April 2016 Clinical Advisor

THE CLINICAL ADVISOR • APRIL 2016

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■ Managing diabetes ■ CDC’s opioid guideline ■ Gluten and celiac disease FEATURE Medical Nutrition Therapy

Dietary goals in diabetes LEGAL ADVISOR

|

APRIL 2 016

| www.ClinicalAdvisor.com

WHEN TO TREAT INFANTILE

HEMANGIOMAS Most hemangiomas are benign, but complications may develop that require treatment.

Collaborative practice ALT MEDS UPDATE

Color therapy

■ Dermatology Clinic

PURPURIC MACULES AND SEPSIS PAGE 55

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YOUR COMMENTS MORE READER COMMENTS ON ETHICAL ISSUES REGARDING USE OF IUDS Regarding “The IUD rumor mill: common misconceptions” [Nov. 2015, p. 32], conception takes place in the fallopian tube near the ovary and then continues its journey to the uterus. The IUD makes the surface of the uterus such that a fertilized ovum cannot attach itself and continue growing and surviving until birth. Therefore, the fertilized ovum cannot survive and is expelled from the mother’s body. In my estimation, this is yet another form of abortion.—JEAN LUCK, LVN, PA, Green Valley Lake, Calif. (208-2) The LNG-IUS also prevents conception. While the progestin affects the endometrium, making it inhospitable to a fertilized egg, it also thickens the cervical mucous—in the words of a lecturer I heard, “turns it into cement.” Thus, the

LNG-IUS also is a barrier method, blocking the entrance of sperm into the uterus.—SUSANNA LEVIN, WHNP, New Rochelle, N.Y. (208-3) The copper IUD also works by disruption of the endometrium and implantation. A previous commenter stated that it works by preventing fertilization. Both are possible, but neither action is acceptable according to certain belief systems.—NANCY SANDROCK, CNM, Weslaco, Texas (208-1)

AVOIDING LABELING PATIENTS AS NONCOMPLIANT Sam Mbugua, MD, wrote about using analogies for education [Advisor Forum, Dec. 2015, p. 54]. I agree that teaching requires visual aids and any other method of teaching and learning that can be used to convey a point of understanding. However, he starts his comment with the word “noncompliance.” Really? I was told in my masters program in the 1980s to never label a patient as noncompliant. My professors said that use of that word only indicates that you do not know why the patient is making the decision that he or she is making.

I work hard to educate patients, friends, and families, but if education, lecturing, and pushing information toward people changed behavior, we would not have any overweight healthcare personnel. All physicians and nurses would be

Advisor F orum

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This forum is devoted successes, to observations prac titioners who OUR CONSULTANTS want to shar below. We , and pear ls invite you e their clinic to participa with their colleague s. Respond al questions, prob te. lems, ing consultan ts are iden tified CONSUL TATION S

PERTUS SIS VAC YOUR COM CINE EFF With the recent incre ICACY MENTS whole cell ase in pertu pertussis ssis, Abimbola Farinde, PhD, PharmD,XYLLaura A. Foster, CRNP, FNP, Deborah L. Cross, MPH, CRNP, what Abby A. Jacobson, PA-C, vacci a confi role woul ITOL,family ne TOX medicine is a physician assistant ICITY, AND I enjoypractices your with Palmetto Primary at Delaware PETSValley cation and AlternativCarepubli Physicians Group appreDermatology e Meds S.C. inciate Wilmington, Del. the inclu DNP, on in Charleston,Upda g Waters, sion of the IEN, PA-C xylitol [The te column by Sherr W.V. , il Xylitol is The older very toxic Clinical Advisor, AprilSego, FNP-C, whole cell . In dogs, glycemia, pertus protec 2015, p. 86]. sis vaccines 50 THE CLINICAL • FEBRUARY 2016 • www.ClinicalAdvisor.com tion andADVISOR it weak can cause vomi ness, lethar funct vaccines. But effectiveness, compa are thought to offer gy, ataxia, ting, red more lead ion, liver failure, and seizures, abnor hypooffer the combithe key aspect that must with the newer acellu coma, all to death. mal liver of which Because be remembered ar can ultim cell vaccines nation of diphtheria is that both items, including oral xylitol is found ately and tetanu is hygiene produ in many house goods (cook AdvisorForum_CA0216.indd 1/28/16 7:07 PM s. The use and it was 50 believed to be effecti of whole hold ve and genera recent cts, gum, stored safely ies and muffins), it pertussis was ly reported that lly inexpensive is vital that candy, baked protec . If a dog , tooth these items is close to vaccines.— observed among those tion from an outbre a piece of ABIM BOL are ak of that paste, or candy, for given whole dropped photo at many clinic example, gum, bottom of A FARINDE, PhD, cell pertussis it ians can are dog be letha l. etc., this page Dr. Farin Phar mD Given for more de.) (200(See are I suggest that any articl owners, dog sitter infor matio 1) s, volunteers, at risk.— e on xylito n about BAR l mentions BAR New York that dogs Send us City (200- A WALTER, MEd your 2) , RNC, GNP Advisor Forum letters with , , The Clinical questions and York, Philip R. Cohen, MD,

play in slowi ned groupANP-BC, is associate d the is clinical associate professor is a professor (such as a NPprogram ng an outbr phyla xis of dermatology, University prisonProgram, Southern and antibdirector, Gerontology eak populationat Columbia in iotics?—A University of Pennsylvania School of Texas Medical Center, MPH University ) versu , NDR EW pro-Ala. of Nursing, Philadelphia.

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NY 10001 comments .You may Advisor, 114 West 26th to: com. If you contac Street, so by includiare writing in respont us by e-mail at editor 4th Floor, New se to a publish @clinicaladvi Letters are ng the number ed sor. in parent heses at letter, please indicat print the edited for length the and clarity. author e will be accept ’s name with The Clinical end of each item. the letter.

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OXYGEN IN A PAT THERAPY IENT WIT When treati H EMPHYS setting who ng a patient with emph EMA requires increappears to be hypo ysema in the acute care xic, ased effort to breathe, short of breath, and be very caref ul before

Philip R.

Cohen, MD, is clinical associa te professo of dermat r ology, of Texas MedicaUniversity l Center, Houston.

60 THE CLINICAL

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CRNP, C, is associa te program director, Geronto logy NP Program University of Pennsyl vania School , of Nursing , Philadelphia.

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CONTENTS APRIL 2016

NEWS AND COMMENT 14 Newsline ■■A synopsis of the American Diabetes Association’s 2016 recommendations for managing diabetes in primary care ■■The CDC issues a guideline for prescribing opioids for chronic pain.

■■Increasing body fat percentage, regardless of BMI, is associated with a higher risk of all-cause mortality.

■■Comparing COPD outcomes in patients treated by NPs/PAs versus those treated by physicians ■■Revised definitions for sepsis and septic shock are issued.

■■Greater gluten intake before age 2 may increase risk of celiac disease.

■■Testosterone treatment is beneficial in older men

40 CME/CE A 75-year-old woman with complaints of forgetfulness An older patient with occasional forgetfulness may be an example of the “worried well”—or is an early stage of Alzheimer’s disease present?

48 CME/CE Feature posttest

Guideline for opioids in primary care 16

8

An exophytic, brown, tender nodule 55

24 Infantile hemangiomas: managing complications Although usually benign, some infantile hemangiomas have complications that are potentially fatal or physically debilitating if untreated.

34 Medical nutrition therapy in diabetes Developing personalized nutrition goals with a registered dietitian can be effective in managing non–insulindependent diabetes.

MAKING CONTACT

TOC_CA0416.indd 4

Follow us on Twitter @ClinicalAdvisor

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

55 Dermatology Clinic n An exophytic, brown, and mildly tender nodule n Purpuric macules on a man with sepsis

79 Commentary A dietary plan for better sleep

FEATURES

DEPARTMENTS

63 Dermatologic Look-Alikes Light spots on the back Continues on page 6

Collaborative practice agreements 70

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CONTENTS DEPARTMENTS, cont’d Legal Advisor Collaborative practice agreements

76

Alternative Meds Update Color therapy

ADVISOR FORUM 50

Your Comments ■ Debating the pros and cons of full-practice authority ■ A need for early autism screening ■ Cannabidiol as medicine ■ Timing of meningococcal vaccine

51

Your Questions ■ Non-narcotic analgesics for musculoskeletal pain

“Yellow? Don’t call us until it’s at least an orange alert.” © The New Yorker Collection 2016 from cartoonbank.com. All Rights Reserved.

70

“I just got fed up with being formal all the time.”

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Medical Nut

Dietary goal

rition The

rapy

s in diabetes

LEGAL ADV

Collaborative

ISOR

practice

FOR NUR SE PRAC TITIO

NERS

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APRI L 2 016

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dvisor.com

WHEN TO

TREAT IN

HEMANG Most hem angiomas are benig n, but complica tions may deve lop require treat that ment.

FANTILE

IOMAS

ALT MED

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■ Managin g diab ■ CDC’s opio etes id ■ Gluten and guideline celiac disease

VOLUM E

TO CONTACT THE EDITOR: • editor@ClinicalAdvisor.com • Call 646.638.6078

D FORU M

NEWSLIN

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FORGETFULse NESS COMPLAIN TS

PAGE 40

3/25/16 1:13 PM

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com The Waiting Room

Web Exclusives

Official Blog of The Clinical Advisor

ClinicalAdvisor.com/News

ClinicalAdvisor.com/WaitingRoom Sharon M. O’Brien, MPAS, PA-C Is obstructive sleep apnea linked to low levels of vitamin D? Understanding the link between vitamin D deficiency and obstructive sleep apnea can be challenging.

CDC releases guideline for prescribing opioids for chronic pain in primary care The CDC’s new guideline regarding opioid therapy for chronic pain focuses on balancing potential benefits and harms to the patient.

