic changes or disease states.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2017 13

GENETIC TESTING: AN OVERVIEW FOR CLINICIANS

Microarray genetic testing is used in pediatric patients with developmental delay, intellectual disability, and autism spectrum disorders. which genetic material either is missing or has been added. Tagging target genes with fluorescent markers reveals differences between microarray patterns in a patient’s sample and patterns in a control so that it is possible to determine whether or not an individual possesses a mutation associated with a particular disease.11 Although other substances can be sampled, in the clinical setting, blood is most often sent for analysis. Microarray is a method of genetic testing that can accurately identify several chromosomal disorders, including almost all known deletion and duplication syndromes, and it recognizes abnormalities that are not detected by other chromosomal testing options. Microarray testing is used in pediatric patients with developmental delay, intellectual disability, multiple congenital anomalies, and autism spectrum disorders.12,13 Although in some cases, microarray has been replaced with DNA sequencing, it continues to be of value in the analysis of genetic diseases and TABLE 2. Pathogens commonly detected by polymerase chain reaction17-19 Bacteria

Viruses

Bacillus anthracis (anthrax)

Adenovirus

Bartonella henselae (cat scratch fever)

Coronavirus

Bordetella pertussis (whooping cough)

Cytomegalovirus

Brucella species

Epstein-Barr virus

Chlamydia pneumoniae

Enterovirus

Chlamydia trachomatis

Hepatitis B virus

Clostridium difficile

Hepatitis C virus

Corynebacterium diphtheriae (diphtheria)

Herpes simplex viruses 1 and 2

Gardnerella vaginalis

Human metapneumovirus

Legionella species

Human herpesvirus 6

Mycoplasma pneumoniae

Human immunodeficiency virus

Neisseria gonorrhoeae

Human papillomavirus

Staphylococcus aureus

Influenza virus

Fungi

Norovirus

Candida species

Parainfluenza virus

Parasites

Respiratory syncytial virus

Trichomonas vaginalis

Rhinovirus

Trypanosoma cruzi (Chagas disease)

Rotavirus

cancer-linked mutations, and in pharmacogenetics.11 Providers and patients should be cautioned that a laboratory may report results as a “variant of unknown significance” (VOUS/VUS), which means that it is unknown whether the genetic variance detected is pathogenic or benign. Although microarray is useful in children with developmental delay or intellectual disability, interpretation of the results can be complex, and referral to a genetic specialist is recommended.12 Polymerase chain reaction

PCR is a quick and efficient way to amplify genetic material from any source, and very small samples of genetic material can be used to assist in the diagnosis of a broad spectrum of diseases. A sample of DNA from nearly any site can be used for analysis, although the sample type is generally determined by the disease or disorder that is being investigated. DNA is denatured with heat, a process that creates inverse copies of single-stranded DNA. With the single-stranded DNA serving as a template, a polymerase enzyme then synthesizes identical copies of doublestranded DNA. The process is repeated through many cycles, creating more than 1 billion copies of the DNA under study.14 PCR is useful in diagnosing infectious diseases, including bacterial, fungal, viral, and parasitic infections; it is particularly helpful in the case of infectious agents that are difficult to isolate with normal culture techniques.15 Additionally, in some situations, the time required to obtain traditional culture results can delay proper treatment, as in cases of sepsis or meningitis. Emerging PCR-based technology has made it possible to detect pathogens more rapidly in such circumstances, reducing the time to results from days to hours, with better patient outcomes.16 The pathogens that are routinely identified through PCR testing are listed in Table 2.17-19 Laboratories commonly use PCR as the first step in isolating genetic material, which can then undergo further testing with other methodologies.14 This is often done in the diagnosis of genetic abnormalities or malignancies caused by certain known mutations. Providers should be aware that false-positive and false-negative results are a concern with PCR testing because of the ease of sample contamination, and that sensitivity and specificity vary greatly depending on the disease for which PCR is being used.15 Fluorescence in situ hybridization

In FISH, fluorescence-tagged probes are used to detect specific DNA sequences, which can then be visualized under the microscope. This process makes it possible to identify

14 THE CLINICAL ADVISOR • JUNE 2017 • www.ClinicalAdvisor.com

Counseling is needed before and after testing to help patients understand the range and types of results that may be obtained. where a particular gene or gene portion is located within the chromosomes of a cell.20 FISH can detect structural rearrangements such as translocations, inversions, and insertions, and the loss of chromosomal regions, including microdeletions.21 The specimen types usually submitted to the laboratory are peripheral blood or bone marrow, but solid tissue can also be used in the analysis of tumor cytogenetics, so FISH has a unique role in confirming cancer types without the need for actively dividing cells.22 FISH testing is most useful in evaluating malignancies, especially hematologic malignancies, but is also used to determine HER2/neu overexpression in breast cancers.22 Accurately and efficiently identifying genetic alterations that lead to malignancy can facilitate early detection, diagnosis, prognosis, and treatment. Although FISH is a very useful test when used in the correct setting, it is not as effective for investigative purposes as some other genetic testing techniques. Generally, it is used to verify the presence of a suspected chromosomal aberration, or as a supplement in the prognosis and treatment of certain malignancies, rather than to search for a genetic abnormality.21,22 Reproductive specialists may use FISH (or PCR) with embryos of couples who have a known inherited disorder, as a screening tool before in vitro fertilization. Post-implant karyotype is still recommended, however, because the results of FISH may be inaccurate.23 Whole-exome sequencing

The exome is the portion of DNA that codes for proteins, and it is the location of about 85% of the mutations that lead to disease-related traits.24 The starting material for WES is doublestranded nuclear DNA. This can be obtained from whole blood, a buccal swab, or a hair follicle.25 WES is useful in identifying variants in the exome associated with conditions such as, but not limited to, Mendelian disorders (e.g., Huntington disease, familial Mediterranean fever, type I Charcot-Marie-Tooth disease, sickle cell anemia, cystic fibrosis, alpha-1-antitrypsin deficiency) and in evaluating severe intellectual disability or developmental delay.26,27 Once variants are found, they can be connected to clinical phenotypes that have already been identified, allowing a diagnosis. The disadvantage is that not every clinical phenotype has been identified, leaving the possibility of a patient with unanswered questions and no diagnosis.28 WES is useful when all other diagnostic avenues have been exhausted; it may then help identify a clinically apparent abnormality. (Table 3 lists examples of genetic diseases for which WES is appropriate, or for which an alternate test

is preferable.10,22,23,26,27,29-36) In addition, WES is useful in identifying diseases and disorders that are not yet clinically apparent or that have not yet reached full clinical expression, thus preventing a misdiagnosis.26,27 Because incidental findings are possible, patients must be prepared for unexpected results, either an unexpected disease state or a genetic variant about which little is currently known. Counseling is needed before and after testing to help patients understand the range and types of results that may be obtained, as well as to determine which results warrant action, which results call for increased screening or surveillance, and which results are of little concern. Considerations for patient education

Genetic testing can be a fearful, daunting, overwhelming, exciting, or joyful experience. In many cases, the emotions of people who pursue genetic testing can be described with more than just one of these words, or others. Therefore, the patients undergoing most avenues of genetic testing require some counseling and education. Although some genetic tests, such as PCR and karyotype, can yield straightforward results, others often do not provide results that are easily interpreted. Genetic counselors have the expertise to offer an informed interpretation, but PCPs are the educators who must explain to patients why genetic testing and counseling should be considered. Patient education is needed even before an appointment with a genetic counselor is arranged. It is important to educate patients regarding all the possibilities, such as false positives, Continues on page 19

POLL POSITION

Which of the following best describes your opinion of genetic testing? n=315

■ Genetic testing is valuable, and the advantages outweigh the disadvantages. ■ I’m concerned about potential misuse and abuse of genetic testing ■ I need to learn more about genetic testing before advising my patients.

34.3%

45.4%

20.3%

For more polls, visit ClinicalAdvisor.com/Polls.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2017 15

GENETIC TESTING: AN OVERVIEW FOR CLINICIANS

TABLE 3. Common genetic diseases and test types used for diagnosis10,22,23,26,27,29-36 Genetic disease

US prevalence, unless otherwise stated

Test type

Down syndrome (trisomy 21)

1:600 births

Karyotype

Edward syndrome (trisomy 18)

1:3000 births

Karyotype

Klinefelter syndrome (47,XXY)

1:1000 males

Karyotype

Turner syndrome (45,X)

1:5000 females

Karyotype

Celiac disease

1:133

PCR

Cystic fibrosis

1:3000 Caucasians 1:8000 Hispanics 1:15,000 blacks 1:32,000 Asians

PCR, WES

BRCA1/BRCA2 mutation

1:500

PCR

HER2/neu overexpression

1:5 women with breast cancer

FISH

Muscular dystrophy Duchenne Becker

1:3500 males 1:19,000 males

PCR

Multiple endocrine neoplasia, types 1 and 2

1:30,000

PCR

Factor V Leiden thrombophilia

Heterozygosity 1:20 Homozygosity 1:5000

PCR

Familial adenomatous polyposis

<1% of colorectal cancer cases

PCR

Fragile X syndrome

1:4000 males 1:8000 females

PCR

Von Willebrand disease

1:100-1:1000

PCR

Hereditary hemochromatosis

1:300

PCR

Huntington disease

1:15,000

PCR, microarray, WES

Marfan syndrome

1:5000-1:10,000

PCR

Neurofibromatosis type 1

1:3000

PCR

Noonan syndrome

1:1000-1:2500

PCR

Hematologic malignancy (CLL, CML, APL)

N/A

Karyotype, FISH

Polycystic kidney disease (autosomal dominant)

1:500-1:1000

PCR

Tay-Sachs disease

1:3000 Ashkenazi Jews

PCR, WES

Developmental delay, intellectual disability, multiple anomalies, autism spectrum disorders

N/A

Microarray, WES

Noninvasive prenatal screening (aneuploidy/microdeletions)

N/A

Microarray

Preimplant screening of embryos before IVF

N/A

PCR, FISH

Microcephaly

1:30,000-250,000 newborns worldwide

WES

Microdeletion syndromes (Williams, cri du chat, Prader-Willi/Angelman, others)

N/A

FISH

Charcot-Marie-Tooth disease, type 1

1:2500

WES

Sickle cell anemia

SCD—1:500 African Americans SCD—1:36,000 Hispanic Americans SCT—1:12 African Americans

WES

Alpha-1-antitrypsin deficiency

1:1500-3500 persons of European ancestry worldwide

WES

Hemophilias A and B Hemophilia A Hemophilia B

1:10,000 worldwide 1:6500 males 1:20,000 males

WES

APL = acute promyelocytic leukemia; BRCA = breast cancer susceptibility gene; CLL = chronic lymphocytic leukemia; CML = chronic myelogenous leukemia; FISH = fluorescence in situ hybridization; IVF = in vitro fertilization; PCR = polymerase chain reaction; SCD = sickle cell disease; SCT = sickle cell trait; WES = whole-genome sequencing.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2017 19

GENETIC TESTING: AN OVERVIEW FOR CLINICIANS

false negatives, incidental findings, unexpected results, and variants of unknown significance. It is also important to inform them that the symptoms of a mutation-caused disease can vary significantly between different people. Furthermore, explaining the value of discovering a genetic disease is an essential part of patient education. If a specific disease is identified, the element of uncertainty is removed, and interventions may be available that will mitigate symptoms. Helping patients think about the potential benefits and challenges of identifying a disease or disease risk should be part of the role of every PCP, before genetic counseling or testing is undertaken. Although a genetic counselor will provide invaluable information to the patient and family, the PCP will coordinate the patient’s ongoing care, so that an interdisciplinary team approach to genetic testing is desirable for optimal outcomes. Test results may enhance the team’s performance by indicating which subspecialty collaboration would be most helpful.

2. Mainous AG 3rd, Johnson SP, Chirina S, Baker R. Academic family physicians’ perception of genetic testing and integration into practice: a CERA study. Fam Med. 2013;45:257-262. 3. Scott J, Trotter T. Primary care and genetics and genomics. Pediatrics. 2013;132(Suppl 3):S231-S237. 4. Chambers CV, Axell-House DB, Mills G, et al. Primary care physicians’ experience and confidence with genetic testing and perceived barriers to genomic medicine. J Fam Med. 2015;2:1024. 5. Karyotyping. Medline Plus. http://www.nlm.nih.gov/medlineplus/ency/ article/003935.htm. Updated October 30, 2016. Accessed April 25, 2017. 6. Genetics Home Reference. http://ghr.nlm.nih.gov. Accessed April 25, 2017. 7. Suhasini AN, Brosh RM. Disease-causing missense mutations in human DNA helicase disorders. Mutat Res. 2013;752:138-152. 8. Keeling KM, Du M, Bedwell DM. Therapies of nonsense-associated diseases. Madame Curie Bioscience Database [Internet]. http://www.ncbi. nlm.nih.gov/books/NBK6183. Accessed April 25, 2017. 9. Ogura Y, Bonen DK, Inohara N. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411:603-606.

Conclusion

10. Saldarriaga W, Garcia-Perdomo HA, Arango-Pineda J, Fonseca J.

Providing patients with information about genetic testing will become more commonplace as our understanding of the field of genetics continues to grow. Patients may seek information from other resources, such as the Internet or a friend, before talking to their PCP. Thus, the PCP must be knowledgeable about genetic testing because many patients will present with a rudimentary understanding of the subject. Acquiring an understanding of genetic testing will also allow PCPs to make the best possible use of this resource in patient care, whether it be in counseling, making a diagnosis, developing a prognosis, providing targeted screening, elaborating on a consult with a genetic counselor, or making an appropriate referral. n

Karyotype versus genomic hybridization for the prenatal diagnosis of chromosomal abnormalities: a metaanalysis. Am J Obstet Gynecol. 2015;212:330.e1-330.e10. 11. DNA microarray technology. National Human Genome Research Institute. http://www.genome.gov/10000533. Updated August 27, 2015. Accessed April 25, 2017. 12. Michelson DJ, Shevell MI, Sherr EH, Moeschler JB, Gropman AL, Ashwal S. Evidence report: Genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2011;77:1629-1635. 13. Miller DT, Adam MR, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet.

Gina R. Brown, MPAS, PA-C, is an associate professor at Wichita State University and a PA in family practice in Wichita, KS; Seth Metzler, MPA, PA-C, is a PA in family practice in Salina, KS; Trisha Desjardins, MPA, PA-C, is a PA in orthopedic trauma in Bangor, ME; and Brittany Seiler, MPA, PA-C, is a PA in family practice in Wichita, KS.

2010;86:749-764. 14. Polymerase chain reaction (PCR). National Human Genome Research Institute. http://www.genome.gov/10000207. Reviewed June 16, 2015. Accessed April 25, 2017. 15. Yamamoto Y. PCR in diagnosis of infection: detection of bacteria in cerebrospinal fluid. Clin Diagn Lab Immunol. 2002;9:508-514. 16. Arabestani MR, Rastiany S, Kazemi S, Mousavi SM. Conventional,

Acknowledgments

molecular methods and biomarker molecules in detection of septicemia.