Jim Anderson, MPAS, PA-C, DFAAPA, ATC Who calls the shots about a physician assistant title change?

The AAPA has again proposed calling physician assistants PAs despite pushback from the House of Delegates.

Body fat percentage, physical fitness are better predictors of mortality and diabetes risk than BMI High body weight percentage may increase mortality, and poor physical fitness in youth can increase diabetes risk later in life.

Jillian Knowles, MMS, PA-C What changes are in store for PA recertification?

As the PA profession continues to grow, the NCCPA looks to the future with new recertification guidelines.

Managing diabetes in primary care: 2016 recommendations from ADA The ADA has published the 2016 Standards of Medical Care in Diabetes that outline the best practices for diabetes care and management.

Multimedia ClinicalAdvisor.com/Multimedia The number of young adults abusing stimulants continues to increase Although the drugs are indicated for the treatment of ADHD, many young adults (especially those in college) use stimulants as so-called “study drugs” to help them focus. Watch it here:

Long-term aspirin use beneficial in cancer prevention A population-based study found that the overall risk of cancer in those on a long-term aspirin regimen was reduced by 3%. Watch it here: ClinicalAdvisor.com/ AspirinCancerVid

New CDC guideline aims to halt opioid epidemic A newly issued CDC guideline aims to curtail the overprescription of opioid medications. Watch it here:

FDA responds to concerns surrounding Essure birth control device The FDA has called for additional clinical studies to determine the potential harms of the permanent birth control device. Watch it here:

ClinicalAdvisor.com/OpioidGuidelineVid

ClinicalAdvisor.com/FDAEssureVid

ClinicalAdvisor.com/StimulantAbuseVid

MAKING CONTACT

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8 THE CLINICAL ADVISOR • APRIL 2016 • www.ClinicalAdvisor.com

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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.

Ortho Dx

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A Popeye deformity A 56-year-old man presents with a left arm deformity after a fall 2 days previously. He believes it developed after he fell backward, landing on his extended arm.

Shortly after the injury, he noticed pain and an obvious deformity in his left bicep muscle.

WHAT IS THE BEST TREATMENT OPTION?

• Arthroscopic proximal biceps tenodesis • Open proximal biceps repair • Observation • Open distal biceps tenodesis ● See the full case at ClinicalAdvisor.com/OrthoDx_April16

Derm Dx Pruritic hyperpigmentation of the upper and lower lips A 22-year-old woman presents with pruritic hyperpigmentation of her upper and lower lips that began approximately 2 weeks previously. She has no other systemic complaints, and vital signs are within normal range. The patient was prescribed oral doxycycline for treatment of recurrent acne 3 weeks previously.

CAN YOU DIAGNOSE THE CONDITION?

• Contact dermatitis • Herpes simplex • Fixed drug eruption • Phytophotodermatitis ● See the full case at ClinicalAdvisor.com/DermDx_April16

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2016 9

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Newsline A P R I L 2 016

Guideline for prescribing opioids page 16

Predictors of mortality and diabetes risk page 18

Gluten intake before age 2 and celiac disease page 23

ADA releases 2016 recommendations for managing diabetes in primary care THE AMERICAN Diabetes Association (ADA) has released a summary of its 2016 recommendations that focus on managing patients with diabetes in primary care, as published March 1 in the Annals of Internal Medicine.

A synopsis of the 2016 Standards of Medical Care in Diabetes highlights 8 key areas for primary care providers: diagnosis, glycemic targets, medical management, hypoglycemia, cardiovascular risk factor management, microvascular disease screening and management, and inpatient diabetes management.

The 2016 ADA Standards diagnostic criteria for prediabetes and diabetes are outlined in Table 1.

Recommendations include the following.

Pregnant women with no history of diabetes should be screened for gestational diabetes between 24 and 28 weeks. This can be done through the “1-step” method of a 75-g oral glucose tolerance test or the “2-step” method of a 50-g (non-fasting) test followed by a 100-g oral glucose tolerance test for women who screen positive (A rating).

Patients should use self-monitoring of blood glucose (SMBG) and HbA1c levels to assess glycemic control. The timing and frequency of SMBG should be tailored based on individual treatment and needs.

Patients should undergo HbA1c testing at least twice a year if they

TABLE 1. Criteria for the diagnosis of prediabetes and diabetes Variable

Prediabetes

Diabetes

HbA1c level

5.7% to 6.4%

≥6.5%

Fasting plasma glucose level (mmol/L)

5.6 to 6.9

7.0

Fasting plasma glucose level (mg/dL)

100 to 125

≥126

Oral glucose tolerance test results* (mmol/L)

7.8 to 11.0

11.1**

Oral glucose tolerance test results* (mg/dL)

140 to 199

≥200**

Random plasma glucose level (mmol/L)

-

11.1

Random plasma glucose level (mg/dL)

-

≥200***

* ** ***

2-h plasma glucose level after a 75-g oral glucose tolerance test In the absence of unequivocal hyperglycemia, results should be confirmed by repeated testing.

Only diagnostic in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis.

The ADA focuses on 8 key areas for managing diabetes in primary care.

are meeting treatment goals and have stable glycemic control (E rating).

If patients are at risk for severe hypoglycemia, providers should prescribe glucagon and ensure that the patient’s close contacts are taught how to administer it (E rating).

For the best possible diabetes management, clinicians should combine behavioral, dietary, lifestyle, and pharmaceutical interventions to create the best regimen for their patients (B rating).

The majority of patients with T1DM should be treated with multiple-dose insulin injections or continuous subcutaneous insulin injection (A rating).

For patients with T2DM, clinicians should take a patientcentered approach. Patients who are newly diagnosed with T2DM and are overweight/obese should

implement lifestyle modifications to lose 5% of their body weight.

If lifestyle modifications on their own are insufficient to achieve glycemic goals, clinicians should add metformin therapy to patients’ regimens (A rating).

If monotherapy at the maximum tolerated dose is unsuccessful over 3 months, clinicians should add a second agent to the patient’s treatment (A rating).

Insulin therapy should be used for patients with T2DM experiencing severe hyperglycemia that causes ketosis or unintentional weight loss (E rating); it should also be used for patients who are not achieving glycemic goals (B rating).

To improve the lipid profile of a patient with diabetes, clinicians should recommend lifestyle modifications. u Please view more complete coverage of this topic at www.ClinicalAdvisor.com

14 THE CLINICAL ADVISOR • APRIL 2016 • www.ClinicalAdvisor.com

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Newsline THE CDC has released a guideline for primary care clinicians who are prescribing opioids to patients with chronic pain in instances other than active cancer treatment, palliative care, and endof-life care. The set of 12 recommendations was published March 15 online ahead of print in JAMA. 1. The preferred treatments for chronic pain and nonpharmacologic therapy and nonopioid pharmacologic therapy.

Opioid therapy should only be considered if clinicians expect the benefits for both the patient’s pain and function to outweigh the anticipated risks associated with opioids.

If a patient is prescribed opioids, clinicians should combine opioid therapy with nonpharmacologic therapy and nonopioid pharmacologic therapy when appropriate.

2. Before initiating opioid therapy for chronic pain, clinicians should work with the patient to determine realistic goals for pain and function, and they should consider how opioid therapy will be discontinued if benefits do not outweigh the risks. Opioid therapy should only be continued if the patient experiences clinically meaningful improvement in pain and function that outweighs opioid-associated risks.

3. Before starting and during opioid therapy, clinicians should talk to patients about the known risks and realistic benefits of opioids as well as responsibilities for managing therapy.

4. When starting opioid therapy for chronic pain, clinicians should prescribe immediaterelease opioids rather than extended-release/long-acting (ER/LA) opioids.

5. At the beginning of opioid therapy, clinicians should prescribe the lowest effective dosage. While they should use caution with any dose, clinicians should be especially critical of the evidence of individual benefits and risks when considering increasing a patient’s dosage to ≥50 morphine milligram equivalents (MME)/day.

6. When using opioids to treat acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids. No greater quantity than needed for the anticipated duration of severe pain should be prescribed – 3 days or less is often sufficient, with more than 7 days rarely necessary.

7. Within 1 to 4 weeks of starting opioid therapy or escalating the dose, clinicians and patients should evaluate the benefits and harms. Continued evaluation should occur at least once every 3 months. If the benefits do not outweigh the harms of continued therapy, clinicians should work with the patient to lower the opioid dosage or discontinue opioid therapy.

8. Both before starting and during continuation of opioid therapy, clinicians should evaluate the patient’s risk factors for opioid-related harms.

Management plan strategies

© THINKSTOCK

CDC guideline: prescribing opioids for chronic pain

The CDC’s that can reduce risk should be incorporated into the patient’s guidelines pain management plan. are designed 9. Using state prescription drug to curb monitoring program data, opioid abuse.

clinicians should review the patients’ history of controlled substance prescriptions to monitor whether they are receiving opioid dosages or drug combinations that put them at a high risk for overdose.

10. Before starting opioid therapy, patients should undergo urine drug testing to test for prescribed medications, controlled prescription drugs, and illicit drugs. Clinicians should consider urine testing for patients using opioid therapy at least annually to reassess.

11. Whenever possible, clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently.

12. For patients with opioid use disorder, clinicians should offer or arrange evidence-based treatment. u Please view more complete coverage of this topic at www.ClinicalAdvisor.com

16 THE CLINICAL ADVISOR • APRIL 2016 • www.ClinicalAdvisor.com

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Newsline Predictors of mortality and diabetes risk

INCREASED BODY fat percentage is associated with a higher risk of all-cause mortality, regardless of BMI, according to a study published in the Annals of Internal Medicine. In a second study, researchers found that young people who are not physically fit have an increased risk of developing type 2 diabetes later in life, regardless of body weight.

The first study, led by Raj Padwal, MD, MSc, included 49,476 women and 4,944 men aged

Increasing body fat, and not BMI, is a primary risk factor for death.

≥40 years who had been referred for bone mineral density testing.

During a median of 6.7 years, 4,965 women died, and over a median of 4.5 years, 984 men died.

The researchers found that high body fat percentage and low BMI were associated with increased mortality in women and men.

“Body mass index is widely used as a proxy for adiposity even though it more closely reflects lean mass than fat mass,” the researchers wrote. “Increasing BMI may therefore ref lect higher fitness levels, greater metabolic reserve, and less cachexia — factors that are associated with greater survival — rather than increasing fat.”

The second study, led by Casey Crump, MD, PhD, included 1,534,425 male military conscripts from 1969 to 1997 with no prior diagnosis of type 2 diabetes. Every participant was aged 18 years at the

time of the examination. Aerobic capacity was measured in watts, and muscle strength was measured in newtons per kilogram of body weight.

During 39.4 million person-years of follow-up, 34,008 participants (2.2%) were diagnosed with type 2 diabetes. Both low aerobic capacity and muscle strength were independently associated with an increased risk of developing type 2 diabetes.

After 20 years of follow-up, the absolute difference in cumulative incidence of type 2 diabetes between the lowest and highest tertiles of aerobic capacity and muscle strength was 0.22%; this increased to 0.76% at 30 years and 3.97% at 40 years. The combination of low aerobic capacity and low muscle strength had the highest associated risk for type 2 diabetes (hazard ratio 3.07), even among participants with a normal BMI.

FOR PATIENTS with chronic obstructive pulmonary disorder (COPD) who have been previously hospitalized, the rates of rehospitalization or readmission for COPD do not differ between patients treated by physicians or those treated by nurse practitioners/ physician assistants, according to a study published in PLoS ONE. There were some differences both in how patients were treated and their outcomes depending on whether they were treated by a physician or NP/PA. NPs/PAs were more likely to prescribe patients short-acting

bronchodilator (adjusted odds ratio [aOR] = 1.18) or oxygen therapy (aOR = 1.25), and they were more likely to refer patients to a pulmonologist (aOR = 1.39).

However, NPs/PAs were less likely to administer influenza vaccines (aOR = 0.67) or pneumonia vaccines (aOR = 0.80) to patients Compared with patients treated by physicians, patients treated

by NPs/PAs had lower rates of emergency room visits for COPD (aOR = 0.84), as well as a higher follow-up rate with a pulmonologist within 30 days of hospitalization (aOR = 1.25).

Patients treated by NPs/PAs had fewer ER visits for COPD.

For their primary care, 1,999 patients saw PAs/NPs, and 5,238 saw physicians. Patients who saw PAs or NPs were more likely to be white, younger, male, living in non-metropolitan areas, and have fewer comorbidities.

“It is estimated that [NPs and PAs] could provide care for 50% to 90% of patients presenting to primary care,” the researchers wrote. “With the increasing number of [NPs and PAs] as primary care providers, they will be more likely to be called upon to manage patients with such chronic conditions as COPD.”

©THINKSTOCK

COPD treatment by NPs/PAs versus physicians

18 THE CLINICAL ADVISOR • APRIL 2016 • www.ClinicalAdvisor.com

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Newsline Definitions for Greater gluten intake before age 2 sepsis, septic may increase risk of celiac disease for tTGA reported a larger intake INCREASED consumption of shock issued of gluten before seroconversion gluten increases the risk of celiac disease at least twofold in genetically susceptible children until age 2 years, according to research published in the March 2016 issue of Clinical Gastroenterology and Hepatology.

Senior author Daniel Agardh, MD, PhD, and colleagues studied 146 cases of Swedish children at genetic risk for celiac disease in 436 case-control pairs matched for sex, birth year, and human leukocyte antigen (HLA) genotype. There was no difference in duration of breastfeeding (median, 32 weeks) and age at first introduction to gluten (median, 22 weeks) between cases and controls who tested negative for tissue transglutaminase (tTGA) autoantibodies. Patients positive

Gluten may boost celiac disease risk in children until age 2 years.

than did controls.

“In this nested case-control study, we showed that a high overall intake of gluten during the first 2 years of life, and in particular at 12 months of age, was associated with an increased risk for celiac disease during childhood,” the authors wrote. “More importantly, this association did not differ between children at very high or increased genetic risk for the disease; a high quantity of gluten still was associated with celiac disease in children with no, 1, or 2 copies of the major celiac disease risk HLA-DR3-DQ2 haplotype.

These findings may contribute to a better understanding of why some, but not all, children at genetic risk develop celiac disease.”

Testosterone treatment beneficial in older men RAISING TESTOSTERONE levels for 1 year in men aged 65 years or older from moderately low to the middle of the range that is considered normal in younger men showed benefit in sexual function, walking, and mood, according to research published in the February 18 issue of the New England Journal of Medicine.

Lead author Peter J. Snyder, MD, and fellow investigators studied the effect of testosterone gel or placebo gel applied for 1 year on 790 men aged 65 years or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism. Each of the men had participated in the Sexual Function

Trial, the Physical Function Trial, and the Vitality Trial, or a combination of these. The researchers found that testosterone treatment increased serum testosterone levels to the mid-normal range for men aged 19 to 40 years and was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire, and significantly increased sexual desire and erectile function. Walking only improved significantly when men in all three trials were included (20.5% of those on testosterone vs. 12.6% of those on placebo). Men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. n

© THINKSTOCK

CONSENSUS definitions for sepsis and septic shock have been revised for the first time since 2001 and published jointly by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine in the February 23 issue of JAMA. • Sepsis should be defined as lifethreatening organ dysfunction caused by a dysregulated host response to infection.

• For clinical operationalization, organ dysfunction can be represented by an increase in the SOFA score of 2 points or more.

• Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone.

• Septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia.

• Adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes if they have at least 2 of the following criteria in a new score called quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less.

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FEATURE: SARAH LUND AND MAURA HOLCOMB, MD

Infantile hemangiomas: managing complications Although usually benign, some infantile hemangiomas have complications that are potentially fatal or physically debilitating if untreated.

Hemangiomas grow during the first year of life and then recede over time.

I

nfantile hemangiomas are common benign tumors that occur in childhood, and it is important for clinicians who work with children to be familiar with methods of identifying these lesions. Although the patient’s caretakers may be concerned about them, many infantile hemangiomas resolve without treatment and complications. When complications do arise, it is important for healthcare providers to know how to recognize them and to be aware of the treatment options available.

Infantile hemangiomas may appear as erythematous lesions or tumors on the body, but they are often seen on the head and neck.1,2 The diagnosis is based mainly on clinical findings.3,4 Infantile hemangiomas occur most often in female or white infants.2 Factors that may predispose infants to the development of hemangiomas are low birth weight and premature birth.4 In most cases, there is no past family history of infantile hemangiomas, although in rare cases, they are associated with a hereditary condition.3,5 Phases and subtypes

There are three different phases observed in infantile hemangiomas. The proliferative phase can occur between 2 to 3 weeks and 5 to 9 months after birth. In this phase, the infantile hemangioma can grow very quickly and may be noncompressible.1,3 Within 5 months, 80% of the growth of the hemangioma is completed, and after approximately 9 months, most hemangiomas are fully developed.1,4 Next is the plateau phase, in which slight variation in the 24 THE CLINICAL ADVISOR • APRIL 2016 • www.ClinicalAdvisor.com

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infantile hemangioma can be observed. The final stage, or involutional phase, occurs between age 1 year and 5 to 10 years. The infantile hemangioma becomes more compressible, and the original erythematous lesion may acquire a purple or gray tone.4 Infantile hemangiomas often regress; however, fibrofatty or scar tissue may remain.3,6 The three clinical subtypes of infantile hemangiomas are superficial, deep, and mixed.2 Superficial hemangiomas are located in the upper portion of the dermis and can appear erythematous. Deep hemangiomas may appear as purple or flesh-colored protuberances and are located in the lower portion of the dermis or in subcutaneous tissue.3 Mixed hemangiomas may combine features of superficial and deep hemangiomas.1,4 Hemangiomas may also be described according to their distribution on the skin. Localized hemangiomas appear more focal, with a round shape, whereas segmented hemangiomas cover a large area and are more likely to ulcerate and cause complications.2,7 Complications

Most infantile hemangiomas do not cause complications or require therapy.3 If the hemangioma is potentially fatal, affects the patient’s ability to function, or is physically deforming, then therapy is warranted.4 Complications that may be observed in patients with infantile hemangiomas are ulcers, infections, bleeding, visceral issues, vision problems, and difficulty breathing.1,3 Ulcers are the most frequently observed complication of infantile hemangiomas.3 Ulcers can cause pain, difficulty eating, and infections. Locations where ulcers commonly develop from infantile hemangiomas are the lower lip, neck, genital and anal areas, and regions of the body where apposed skin surfaces may rub against each other.3,4 If an infection develops, a culture may be required, followed by the administration of appropriate antibiotics. Pulsed dye laser can also be used to treat ulcers that are a complication of infantile hemangiomas.1,3 Vision may also be affected; periorbital infantile hemangiomas most often lead to astigmatism.4 Amblyopia may occur, resulting in blindness, and exophthalmos can arise if an infantile hemangioma is located in the posterior region of the eye.3 An ophthalmologist should be consulted when a patient has a periorbital infantile hemangioma, and therapy should be considered if needed.1,3 A beta-blocker, such as oral propranolol, may be useful for treating periorbital hemangiomas associated with astigmatism, causing them to involute.4 Difficulty breathing may develop if an airway is obstructed by an infantile hemangioma. Respiratory difficulty may become apparent when the patient is aged between 6 and

FIGURE 1. Factors that may predispose infants to the development of hemangiomas are low birth weight and premature birth.