The authors would like to thank Claire Chappell, PA-C, Brandi Jensen, PA-C, and Melissa Short, PA-C, for providing the initial foundational direction for this article.

Adv Biomed Res. 2015;4:120. 17. Infectious Diseases Laboratory Test Directory. Centers for Disease Control and Prevention. http://www.cdc.gov/laboratory/specimen-submission/cdc-lab-tests.pdf. Published December 2016, Version 7.0. Accessed

References

April 25, 2017.

1. Collins F. Genomics and the family physician: realizing the potential.

18. Abreu AL, Souza RP, Gimenes F, Consolaro ME. A review of methods

Am Fam Physician. 2004;70:1637-1642.

for detect human Papillomavirus infection. Virol J. 2012;9:262.

20 THE CLINICAL ADVISOR • JUNE 2017 • www.ClinicalAdvisor.com

19. Ginocchio C, McAdam AJ. Current best practices for respiratory virus testing. J Clin Microbiol. 2011;49(9 Suppl):S44-S48. 20. Fluorescence in situ hybridization (FISH). National Human Genome Research Institute. http://www.genome.gov/10000206. Updated July 9, 2015. Accessed April 25, 2017. 21. Wan TSK. Cancer cytogenetics: methodology revisited. Ann Lab Med. 2014;34:413-425. 22. Diagnostic testing by FISH. Specialty Laboratories. http://www. specialtylabs.com/education/download_PDF/tn_1082.pdf. Accessed May 27, 2016. 23. Holt RL. Preimplantation genetic diagnosis. JAAPA. 2011;24:63-64. 24. Lalonde E, Albrecht S, Ha KC, et al. Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing. Hum Mutat. 2010;31:918-923. 25. Hong YC, Liu HM, Chen PS, et al. Hair follicle: a reliable source of recipient origin after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2007;40:871-874. 26. Gilissen C, Hoischen A, Brunner HG, Veltman JA. Unlocking Mendelian disease using exome sequencing. Genome Biol. 2011;12:228. 27. O’Roak BJ, Deriziotis P, Lee C, et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011;43:585-589. 28. Bamshad MJ, Ng SB, Bigham AW, et al. Exome sequencing as a tool for 29. ARUP genetics test menu. ARUP Laboratories. http://www.aruplab. com/genetics/tests. Accessed April 25, 2017. 30. Bilgüvar K, Öztürk AK, Louvi A, et al. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature. 2010;467:207-210. 31. Autosomal recessive primary microcephaly. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/autosomal-recessive-primary-microcephaly. Reviewed April 2011. Accessed April 25, 2017.

“What do the instructions say?”

32. Charcot-Marie-Tooth disease fact sheet. National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/disorders/ charcot_marie_tooth/detail_charcot_marie_tooth.htm. Accessed April 25, 2017. 33. Sickle cell disease. Centers for Disease Control and Prevention. http://www.cdc.gov/ncbddd/sicklecell/data.html. Updated August 31, 2016. Accessed April 25, 2017. 34. Alpha-1 antitrypsin deficiency. Genetics Home Reference. http://ghr. nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency. Reviewed January 2013. Accessed April 25, 2017. 35. Konkle BA, Josephson NC, Nakaya Fletcher S. Hemophilia B. GeneReviews [Internet]. http://www.ncbi.nlm.nih.gov/books/NBK1495. Published October 2, 2000. Updated June 5, 2014. Accessed April 25, 2017. 36. Konkle BA, Huston H, Nakaya Fletcher S. Hemophilia A. GeneReviews [Internet]. http://www.ncbi.nlm.nih.gov/books/NBK1404. Published September 21, 2000. Updated February 2, 2017. Accessed April 25, 2017.

“It’s mostly mouse weight.”

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2017 21

Mendelian disease gene discovery. Nat Rev Genet. 2012;12:745-755.

CME FEATURED COURSE

■ LEARNING OBJECTIVES After completing the activity, the participant should be better able to: • Identify patients diagnosed with partial-onset seizures who may be suboptimally treated or experiencing drug-resistant/refractory epilepsy • Differentiate the safety, efficacy, mechanisms of action, and drug technologies among newer antiepileptic drugs (AEDs) • Develop a therapeutic regimen that achieves the goal of therapy: eliminating seizures while minimizing adverse effects, which may include utilizing drug-sparing strategies and monotherapy • Formulate care plans with a patient‐centric approach and more effective patient-caregiver communication in regard to treatment options, pill burden, adherence, improving outcomes, and quality of life ■ COMPLETE THE POST-TEST: Page 38

Release Date: January 31, 2017 Expiration Date: January 31, 2018 Estimated Time to Complete: 1 hour Accredited Provider: This program is provided by Haymarket Medical Education. Commercial Supporter: This activity is supported by an educational grant from Sun Pharmaceutical Industries Ltd. Program Description: Epilepsy affects about 4.3 million adults in the United States. For patients with epilepsy, the goal of treatment is to achieve seizure freedom with minimal or no adverse events. At this time, more than one-third of patients who experience seizures continue to have them despite diagnosis and treatment. Patients who experience refractory seizures have higher morbidity and mortality along with poorer quality of life compared with those who achieve adequate seizure control. The development of new antiepileptic drugs (AEDs) over the last decade has been prompted by the fact that available AEDs did not provide optimal care in managing epilepsy. Many patients failed all available options because their seizures were not adequately controlled, they were experiencing severe side effects, or nonadherence was a factor. Because treatment options have increased, drug therapy can now be tailored to the requirements of individual patients. Intended Audience: Neurologists and primary care clinicians (eg, internists, family physicians/general practitioners, nurse practitioners, and physician assistants) engaged in the management and care of patients with epilepsy Educational Objectives Upon completion of this activity, participants should be better able to: • Identify patients diagnosed with partial-onset seizures who may be suboptimally treated or experiencing drug-resistant/refractory epilepsy • Differentiate the safety, efficacy, mechanisms of action, and drug technologies among newer antiepileptic drugs (AEDs) • Develop a therapeutic regimen that achieves the goal of therapy: eliminating seizures while minimizing adverse effects, which may include utilizing drug-sparing strategies and monotherapy • Formulate care plans with a patient-centric approach and more effective patient-caregiver communication in regard to treatment options, pill burden, adherence, improving outcomes, and quality of life Conflict of Interest Disclosure Policy: In accordance with the ACCME Standards for Commercial Support, HME requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational activities. Faculty Joseph I. Sirven, MD Professor of Neurology and Chairman Department of Neurology Mayo Clinic Scottsdale, AZ Sheryl Haut, MD Director, Adult Epilepsy Program Montefiore Medical Center Albert Einstein College of Medicine Bronx, NY

Faculty Reviewer Marcello Morgan, MD, MPH, CHCP Associate Medical Director Haymarket Medical Education Paramus, NJ Faculty Disclosures: Dr. Sirven has received consulting fees from Acorda Therapeutics, Inc; Upsher-Smith Laboratories, Inc; UCB, Inc; and NeuroPace, Inc. Dr. Haut has received consulting fees from Acorda Therapeutics, Inc, and Siga Technologies, Inc, and research grants from GW Pharmaceuticals. Dr. Morgan has nothing to disclose with regard to commercial support. Publishing Staff Disclosures: Priya Wanchoo, MD, Java Solis, and Lori Marrese of Haymarket Medical Education have nothing to disclose with regard to commercial support. Accredited Provider Disclosure: Haymarket Medical Education staff involved in the planning and content review of this activity have no relevant financial relationships to disclose. Accreditation Statement: Haymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation Statement: Haymarket Medical Education designates this enduring material for a maximum of 1.00 AMA PRA Category 1 CreditTM . Physicians should claim only the credit commensurate with the extent of their participation in the activity. Disclosure of Unlabeled Use: This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specific patient’s medical condition. Disclaimer: The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Haymarket Medical Education or Sun Pharmaceutical Industries Ltd. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. If you have any questions relating to the accreditation of this activity, please contact cmequestions@haymarketmedical.com. Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period January 31, 2017 through January 31, 2018, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the pre-assessment test; 3) study the educational activity; 4) complete the polling questions; and 5) complete the post-test and submit it online. A statement of credit will be issued only upon receipt of the above elements and a post-test score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/June17feature. Provided by

CME

FEATURED COURSE: JOSEPH I. SIRVEN, MD; SHERYL HAUT, MD

Paving the way to better epilepsy outcomes Tailoring treatment using new antiepileptic drugs helps improve patient adherence to therapy by improving seizure control and minimizing side effects.

EEG of benign focal epilepsy of the centrotemporal area in an 11-year-old girl.

pilepsy affects approximately 2.9 million people in the United States (US)1 and is characterized by a history of at least 1 seizure, brain alterations that increase the likelihood of future seizures, and the neurobiologic, psychological, cognitive, and social consequences of the condition. 2 It is associated with higher mortality3 and morbidity, including higher rates of depression and anxiety.1,4 In adolescents, the psychosocial impact is particularly severe.5 More than one-third of patients continue to experience seizures despite treatment.6 Among patients who experience breakthrough seizures, morbidity and mortality are higher and quality of life (QoL) is poorer compared with those who achieve adequate seizure control.3,7 POLLING QUESTION

Which of the following best characterizes the term focal seizure? a. A seizure that is triggered by flashing lights b. A seizure that induces convulsion involving either the upper or lower extremities only c. A seizure that originates in a discrete location d. A seizure that manifests despite normal electrical activity in the brain

Newer medications, and more advanced drug technology that helps foster better patient adherence and persistence with treatment, may help improve outcomes for this disorder. Notably, www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2017 25

CME

FEATURED COURSE

TABLE 1. Third-generation AEDs approved in the US AED name • Eslicarbazepine acetate

• Oxcarbazepine

• Stiripentol

• Felbamate

• Perampanel

• Tiagabine

• Gabapentin

• Pregabalin

• Topiramate

• Lacosamide

• Progabide

• Vigabatrin

• Lamotrigine

• Retigabine (ezogabine)*

• Zonisamide

• Levetiracetam

• Rufinamide

*Note that retigabine/ezogabine will be discontinued as of June 2017.12 Adapted from Loscher et al.10

extended-release medications can reduce pill burden— thereby improving user convenience and promoting adherence—while also achieving stable serum levels.

Epileptic seizures are recurrent unpredictable interruptions in normal electrical activity in the brain due to excessive or synchronous neuronal activity.2 Seizures may be either focal (originating in a discrete area of the brain due to focal functional disruption) or generalized (originating in both brain hemispheres due to a lowering of seizure threshold that is usually genetically determined).8,9 In both cases, there is an overall increase in cellular excitability. Therapeutic matchmaking: Pairing medication with patient

Epilepsy treatment aims to achieve freedom from seizures while minimizing treatment-related adverse effects (AEs). The mainstay of treatment is antiepileptic drugs (AEDs), which decrease the excitation, increase the inhibition, or prevent the abnormal burst-firing of neurons.9 The main targets of these medications are modulation of voltage-activated ion channels, potentiation of gamma-aminobutyric acid (GABA), and inhibition of glutamate receptor 9,10(Figure 1).

Adapted from Bialer et al.11

FIGURE 1. Proposed mechanisms of action of currently available AEDs at excitatory and inhibitory synapses 26 THE CLINICAL ADVISOR • JUNE 2017 • www.ClinicalAdvisor.com

FEATURED COURSE

POLLING QUESTION

Which of the following is a true statement about current AEDs? a. They all have a similar mechanism b. They prevent epilepsy from developing in susceptible individuals c. They work for all types of epilepsy d. They suppress seizures in a person diagnosed with epilepsy

Current AEDs suppress seizures rather than addressing the underlying tendency to generate seizures.9 The past 3 decades have seen the launch of more than 15 third-generation AEDs that symptomatically suppress seizures (Table 1); none has been proven to prevent epilepsy to date.10 Not all medications work for all types of epilepsy or for every individual. Knowledge of the properties and profile of each AED allows for earlier successful pairing of treatment to patient. Mechanisms of action AEDs vary in their mechanisms of actions (Table 2), which include GABA potentiation, glutamate (NMDA) inhibition, sodium channel blockade, synaptic vesicle glycoprotein 2A modulation, and T-type calcium channel blockade.10 Most AEDs have more than 1 mechanism of action, and in several the mechanisms of action remain unclear.13 Moreover, in initial add-on trials, the efficacy of various AEDs did not seem to differ substantially, suggesting that apparently similar antiseizure activity can be enacted via diverse targets.10 Safety considerations Compared with older agents, modern AEDs are associated with more treatment-related intolerable AEs,14 although most AEs are mild and reversible.15 Nonetheless, AEs may determine QoL for people with epilepsy.16 Patients and physicians alike should be aware of potential AEs associated with AEDs and monitor for tolerability. Serious AEs have been associated with a number of AEDs, including felbamate, which poses a substantial risk of aplastic anemia and/or liver failure and is therefore indicated only in severe epilepsies that do not respond adequately to other medications.13 Stevens-Johnson syndrome and other severe hypersensitivity reactions have been associated with carbamazepine, lamotrigine, phenobarbital, and phenytoin; hypohidrosis and renal calculi have been associated with topiramate and zonisamide; and open-angle glaucoma has been associated with topiramate.8 Valproic acid has been associated with hepatotoxicity, pancreatitis, and teratogenicity.17 AED-associated toxicity may be subclinical, so effective detection is key to optimizing care.18 For example, with

levetiracetam, it is important to monitor for signs of depression, agitation, aggression, insomnia, nervousness or irritability, mood swings, and abnormal thinking.8 In children, the AEs more commonly associated with levetiracetam are somnolence and behavioral problems, particularly in those taking at least 1 other AED,19 although preexisting psychiatric conditions may predispose patients of all ages to the behavioral AEs associated with levetiracetam.20 Weight gain, which can negatively affect QoL, is associated with gabapentin, phenytoin, pregabalin, valproic acid, perampanel, and vigabatrin.10,21 Dose titration may help manage safety issues posed by AEDs. For instance, valproic acid may be effective at lower doses that also pose less risk of teratogenicity.16 There is TABLE 2. Mechanisms of action of AEDs Mechanism of action

Agents

Blockers of repetitive action of sodium channel

Phenytoin Carbamazepine Oxcarbazepine Lamotrigine Topiramate

Enhancers of slow inactivation of sodium channel

Lacosamide Rufinamide

Activator of potassium channel

Retigabine (ezogabine)

GABA-A receptor enhancers

Phenobarbital Benzodiazepines

Glutamate modulators

Topiramate Lamotrigine Felbamate

T-calcium channel blockers

Ethosuximide Valproate

N- and L-calcium channel blockers

Lamotrigine Topiramate Zonisamide Valproate

GABA reuptake inhibitors

Tiagabine

Drugs binding to unique receptors

abapentin and pregabalin G (alpha-2-delta receptor) Levetiracetam (synaptic vesicle 2A receptor)