12 weeks. An airway hemangioma may manifest as coughing or stridor.1 For patients with airway hemangiomas, it is necessary to consult an otolaryngologist, and a coordinated medical team should treat this condition.3 Hemangiomas may develop in the viscera. If a patient has 5 or more skin hemangiomas, then an ultrasound should be performed to check for hepatic and other visceral involvement. Heart failure may arise in patients with hepatic hemangiomas.1,3 Hemangiomas in the lumbosacral region may be associated with spinal dysraphism, and magnetic resonance imaging may be required in these cases.3 A patient may have multiple hemangiomas, although multiple hemangiomas on the skin are found in only approximately 30% of cases.1 Treatment

In most cases, infantile hemangiomas do not require therapy unless they are causing complications. The choice of

Quick facts about infantile hemangiomas • They often occur in female or white infants.

• They frequently appear on the head and neck.

• Infantile hemangiomas evolve through a proliferative phase, a plateau phase, and an involutional phase.3 • Some types of infantile hemangiomas are cutaneous, periorbital, hepatic, lumbosacral, and airway.

• Treatments for the complications of infantile hemangiomas include propranolol, corticosteroids, laser therapy, and surgery.

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INFANTILE HEMANGIOMAS: MANAGING COMPLICATIONS

POLL POSITION

When treatment is required for infantile hemangiomas, which of the following do you most frequently recommend? n=704

■ Oral propranolol

34.66% 48.72%

■ Oral corticosteroids ■ Other

16.62%

For more polls, visit ClinicalAdvisor.com/Polls.

treatment may be based on the age of the patient, as well as the size, depth, and stage of the hemangioma.4,7 The treatments currently used for infantile hemangiomas are propranolol, off-label medications, laser therapy, and surgery.1,3 Oral propranolol is now approved by the US Food and Drug Administration as a treatment for infantile hemangiomas and may work more quickly than steroids.2,8 It is important to try to treat complicated infantile hemangiomas during the proliferative phase to prevent expansion and allow regression to take place.5 Beta-blockers, such as propranolol, are used to treat infantile hemangiomas and have been shown to stop expansion and result in regression of the lesions.1,5 Oral propranolol can lead to involutional changes in skin infantile hemangiomas and can alleviate stridor due to airway hemangiomas. In some cases, skin infantile hemangiomas may fully involute within 6 months of propranolol use.5 Propranolol may cause severe side effects, such as bradycardia and hypoglycemia.1,3 Therefore, it is best to administer propranolol when an infant feeds, and it is important for caregivers to be aware of indications of hypoglycemia in infants and know how to respond.3 A cardiology consult should be obtained and the patient’s electrocardiogram, vital signs, and serum glucose level should be evaluated before beta-blockers are administered to determine if they are appropriate for the patient.7 Topical beta-blockers can also be used for superficial cutaneous infantile hemangiomas. In particular, topical timolol appears to be helpful in resolving some small skin infantile hemangiomas by decreasing erythema and causing involution.5,8 Although timolol is recommended for some patients with

cutaneous infantile hemangiomas, the safety of its use over time for this condition is still not fully known, and therefore caution is advised.5 Before oral propranolol, oral corticosteroids were commonly used to treat infantile hemangiomas. Corticosteroids help to prevent infantile hemangiomas from expanding but may not lead to full involutional changes.1,5 Corticosteroids also cause side effects, such as cushingoid characteristics, stunted growth, and immune system suppression, which may increase the risk for infections.3,7 Often, growth that is lost during corticosteroid treatment is regained once the corticosteroids are stopped.3 Intralesional corticosteroids have been used to treat infantile hemangiomas on the head and neck, and topical corticosteroids have been administered for localized superficial hemangiomas.6 Vincristine has been used to treat infantile hemangiomas unresponsive to corticosteroid treatment.3,7 Propranolol is a more common drug of choice for infantile hemangiomas than vincristine; however, vincristine is preferred to interferon alfa.7 Side effects of vincristine are constipation, pain in the abdominal region, and foot drop due to toxic effects of the drug on the nervous system.1,3 Interferon alfa has been used to treat infantile hemangiomas; however, it has severe side effects, such as neurotoxicity and spastic diplegia.3,4 Recommendations in the literature regarding the use of interferon alfa for infantile hemangiomas are variable. Some authors recommend interferon alfa for infants older than 1 year with infantile hemangiomas that are potentially fatal or unresponsive to treatment and who receive close neurological monitoring, whereas others advise against the use of interferon alfa for infantile hemangiomas.1,3,4,7 Pulsed dye laser is the most frequently used laser for treating infantile hemangiomas, especially those that Continues on page 29

Complications of infantile hemangiomas • Bleeding • Difficulty breathing • Infections • Ulcers • Visceral issues • Vision problems

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INFANTILE HEMANGIOMAS: MANAGING COMPLICATIONS

ulcerate.3,4,8 This laser therapy is used to treat superficial infantile hemangiomas, and multiple treatments may be required.4,7 Pulsed dye laser may diminish the pain caused by ulcerated infantile hemangiomas. 3 However, scars, hypopigmented skin, and even ulcers may result from pulsed dye laser treatment.1,3,4 Surgery is a useful therapy for deep infantile hemangiomas and can remove excess fibrofatty tissue and scarring.1,4 A risk of surgery is bleeding; however, new techniques may prevent this complication.7 Surgery can also treat infantile hemangiomas if drug therapy is unsuccessful or the infantile hemangioma is potentially fatal or deforming. Surgery is used to treat airway and periorbital hemangiomas.3,7 Conclusions

Infantile hemangiomas are benign lesions that commonly affect children and are generally diagnosed based on clinical findings. They are often found on the head and neck.

Many of them resolve without treatment; however, complications may arise, including ulcers, infections, bleeding, visual problems, difficulty breathing, and visceral issues.

Depending on the complication, propranolol, corticosteroids, vincristine, interferon alfa, laser therapy, and surgery may be therapeutic options. n

“Dumbledore smiled, his eyes twinkling.”

Sarah Lund is a medical student at University of Texas Medical School at Houston, and Maura Holcomb, MD, is a resident at Baylor College of Medicine in Houston.

References 1. Holland KE, Drolet BA. Infantile hemangioma. Pediatr Clin North Am. 2010;57(5):1069-1083. © The New Yorker Collection 2016 from cartoonbank.com. All Rights Reserved.

2. Hartzell LD, Buckmiller LM. Current management of infantile hemangiomas and their common associated conditions. Otolaryngol Clin North Am. 2012;45(3):545-556.

3. Kwon EK, Seefeldt M, Drolet BA. Infantile hemangiomas. Am J Clin Dermatol. 2013;14(2):111-123.

4. Callahan AB, Yoon MK. Infantile hemangiomas: a review. Saudi J Ophthalmol. 2012;26(3):283-291.

5. Lee KC, Bercovitch L. Update on infantile hemangiomas. Semin Perinatol.

2013;37(1):49-58.

6. Craiglow BG, Antaya RJ. Management of infantile hemangiomas: current and potential pharmacotherapeutic approaches. Paediatr Drugs.

2013;15(2):133-138.

7. Fay A, Nguyen J, Waner M, Conceptual approach to the management of infantile hemangiomas. J Pediatr. 2010;157(6):881-888.

8. Reddy KK. Management of infantile hemangiomas. J Cutan Aesthet Surg.

2014;7(2):85-86.

“I love the convenience, but the roaming charges are killing me.”

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FEATURE: JILL NORRIS WHITE, RN, BSN, CMSRN

Medical nutrition therapy in diabetes Developing personalized nutrition goals with a registered dietitian can be effective in managing non–insulin-dependent diabetes.

© ISTOCK

A

Medical nutrition therapy helps patients better manage their diabetes.

lthough type 2 diabetes is preventable, its prevalence and incidence are rapidly increasing in the United States and worldwide.1 Currently, more than 5.4% of adults worldwide have a diagnosis of diabetes, and an estimated 300 million will have diabetes by 2025.2 In 2012, the American Diabetes Association estimated the total cost of diabetes in the United States to be $245 billion, compared with $174 billion in 2007—a 41% increase over this 5-year period. People who have a diagnosis of diabetes spend approximately $13,700 per year on medical expenses, with $7,900 of that going toward diabetes management.3 To reduce medical complications and optimize blood glucose control, medications are only part of the solution. Clinicians and patients must work together to change behaviors that lead to subsequent problems of uncontrolled blood glucose levels.2 With no cure available for diabetes, primary prevention through diet and exercise is important.1 According to Bantle et al4, medical nutrition therapy is a crucial component of glycemic control to help manage existing diabetes and prevent or slow the rate of complications of the disease. Medical nutrition therapy in diabetes is based on an assessment of the patient’s nutrition status; it consists of diabetes self-knowledge, individually identified and designed nutrition goals, meal planning that is flexible for the patient and easily implemented, and last, the evaluation of outcomes to ascertain if further changes are needed.5 The Institute of Medicine

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found that medical nutrition therapy improves clinical outcomes and decreases the cost of managing diabetes.5 The purpose of this review is to examine the literature on the benefits of medical nutrition therapy as part of controlling diabetes and preventing complications, which in turn can reduce the overall costs of diabetes care.

Search strategy

To search specifically for articles on medical nutrition therapy in patients with type 2 diabetes, two databases were used: CINAHL (Cumulative Index of Nursing and Allied Health Literature) and PubMed. The terms used for the CINAHL search were diabetes type 2 interventions and diabetic medical nutrition therapy; for the PubMed search, they were diabetes type 2, interventions, medical nutrition therapy, cost-analysis, and nutrition therapy. MeSH (Medical Subject Headings) terms used were diabetes mellitus type 2 and nutrition therapy. The CINAHL search yielded one relevant article, and the PubMed search 223 articles. The PubMed search was most useful after it had been narrowed to include only randomized controlled trials and systematic reviews; 63 relevant articles were then found based on title and publication date. After a review of information in the abstracts, 11 articles were chosen, and following further narrowing to focus specifically on medical nutrition therapy in diabetes, four studies remained for detailed review.