Carbonic anhydrase inhibitors

Topiramate Zonisamide

GABA-transaminase inhibitors

Vigabatrin

Adapted from Privitera.13

www.ClinicalAdvisor.com â&#x20AC;˘ THE CLINICAL ADVISOR â&#x20AC;˘ JUNE 2017 27

CME

FEATURED COURSE

wide variation in therapeutic dose among individuals with all AEDs, so dosages are adjusted over time according to individual patient response to ensure optimal dosage while avoiding toxicity. Phenytoin, carbamazepine, and valproate all have narrow therapeutic indexes (a small relative difference in dose between therapeutic and toxic effects), but even AEDs with a wide therapeutic index and low toxicity (eg, lamotrigine) require titration to achieve dose optimization.22 More than 90% of patients newly diagnosed with epilepsy who respond to monotherapy require only moderate or even modest doses.23 All AEDs can cause doserelated AEs such as drowsiness, fatigue, dizziness, blurry vision, and uncoordination, especially at initiation of AED therapy and with polytherapy. Employing monotherapy at the lowest effective dose and reserving polytherapy for refractory epilepsy may prevent or minimize AEs.16 POLLING QUESTION

Which of the following is not a characteristic of extendedrelease (XR) formulations of AEDs? a. They exhibit increased AEs b. They lower fluctuation in drug concentrations c. They enable less frequent dosing d. They are associated with better adherence

XR formulations that allow once-daily dosing can improve overall AED tolerability. Such formulations have been approved for gabapentin, lamotrigine, levetiracetam, and topiramate. In general, modified or XR formulations offer potential benefits including less fluctuation in drug concentration and milder AEs. For patients, less frequent dosing means greater convenience that translates to improved adherence while also improving QoL and patient satisfaction with treatment.24,25 Fewer breakthrough seizures Moreover, reducing treatment burden and fostering better adherence through XR formulations may in turn reduce the opportunity for breakthrough seizures. Taking a greater number of AED tablets/capsules has been shown to increase the odds of having a seizure after missing a dose by 43%.26 Carefully monitored patients with epilepsy on average took only 76% of their medication as prescribed, which is likely much higher than patients in a real-world settings.27 Once-daily dosing can be a particular advantage to those patients who experience short-term memory loss, a frequent comorbidity of epilepsy.28,29 A European study reported reductions in seizure frequency and AEs, along with improvements in adherence

and satisfaction, in patients switched from an immediaterelease to an XR formulation of valproate. 30 Reduced AEs with XR dosing have also been demonstrated with once-daily levetiracetam XR for partial-onset seizures in patients with refractory epilepsy.31 The reduction in AEs with this formulation may be attributed to the steadier serum concentrations of the medication.32 XR formulations of divalproex and phenytoin have also demonstrated reduced AE profiles and effective prevention of seizures by achieving more consistent serum levels without marked peak-to-trough fluctuations.25 With valproic acid, an XR formulation has also been associated with less weight gain.17 Early identification of patients at risk for high AE burden helps counter potential treatment failures. The predictors for increased AE risk include female gender, younger age at epilepsy onset, older age at investigation, symptomatic epilepsy, higher seizure frequency, antiepileptic polytherapy, and depression.28,33-37 For such patients, optimizing antiepileptic treatment may decrease the general burden of AEs and the occurrence of specific AEs to improve QoL and lessen the risk of nonadherence and premature treatment failure. Efficacy and bioavailability Not all AEDs offer broad-spectrum efficacy to address both partial and generalized-onset seizures; some agents are effective for partial-onset seizures but can exacerbate some types of generalized-onset seizures. All AEDs approved by the US Food and Drug Administration (FDA) other than rufinamide, however, are effective in treating partial-onset focal seizures.13 AEDs that are considered to be effective in treating both partial-onset and generalized-onset seizures are levetiracetam, lamotrigine, zonisamide, topiramate, clonazepam, phenobarbital, rufinamide, valproate, clobazam, and perampanel.21 Among these broad-spectrum AEDs, lamotrigine is indicated as adjunctive therapy in treating partial focal seizures, primary generalized tonic-clonic seizures, generalized seizures, or in conversion to monotherapy in patients with partial seizures receiving a different single agent; levetiracetam is effective as adjunctive therapy for partial-onset, myoclonic, and primary-generalized tonicclonic seizures; topiramate is indicated as monotherapy for partial-onset or primary-generalized tonic-clonic seizures; and valproate is indicated as monotherapy in the treatment of complex partial seizures and complex absence seizures.13 Narrow-spectrum agents include oxcarbazepine, eslicarbazepine, gabapentin, and pregabalin, which is efficacious for partial seizures,10 and ethosuximide, which is effective only against absence seizures.21

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Some AEDs are known to exacerbate specific seizure types. For instance, carbamazepine and its sister compounds oxcarbazepine and eslicarbazepine may increase the risk of absence, atonic, and myoclonic seizures in some patients with generalized epilepsy, but it has demonstrated a good balance of efficacy and tolerability in patients with partialonset focal seizures and is widely used as an effective firstline option for these patients.14 Phenytoin, gabapentin, and vigabatrin have also been associated with an increased risk of seizures.13 Valproic acid and carbamazepine have been shown to aggravate absence seizures.38,39 Idiopathic generalized and myoclonic seizures may be exacerbated by carbamazepine, vigabatrin, tiagabine, and gabapentin.39 Efficacy comparisons of AEDs have produced no clear evidence showing an overall advantage for 1 therapy over another,13 and it is not possible to predict whether a given AED will prove to be effective in a particular patient. An

additional challenge is that new AEDs are required only to demonstrate efficacy over placebo when added to baseline therapy, so the lack of trials examining the comparative effectiveness of emerging agents makes it harder for clinicians to make informed decisions about the available treatment options.14 As defined by regulatory bodies, bioequivalence does not always correspond to therapeutic equivalence for AEDs due to the permitted range of bioavailability for generics, methodology that relies on small numbers of young healthy volunteers, and individual variation.22 Treatment algorithms Determining which agent(s) will be most effective for a patient’s particular seizure type, whether focal or generalized, and considering the AE and tolerability profiles of the AED are the first steps in selecting an appropriate AED.13,21 Possible drug interactions and other pharmacokinetic

Diagnosis of epilepsy

Classify seizure type

Not sure

Valproate Rufinamide Clobazam Lamotrigine

Generalized/multifocal onset

Generalized/ bihemispheric seizures

Tonic atonic

Absence

Simple partial Complex partial 2˚ GTC

Ethosuximide

Myoclonic 1˚ GTC

Vigabatrin ACTH

Spasms

Focal seizures

Atypical absence GTC Broad spectrum

Mood/Anxiety/Irritability Possibly helpful

Potential horsening

Potential weight gain

VPA GPN PGN

VGN PB PER

Weight neutral

LTG CBZ OXC/ESL CLN/CLB

LVT PRM

Potential weight loss

ETH ZNS TPM FBM

Unknown/ minimal

LCS RFN PHT

LEV LTG TPM ZNS VPA

CLB RFN FBM PER PB

Narrow spectrum PRM CLN

ACTH=adrenocorticotropic hormone CBZ=carbamazepine (Tegretol, Carbatrol) CLB=clobazam (Onfi/Frisium) CLN=Clonazepam (Klonopin) ESL=eslicarbazepine (Aptiom) EZG=ezogabine/retigabine (Potiga) FBM=felbamate (Felbatol) GPB=gabapentin (Neurontin)

LCM PGN GBP CBZ

OKC ESL PHT VGB

GTC = generalized tonic-clonic LCM=lacosamide (Vimpat) LTG=lamotrigine (Lamictal) LVT=levetiracetam (Keppra) OXC=oxcarbazepine (Trileptal) PB=phenobarbital (Phenobarb) PER=perampanel (Fycompa) PGN=pregabalin (Lyrica) PHT=phenytoin (Dilantin)

EZG TGB

PRM=primidone (Mysoline) RFN=rufinamide (Banzel) TGB=tiagabine (Gabatril) TPM=topiramate (Topamax) VGB=vigabatrin (Sabril) VPA=valproate (Depakene/Depakote) ZNS=zonisamide (Zonegran)

The first step is to assess whether seizures originate focally or from both hemispheres. When that is unknown, broad-spectrum agents are best. There are multiple options for each seizure type, and AE profiles can be used to narrow the range of choices. Patients find psychobehavioral side effects and weight gain the most concerning AEs.21 Note: Brivaracetam was approved as adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older after the publication of this algorithm.

FIGURE 2. An algorithm outlining steps in the choice of an AED for a patient diagnosed with epilepsy www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2017 29

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considerations should also be weighed alongside dosing issues.13 Selection of AED by seizure type is summarized in Figure 2. The number of AEDs reached 24 in early 2016. Perampanel and ezogabine added new mechanisms of action to the armamentarium, eslicarbazepine presented a third generation of the carbamazepine line, clobazam and perampanel provided additional broad-spectrum options, and XR formulations of oxcarbazepine and topiramate were introduced with the aim of reducing peak dose effects and toxicity, thereby improving compliance. 21 Most recently, brivaracetam was approved by the FDA as adjunctive therapy to treat partial-onset seizures in patients age 16 years and older. Clinicians who manage the care of patients with epilepsy need to familiarize themselves with newer agents, as many demonstrate improved day-to-day tolerability profiles, making seizure freedom without AEs possible for greater numbers of patients.

researchers suggest that treatment algorithms should be guided by other factors, including cost and dosing regimen, as well as indications and contraindications.14 Although more than 15 third-generation AEDs have been introduced in recent years, available medications fail to control seizures in up to 30% of patients.9,10 The cause of pharmacoresistance is still unknown, but multidrug resistance proteins are a potential factor.21 Individuals who exhibit an inadequate response to initial treatment with AEDs or who have many seizures before initial treatment are likely to have refractory epilepsy.35 In these cases, it becomes necessary to select an alternative agent or add adjunctive therapy to prevent seizures. Therapy should always be individualized, but systematic screening may be helpful in determining toxicity and guiding medication changes to reduce AEs.18 Rational polytherapy advocates harmonizing mechanisms of action when deciding which AEDs to combine,21 although there is a paucity of robust evidence to guide clinicians in how and when to combine AEDs.41

POLLING QUESTION

Which of the following populations has a particular vulnerability to AED toxicity and sensitivity to fluctuations in AED serum levels?

Formulation technologies Newer AEDs include not only novel agents, but also novel preparations or formulations of existing drugs.

a. Adolescents b. People who experience tonic-clonic seizures c. Patients newly diagnosed with epilepsy d. Older adults

In addition to selecting the appropriate AED for each seizure type, there are special considerations for specific populations, namely women of childbearing age and older adults. Special concerns for women with epilepsy are related to diminished efficacy of oral contraceptives when used concurrently with AEDs, the potential teratogenic effects of AEDs, and fluctuations in seizure patterns associated with menopause.25 Older adults are particularly vulnerable to AED toxicity. Several trials suggest that newer AEDs may offer superior tolerability to earlier-generation AEDs in older patients.16 Some evidence suggests that older adults exhibit higher rates of nonadherence.40 Older adults may also be most sensitive to fluctuations in AED serum levels, which may cause AEs or drug interactions, potentially disrupting therapy.25 Definitive evidence indicating the clinical superiority or tolerability of one AED over another is lacking (with the notable exception of vigabatrin, whose long-term use is associated with visual field defects). Accordingly, some

The technology • Novel oral controlled drug-delivery system based on predefined, precise, and selective surface exposure Key advantages • Once-a-day dosing • Ability to handle products with larger daily dose • Suitable for drugs with very high solubility • No residual drug in dosage form on evacuation • Minimal food effect • Difficult to reproduce bioequivalence using any other formulation technology – Low risk of generics

FIGURE 3. Wrap Matrix technology of Elepsia XR (levetiracetam)43

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Modified-release preparations are designed to decrease the frequency of dosing for drugs with rapid elimination, improving patient convenience as a route to improved adherence.24 In addition, these formulations reduce fluctuations in serum concentrations, which may improve therapeutic benefits.24 One such example is a newer extended-release (XR) formulation of levetiracetam indicated as adjunctive therapy and monotherapy.42 This newer formulation offers potential cost savings, pill burden reduction, and improvements in managed care, convenience, and adherence. XR formulations enable patients to obtain higher doses of a drug in a single, sometimes smaller, pill taken once daily, potentially improving patient adherence.43 For example, the Wrap Matrix™ novel drug-delivery technology (Figure 3) of Elepsia XR offers advantages that may translate to better seizure control and QoL. While most major insurance formularies do not cover XR formulations, making out-of-pocket expenses prohibitive for patients, branded generic formulations are available.24 Newer branded generic formulations of drugs, like traditional generics,

must contain the same active ingredient as the original product, but they need not demonstrate bioequivalence. However, recent studies have demonstrated bioequivalence between generic and branded lamotrigine44 and between 2 generic lamotrigine products.45 Examples of newer agents and their formulations are listed in Table 3. Addressing breakthrough seizures

While the majority of patients with epilepsy achieve effective remission approximately 5 years postdiagnosis, a sizable portion exhibit medically intractable epilepsy, with AEDs failing to adequately suppress seizures.21,46,47 Some of the lack of treatment success is attributable to inadequate adherence to treatment, which contributes to increased utilization of inpatient and emergency department services48 and severe clinical consequences that include more than a 3-fold increased risk of death.49 Nonadherence is the leading cause of status epilepticus50 and is associated with sudden unexplained death.51 Barriers to adherence are described in Figure 4.

TABLE 3. Novel agents and preparations in the treatment of epilepsy Brand name (generic)

Manufacturer

Dosage, administration

Indications

Carnexiv (carbamazepine)

Lundbeck, Inc.

200-mg/20-mL single-dose injection vial (10 mg/mL carbamazepine and 250 mg/mL betadex sulfobutyl ether sodium) Administered in four 30-minute infusions, separated by 6 hours

Replacement therapy for oral carbamazepine formulations in adults with partial-onset, generalized tonic-clonic, or mixed seizure patterns including other partial or generalized seizures

Spritam (levetiracetam)

Aprecia Pharmaceuticals Co.

250-mg, 500-mg, 750-mg, and 1000-mg tablets for oral suspension Administered twice daily

Partial-onset seizures in people 4 years of age and older with epilepsy, myoclonic seizures in people 12 years of age and older with juvenile myoclonic epilepsy, and primary generalized tonic-clonic seizures in people 6 years of age and older with certain types of generalized epilepsy

Elepsia XR (levetiracetam)

Sun Pharmaceutical Industries

1000-mg and 1500-mg XR tablets Administered once daily

Partial-onset seizures in people at least 4 years old, tonic-clonic seizures in people at least 6 years old, and myoclonic seizures in people at least 12 years old

Keppra XR (levetiracetam)

UCB, Inc.