Literature review

In a randomized controlled trial, Franz F et al6 focused on the cost-effectiveness of medical nutrition therapy for patients with non–insulin-dependent diabetes. Participants received either medical nutrition therapy based on practice guidelines or basic nutrition therapy. Therapy consisted of three visits with a dietitian. The basic nutrition group met with a dietitian once and collaborated with a physician to formulate a nutrition care plan. The outcome defining cost-effectiveness was the effect of medical nutrition therapy on glucose control, which was determined by measuring the fasting blood sugar and hemoglobin A1C levels after 6 months. As the hemoglobin A1C decreases as a result of dietary restrictions, insulin sensitivity increases; therefore, less medication is needed to control blood glucose. The medical nutrition therapy group had medication cost savings of $31.49 per year, whereas the basic nutrition group had savings of $3.13.6 A randomized controlled trial by Franz MJ et al7 assessed the effects of medical nutrition therapy on patients with a new diagnosis of non–insulin-dependent diabetes. Patients were placed into two groups, with the first receiving medical

nutrition therapy and the second receiving only basic nutrition therapy from a dietitian. The main difference between the groups was the intensity of the dietary instruction by the dietitians. The authors tracked glucose control in both groups. The group receiving medical nutrition therapy had significantly better glycemic control than the basic nutrition group. An indirect finding of the study was that patients who had had diabetes for a longer period of time benefited more from intense medical nutrition therapy than did those with newly diagnosed diabetes.7 A clinical trial by Johnson and Valera8 evaluated the use of medical nutrition therapy in primary care for patients with non–insulin-dependent diabetes. The patients had at least three visits with a registered dietitian, and each time they were seen in the office, a random finger stick was done to check the blood sugar. Within 2 weeks, a 41% decrease in the blood sugar level was observed in 14 of 21 patients. At the end of the study, the blood sugar levels were 50% lower in 16 of the 21 patients.8 Pastors et al9 reviewed randomized controlled trials, observational studies, and meta-analyses of studies of medical nutrition therapy in patients with diabetes. The authors found that medical nutrition therapy was successful in obtaining better glycemic control, if dietitians follow clinical guidelines in managing patients with diabetes. In order for patients to benefit from medical nutrition therapy, they should be seen and followed by a dietitian. Patients should be seen 6 weeks after their initial consultation to determine

Recommendations for providers • Do not manage diabetes with medications alone.

• Refer patient to registered dietitian with knowledge of diabetes. Allow dietician access to patient’s labs and medications.

• Medical nutrition therapy should be initiated for patients classified in the pre-diabetic range to prevent diabetes.

• Insurance covers dietary counseling for diabetes management in those diagnosed with diabetes.

• Monitor hemoglobin A1C throughout dietary changes.

As nutrition improves, less medication may be needed to control blood glucose.

• To provide the patient with incentive to see a registered dietician, suggest cost-savings and discontinuation of some diabetic medications as potential benefits.

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MEDICAL NUTRITION THERAPY

A registered dietitian with experience in diabetes management is needed to counsel patients on the appropriate dietary changes. their progress and make changes if needed. After 6 weeks to 3 months, the changes in the hemoglobin A1C level should be notable, and adjustments to diet and/or medication can be made at that time.9 Findings from these studies suggest strong evidence for using medical nutrition therapy to achieve better glycemic control. A registered dietitian with experience in diabetes management is needed to counsel patients on the appropriate dietary changes. Dietitians must have access to patients’ laboratory data in order to track their progress, and they must collaborate with providers to make changes to medications when necessary. Dietitian interventions that follow clinical practice guidelines enable patients to achieve better metabolic control. This saves them the cost of medication therapy and prevents the early pancreatic burnout that leads to insulin-dependent diabetes. These studies show that medical nutrition therapy administered by a registered dietitian is beneficial for patients with non–insulin-dependent diabetes.

4. Bantle JP, Wylie-Rosett J, Albright AL, et al; American Diabetes

Implications for practice

All electronic documents accessed March 9, 2016.

Association. Nutrition recommendations and interventions for diabetes: a position statement of the American Diabetes Association. Diabetes Care.

2008:31 Suppl 1:S61-S78.

5. Pastors JG, Warshaw H, Daly A, Franz M, Kulkarni K. The evidence for the effectiveness of medical nutrition therapy in diabetes management.

Diabetes Care. 2002;25(3):608-613.

6. Franz F, Splett P, Monk A, et al. Cost-effectiveness of medical nutrition therapy provided by dietitians for persons with non-insulin-dependent diabetes mellitus. J Am Diet Assoc. 1995;95(9):1018-1024.

7. Franz MJ, Monk A, Barry B, et al. Effectiveness of medical nutrition therapy provided by dietitians in the management of non–insulin-dependent diabetes mellitus. J Am Diet Assoc. 1995;95(9):1009-1017.

8. Johnson EQ, Valera S. Medical nutrition therapy in non-insulindependent diabetes mellitus improves clinical outcome. J Am Diet Assoc.

1995;95(6):700-701.

9. Pastors JG, Franz MJ, Warshaw H, Daly A, Arnold MS. How effective is medical nutrition therapy in diabetes care? J Am Diet Assoc.

2003;103(7):827-831.

Jill Norris White, RN, BSN, CMSRN, is a certified medical surgical registered nurse working in a digestive disease unit at the Medical University of South Carolina (MUSC). She currently is a student in MUSC’s Doctor of Nursing Practice Program and will graduate in May 2016.

References 1. Hu FB, Liu S, van Dam RM. Diet and risk of type II diabetes: the role of types of fat and carbohydrate. Diabetologia. 2001;44(7):805-817.

2. Johnson W, Shaya FT, Winston R, et al. Diabetes control through an educational intervention. Ethn Dis. 2014:24(2):182-188.

3. The cost of diabetes. American Diabetes Association Web site. http:// www.diabetes.org/advocacy/news-events/cost-of-diabetes.html. Edited June 22, 2015.

© The New Yorker Collection 2016 from cartoonbank.com. All Rights Reserved.

The findings of this review can inform providers on the benefits of using medical nutrition therapy to manage patients with non–insulin-dependent diabetes. Collaborating with a registered dietitian who has experience in diabetes management can allow patients to achieve better glycemic control, thus reducing the medications taken and saving costs. Future studies are necessary to determine if medical nutrition therapy can delay or prevent pre-diabetes from developing into type 2 diabetes. n

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CME CE FEATURED COURSE

n EDUCATIONAL OBJECTIVES After participating in this activity, practitioners should be better able to: • Identify the clinical relevance of ongoing research on treatment approaches to Alzheimer’s disease (AD) • Initiate measures intended to delay or slow the progression of AD in patients who may be at risk or are exhibiting signs suggesting early disease • Identify resources and strategies to provide a continuum of care for patients and their caregivers while patients are in the early stages of, or at risk for, AD n COMPLETE THE POST-TEST: Page 48

Maximum Credits: 0.50 AMA PRA Category 1 CreditTM Release Date: August 28, 2015 Expiration Date: December 31, 2016 Accredited Provider: This activity is provided by Albert Einstein College of Medicine of Yeshiva University in collaboration with Haymarket Medical Education (HME).

Commercial Supporter: This activity is supported by an educational grant from Lilly.

INC Research, Lundbeck, MedAvante, Medivation, Inc., Merck & Co., Inc., Novartis, Pfizer, Prana Biotechnology, QR Pharma, Roche, Sanofi-Aventis, Schering-Plough, Taisho Toyama Pharmaceutical Co., Takeda, and UCB. He also serves on the speakers’ bureaus for Eisai, Eli Lilly, Forest, Pfizer, and Novartis and has received grant/research support from Accera, Biogen, Chase Pharmaceuticals, Eisai, Eli Lilly, Genentech, Lundbeck, and Roche. Dr. Farlow has a patent that is licensed to Elan.

Program Description: An older patient who complains of occasional forgetfulness but is otherwise able to function normally may be an example of the “worried well” or may in fact be in an early stage of Alzheimer’s disease (AD).

Current research suggests that early intervention aimed at slowing symptom progression may be more successful than later attempts to treat individuals who are already experiencing more significant cognitive deficits.

Planners’ and Managers’ Disclosures: Jill Rovitzky Black, Margot Embree Fisher, and Sarah Taegder of Haymarket Medical Education have nothing to disclose with regard to commercial support.

Intended Audience: Neurologists and other healthcare professionals who provide care for patients with or at risk for AD and related dementias Conflict of Interest Disclosure Policy: It is the policy of Albert Einstein College of Medicine of Yeshiva University to ensure balance, independence, objectivity, and scientific rigor in all its educational activities. All faculty participating in our programs are expected to disclose any relationships they may have with commercial companies whose products or services may be mentioned, so that participants may evaluate the objectivity of the presentations. In addition, any discussion of off-label, experimental, or investigational uses of drugs or devices will be disclosed by the faculty.

Accredited Provider Disclosure: The staff of the Center for Continuing Medical Education of Albert Einstein College of Medicine of Yeshiva University has no disclosures to report with any commercial interests relative to this CME activity.

Accreditation Statement: Albert Einstein College of Medicine of Yeshiva University is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Designation Statement: Albert Einstein College of Medicine of Yeshiva University designates this enduring activity for a maximum of 0.50 AMA PRA Category 1 CreditTM. Physicians should claim only credit commensurate with the extent of their participation in the activity.

Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Lilly, Albert Einstein College of Medicine of Yeshiva University, and Haymarket Medical Education do not recommend the use of any agent outside of the labeled indications.

Faculty Course Director Victor B. Hatcher, PhD Professor of Medicine and Biochemistry Montefiore Medical Center, Bronx, NY

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Eli Lilly, Albert Einstein College of Medicine of Yeshiva University, or Haymarket Medical Education. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Peer Reviewer Gary Kennedy, MD Professor of Psychiatry Montefiore Medical Center, Bronx, NY

Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Bradford C. Dickerson, MD Associate Professor of Neurology, Harvard Medical School Director of Clinical Applications, Morphometry Service Director, Frontotemporal Disorders Unit Massachusetts General Hospital Co-Director, Neuroimaging Group, Gerontology Research Unit, Boston, MA Martin R. Farlow, MD Professor and Vice Chairman of Research, Department of Neurology Associate Director, Indiana Alzheimer Disease Center Indiana University School of Medicine, Indianapolis, IN Faculty Dislosures: Dr. Hatcher has nothing to disclose.

Dr. Kennedy has received grant/research support from Lilly.

Dr. Dickerson received royalties from Oxford University Press for the book Dementia: Comprehensive Care and Practice, and he is a consultant to Merck, FORUM Pharmaceuticals, and Isis Pharmaceuticals.

Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period August 28, 2015 through December 31, 2016, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the pre-assessment test online; 3) study the educational activity; 4) complete all polling questions online; 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 myCME.com/April16CAfeature.

Provided by

In collaboration with

Dr. Farlow serves as a consultant for Accera, Alltech, Avanir, Biogen, Eisai Medical Research, Inc., Eli Lilly, FORUM Pharmaceuticals, GliaCure, Grifols, Helicon,

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CME FEATURED COURSE: VICTOR B. HATCHER, PHD; GARY KENNEDY, MD; CE BRADFORD C. DICKERSON, MD; MARTIN R. FARLOW, MD

A 75-year-old woman with complaints of forgetfulness An older patient with occasional forgetfulness may be an example of the “worried well”—or is an early stage of Alzheimer’s disease present?

A

ccording to projections commissioned by the Alzheimer’s Association, if a treatment to delay the onset of Alzheimer’s disease (AD) by just 5 years became available in 2025, the proportion of Americans aged 65 years and older with AD would be reduced from 11% to 8% by 2030, representing an estimated $83 billion savings in the cost of care.1 This case explores emerging concepts undergoing research with the goal of developing approaches to promote healthy brain aging and, potentially, delay AD-related functional decline.

© THINKSTOCK

Case introduction

Alzheimer's disease, neurons with amyloid plaques.

Ms. Weitzel is a vigorous, well-kempt 75-year-old retired social worker who presents to her primary care clinician for a routine evaluation. Although she says that she has been in very good health, Ms. Weitzel explains that her real reason for making the appointment is that she is afraid she may be developing AD because she has become increasingly forgetful.

On questioning about her daily activities, Ms. Weitzel reveals that, in addition to spending time with her grandchildren, she is very active in her suburban community. She lives by herself in a seniors-only condominium community where she takes care of all her own shopping and housekeeping chores. She gets regular exercise, either walking or swimming at least 4 days a week. She volunteers as “reading buddy” once a week at the local elementary school and organizes seasonal www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2016 41

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CME CE

FEATURED COURSE

It is important to assess clinical status, identify any risk factors for AD or other dementia syndromes, and address potentially reversible conditions. fund-raisers for her house of worship. However, she complains that she is constantly forgetting the names of the children at school and has misplaced important paperwork, including financial records.

Ms. Weitzel is very worried that her forgetfulness is an early sign of AD. She reports that both her parents, who lived into their late 80s, “went gaga” as they got older, although they both lived independently until their deaths from heart disease and stroke, respectively. She also related the story of a close friend who developed AD dementia some years ago and was recently admitted to a residential facility because her family could no longer manage her care. Ms. Weitzel says she wants to “take something” to prevent AD so she does not end up being a burden to her own children.

Detailed questioning reveals no depressive symptoms other than substantial anxiety about aging and cognitive decline. Ms. Weitzel reports no sleep disturbances, and the only medications she is taking are atenolol for hypertension and atorvastatin for hyperlipidemia, both of which are well controlled. In addition, she is taking several over-thecounter vitamins and herbal supplements, including ginkgo biloba, B12, folate, and alpha-lipoic acid, which she has read will protect her from AD. She also plays computer-based “brain training” games.

Diagnostic workup

The first step in the evaluation of a patient with memory concerns is a diagnostic assessment, since there are a number of conditions that may cause or contribute to memory impairment.2 In Ms. Weitzel’s case, her complaints seem suggestive of the mild memory difficulties that are common in many older adults. Nevertheless, it is important to assess her current clinical status, identify any risk factors for AD or other dementia syndromes, and address any potentially reversible medical or neuropsychiatric conditions.

The history reveals that Ms. Weitzel is a nonsmoker with no history of drug or alcohol abuse. She denied concerns regarding orientation in space or time, judgment, or problem solving or an impact of her memory difficulties on routine activities at home or in the community. It is often invaluable to obtain additional history through the perspective of someone who knows the patient well, since in some cases a person’s insight may be compromised and they may underestimate the problem. She gave permission for a phone call with a friend who knows her well, and the

friend agreed that the patient has mild forgetfulness that does not appear to be substantially impacting her daily function.

Ms. Weitzel is not found to have any laboratory abnormalities (eg, thyroid function, vitamin B12) that might contribute to her self-reported perception of memory and cognition problems. A brief structured interview for depression using the Geriatric Depression Scale produced a low score consistent with no depression. After additional discussion with her physician, they together opt for comprehensive neuropsychological testing, which reveals no overt objective deficits that would be consistent with a diagnosis of mild cognitive impairment (MCI). She demonstrates high average intellectual abilities and performs within expectations on all measures compared with others her age. Her Mini-Mental State Examination (MMSE) score is 29/30, with 1 point lost on recall; her global Clinical Dementia Rating (CDR) scale score is 0; and scores on Wechsler testing (including Auditory Memory, Visual Memory, Visual Working Memory, Immediate Memory, and Delayed Memory) are all within normal limits.

Based on this assessment, Ms. Weitzel is told that she fits into a category of people referred to as having “subjective cognitive impairment” or “subjective cognitive concern,” a group that is currently a focus of research to try to identify those who might be in early preclinical stages of AD or other illnesses. There is evidence that people who are clinically normal but express concern over changes in their cognitive function are at increased for risk for AD.3 There is also evidence linking subjective cognitive symptoms to biomarkers of AD and subsequent development of MCI and dementia.4,5 The ongoing Subjective Cognitive Decline Initiative, begun in November 2012, aims to better define and characterize the concept and encourage further research in this area.6 Role of biomarkers

AD biomarkers, which comprise a variety of physiological, biochemical, and anatomic parameters that can be measured in vivo, play a fundamental role in our current understanding that there appear to be 3 major phases of AD.7 When a person clearly has dementia, biomarkers can help establish the likelihood that an individual’s symptoms are due to AD or not due to AD. In many patients with a clinical history and examination consistent with typical AD dementia, a brain magnetic resonance imaging (MRI) scan with evidence of hippocampal and parietotemporal atrophy

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In patients with MCI but without dementia, biomarkers are often useful in raising or lowering a clinician's confidence in a prodromal AD diagnosis. would convince many clinicians that the likely diagnosis is AD. In contrast, some patients may have an unusual form of dementia or an unrevealing MRI and it may be valuable to obtain additional biomarkers, potentially including FDG-PET or spinal fluid measures of tau and amyloid.8 In patients with MCI who do not have dementia, biomarkers are often useful in raising or lowering a clinician’s confidence in the diagnosis of prodromal AD. In this setting, the presence of a positive amyloid biomarker (spinal fluid or amyloid imaging) and a positive marker showing neurodegeneration (hippocampal or temporoparietal atrophy on MRI or temporoparietal hypometabolism on FDG-PET) makes it highly likely that the patient’s MCI is due to underlying AD. Negative biomarkers indicate a low likelihood of MCI due to AD.9 In people with no symptoms or with memory concerns but no evidence of impairment on cognitive testing, biomarkers should be used exclusively to establish the presence of AD pathology in the context of research studies, including clinical trials of potential therapeutic drugs10,11 In people with evidence of preclinical AD, there are 3 stages that are being used in research10; the value of these stages

is not yet clear but they are the active subject of substantial research and are outlined in Table 1.

Biomarkers of amyloid-beta (Abeta [Aβ]) accumulation (ie, abnormal tracer retention on amyloid PET imaging and/or low CSF Abeta 42) become abnormal many years—even decades—prior to the development of noticeable clinical symptoms.7 By contrast, biomarkers of neuronal degeneration or injury tend to become apparent a shorter period of time before clinical symptoms first appear. The biomarkers of neurodegeneration include elevated CSF tau (both total and phosphorylated tau); decreased FDG uptake on PET in a specific topographic pattern involving the temporoparietal cortex; and atrophy on structural MRI in a specific topographic pattern involving medial, basal, and lateral temporal lobe, and medial and lateral parietal cortices.

The amyloid hypothesis posits that early brain deposits of Abeta initiate a cascade resulting in AD disease progression, with sequelae such as neuronal loss and eventual dementia.12 Approximately 30% of cognitively normal elderly people (ie, ≥65 years of age) meet neuropathologic criteria for AD; about the same percentage show amyloid positivity on PET

TABLE 1. Stages of preclinical Alzheimer’s disease

Stage

Description

Amyloid-beta (PET or CSF)

Markers of neuronal injury (tau, FDG, sMRI)

Evidence of subtle cognitive change

Stage 1

Asymptomatic cerebral amyloidosis

Positive

Negative

Negative

Stage 2

Asymptomatic amyloidosis + “downstream” neurodegeneration

Positive

Positive

Negative

Stage 3

Amyloidosis + neuronal injury + subtle cognitive/ behavioral decline

Positive

Positive

Positive

PET, positron emission tomography; CSF, cerebrospinal fluid; FDG, fluorodeoxyglucose (18F); sMRI, structural magnetic resonance imaging.