500-mg and 750-mg XR tablets Administered once daily

Partial-onset seizures in people 12 years of age and older

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Quality of life Inadequate seizure control significantly detracts from patient QoL.3,7 In 9 studies examining the impact of seizure frequency on various aspects of patient QoL, seizure frequency was found to significantly affect social and cognitive functioning.53 The impact of seizures on specific QoL subscales are presented in Figure 5. Reducing AED dosing frequency may lessen the negative impact on QoL by improving convenience and adherence.24,25 A significant improvement in QoL has been demonstrated for adjunctive levetiracetam therapy in patients with refractory epilepsy,8 including the seizure worry, overall QoL, emotional wellbeing, energy/fatigue, and social function subscales.54,55 Poor provider-patient communication Patient has a poor understanding of the disease Patient has a poor understanding of the benefits and risks of treatment Patient has a poor understanding of the proper use of the medication Physician prescribes overly complex regimen

Patient

Provider

The most comprehensive strategy to address poor adherence combines elements of both medical and social/ behavioral approaches, as neither is adequate on its own.56 Involving patients in the treatment process, reinforcing the importance of adherence, improving communication, providing adherence enhancers, and simplifying the treatment regimen are all important ways that clinicians can promote adherence.51 Specific sources of inadequate adherence and corresponding multidisciplinary interventions are presented in Table 4. Addressing drug-resistance issues Clinicians face the difficult determination of whether, when, and how to switch to a different agent in patients who do not respond adequately to AED treatment. While patients should Nonsignificant

Significant

9 8 7

Number of studies

CME

6 5 4 3 2 1 0 Social functioning

Seizure worry

Cognitive functioning

Medication effects

Energy/ fatigue

Emotional well-being

Overall quality of life

QOL subscales

Healthcare system

P atient’s interaction with the healthcare system Poor access or missed clinic appointments Poor treatment by clinic staff Poor access to medications Switching to a different formulary Inability of patient to access pharmacy High medication costs P hysician’s interaction with the healthcare system P oor knowledge of drug costs P oor knowledge of insurance coverage of different formularies L ow level of job satisfaction Interactions among patients, healthcare providers, and the healthcare system can undermine patients’ ability to follow a medication regimen.52

FIGURE 4. Barriers to adherence

The 9 studies that were included: Azuma H, Akechi T. Effects of psychosocial functioning, depression, seizure frequency, and employment on quality of life in patients with epilepsy. Epilepsy Behav. 2014;41:18-20. doi:10.1016/j.yebeh. 2014.09.025; Nabukenya AM, Matovu JK, Wabwire-Mangen F, et al. Health-related quality of life in epilepsy patients receiving anti-epileptic drugs at National Referral Hospitals in Uganda: a crosssectional study. Health Qual Life Outcomes. 2014;12(1):49. doi:10.1186/1477-752512-49; Ranjana G, Dwajani S, Kulkarni C, Sarma GR. The sociodemographic, clinical and pharmacotherapy characteristics influencing quality of life in patients with epilepsy: a cross-sectional study. J Neurosci Rural Pract. 2014;5(suppl 1):S7-S12. doi:10.4103/09763147.145193; Melikyan E, Guekht A, Milchakova L, et al. Health-related quality of life in Russian adults with epilepsy: the effect of socio-demographic and clinical factors. Epilepsy Behav. 2012;25(4):670-675. doi:10.1016/j.yebeh.2012.09.042; Gordon-Perue G, Gayle F, Fraser R, Ali A. Quality of life of patients with epilepsy living in Kingston, Jamaica. Epilepsy Behav. 2011;21(1):23-26. doi:10.1016/j.yebeh.2011.02.019; McLaughlin DP, Pachana NA, McFarland K. The impact of depression, seizure variables and locus of control on health related quality of life in a community dwelling sample of older adults. Seizure. 2010;19(4):232-236. doi:10.1016/j.seizure.2010.02.008; McLaughlin DP, Pachana NA, McFarland K. Stigma, seizure frequency and quality of life: the impact of epilepsy in late adulthood. Seizure. 2008;17(3):281-287. doi:10.1016/j.seizure.2007.09.001; Lee SJ, Kim JE, Seo JG, et al. Predictors of quality of life and their interrelations in Korean people with epilepsy: a MEPSY study. Seizure. 2014;23(9):762-768. doi:10.1016/j.seizure.2014.06.007; Senol V, Soyuer F, Arman F, Öztürk A. Influence of fatigue, depression, and demographic, socioeconomic, and clinical variables on quality of life of patients with epilepsy. Epilepsy Behav. 2007;10(1):96-104. doi:10.1016/j.yebeh.2006.08.006.

FIGURE 5. Impacts of seizures on QoL subscales53

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not be considered to have refractory epilepsy without significant manipulation of drug and dosage,51 therapeutic failure of 3 AEDs has traditionally defined refractory epilepsy, and the likelihood of successful treatment with other drugs diminishes with each AED failure.35 For example, in a study of 1098 patients initiating AED use, 49% became seizure-free with the first drug; an additional 13% achieved remission with the second AED; and only an additional 4% became seizure-free with a third AED.57 While some argue that even after further drug trials, all hope for a good prognosis is not lost,57 sequential drug trials have a small likelihood of inducing remission in those who have already failed 2 or more regimens. If the first AED is not well tolerated at a low or moderate dose, produces an idiosyncratic reaction, or fails to improve seizure control, it may be better to switch to an alternate agent rather than combine AEDs.58 However, a change in seizure control might not be related to medication, so switching AEDs is not always warranted. Moreover, successive AED trials are unlikely to be helpful if the patient was not controlled on the first drug.59 One study found that the efficacy of switching to an alternative monotherapy after a first AED failed was only 16%,60 so combination therapy may be warranted in these cases. In adults with epilepsy, incomplete seizure control often requires adjunctive therapy,61 sometimes using an AED with a different mechanism of action. However, given differing mechanisms of action and pharmacokinetics among AEDs, clinicians must not consider seizure reduction as the sole

goal when changing a medication or initiating combination therapy. Clinicians must also consider safety and tolerability given the possibility of increased side effects due to synergy between the agents and the potential for unexpected reactions. When a patient develops resistance to an AED after a long period of successful monotherapy treatment, adding an adjunctive agent may improve seizure control.62 Because adjunctive therapy may be associated with marginal therapeutic gains and increased toxicity, clinicians are sometimes faced with the difficult conversion from 2 or more AEDs to a single drug.63 In order to minimize AEs when converting from polytherapy to monotherapy, it is best to withdraw the first drug slowly while increasing the daily dose of the added AED until the optimal therapeutic dose is reached.63 POLLING QUESTION

Which of the following is not a potential cause of breakthrough seizure? a. High blood sugar b. Lack of sleep c. Infection d. Video games

Minimizing emergency department visits and hospital admissions Epilepsy-related hospitalization in the United States underwent a 2.7-fold increase during the period 2006–2010

TABLE 4. Methods to improve adherence to AED treatment50 Problem areas

Interventions

Complex drug regimens

Reduction of unnecessary polytherapy and dosing frequency; simple dosing tailored to individual habits and daily routines

Cognitive problems/memory impairment

Drug dispensers/alarms (smartphone, wristwatch); alliance with proxies; social support with regular visits from community nurses

Insufficient knowledge, motivation, and awareness of the need for treatment; negative attitude toward pharmaceuticals

Education and increased frequency of outpatient follow-up; clear procedures related to missed drug intake; more involvement in treatment decisions; epilepsy nurse and pharmacist support; telephone contacts

Adverse drug reactions

Improved communication and treatment modification

Depressed mood

Antidepressive and cognitive treatment

Oral intake barriers (swallowing/motor and intellectual deficits/behavior/aversion to medication/intercurrent illness)

Modified drug formulations (soluble, liquid, granular, powder) as well as taste of tablets; alternative routes (rectal, intravenous)

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compared with 1996–2005.46 Seizures are a frequent presenting complaint in emergency departments, with 6% of these patients in status epilepticus and more than 25% requiring hospitalization.64 Therapeutic drug monitoring should be performed at admission to identify and assess the extent of underlying failed prophylactic treatment in patients with status epilepticus, and preventing recurrent episodes are crucial.65 Nonadherence to AEDs is associated with higher utilization of inpatient and emergency services.48 XR formulations of AEDs such as topiramate, oxcarbazepine, carbamazepine, and levetiracetam XR may improve adherence through reducing pill burden and improving convenience for patients. While breakthrough seizures are often blamed on nonadherence or changes in medication, other potential causes include infection onset, severe emotional stress, sleep deprivation, and environmental provocation such as video games or other flashing lights.6 Breakthrough seizures have serious consequences that can include head injuries, fractures, motor vehicle accidents, emergency department visits, and hospitalization, along with the associated increase in healthcare costs.6 Rescue medications may allow people with epilepsy to manage breakthrough seizures at home. The most common of these medications are fast-acting benzodiazepines, including diazepam, lorazepam, and midazolam. Clonazepam may also be used for this purpose.21 While only a rectal diazepam gel has been approved by the FDA for treating acute seizures outside the hospital setting, other formulations of benzodiazepines are under investigation including nasal and buccal routes, and oral benzodiazepines are frequently prescribed for this purpose. Medication adherence is an important preventive measure against emergencies and breakthrough seizures. One study found that nonadherence was significantly more prevalent among patients with generalized than focal epilepsy at hospital admission, and that these patients may be more vulnerable to the effect of nonadherence, with seizure breakthrough more commonly resulting in hospitalization.66 Many patients seem to be unaware of missed AED intake, with 44% of nonadherent patients claiming that they take their medications regularly.66 Thus, it is also important to determine nonadherence prior to hospital discharge in order to adequately address the issue and prevent future emergencies and hospitalization. While medication adherence is an important factor in preventing emergencies, additional selfmanagement strategies for seizure control include getting adequate sleep, reducing alcohol intake, and avoiding stress.56 Newly developed patient tools help to address issues of medication adherence, drug interactions, and seizure detection

and prevention. Smartphone applications and electronic pill dispensers with alerting systems offer an important practical intervention to promote regular intake of AEDs.52,67 Seizure diaries, medication trackers/reminders, and seizure monitors are all available as mobile applications, and other applications alert prescribers to potential drug interactions. In addition to these technologies, experimental devices such as an oral drug-delivery system offering a range of preprogrammed controlled-release patterns suggest promising new modalities.68 Finally, neuromodulation therapies such as vagus nerve, thalamic deep brain, and trigeminal nerve stimulation are established therapeutic options that offer promising AE profiles and efficacy.69,70 Trigeminal nerve stimulation, a novel investigational neuromodulation therapy for patients with drug-resistant epilepsy, was demonstrated to be safe and effective in a double-blind randomized trial.71 Responsive neurostimulation, which requires identification of 1 or 2 seizure foci and may be effective where vagal nerve stimulation has not produced an optimal response, detects epileptiform activity and delivers stimulation in response.72 Table 5 lists a sampling of patient tools aimed at treating epilepsy. Importance of patient-physician communication

Clinicians managing epilepsy have a great opportunity to improve communication with patients and their families.73 Effective patient education should be individualized and delivered in a variety of methods and settings outside the examining room, because patients typically remember only half of what is discussed during a medical encounter.74 Moreover, a collaborative approach may be best. With constantly evolving guidelines that recommend individualized medicine, clinicians need to respect and support patients in taking a more active role in their own medical decisionmaking—through arriving at decisions together, prioritizing the patient’s preferences, and formulating practice decisions based on the patient’s individual needs and circumstances.50 Patient-physician interactions are particularly crucial to conveying the importance of AED adherence. One study reported that 90.9% of nonadherent patients were unaware that poor adherence could be the cause of repeated seizures.66 Patients’ perception of their relationship with a clinician is important in determining treatment adherence.56 Educating patients and their caregivers about the risks associated with poor adherence and potential behavioral interventions has significant potential to improve adherence.75 Education efforts should be individualized to the patient, with a more intensive approach for those patients exhibiting great difficulty maintaining a regimen than for those with less difficulty with

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adherence, a more forgiving AED regimen, or both.52 Most important, these interventions should involve nonjudgmental communication and address healthcare provider determinants rather than only those focused on the patient.76 Making the patient an active participant in treatment planning is at least as important as patient education.77 However, aiming for total adherence may be unrealistic. To achieve the best

outcome for patients, emphasis has instead shifted toward a compromise involving both the patient and clinician in a joint process of negotiating treatment-making decisions.56 Actively involving patients in treatment decisions when possible is a key factor in improving adherence, because patients who feel empowered are more likely to be motivated to manage their disease and adhere to their medications.74 n

TABLE 5. Patient tools in the treatment of epilepsy Technology/device name

Features

My Seizure Diary

• Web-based self-management tool • Record medical history, seizures, medications, side effects, moods, and other personal experiences to identify triggers to avoid • Track changes over time, keep records of medications, and create a seizure response plan to share with family, friends, and healthcare team • Set reminders for medications, refilling prescriptions, or medical appointments • Free • Provided by the Epilepsy Foundation • Available at http://www.epilepsy.com/get-help/my-epilepsy-diary

Epdetect

• Accelerometer-based mobile application • Uses advanced signal processing to detect epileptic seizures • Monitors the wearer’s movements, distinguishing between normal movement and movement associated with a tonic-clonic seizure • Contact and alert caregiver with status and GPS position if seizure is detected • Free • Available at http://www.epdetect.com

Seizure Tracker

• Mobile device application • Log and track seizure activity, appointments, and medication schedules through simple calendar interface • Customize reports with graphs comparing seizure activity and medication dosages • Accessible from a computer or mobile phone • Free • Available at https://www.seizuretracker.com

Responsive neurostimulation (RNS System, NeuroPace)

• Electrodes are placed intracranially • Interferes early on with accumulation of seizure activity to prematurely abort or prevent an upcoming seizure69 • Delivers stimulation only in response to the detection of epileptiform activity72 • Enables long-term monitoring of electrographic seizures72 • Indicated for medically refractory partial-onset seizures in patients 18 years and older • Granted premarket FDA approval in 2013

Vagus nerve stimulation

• Delivers electrical impulses to the vagus nerve on a scheduled basis, in response to patient activation, or in response to heart rate increases72 • FDA approved only for use in partial epilepsy, but commonly used off-label to treat generalized seizures72 • Also indicated for depression

Trigeminal nerve stimulation system (Monarch eTNS System, NeuroSigma, Inc.)

• Transdermal electrodes are applied to the skin, usually at night • Provides external electrical stimulation of the trigeminal nerve to decrease seizures • Delivers stimulation on a scheduled basis, in response to patient activation, or in response to heart rate increases72 • Indicated as adjunctive therapy for treatment of drug-resistant epilepsy in patients 7 years and older • May also have antidepressant effects • Novel investigational therapy; has not received FDA approval

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7. Bautista RE, Glen ET. Seizure severity is associated with quality of life

Drugs. 2015;29(8):669-681.

independent of seizure frequency. Epilepsy Behav. 2009;16(2):325-329.

25. Pellock JM, Smith MC, Cloyd JC, et al. Extended-release formulations:

8. Lyseng-Williamson KA. Levetiracetam: a review of its use in epilepsy.

simplifying strategies in the management of antiepileptic drug therapy.

Drugs. 2011;71(4):489-514.

Epilepsy Behav. 2004;5(3):301-307.

9. Duncan JS, Sander JW, Sisodiya SM, Walker MC. Adult epilepsy. Lancet.

26. Cramer JA, Glassman M, Rienzi V. The relationship between poor

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10. Loscher W, Klitgaard H, Twyman RE, Schmidt D. New avenues for

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28. Perucca P, Carter J, Vahle V, Gilliam FG. Adverse antiepileptic drug

11. Bialer M, White HS. Key factors in the discovery and development of

effects: toward a clinically and neurobiologically relevant taxonomy.

new antiepileptic drugs. Nat Rev Drug Discov. 2010;9(1):68-82.

Neurology. 2009;72(14):1223-1229.

12. GlaxoSmithKline. Advance notification of Trobalt ® discontinuation

29. de Boer HM, Mula M, Sander JW. The global burden and stigma of

[letter to healthcare providers]; August 26, 2016. UK/RET/0091/16. https://

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assets.publishing.service.gov.uk/media/57fe4b6640f0b6713800000c/

30. Doughty J, Baker GA, Jacoby A, Lavaud V. Compliance and satisfaction

Trobalt_letter.pdf.

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Am J Manag Care. 2011;17(suppl 7):S195-S203.

31. Peltola J, Coetzee C, Jimenez F, et al. Once-daily extended-release

14. Bodalia PN, Grosso AM, Sofat R, et al. Comparative efficacy and

levetiracetam as adjunctive treatment of partial-onset seizures in patients

tolerability of anti-epileptic drugs for refractory focal epilepsy: system-

with epilepsy: a double-blind, randomized, placebo-controlled trial.

atic review and network meta-analysis reveals the need for long term

Epilepsia. 2009;50(3):406-414.

comparator trials. Br J Clin Pharmacol. 2013;76(5):649-667.

32. Sonmezturk HH, Azar NJ. Levetiracetam extended release as

15. Krumholz A, Shinnar S, French J, et al. Evidence-based guideline:

adjuvant therapy for the control of partial-onset seizures. J Cent Nerv Syst

management of an unprovoked first seizure in adults: report of the Guideline

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the American Epilepsy Society. Neurology. 2015;85(17):1526-1527.

effects of mono and polytherapy for epilepsy. Seizure. 2012;21(8):610-613.

16. Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent teratoge-

34. Canevini MP, De Sarro G, Galimberti CA, et al. Relationship between

nicity of valproate in mono- and polytherapy: an observational study.

adverse effects of antiepileptic drugs, number of coprescribed drugs, and

Neurology. 2015;85(10):866-872.

drug load in a large cohort of consecutive patients with drug-refractory

17. Montouris G, Abou-Khalil B. The first line of therapy in a girl with juve-

epilepsy. Epilepsia. 2010;51(5):797-804.

nile myoclonic epilepsy: should it be valproate or a new agent? Epilepsia.

35. Kwan P, Brodie MJ. Early identification of refractory epilepsy.

2009;(50 suppl 8):16-20.

N Engl J Med. 2000;342(5):314-319.

36 THE CLINICAL ADVISOR • JUNE 2017 • www.ClinicalAdvisor.com

FEATURED COURSE

36. Martins HH, Alonso NB, Vidal-Dourado M, et al. Are adverse effects

54. Lee JJ, Song HS, Hwang YH, et al. Psychiatric symptoms and quality of

of antiepileptic drugs different in symptomatic partial and idiopathic gen-

life in patients with drug-refractory epilepsy receiving adjunctive leveti-

eralized epilepsies? The Portuguese-Brazilian validation of the Liverpool

racetam therapy. J Clin Neurol. 2011;7(3):128-136.

Adverse Events Profile. Epilepsy Behav. 2011;22(3):511-517.

55. Cramer JA, Arrigo C, Van Hammee G, et al. Effect of levetiracetam on

37. Perucca P, Jacoby A, Marson AG, et al. Adverse antiepileptic drug effects

epilepsy-related quality of life. Epilepsia. 2000;41(7):868-874.

in new-onset seizures: a case-control study. Neurology. 2011;76(3):273-279.

56. Eatock J, Baker GA. Managing patient adherence and quality of life in

38. Lerman-Sagie T, Watemberg N, Kramer U, et al. Absence seizures

epilepsy. Neuropsychiatr Dis Treat. 2007;3(1):117-131.

aggravated by valproic acid. Epilepsia. 2001;42(7):941-943.

57. Brodie MJ, Barry SJ, Bamagous GA, et al. Patterns of treatment

39. Genton P. When antiepileptic drugs aggravate epilepsy. Brain Dev.

response in newly diagnosed epilepsy. Neurology. 2012;78(20):1548-1554.

2000;22(2):75-80.

58. Stephen LJ, Brodie MJ. Antiepileptic drug monotherapy versus poly-

40. Davis KL, Candrilli SD, Edin HM. Prevalence and cost of nonadherence

therapy: pursuing seizure freedom and tolerability in adults. Curr Opin

with antiepileptic drugs in an adult managed care population. Epilepsia.

Neurol. 2012;25(2):164-172.

2008;49(3):446-454.

59. Wang SP, Mintzer S, Skidmore CT, et al. Seizure recurrence and remis-

41. Brodie MJ, Sillis GJ. Combining antiepileptic drugs—rational polytherapy?

sion after switching antiepileptic drugs. Epilepsia. 2013;54(1):187-193.

Seizure. 2011;20:369-375.

60. Kwan P, Brodie MJ. Epilepsy after the first drug fails: substitution or

42. Kirmani B, Jones G, Crisp E. Retrospective analysis of efficacy and toler-

add-on? Seizure. 2000;9(7):464-468.

ability of Keppra XR in an outpatient setting. Internet J Neurol. 2012;14(1):1-4.

61. Cretin B, Hirsch E. Adjunctive antiepileptic drugs in adult epilepsy: how the

43. Data on file. Sun Pharma Advanced Research Company Ltd.

first add-on could be the last. Expert Opin Pharmacother. 2010;11(7):1053-1067.

Levetiracetam ER 1000mg/1500mg [PowerPoint presentation]; 2013.

62. Mbizvo GK, Dixon P, Hutton JL, Marson AG. Levetiracetam add-on

44. Ting TY, Jiang W, Lionberger R, et al. Generic lamotrigine versus

for drug-resistant focal epilepsy: an updated Cochrane review. Cochrane

brand-name Lamictal bioequivalence in patients with epilepsy: a field test

Database Syst Rev. 2012;(9):CD001901.

of the FDA bioequivalence standard. Epilepsia. 2015;56(9):1415-1424.

63. Baulac M. Rational conversion from antiepileptic polytherapy to mono-

45. Privitera MD, Welty TE, Gidal BE, et al. Generic-to-generic lamotrigine

therapy. Epileptic Disord. 2003;5(3):125-132.

switches in people with epilepsy: the randomised controlled EQUIGEN

64. Huff JS, Morris DL, Kothari RU, Gibbs MA. Emergency department

trial. Lancet Neurol. 2016;15(4):365-372.

management of patients with seizures: a multicenter study. Acad Emerg

46. Cardenas VM, Roman GC, Perez A, Hauser WA. Why U.S. epilepsy

Med. 2001;8(6):622-628.

hospital stays rose in 2006. Epilepsia. 2014;55(9):1347-1354.

65. Lie IA, Hoggen I, Samsonsen C, Brodtkorb E. Treatment non-adher-

47. Osborne A, Taylor L, Reuber M, et al. Pre-hospital care after a sei-

ence as a trigger for status epilepticus: an observational, retrospective

zure: evidence base and United Kingdom management guidelines. Seizure.

study based on therapeutic drug monitoring. Epilepsy Res. 2015;113:28-33.

2015;24:82-87.

66. Samsonsen C, Reimers A, Brathen G, et al. Nonadherence to treat-

48. Faught RE, Weiner JR, Guerin A, et al. Impact of nonadherence to

ment causing acute hospitalizations in people with epilepsy: an observa-

antiepileptic drugs on health care utilization and costs: findings from the

tional, prospective study. Epilepsia. 2014;55(11):e125-e128.

RANSOM study. Epilepsia. 2009;50(3):501-509.

67. Wilder-Smith E. Nonadherence to treatment causing acute hospitaliza-

49. Faught E, Duh MS, Weiner JR, et al. Nonadherence to antiepilep-

tions in people with epilepsy. Epilepsia. 2015;56(2):320.

tic drugs and increased mortality: findings from the RANSOM Study.

68. Dharmadhikari NB, Zala YR. Novel oral controlled drug delivery sys-

Neurology. 2008;71:1572-1578.

tem. Poster presented at: 33rd Controlled Release Society (CRS) Annual

50. Ettinger AB, Good MB, Manjunath R, et al. The relationship of depres-

Meeting and Exposition; July 22-26, 2006; Vienna, Austria.

sion to antiepileptic drug adherence and quality of life in epilepsy. Epilepsy

69. Carrette S, Boon P, Sprengers M, et al. Responsive neurostimulation in

Behav. 2014;36:138-143.

epilepsy. Expert Rev Neurother. 2015;15(12):1445-1454.

51. Garnett WR. Antiepileptic drug treatment: outcomes and adherence.

70. Krishna V, Sammartino F, King NK, et al. Neuromodulation for epilepsy.

Pharmacotherapy. 2000;20(8):191S-199S.

Neurosurg Clin N Am. 2016;27(1):123-131.

52. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med.

71. DeGiorgio CM, Soss J, Cook IA, et al. Randomized controlled trial

2005;353(5):487-497.

of trigeminal nerve stimulation for drug-resistant epilepsy. Neurology.

53. Data on file, from Elsevier’s Embase® database (www.embase.com;

2013;80(9):786-791.

accessible via paid service/subscription only). Nine studies examining the

72. Nune G, DeGiorgio C, Heck C. Neuromodulation in the treatment of

impact of seizure frequency on various aspects of patient QoL and seizure

epilepsy. Curr Treat Options Neurol. 2015;17(10):375.

frequency. Accessed database November 16, 2016. [Studies used can be

73. Shallcross AJ, Becker DA, Singh A, et al. Psychosocial factors associated

found listed individually beneath Figure 5 in this activity.]

with medication adherence in ethnically and socioeconomically diverse

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2017 37

CME

FEATURED COURSE

patients with epilepsy. Epilepsy Behav. 2015;46:242-245.

Neurol Scand. doi:10.1111/ane.12703.

74. Brown MT, Bussell JK. Medication adherence: WHO cares? Mayo Clin

76. Faught E. Adherence to antiepilepsy drug therapy. Epilepsy Behav.

Proc. 2011;86(4):304-314.

2012;25(3):297-302.

75. Malek N, Heath CA, Greene J. A review of medication adherence

77. Nicholl JS. Noncompliance with treatment of neurologic disease.

in people with epilepsy [published online October 26, 2016]. Acta

Curr Treat Options Neurol. 2002;4(6):469-476.

CME

POST-TEST Expiration date: January 31, 2018

Credit Designation: Haymarket Medical Education designates this enduring material for a maximum of 1.00 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. A statement of credit will be issued only upon receipt of a completed pre-assessment test, polling questions, activity evaluation form, and post-test with a score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/June17feature. CREDITS: 1.00 | Paving the way to better epilepsy outcomes

1. Which of the following is an example of how a patient’s interaction with the healthcare system may contribute to a lack of medication adherence? a. Poor provider-patient communication b. Patient has a limited understanding of the benefits and risks of treatment c. Physician prescribes an overly complex regimen d. Limited clinic access or missed clinic appointments 2. What is the mechanism of action of phenytoin? a. It is a potassium channel activator b. It is a blocker of repetitive action of the sodium channel c. It is a carbonic anhydrase inhibitor d. It is a glutamate modulator 3. Of the antiepileptic drugs (AEDs) listed below, which one is known to pose a risk for aplastic anemia and liver failure? a. Felbamate c. Levetiracetam b. Gabapentin d. Pregabalin 4. When used with levetiracetam extended release (XR), what is the principal characteristic of the Wrap MatrixTM novel drug-delivery technology in terms of seizure control and quality of life? a. It is suitable for drugs with very high solubility b. It is suitable for drugs with very low solubility c. It allows for higher doses and increased dosing intervals d. It allows for lower doses and decreased dosing intervals

5. Which of the following is a predictor for increased adverse events (AEs) associated with AEDs? a. Female sex b. Older age at epilepsy onset c. Younger age at initiation d. Asymptomatic epilepsy 6. Drug dispensers and/or alarms may help with what specific problem area? a. Cognitive problems b. Motivation to take medication c. Depressed mood d. Complex drug regimens 7. Reductions in adverse events (AEs) with levetiracetam extended-release (XR) are due to: a. A longer half-life b. Its mechanism of action c. Steadier serum concentrations d. Immediate-release formulation 8. What percentage of patients with epilepsy may not have their condition under control with currently available AEDs? a. 20% b. 30% c. 40% d. 50%

TO TAKE THE POST-TEST please go to: ClinicalAdvisor.com/June17feature

38 THE CLINICAL ADVISOR • JUNE 2017 • www.ClinicalAdvisor.com

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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.

YOUR COMMENTS WORKING WITH MULTIPLE ATTENDING PHYSICIANS IN THE EMERGENCY DEPARTMENT The other day I was working with one of my attending physicians, and we were busy dealing with a large influx of patients. I evaluated a child who had clear breath sounds and a fever. I administered ibuprofen with plans to check back on the child later to see if there was any improvement in the child’s overall appearance. A few minutes later, the attending physician came into the station and mentioned that he had ordered a breathing treatment on the patient because he had thought he heard some wheezing. I decided to pop back into the room to see if I could auscultate this wheeze. Again, I did not hear it. Oh well, I thought, he must hear a wheeze somewhere, and I moved along to see the next patient. A few hours later, we encountered another child with a similar presentation. I gave the Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001.You may contact us by e-mail at editor@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.

child ibuprofen, but this time I added a breathing treatment because I thought there might be a slight wheeze present. I was not overwhelmed by what I heard and probably would not have ordered it if the attending physician had not just ordered one for the other child. However, I was trying to think like the attending physician, to be one step ahead. A few minutes later, he sat down at the station again and asked why I had ordered a breathing treatment on the patient, because he did not hear any significant wheezing. I told him that I thought I might have heard a wheeze and decided to be proactive about it. The attending physician mentioned that we could always see how the ibuprofen worked and reevaluate the breathing to see if a treatment was necessary. I laughed to myself and thought —didn’t we just have this reverse situation a few hours ago? This attending physician happens to be one of my favorites to work with because we work well together, he vocalizes his opinions, and he has a way of making work fun. This situation made me think about one of the biggest difficulties of being an advanced practice provider—trying to work with a large number of attending physicians. Physicians develop their own practice styles, and if you work repeatedly with them you begin to anticipate their next moves and think like they do. You begin to understand what tests they would order in a certain situation, and you try to work along these lines. This becomes a little more difficult if you work in a hospital or in an emergency department

OUR CONSULTANTS

Philip R. Cohen, MD,

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.

Abimbola Farinde, PhD, PharmD,

is a professor at Columbia Southern University in Orange Beach, Ala.

40 THE CLINICAL ADVISOR • JUNE 2017 • www.ClinicalAdvisor.com

Laura A. Foster, CRNP, FNP,

Abby A. Jacobson, MS, PA-C,

practices family medicine with Palmetto Primary Care Physicians in Charleston, S.C.

is an assistant professor at Thomas Jefferson University and a dermatology PA at Family Dermatology of Reading, Pa.

where there are a large number of attending physicians, each with his or her own approach to evaluating patients. In the emergency department where I work, the attending physicians see each patient. Therefore, trying to think like they do and trying to run tests that they would order can save the patient a lot of time—especially if it is going to be a while before the physician can see the patient. The patient may have already gone for imaging studies and the results of his or her laboratory studies may be available before you present the patient to the attending physician. If the attending physician wants to add on a different test, this can add a few more hours to the total length of stay for the patient. However, it can become confusing to try to remember which attending physician is going to undoubtedly order a certain test. Do they prefer to order lactic acid tests? Do they prefer to order ultrasounds in women with right lower quadrant pain? Do they love tissue adhesive, or do they refuse to use tissue adhesive? Sometimes I feel like I need to write down a list to keep everyone straight. Over time, I have realized that I am never going to be able to get a perfect read on each attending physician. In the world of medicine where everything is changing rapidly, physicians may develop a new style that will keep you on your toes. I have learned that in situations such as the one that I experienced, the best thing you can do is to use your best judgment. Unless you know for sure that the attending physician is going to order that lactic acid, if you don’t think that the patient needs it, then don’t order it. You have to be confident that your history and physical skills will lead you in the right direction to determine what tests the patient needs. The attending physicians may want to add on a test, and if they do, so be it. Trying to predict what the attending physician is going to want will only end up driving you crazy in the end.—JILLIAN KNOWLES, MMS, PA-C, Philadelphia (224-1)

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.

CONSULTATIONS TREATMENT FOR CUTANEOUS ABSCESSES Are antibiotics always needed for cutaneous abscesses?— BONNIE KEISLER, MSN, CRNP, CWOCN, LDE, Birmingham, Ala. (200-2) The development of cutaneous abscesses is viewed as a commonplace complaint that can be found in pediatric and adult emergency department populations. Patients that present with the simple form of this condition can undergo an incision and drainage (I&D), which may or may not require a prescription for an antibiotic. Once this procedure is performed, the patient can be discharged. The performance of an I&D remains the standard course of treatment for addressing cutaneous abscesses. Antibiotics can be recommended for abscesses that can be associated with a chronic or severe disease, the rapid progression in the presence of an associated cellulitis, signs and symptoms of a systemic illness, and when there is no response to incision and draining. Antibiotics do not always need to be used for cutaneous abscesses, but the condition and presentation must be evaluated on a case-by-case basis to make a final decision regarding the appropriate course of treatment for any individual. For more information, see the following references: 1. Liu C, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:e18-e55. 2. Hankin A, Everett W. Are antibiotics necessary after incision and drainage of a cutaneous abscess? Ann Emerg Med. 2007;50:49-51. 3. Schmitz G, et al. The treatment of cutaneous abscesses: comparison of emergency medicine providers’ practice patterns. West J Emerg Med. 2013;14:23–28. doi: 10.5811/westjem.2011.9.6856. —Abimbola Farinde, PhD, PharmD (224-2) n

Claire O’Connell, MPH, PA-C,

an associate professor at the Rutgers University Physician Assistant Program, Piscataway, N.J.

Katherine Pereira, DNP, FNP,

is assistant professor, Duke University School of Nursing, Durham, N.C.

Sherril Sego, FNP-C, DNP,

is an independent consultant in Kansas City, Mo.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2017 41

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Dermatology Clinic CASE #1

Groin rash, profuse bleeding, and a large, eroded plaque ROBERT M. SIMONDS JR, BS, AND JULIA R. NUNLEY, MD

A 79-year-old white man with an extensive history of nonmelanoma skin cancer presents for a routine skin examination. He asks to have a groin rash checked. For 1 to 2 years, he has been using OTC and prescription antifungal and antibiotic creams for a presumed “jock itch.” Recently, he has developed more discomfort and episodic, profuse bleeding from the area. Examination reveals a large erythematous, eroded plaque on the posterior right scrotum extending anteriorly to the right upper thigh. A nodule is present within the plaque. What is your diagnosis? Turn to page 44.

CASE #2

A pink and brown nodule years after a mosquito bite ESTHER STERN, NP

A 44-year-old woman presents for her annual full skin examination. She has a specific concern regarding a lesion on her left lower leg. She recalls having a mosquito bite in that area a few years earlier, but it never went away. The lesion is bothersome only when she shaves her legs and nicks it; otherwise, there is no associated pain or tenderness. Physical examination reveals a firm, flat, pink and brown nodule on the left anterior proximal shin. The lesion dimples inward when pressure is applied. What is your diagnosis? Turn to page 45. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2017 43

Dermatology Clinic CASE #1

Extramammary Paget disease

Paget disease is a rare cutaneous adenocarcinoma that is thought to originate from cutaneous apocrine glands. The disease was originally described by, and named for, Sir James Paget. In 1874, Paget described cutaneous changes of erythema, excoriations, itching, and nipple discharge associated with an underlying carcinoma of the breast.1 Subsequently, Paget disease has been described in other anatomic sites, as well; thus, it is classified as either mammary or extramammary based on the anatomic location. In 1889, Crocker described the first case of extramammary Paget disease (EMPD) affecting the penis and scrotum, associated with an underlying bladder cancer.1 Since then, EMPD has been further classified into primary or secondary disease, depending upon the presence or lack of a coexistent urogynecologic or gastrointestinal malignancy.1,2 Typically affecting older individuals, EMPD is more common in patients aged 60 to 80 years, with a peak incidence in patients aged 65 years.1,2 Postmenopausal white women are affected most often. Originating primarily from cutaneous apocrine glands, EMPD principally affects areas with a high apocrine gland concentration, including the axillae, anus, and genital skin.1,3-5 In women, the vulva is most commonly affected and accounts for nearly 65% of all cases of EMPD. In men, the penoscrotal junction, scrotum, and inguinal areas are most commonly affected.1,2,4,6 Despite the perineal and genital predominance, EMPD has infrequently been reported in the umbilicus, as well as on the eyelid, ear, and cheek.3,4 EMPD may be asymptomatic or cause variable degrees of burning or pruritus.1,3 As these are nonspecific symptoms, EMPD is usually not suspected early in its course and is treated empirically as eczema, intertrigo, psoriasis, or a fungal infection.2,3,6 However, EMPD is unresponsive to any of these conventional therapies. Similarly, the initial lesions of EMPD mimic the various dermatitides mentioned, but with time, develop into an erythematous, ulcerated, or eczematous plaque; fine scale may be present.1,6 Although growth is slow, EMPD tends to be multifocal, with subclinical extension to surrounding tissues. Persistence of symptoms or lesions, and therapeutic failure, should alert the clinician that the original diagnosis is incorrect

and further studies are necessary. Appropriate cultures will exclude infectious etiologies. However, a skin biopsy is necessary to make the diagnosis of EMPD. Unfortunately, the correct diagnosis is usually delayed by 3 years or more.3,6 Biopsy specimen analysis should include routine as well as immunohistochemical staining.1-3 The malignant Paget cells are large, round, atypical intraepithelial cells with palestaining vacuolated cytoplasm and large nuclei. Abundant mucin is responsible for the large cytoplasmic vacuoles and is easily recognized with routine histochemical stains.1-3,6 Specific immunohistochemical stains help to differentiate between primary and secondary EMPD and exclude the other potential diagnoses, such as Bowen disease (squamous cell carcinoma in situ), Langerhans cell histiocytosis, and amelanotic melanoma.1

Extramammary Paget disease may be asymptomatic, or it may cause variable degrees of burning or pruritus. Stains for CK7 and CK20 are used to categorize EMPD. Results of staining for primary EMPD are usually positive for CK7 and negative for CK20, whereas results for secondary EMPD are usually positive for both CK7 and CK20.6 Stain results used to identify potential conditions are negative in EMPD and include p63, S100, melan-A, CD1a, and HMB-45.1-3,5,6 Primary EMPD is more common than secondary EMPD; however, it has the potential to become an invasive adenocarcinoma, possibly metastasizing to nearby lymph nodes or even distant organs. The malignancies associated with secondary EMPD are typically within an organ or tissue adjacent to the EMPD.1,6 For example, secondary vulvar EMPD is more commonly associated with a primary carcinoma of the vulva, vagina, cervix, uterus, bladder, colon, and rectum.1 Once the diagnosis of EMPD is established, imaging studies and age-appropriate cancer screening should be performed.1,2,4 Examinations to be considered include a pelvic examination, Papanicolaou smear, cystoscopy, and colonoscopy. Suggested imaging studies include computed tomography (CT) studies of the chest, abdomen, and pelvis.4 For patients with invasive disease, a sentinel lymph node (SLN) biopsy should be considered.4,7 If the SLN biopsy results are positive, or if other signs of widespread

44 THE CLINICAL ADVISOR â&#x20AC;˘ JUNE 2017 â&#x20AC;˘ www.ClinicalAdvisor.com

involvement exist, a positron emission tomography (PET) scan is indicated to determine the extent of the disease.4 Important prognostic indicators include the depth of invasion of the primary lesion, the presence of nodules within the primary lesion, the presence of extracutaneous involvement, clinically enlarged lymph nodes, specific genetic/protein expression profiles, and site of involvement.4 Among these factors, the depth of invasion and presence of extracutaneous involvement appears to have the strongest correlation with a poor outcome.2,4-6 Wide local excision has long been regarded as the standard of care for therapy.2,5,6,8 However, due to subclinical extension and the multifocal nature of EMPD, wide local excision does not ensure a complete cure; recurrent disease is common, affecting 20% to 60% of those surgically treated.2,8,9 Because recurrence following surgery is so high, other treatment methods have been investigated, including imiquimod, a topical immune response modulator that is approved by the US Food and Drug Administration for the treatment of superficial basal cell carcinomas. By stimulating the production of multiple cytokines including tumor necrosis factor-α, interferon-α, and interleukin-12, imiquimod activates both the innate and adaptive immune systems to create an antitumor effect.9 Multiple studies report topical imiquimod 5% cream to be effective for treatment of EMPD.9-11 However, because these favorable results have only been seen in relatively small cohorts, the consensus is that further trials are needed to confirm efficacy and establish treatment guidelines.9-11 Other nonsurgical treatment options have variable success and include topical 5% 5-fluorouracil cream, radiotherapy, laser therapy, and photodynamic therapy.1,2 Regardless of the treatment modality used, recurrence rates are high, so close follow-up for an extended period of time is recommended.1 For the patient in our case, a biopsy revealed the diagnosis to be EMPD; results of CK staining were positive for CK7 and negative for CK20, an immunohistochemistry profile favoring primary EMPD. He had recently had a negative colonoscopy result and imaging PET/CT scan results were negative for intra-abdominal or pelvic lymphadenopathy or tumors. He has been referred to medical and urologic oncology specialists. The medical oncologist has recommended topical imiquimod; however, tumor size may limit its use due to associated adverse effects. At the time of writing, we are awaiting recommendations from the urologic oncologist. Robert M. Simonds Jr., BS, is a medical student and Julia R. Nunley, MD, is a professor of dermatology and program director of dermatology at the Medical College of Virginia Hospitals of Virginia Commonwealth University in Richmond.

References 1. Lopes Filho LL, Lopes IM, Lopes LR, Enokihara MM, Michalany AO, Matsunaga N. Mammary and extramammary Paget’s disease. Ann Bras Dermatol. 2015;90:225-231. 2. Haydon N, Ting F, Southwell-Keely J. An important differential: extramammary Paget’s disease. Eplasty. 2015;15:ic16. 3. Kang Z, Zhang Q, Zhang Q, et al. Clinical and pathological characteristics of extramammary Paget’s disease: report of 246 Chinese male patients. Int J Clin Exp Pathol. 2015;8:13233-13240. 4. Cohen JM, Granter SR, Werchniak AE. Risk stratification in extramammary Paget disease. Clin Exp Dermatol. 2015;40:473-478. 5. Carbotta G, Sallustio P, Prestera A, Laforgia R, Lobascio P, Palasciano N. Perineal Paget’s disease: a rare disorder and review of literature. Ann Med Surg (Lond). 2016;9:50-52. 6. Bagby CM, MacLennan GT. Extramammary Paget’s disease of the penis and scrotum. J Urol. 2009;182:2908-2909. 7. Fujisawa Y, Yoshino K, Kiyohara Y, et al. The role of sentinel lymph node biopsy in the management of invasive extramammary Paget’s disease: multicenter, retrospective study of 151 patients. J Dermatol Sci. 2015;79:38-42. 8. Hunter CL, Skinner EC, Lee GK. Reconstruction with pedicled anterolateral thigh flap after wide local excision of penoscrotal extramammary Paget’s disease: a case report and comprehensive literature review. Eplasty. 2015;15:e26. 9. Liau MM, Yang SS, Tan KB, Aw CW. Topical imiquimod in the treatment of extramammary Paget’s disease: a 10 year retrospective analysis in an Asian tertiary centre. Dermatol Ther. 2016;29:459-462. 10. Baiocchi G, Begnami MD, Fukazawa EM, et al. Conservative management of extramammary paget disease with imiquimod. J Low Genit Tract Dis. 2012;16:59-63. 11. Cowan RA, Black DR, Hoang LN, et al. A pilot study of topical imiquimod therapy for the treatment of recurrent extramammary Paget’s disease. Gynecol Oncol. 2016;142:139-143.

CASE #2

Dermatofibroma

Dermatofibroma, also known as a cutaneous fibrous histiocytoma, is a common benign lesion that was first described by Stout and Lattes in 1967.1 It was previously thought to have a reactive etiology, as lesions often present after trauma, such as a shaving nick, insect bite, or thorn injury. Recent literature, however, points to a clonal neoplastic process.2

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Dermatology Clinic A dermatofibroma presents as a flat, firm nodule that appears tethered to the skin surface, although it is freely mobile over subcutaneous fat. Color varies from white to pink or brown, with a paler pigment in the center. Size generally ranges from 5 to 10 mm. A patient may present with more than one dermatofibroma. However, the presence of numerous dermatofibromas should raise suspicion of misdiagnosis or severe immunosuppression. A subcutaneous (deep) benign fibrous histiocytoma is a clinical subtype of the dermatofibroma and has a more aggressive nature, with a propensity for local recurrence.3

A dermatofibroma is benign and does not require treatment unless the lesion is progressively changing. Dermatofibromas are seen in adults of all ages, are rarely seen in children, and occur equally across all ethnicities. Women appear to be affected at a slightly higher rate. Although dermatofibromas can occur anywhere, they frequently appear on the lower legs, particularly in women, as well as the upper arms and shoulders. Two recent reports presented unique cases of dermatofibroma occurring on a middle-aged woman’s finger4 and on a young woman’s nipple.5 Most dermatofibromas are asymptomatic. However, some patients may report itching or tenderness associated with the lesion. Lesions on the lower legs are often prone to trauma, particularly in patients who shave their legs. There are several lesions that can look like a dermatofibroma. Basal cell carcinoma, both the nodular and superficial types, frequently appears on the legs and poses a diagnostic challenge. Keloids, neurofibromas, and dysplastic nevi are other common lesions to consider in the differential diagnosis. Dermatofibrosarcoma protuberans (DFSP) is a relatively uncommon spindle cell tumor of the skin that mimics dermatofibroma clinically. DFSP is locally aggressive and rarely can metastasize. The diagnosis of dermatofibroma is often clinical. A positive dimple sign indicates that the lesion dimples inward and downward when peripheral pressure is applied. A dermoscope used by a trained clinician can further support the clinical diagnosis. A white central patch with a peripheral fine brown network is the classic stereotypical pattern seen on dermoscopy.6 Unfortunately, dermatofibromas may present with nonclassic patterns that can mimic other benign

or malignant lesions. If the diagnosis is questionable or if the lesion has atypical features, such as ulceration or asymmetry, a shave biopsy sent for histopathologic examination can confirm the diagnosis. Histology of a dermatofibroma reveals a poorly defined proliferation of fibrohistiocytic cells with excessive collagen entrapment in the dermis. There is often an overlying grenz zone of normal papillary dermis. Occasionally, the overlying epidermis shows acanthosis and pigmentation of the basal layer. The presence of Touton giant cells containing hemosiderin confirms the diagnosis.7 Lesions that microscopically display cellular, aneurysmal, epithelioid, palisading, or other atypical patterns predict a more aggressive nature. A dermatofibroma is benign and does not require treatment unless the lesion is progressively changing. If the lesion is bothersome to a patient, it can be electively removed. Surgical excision is the preferred method for removal, although patients should be warned that there can be significant scarring. Cryosurgery, electrodessication, and laser have rarely been successful. For the patient in our case, a skin biopsy confirmed the diagnosis of dermatofibroma. The patient was educated regarding the diagnosis and reassured regarding its benign nature. Due to the uncertain cosmetic outcome with local excision, the patient chose to leave the lesion alone. She was encouraged to return for annual full skin examinations. n Esther Stern, NP, is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. References 1. Stout AP, Lattes R. Tumors of the Soft Tissues. Washington, DC: Armed Forces Institute of Pathology; 1967. 2. Chen TC, Kuo T, Chan HL. Dermatofibroma is a clonal proliferative disease. J Cutan Pathol. 2000;27:36-39. 3. Gleason BC, Fletcher CD. Deep “benign” fibrous histiocytoma: clinicopathologic analysis of 69 cases of a rare tumor indicating occasional metastatic potential. Am J Surg Pathol. 2008;32:354-362. 4. Raghavendran RR, Jenkins R. Digital dermatofibroma: common lesion, uncommon site. J Am Acad Dermatol. 2013;68(suppl):AB48. 5. Lee YB, Cho BK, Park HJ, Eun YS. Dermatofibroma on the nipple: a rare and interesting case. J Am Acad Dermatol. 2012;66(suppl 1):AB48. 6. Espasandín-Arias M, Moscarella E, Mota-Buçard A, et al. The dermoscopic variability of dermatofibromas. J Am Acad Dermatol. 2015;72(1 suppl):S22-S24. 7. James WD, Berger TG, Elston DM, Neuhaus IM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, PA: Saunders-Elsevier; 2011.

46 THE CLINICAL ADVISOR • JUNE 2017 • www.ClinicalAdvisor.com

Dermatologic Look-Alikes Hyperpigmented patches AUSTIN JONES, BS, DAVID RIZK, BA, AND CONNIE WANG, MD

CASE #1

CASE #2

A 2-day-old infant boy who was born with large, ill-defined, blue-gray hyperpigmented patches on his posterior trunk and sacral area presents to a clinician for an examination. The child’s parents are healthy, and they have no medical problems. No one in the child’s family has had similar dermatologic findings. The mother’s pregnancy was normal, and the child was born without any complications. The infant has been eating and sleeping well, and he has had no concerning signs or symptoms of systemic disease.

A 4-day-old infant boy who was born with a large, well-defined brown-black hyperpigmented patch on his posterior trunk presents. There are several smaller satellite brown macules around the large brown patch. The child’s parents are healthy and have no medical problems. No one in the child’s family has had similar dermatologic findings. The pregnancy was normal and the child was born without complications. The infant has been eating and sleeping well and currently has no concerning signs or symptoms of systemic disease.

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Dermatologic Look-Alikes CASE #1

Congenital dermal melanocytosis

Congenital dermal melanocytosis (CDM), also known colloquially as Mongolian spots, are benign lesions present at birth as blue or bluegray patches on the skin; they typically resolve within the first few years of life.1-2 CDM affects boys and girls equally; however, prevalence varies greatly with race and the population sampled. Asian and African populations are the most commonly affected, with some studies showing a frequency of 100%.1 White populations are the least commonly affected.3 Although the lumbosacral region is the most common location of presentation, other locations, including the shoulders, hands, and thighs, have been reported.3 Dermal melanocytosis results from the abnormal persistence of melanocytes in the dermis after the 20th week of embryologic development. In normal development, melanocytes differentiate from neural crest cells and form in the dermis at the 10th week of gestation; in all locations, except for the scalp, sacrum, and extensor surfaces of the extremities, these melanocytes then either move into the epidermis or are removed by macrophages.1,3 CDM appears blue due to the increased dermal reflection of short wavelengths of light, called the Tyndall effect.1,3 Persistence of CDM past the first few years of life can be due to a protective sheath surrounding melanocytes or the presence of growth factors in the dermis that support melanocyte growth.3,4 Associated risk factors for the development of CDM include drug use by the pregnant mother and premature birth.5 Clinically, CDM presents as a single, blue-green, irregularly shaped spot, smaller than 5 cm, at the sacrum.5 In rare cases, there are multiple spots, spots greater than 10 cm in size, oval and linear shapes, spots of varying colors, and lesions located across the body.5 CDM can be clinically classified based on the age of spot regression; the common type, extensive type, and persistent type regress early in childhood, later in childhood, and after childhood, respectively.3 Most spots (57%) resolve or start to regress by age 1 year.5 CDM is benign, but extensive involvement can be associated with many conditions, including metabolic disorders, cleft lip and palate, mucopolysaccharidosis, and lysosomal storage diseases.3,4 Histologically, collagen bundles intermixed with abnormal dendritic melanocytes are seen

in the lower half or two-thirds of the dermis, where melanocytes are not normally present.1,4 These melanocytes are spindle or pear-shaped, and they are small enough that they do not disrupt the normal structure of the dermis.1-3 The differential diagnosis of CDM includes other congenital lesions, including congenital melanocytic nevus (CMN), nevus of Ota, nevus of Ito, Hori nevus, ecchymosis, and child abuse.1-3 CMN is a tan or dark spot of hyperpigmentation present at birth; it is differentiated from CDM by its brown color and frequent association with overlying hypertrichosis.1 Nevus of Ota and nevus of Ito present before age 1 year or near puberty as blue or brown patches on the skin on the face, specifically within the dermatomal distributions of the ophthalmic and maxillary branches of the trigeminal nerve and the supraclavicular/deltoid region, respectively.1 These conditions do not spontaneously regress and rarely can undergo malignant transformation.

The differential diagnosis of CDM includes congenital melanocytic nevus, nevus of Ito, Hori nevus, ecchymosis, and child abuse. Although similar in color, CDM is differentiated from nevus of Ota and nevus of Ito by its location, time of onset, and early regression.2-3 Hori nevus consists of brown- or graycolored skin patches that develop during adulthood and most commonly affect the face.1 The onset of presentation and location of hyperpigmentation thus distinguish CDM from Hori nevus. In rare cases, bruises from child abuse can mimic CDM and are excluded from the differential if the lesions are nontender, maintain their color, and regress over the course of months.3 Because the lesions most commonly regress with normal aging, particularly those in the sacral region, no treatment is usually needed.3 For small lesions that cause psychosocial distress, cosmetic masking agents can be used.1,3 A Q-switched alexandrite or ruby laser effectively treats most lesions, although some patients experience residual hyper- or hypopigmentation.6-7 Treatment before age 20 years and administration of bleaching creams before treatment can improve outcomes and reduce postlaser pigmentation.3,4 In our case, the parents of the patient were reassured that the lesion was benign and would most likely resolve with age.

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CASE #2

Congenital melanocytic nevus

Congenital melanocytic nevi (CMN) occur at birth or soon after and are variable in size, but generally appear as round or oval, slightly raised or flat brown lesions on the trunk, legs and arms, head and neck, and extremities.1,8-10 There may be associated hypertrichosis, hyperkeratosis, erosions, or ulcerations.11 Multiple congenital nevi are seen in 3% of patients.8,11-12 The physical appearance of congenital nevi may change over time, with thickening, changes in texture, or development of papules and nodules within the lesion.8 CMN are classified by projected adult size, with small, medium, and giant nevi described as less than 1.5 cm in diameter, between 1.5 and 19.9 cm, and greater than 20 cm, respectively.1,8 The prevalence of congenital nevi is variable. Smalland medium-sized congenital nevi have an incidence of approximately 1%, whereas giant congenital nevi are more infrequent, with an incidence of 0.005% or less.1,4,8 African and Japanese populations are more commonly affected than Hispanic or white populations, and girls and women are more commonly affected than boys and men.8 Giant congenital nevi, specifically, are most commonly located on the posterior trunk, often have smaller satellite nevi distributed throughout the body and are associated with an increased risk of melanoma.1,8-12 Whereas patients with small- or mediumsized congenital nevi have no increased risk for development of melanoma, patients with giant congenital nevi have a 5-year risk for melanoma of 4.5%.1 Approximately 60% of melanomas in patients with giant congenital nevi develop within 10 years after birth.4 CMN are associated with many more malignant conditions8; thus, suspicious lesions arising within CMN should be biopsied and evaluated to rule out malignancy. Another concern in patients with giant congenital nevi, particularly those in an axial location with multiple satellite lesions, is neurocutaneous melanosis. This condition is characterized by CMN associated with meningeal melanosis or melanoma. Magnetic resonance imaging (MRI) should be performed if risk factors or symptoms of increased intracranial pressure are present. Congenital nevi arise from melanocytes and develop between 40 days and 6 months of gestation.1 Although the exact etiology is unknown, there is an established association between congenital nevi and NRAS mutations; however,

results of studies on familial inheritance are inconsistent.1,8,9 Unlike acquired nevi, congenital nevi lack BRAF mutations.1,8 There are no definitive histologic criteria for congenital nevi. Congenital nevus cells are found in the lower reticular dermis, subcutaneous fascia, and deeper.1,4 Histologic diagnosis can be difficult because congenital nevi cells show identical features to normal acquired nevi.1,10 Congenital nevi cells often extend in a linear pattern or between collagen bundles, and involve blood vessels, hair follicles, sweat glands, arrector pili, and cutaneous nerves, which can support the diagnosis.1,4,8,10 CMN are fairly easy to diagnose when seen at birth. Other congenital birthmarks, including hemangiomas and dermal melanocytosis, are distinguished by clinical appearance. Becker nevus is a pigmented patch on the upper trunk and proximal extremities that most commonly appears during childhood or adolescence.1 During puberty, the lesion can undergo thickening and darkening and develop overlying hypertrichosis. Its location and clinical history help differentiate this lesion from CMN. Another differential diagnosis of CMN is plexiform neurofibroma. This lesion, pathognomonic for neurofibromatosis, is a proliferation of nerves that becomes apparent in early childhood; it presents as a soft subcutaneous nodule or plaque, sometimes with overlying hyperpigmentation and hypertrichosis. Other findings of neurofibromatosis, the soft and boggy texture, and histologic diagnosis of plexiform neurofibroma aid in differentiation. The decision to remove a nevus can be based on a patientâ&#x20AC;&#x2122;s risk for developing melanoma, and the size, location, and cosmetic appearance of the nevus.1 The treatment for most small- and medium-sized CMN is yearly monitoring, given the low risk for development of melanoma. Removal of the entire nevus has been shown to improve patient satisfaction for nevi smaller than 20 cm but may not improve the risk for cancer development when compared with a partial removal.13 For large congenital nevi, delaying surgery until 6 months after birth is the preferred treatment for high-risk patients, but the risks of anesthesia and location of the nevus must be weighed.1,4,11 Dermabrasion, curettage, and lasers have all been used as alternative treatments for congenital nevi by reducing the elevation and pigmentation; however, these treatments do not decrease cancer risk.1 In all cases of CMN, the risk for scarring, deformities, or decreased quality of life should be considered.13 In our case, due to the size of the nevus, MRI was ordered, and the patient was referred to a pediatric dermatology specialist. MRI was ordered to rule out possible neurocutaneous melanosis, which has been associated with giant axial congenital nevi. The patient will be routinely followed to screen for the development of melanoma within or outside the lesion. n

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Dermatologic Look-Alikes Congenital dermal melanocytosis vs congenital melanocytic nevus Presentation

Congenital dermal melanocytosis • Blue-gray, blue-green patches typically 5 cm in size but can vary • Incidence is highly variable (11%-74%) • Present at birth

Congenital melanocytic nevus • Tan or brown patches of varying size • Small < 1.5 cm • Medium 1.5 –19.9 cm • Giant > 20 cm • Incidence is 1% for small and medium nevi, and ≤ 0.005% for giant nevi • Present at birth

Etiology

Persistence of melanocytes within the dermis

Exact mechanism is unknown, but NRAS mutations are common

Characteristic location

Sacrum

Trunk

Sex affected

Equal

Girls and women > boys and men

Potential for malignant development

Yes

Associated conditions

• • • • • • •

• • • • •

Histology

• Melanocytes in the lower 1/2 to 2/3 of the dermis between collagen bundles • Normal dermal architecture

• Nevi cells often extend in a linear pattern • Congenital cells often have identical features in comparison to normal acquired nevi • Nevi cells may involve blood vessels, hair follicles, sweat glands, and cutaneous nerves • Disrupted dermal architecture

Diagnosis

• Clinical presentation: size, color, location, and patient ethnicity can be useful

• Clinical presentation: size, color, location • Histologic examination of a nevus can be helpful

Treatment

• Often not needed • Q-switched alexandrite and ruby lasers are effective

• Decision to treat is based on risk for developing melanoma and expected surgical outcomes • Surgical removal is first-line treatment • Dermabrasion, curettage, and lasers are alternative treatments with varying efficacies

Metabolic disorders Cleft lip/palate Phakomatosis pigmentovascularis Sjögren-Larsson syndrome Hunter and Hurler syndromes Lysosomal storage diseases Trisomy 20

Austin Jones, BS, is a medical student and Connie Wang, MD, is a dermatology resident at Baylor College of Medicine in Houston. David Rizk, BA, is a medical student at the University of South Alabama in Mobile.

Melanoma Rhabdomyosarcoma Neurosarcoma Malignant blue nevi Congenital malformations

7. Shirakawa M, Ozawa T, Ohasi N, Ishii M, Harada T. Comparison of regional efficacy and complications in the treatment of aberrant Mongolian spots with the Q-switched ruby laser. J Cosmet Laser Ther. 2010;12:138-142. 8. Alikhan A, Ibrahimi OA, Eisen DB. Congenital melanocytic nevi: where are we now? Part I. Clinical presentation, epidemiology, pathogenesis,

References

histology, malignant transformation, and neurocutaneous melanosis. J Am

1. Bolognia JL, Jorizzo JL, Schaffer JZ. Dermatology. 3rd ed. Philadelphia, PA:

Acad Dermatol. 2012;67:495.e1-495.e17.

Elsevier Saunders; 2012.

9. Chitsazan A, Ferguson B, Ram R, et al. A mutation in the Cdon gene

2. Cordova A. The Mongolian spot: a study of ethnic differences and a

potentiates congenital nevus development mediated by NRAS (Q61K).

literature review. Clin Pediatr (Phila). 1981;20:714-719.

Pigment Cell Melanoma Res. 2016;29:459-464.

3. Gupta D, Thappa DM. Mongolian spots. Indian J Dermatol Venereol

10. Tannous ZS, Mihm MC Jr, Sober AJ, Duncan LM. Congenital melano-

Leprol. 2013;79:469-478.

cytic nevi: clinical and histopathologic features, risk of melanoma, and

4. James WD, Berger TG, Elston DM, Neuhaus IM. Andrews’ Diseases of

clinical management. J Am Acad Dermatol. 2005;52:197-203.

the Skin: Clinical Dermatology. 12th ed. Philadelphia, PA: Elsevier; 2016.

11. Lyon VB. Congenital melanocytic nevi. Pediatr Clin North Am. 2010;57:1155-1176.

5. Gupta D, Thappa DM. Mongolian spots—a prospective study. Pediatr

12. Zayour M, Lazova R. Congenital melanocytic nevi. Clin Lab Med. 2011;31:267-280.

Dermatol. 2013;30:683-688.

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

6. Kagami S, Asahina A, Uwajima Y, et al. Treatment of persistent Mongolian

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

spots with Q-switched alexandrite laser. Lasers Med Sci. 2012;27:1229-1232.

Acad Dermatol. 2012;67:515.e1-515.e13.

50 THE CLINICAL ADVISOR • JUNE 2017 • www.ClinicalAdvisor.com

LEGAL ADVISOR CASE

Fired for falling asleep on the job After a nurse is fired for falling asleep at her job at a hospital, she claims that it was in retaliation for taking time off under the FMLA. BY ANN W. LATNER, JD

Ms N, 30, was exhausted. It was mid-September 2013, and she had just finished her fourth consecutive 12-hour, 7 pm to 7 am shift in the pediatric department of the hospital where she worked. She had been a nurse at the hospital since graduating from nursing school in 2010. The job itself was rewarding. Ms N enjoyed working with children, and her performance reviews reflected that—her appraisals always indicated that she consistently met or exceeded expectations. Her most recent review praised her work, noting that Ms N “displayed a calm, compassionate, confident manner when interacting with patients and families,” “interacted well with physicians,” and had “expanded her clinical skills.” She had recently been promoted to the Pediatric Emergency Department in the hospital. Everything was good, except for Ms N’s health. She had had a series of medical issues that forced her to take time off under the Family and Medical Leave Act (FMLA) starting in 2011. That year, Ms N needed time off for sinus surgery. In 2012, she took FMLA leave

Video showed a nurse sleeping intermittently for 3 minutes and then continuously for another 3 minutes at her station at the hospital.

for 8 days due to severe asthmatic bronchitis. In April 2013, she took 3 weeks of FMLA leave after her asthmatic bronchitis worsened, requiring a hospital stay for 9 of those days. In August 2013, she was again hospitalized and took another 2 weeks of FMLA leave. While she was in the hospital, her supervisor relocated and was replaced by a new supervisor. Ms N met with the new supervisor when she returned to work in September. She explained to her supervisor that her doctor wanted to do additional testing, but that she would try to schedule it on an outpatient basis so as not to miss any more work. Now it was mid-September, and Ms N had just finished a busy 7 pm to 7 am shift, so busy that she had not been able to take her half-hour break. It was 7 am, but she had a staff meeting at 7:30 am, so she remained on the clock and took Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JUNE 2017 51

LEGAL ADVISOR

The court was sympathetic to Ms N but agreed that her violation of the hospital’s rules was adequate reason for termination. fired for sleeping was a pretext. To prove this, she had to come up with comparable situations in the hospital in which an employee who was sleeping on the job was not fired. The district court did not believe that Ms N had introduced sufficient evidence showing this and dismissed the case. Ms N appealed, and the case went to the US Court of Appeals. Legal background

At that point, the burden shifted back to Ms N to prove that being fired for sleeping on the job was a pretext. The way this is proven is by introducing a comparison situation in which an employee was not fired. Ms N introduced a situation in which a medical technologist in the laboratory department fell asleep in the lab. The appeals court agreed with the lower court that a nurse is very different from a lab technician. “Nurses—unlike technologists—have a responsibility to respond with immediacy to patient needs,” wrote the court. “Moreover, a nurse sleeping in a public area could undermine the public’s confidence in the hospital, which has an interest in putting forth a professional image.” The court found that the differences in responsibilities between Ms N and the lab tech made it an unsuitable comparison. Although the court was sympathetic to Ms N and noted her consistently positive reviews, it agreed that her violation of the hospital’s rule was an adequate reason for her termination. Protecting yourself

Ms N’s punishment for falling asleep does indeed seem overly harsh, but employers can terminate employment for violation of their rules, even if their rules seem overly restrictive. Thus, it is essential that you always familiarize yourself with your employee handbook and your employer’s rules when you start a new job, and stay up-to-date on changes. Protect yourself by knowing the rules, and working within them. n Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

On appeal, the court explained that to prove a retaliation claim, an employee must allege that: 1) she engaged in a statutorily protected activity (FMLA leave); 2) she had an adverse employment decision; and 3) the decision was causally related to the protected activity. If those things are proven, then the burden shifts to the employer to prove that it had a legitimate reason for the adverse employment action. If that is proven, then the plaintiff (Ms N) would have to show that the employer’s stated reason was simply a pretext. The court held that Ms N had proven her first burden by showing that she had taken FMLA leave (a statutorily protected activity), she was fired (had an adverse employment decision), and that it could be causally related to her taking FMLA leave. The hospital then had the burden of producing a legitimate reason for firing her. The hospital introduced its policy and stated that Ms N was fired for sleeping on the job, not for taking FMLA leave. 52 THE CLINICAL ADVISOR • JUNE 2017 • www.ClinicalAdvisor.com

her break from 7 to 7:30 am. She sat at the nurse’s station and closed her burning eyes for a moment. The next thing she knew, her supervisor was standing over her, loudly and pointedly saying “Good morning, Ms N.” Two days later, Ms N was summoned to human resources (HR) where her supervisor and the HR director informed her that she had violated the hospital’s policy, which specified that the hospital “does not allow sleeping during meal periods or rest periods.” She was shown a video that showed her sleeping intermittently for 3 minutes and continuously for another 3 minutes at the nurse’s station. Based on this, and to her great shock, Ms N was fired from her job. Ms N hired an attorney and filed suit against the hospital, alleging that she was fired in retaliation for taking FMLA leave. She argued that the hospital’s claim that she had been

ALTERNATIVE MEDS UPDATE

What you should know about the herbs and supplements patients use By Sherril Sego, FNP-C, DNP Ms. Sego is an independent consultant in Kansas City, Mo.

Coal tar

Coal tar, also known as liquor carbonis detergens, is a thick, black sticky material occurring as a byproduct in the industrial use of coal for fuel.1 A naturally occurring phenomenon of tar is found in the famed La Brea Tar Pits in Los Angeles, California. Coal tar products are most often used topically for a variety of skin conditions, including psoriasis. Coal tar is one of the oldest known treatments for psoriasis, as it reduces scaling, itching, and inflammation. Its exact working mechanism is not known.

Background Coal tar was supposedly discovered in 1665, but it is discussed in many cultural writings as being used for medicinal purposes centuries earlier.2 Today, it is listed in the World Health Organization’s “List of Essential Medications.”3 Coal tar products are most commonly used for psoriasis, an autoimmune inflammatory condition primarily of the skin that affects an estimated 125 million people around the world.4

Science Coal tar products’ mechanism of action for this condition is felt to involve suppression of specific deoxyribonucleic acid (DNA) synthesis, thereby inhibiting keratinocyte proliferation that results in the thick, plaque formations.5 In addition to blocking the formation of these plaques, coal tar breaks down keratin layers that are already formed.6 There also may be direct anti-inflammatory and antimicrobial action.4

Further studies have examined the levels of helper T-cells and interleukin-12 (IL-12) in patients with psoriasis and found significant differences in pre- and post-treatment levels. IL-12 is a recognized pro-inflammatory cytokine that is consistently elevated in psoriasis patients.7 IL-12 appears to suppress the production of specific T-cell production. In one study of 27 psoriasis patients, the level of these beneficial T-cells was significantly higher in patients after a prescribed topical coal tar treatment known as the Goeckerman Regimen.7 A similar trial of 55 psoriasis patients measured pre- and post-treatment serum levels of IL-12, with serum levels of IL-12 lower after Goeckerman therapy than before treatment, potentially confirming the anti-inflammatory effect of this coal tar therapy.8 More recently, increased attention has been given to the use of the Goeckerman therapy in cases of severe psoriasis that have proven resistant to biologic therapy. The Goeckerman Regimen typically consists of a pre-treatment of topical corticosteroid creams or liquids in the most severe cases. Then, patients are Continues on page 55

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ALTERNATIVE MEDS UPDATE

Safety The U.S. Food and Drug Administration has approved products containing 0.5% to 5.0% coal tar for sale without a prescription. There has been concern over the years about the possible carcinogenic risk of continued application of coal tar, especially in the amounts used in controlled treatments like the Goeckerman Regimen. Multiple studies, however, have concluded that there is no significant increase in cancer risk when coal tar is used in prescribed therapy regimens.

How supplied, cost

Summary Considering the burden of psoriasis and its potential for disability, along with the increasing use and cost of biologic therapies, treatment with coal tar presents an intriguing, efficacious, and attractive alternative. For milder cases of psoriasis, such as those isolated to the scalp or other small body surface areas, treatment with any of the multiple nonprescriptive forms of coal tar is ideal. n References Coal tar products are commonly used as a treatment for psoriasis.

Coal tar is most commonly found in shampoos, soaps, salves, and ointments. Most cost between $10 and $15 for a 1-month supply.

1. Paghdal KV, Schwartz RA. Topical tar: back to the future. J Am Acad Dermatol. 2009;61:294-302. 2. Levell N, Peters T. Care and punishment: a history of coal tar and wood tar in dermatology. British Association of Dermatologists website. www.bad.org.uk/shared/get-file. ashx?itemtype=document&id=1398 (Accessed May 4, 2017). 3. WHO model list of essential medicines. World Health Organization website. http://www.who.int/medicines/ publications/essentialmedicines/en (Accessed May 4, 2017). 4. About psoriasis: statistics. National Psoriasis Foundation website. https://www.psoriasis.org/about-psoriasis (Accessed May 13, 2017). 5. Zeichner JA. Use of topical coal tar foam for the treatment of psoriasis in difficult-to-treat areas. J Clin Aesthet Dermatol. 2010;3:37-40. 6. Coal tar. The Psoriasis and Psoriatic Arthritis Alliance website. http://www.papaa.org/psoriasis-treatments/ coal-tar (Accessed May 4, 2017). 7. Kondelková K, Vokurková D, Krejseka J, et al. The number of immunoregulatory T cells is increased in patients with psoriasis after Goeckerman therapy. Acta Medica (Hradec Kralove). 2012;55:91-95. 8. Borska, L, Andrys, C, Krejsek, J, et al. Serum levels of the proinflammatory cytokine interleukin-12 and the anti-inflammatory cytokine interleukin-10 in patients with psoriasis treated by the Goeckerman regimen. Int J Dermatol. 2008;47:800-805. 9. Gupta R, Debbaneh M, Butler D, et al The Goeckerman

There are multiple over-the-counter products containing coal tar. All products are topical. Most products are shampoos or other soaps. Other products include salves and ointments. Some of these are allowed to contain up to 20% coal tar and are blended and diluted with isopropyl alcohol and combined with a neutral base such as petroleum jelly. Most products cost between $10 to $15 for a month’s supply.

regimen for the treatment of moderate to severe psoriasis. J Vis Exp. 2013;(77):e50509. 10. Fitzmaurice S, Bhutani T, Koo J. Goeckerman regimen for management of psoriasis refractory to biologic therapy: the University of California San Francisco experience. J Am Acad Dermatol. 2013;69:648-649. 11. Thorns A, Edmonds P. Pruritis. In: Sykes N, Edmonds P, Wiles J, eds. Management of Advanced Disease. 4th ed. New York, NY: Oxford University Press; 2004:206-213.

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treated with a regimen of total-body coverage of a coal tar preparation for 4 to 5 hours daily for up to 6 weeks.9 Ultraviolet B phototherapy treatments are prescribed because coal tar is a photosensitizer that can increase the effectiveness of traditional phototherapy.9 In a retrospective review, researchers at the University of California at San Francisco examined records of 53 patients with severe plaque psoriasis who had been treated with various biologic therapies without success.10 These patients were then treated with either addon therapy with the Goeckerman Regimen or the Goeckerman Regimen alone. The results of this review showed that 40 patients (74%) experienced > 80% skin clearing of the condition.10 Additionally, there is evidence to suggest that topical coal tar may help reduce the bothersome pruritus associated with psoriasis.11 The proposed mechanism of this amelioration is the interference of the C-fiber nerve transmission of substance P. Substance P is a generalized cytokine that is strongly associated with any anti-inflammatory condition, especially that of the skin.