Adapted from Sperling RA, et al. Alzheimers Dement. 2011;7(3):280-292.

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Among Americans older than age 65, 1 in 9 has Alzheimer's disease, and about one-third of people 85 years of age and older have AD. imaging and CSF assays. The 30% figure also roughly corresponds to the prevalence of AD dementia approximately a decade later.7 A growing body of literature confirms that biomarkers of amyloid positivity indicate early AD.7,13-15 In addition, amyloid positivity in persons without dementia has also been shown to be associated with subtle memory loss and cognitive decline, as well as brain atrophy and mortality.16-19 Despite these very interesting research findings, the clinical significance of brain amyloid in a cognitively intact older adult is unclear; thus, consensus recommendations currently state that these markers should not be obtained in clinical practice as part of a risk assessment or similar effort.11 At this point, therefore, most clinicians would advocate that a patient like Ms. Weitzel should either consider enrolling in a clinical trial focused on early AD risk factors or continue with regular medical monitoring of her condition without additional diagnostic procedures or testing of biomarkers in routine clinical practice.

Considerations for management

It is reasonable for Ms. Weitzel to be concerned about her risk for developing AD. According to a 2015 report from the Alzheimer’s Association, some 5.3 million Americans currently have AD.20 Among Americans over the age of 65, 1 in 9 has AD, and about one-third of people 85 years of age and older have AD. Researchers, doctors, and other experts are working intensively to try to develop interventions that may one day delay or prevent the disease.

Ms. Weitzel’s desire for a preventive treatment also is understandable. Unfortunately, the 2 classes of medications currently approved to treat the cognitive symptoms of AD dementia—cholinesterase inhibitors and memantine—are each limited in efficacy and duration and are not considered useful in people without dementia. Other than that, she is already engaging in the kind of social and intellectual activities, as well as physical exercise, that have been associated with optimal cognitive function.21 Potentially preventive measures include the control of vascular risk factors (eg, midlife obesity, dyslipidemia, diabetes, high blood pressure, cigarette smoking, and cerebrovascular lesions).22-25 Cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) have been shown—in patients with mild to moderate AD dementia—to modestly improve or stabilize dementia symptoms for 6 to 12 months, but only in about

50% of those who use them.26 A Cochrane Review concluded that current cholinesterase inhibitors are efficacious for mild to moderate AD dementia, but there is essentially no evidence for a beneficial effect in people with MCI.27 In multiple prior studies of cholinesterase inhibitors in patients with MCI, a substantial portion of patients discontinued treatment due to adverse events (primarily nausea, vomiting, and diarrhea).28 Memantine is better tolerated in patients with AD dementia than cholinesterase inhibitors. It is approved for use in patients with moderate to severe AD dementia, has modest positive impact on cognition, and is associated with reducing incidence of agitation in those with AD dementia.29 Cholinesterase inhibitors and memantine are often prescribed in tandem, and evidence supports their use as complementary agents.30,31 A fixed-dose combination of memantine with the cholinesterase inhibitor donepezil was approved by the US Food and Drug Administration late in 2014.32 The observation that there is a period of time when patients are cognitively normal despite evidence of some AD pathology in their brain suggests a tantalizing “window of opportunity” for early intervention. Once symptoms emerge, significant damage has already been done.

The hope is that early treatment may slow or even arrest the progress of AD. There has been particular interest in immunotherapeutics, despite initially disappointing results in phase 3 studies of several highly anticipated experimental monoclonal antibody treatments in patients with AD dementia or prodromal AD. Case outcome

After being educated about her options, Ms. Weitzel decides to enroll in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s, or A4, study of solanezumab.33 She meets the inclusion criteria for the trial, which include age of 65 to 85 years, an MMSE score of 25 to 30, a global CDR scale score of 0, a Wechsler Logical Memory II score of 6 to 18, and evidence of brain amyloid pathology on PET scan.

Additional clinical trials with other immunotherapies, including active vaccination generating anti-Abeta antibodies using a DNA Aβ42 vaccine, are also on the horizon.10,13 As part of the A4 trial screening protocol, Ms. Weitzel undergoes florbetapir PET scanning after having been counseled about the study purpose and procedures, including the potential impact of disclosure of this information. She is told that she has evidence of brain amyloid pathology, with

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There will be a paradigm shift for practitioners to prioritize early intervention as opposed to just focusing on treating patients with established symptoms. tracer retention indicative of abnormal Abeta accumulation.

Ms. Weitzel understands that there is a 50-50 chance that she will receive a placebo rather than the active drug.

However, she is highly motivated to do whatever she can to reduce the potential impact of progressive impairment due to AD. She is also willing to discontinue any vitamins or herbal remedies that are exclusionary by the trial protocol.

Ms. Weitzel is particularly sensitive to the fact that any interventions that may delay the development of more substantial cognitive symptoms or AD dementia can exert a ripple effect, improving the quality not only of her own life, but also that of her grown children and their families.34-36 She recognizes from her own experience how family members and other caregivers of patients with AD are

Phase 3 Alzheimer’s disease trials: A selected list The following is a list of selected US-based Alzheimer’s disease intervention trials that are posted on ClinicalTrials.gov.

All are phase 3 trials described as open and recruiting participants and status was determined as of issue publication.

Consult ClinicalTrials.gov for updates to this list or to locate trials recruiting in other countries. In addition, the following websites can be used to locate relevant clinical trials that may be enrolling participants.

Efficacy and safety trial of MK-8931 in participants with prodromal Alzheimer’s disease (MK-8931-019) (APECS) • ClinicalTrials.gov Identifier: NCT01953601 • https://clinicaltrials.gov/ct2/show/NCT01953601

• Alzheimer’s Association TrialMatch http://www.alz.org/research/clinical_trials/find_clinical_ trials_trialmatch.asp • National Institute on Aging's Alzheimer’s Disease Education and Referral Center https://www.nia.nih.gov/alzheimers/clinical-trials

Efficacy and safety of MK-7622 as adjunct therapy in participants with Alzheimer’s disease (MK-7622-012) • ClinicalTrials.gov Identifier: NCT01852110 • https://clinicaltrials.gov/ct2/show/NCT01852110

RECRUITING Clinical trial of solanezumab for older individuals who may be at risk for memory loss • ClinicalTrials.gov Identifier: NCT02008357 • https://clinicaltrials.gov/ct2/show/NCT02008357

Computerized cognition testing in participants with mild Alzheimer’s disease (AD) treated with donepezil (MK-0000-318) • ClinicalTrials.gov Identifier: NCT02064920 • https://clinicaltrials.gov/ct2/show/NCT02064920

An efficacy and safety study of AZD3293 in early Alzheimer’s disease (AMARANTH) • ClinicalTrials.gov Identifier: NCT02245737 • https://clinicaltrials.gov/ct2/show/NCT02245737 Dose-finding study to evaluate safety, tolerability, and efficacy of E2609 in subjects with mild cognitive impairment due to Alzheimer’s disease (prodromal Alzheimer’s disease) and mild dementia due to Alzheimer’s disease • ClinicalTrials.gov Identifier: NCT02322021 • https://www.clinicaltrials.gov/ct2/show/NCT02322021 A study to evaluate safety, tolerability, and efficacy of BAN2401 in subjects with early Alzheimer’s disease • ClinicalTrials.gov Identifier: NCT01767311 • https://clinicaltrials.gov/ct2/show/NCT01767311

A study of crenezumab in patients with mild to moderate Alzheimer disease (AD) • ClinicalTrials.gov Identifier: NCT02353598 • https://clinicaltrials.gov/ct2/show/NCT02353598 A study of gantenerumab in patients with mild Alzheimer disease • ClinicalTrials.gov Identifier: NCT02051608 • https://clinicaltrials.gov/ct2/show/NCT02051608 Evaluation of the efficacy and safety of azeliragon (TTP488) in patients with mild Alzheimer’s disease (STEADFAST) • ClinicalTrials.gov Identifier: NCT02080364 • https://clinicaltrials.gov/ct2/show/NCT02080364

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Additional resources

2. Budson AE, Price BH. Memory dysfunction. N Engl J Med. 2005;352

The following websites provide comprehensive information and resources for clinicians, patients, families, and other caregivers, free of charge.

3. Kaduszkiewicz H, Eisele M, Wiese B, et al. Prognosis of mild cognitive

(7):692-699. impairment in general practice: results of the German AgeCoDe study.

Ann Fam Med. 2014;12(2):158-165.

4. Amariglio RE, Becker JE, Carmasin J, et al. Subjective cognitive com-

• National Institute on Aging's Alzheimer’s Disease Education and Referral Center https://www.nia.nih.gov/alzheimers

plaints and amyloid burden in cognitively normal older individuals.

• Alzheimer’s Association http://www.alz.org

den in a population-based study of cognitively normal elderly. Neurology.

• Alzforum http://www.alzforum.org

Neuropsychologia. 2012;50(12):2880-2886.

5. Mielke MM, Wiste HJ, Weigand SD, et al. Indicators of amyloid bur2012;79(15):1570-1577.

6. Jessen F, Amariglio RE, van Boxtel M, et al. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer’s disease.

Alzheimers Dement. 2014;10(6):844-852.

7. Jack CR Jr, Albert MS, Knopman DS, et al. Introduction to the recom-

subject to stress in multiple domains, including emotional, physical, and sometimes financial.34 Comprehensive AD care, therefore, includes support for families and caregivers, as well as for the patients themselves.

mendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):257-262.

8. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National

Summary: Changing paradigms for AD management

Institute on Aging–Alzheimer’s Association workgroups on diagnostic

Although we are still in the early stages of effective early detection and treatment, it is important for practitioners to understand how all these efforts will ultimately change the paradigm of AD care. Results of recent investigations suggest that improving or stabilizing symptoms in patients with established AD dementia may be considerably harder to achieve than preventing and slowing AD progression when symptoms are mild or not yet present. As AD experts shift their focus to targeting the prevention or delay of dementia and other aspects of AD, there will be a paradigm shift for practitioners to prioritize early intervention as opposed to just focusing on treating patients with established symptoms of the disease. New interventions and tools may reduce the prevalence and burden of AD. Today’s clinicians need to understand the direction of contemporary AD research, the rationales for early intervention, and how these translate into appropriate patient care now and in the future.

In addition, clinicians should be better prepared to help families and other caregivers manage the care of patients at any stage of AD. ■

9. Albert MS. Changes in cognition. Neurobiol Aging. 2011;32(suppl 1):S58-S63.

guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263-269.

10. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280-292.

11. Johnson KA, Minishima S, Bohnen NI, et al. Appropriate use criteria for amyloid PET. A report of the Amyloid Imaging Task Force (AIT), the Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the Alzheimer Association (AA). Alzheimers Dement. 2013;9(1):e1-e16.

12. Hardy J, Bogdanovic N, Winblad B, et al. Pathways to Alzheimer’s disease. J Intern Med. 2014;275(3):296-303.

13. Rosenberg RN. Defining amyloid pathology in persons with and without dementia syndromes. Making the right diagnosis. JAMA. 2015;313(19):1913-1914.

14. Jansen WJ, Ossenkoppele R, Knol DL, et al. Prevalence of cerebral amyloid pathology in persons without dementia. JAMA. 2015;313(19):1924-1938.

15. Ossenkoppele R, Jansen WJ, Rabinovici GD, et al. Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA. 2015;313(19):1939-1949.

16. Hedden T, Oh H, Younger AP, Patel TA. Meta-analysis of amyloid-

References

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1. Alzheimer’s Association. Changing the Trajectory of Alzheimer’s

2013;80(14):1341-1348.

Disease: How a Treatment by 2025 Saves Lives and Dollars. Chicago, IL:

17. van Harten AC, Visser PJ, Pijnenburg YA, et al. Cerebrospinal fluid

Alzheimer’s Association; 2015. http://www.alz.org/documents_custom/

Aβ42 is the best predictor of clinical progression in patients with subjec-

trajectory.pdf. Accessed August 10, 2015.

tive complaints. Alzheimers Dement. 2013;9(5):481-487.

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18. Vos SJ, Xiong C, Visser PJ, et al. Preclinical Alzheimer’s disease and its

29. McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia.

outcome. Lancet Neurol. 2013;12(10):957-965.

Cochrane Database Syst Rev. 2006;(2):CD003154.

19. Villenmagne VL, Burnham S, Bourgeat P, et al. Amyloid β deposition,

30. Matsunaga S, Kishi T, Iwata N. Combination therapy with cholinester-

neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease.

ase inhibitors and memantine for Alzheimer’s disease: a systematic review

Lancet Neurol. 2013;12(4):357-367.

and meta-analysis. Int J Neuropsychopharmacol. 2014;18(5).

20. Alzheimer’s Association. 2015 Alzheimer’s disease facts and figures.

31. Atri A, Hendrix SB, Pejovic V, et al. Cumulative, additive benefits of

http://www.alz.org/alzheimers_disease_facts_and_figures.asp#quickFacts.

memantine-donepezil combination over component monotherapies in

Accessed August 11, 2015.

moderate to severe Alzheimer’s dementia: a pooled area under the curve

21. Desai AK, Grossberg GT, Chibnall JT. Healthy brain aging: a road map.

analysis. Alzheimers Res Ther. 2015;7(1):28.

Clin Geriatr Med. 2010;26:1-16.

32. Han DH. New combo drug approved for Alzheimer’s dementia. eMPR

22. Solomon A, Mangialasche F, Richard E, et al. Advances in the preven-

(Monthly Prescribing Reference) website. December 29, 2014. http://

tion of Alzheimer’s disease and dementia. J Intern Med. 2014;275:229-250.

www.empr.com/new-combo-drug-approved-for-alzheimers-dementia/

23. Harrison SL, Ding J, Tang EY, et al. Cardiovascular disease risk mod-

article/390060/. Accessed August 11, 2015.

els and longitudinal changes in cognition: a systematic review. PLoS One.

33. Eli Lilly and Co. Clinical trial of solanezumab for older individuals who

2014;9(12):e114431.

may be at risk for memory loss (A4). http://www.clinicaltrials.gov/ct2/

24. Biessels GJ. Capitalising on modifiable risk factors for Alzheimer’s dis-

show/NCT02008357. NLM identifier: NCT02008357. Accessed August

ease. Lancet Neurol. 2014;13(8):752-753.

11, 2015.

25. Norton S, Matthews FE, Barnes DE, et al. Potential for primary preven-

34. Iavarone A, Ziello AR, Pastrore F, et al. Caregiver burden and coping

tion of Alzheimer’s disease: an analysis of population-based data. Lancet

strategies in caregivers of patients with Alzheimer’s disease. Neuropsych

Neurol. 2014;13(8):788-794.

Dis Treat. 2014;10:1407-1413.

26. Casey DA, Antimisiaris D, O’Brien J. Drugs for Alzheimer’s disease: are

35. Kang HS, Myung W, Na DL, et al. Factors associated with care-

they effective? P T. 2010;35(4):208-211.

giver burden in patients with Alzheimer’s disease. Psychiatry Investig.

27. Russ TC, Morling JR. Cholinesterase inhibitors for mild cognitive

2014;11(2):152-159.

impairment. Cochrane Database Syst Rev. 2012;(9):CD009132.

36. Hayajneh FA, Shehadeh A. The impact of adopting a person-centered

28. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane

care approach for people with Alzheimer’s on professional caregivers’

Database Syst Rev. 2006;(1):CD005593.

burden: an interventional study. Int J Nurs Pract. 2014;20(4):438-445.

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POST-TEST

Expiration date: December 31, 2016 Credit Designation: Albert Einstein College of Medicine of Yeshiva University designates this enduring material for a maximum of 0.50 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 better. All components must be completed and submitted online at myCME.com/April16CAfeature.

CREDITS: 0.50

| A 75-year-old woman with complaints of forgetfulness

1. Which of the following statements regarding complaints of memory loss in older patients (ie, ≥65 years of age) is correct? a. In the absence of Alzheimer’s disease (AD) risk factors or evidence of cognitive impairment, there is little reason for concern regarding mild memory difficulties. b. There is evidence that people who are clinically normal but express concern over changes in their cognitive function are at increased risk for AD. c. Subjective cognitive impairment has been recognized as one of the early preclinical stages of AD. d. There is no evidence of an association between subjective cognitive symptoms and biomarkers of AD or subsequent development of MCI and dementia.

2. Which of the following statements regarding the role of biomarkers in AD is correct? a. Biomarker testing is not recommended in people with no symptoms or with memory concerns but no evidence of impairment on cognitive testing. b. There is little difference in the expression of biomarkers in the different stages of AD. c. Evidence of neurodegeneration, including elevated CSF tau and decreased fluorodeoxyglucose uptake on PET, becomes apparent before amyloid abnormalities are seen. d. Biomarker testing is critical to establish the presence of AD pathology in patients with subtle cognitive symptoms in routine clinical practice.

3. Which of the following statements regarding the current understanding of the preclinical stages of AD is correct? a. In stage 1, patients have no cognitive symptoms or biomarkers of cerebral amyloidosis. b. In stage 2, patients have evidence of both cognitive deficits and biomarkers of amyloidosis and neuronal injury.

c. In stage 3, patients have evidence of subtle cognitive impairment and cerebral amyloidosis but neuronal injury is not evident until AD dementia is present. d. Subtle cognitive impairment, cerebral amyloidosis, and neuronal injury are typically all evident before AD dementia becomes manifest.

4. Which of the following statements regarding the role of Abeta in the assessment of AD risk is true? a. More than 45% of cognitively normal elderly people (ie, ≥65 years of age) meet neuropathologic criteria for AD. b. Fewer than 15% of cognitively normal elderly people show amyloid positivity on positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) assays. c. The prevalence of amyloid positivity among cognitively normal elderly people roughly corresponds to the prevalence of AD dementia approximately a decade later. d. No association has been found between amyloid positivity and mortality.

5. Which of the following statements regarding the potential for treatment of preclinical AD is true? a. A treatment to delay the onset of AD by just 5 years could reduce the prevalence of individuals with AD by 25% or more over the next 5 years. b. Cholinesterase inhibitors have been shown to delay the onset of symptoms in patients with preclinical (ie, asymptomatic) AD. c. Memantine shows more promise than cholinesterase inhibitors for the prevention of cognitive decline in patients with preclinical AD. d. Efforts to develop immunotherapies to slow the progression of preclinical AD have been largely abandoned.

TO TAKE THE POST-TEST please go to: myCME.com/April16CAfeature

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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 DEBATING THE PROS AND CONS OF FULL-PRACTICE AUTHORITY Thank you for this article [Advisor Forum, “No thanks, on full-practice authority,” March, p. 46]. I’ve been a practicing PA for 32 years, and I totally agree with you. Long-term opiates are bad news, and they ruin our patients’ lives. I work in spine surgery and have yet to meet even 1 patient who is better on opiates beyond about 2 to 4 weeks postoperation.— ALLYSON JOGGERST, PA, Chesterfield, Mo. (210-1) Full-practice authority in this situation means we would potentially have greater leverage to refuse to prescribe this medication in our practices. As mentioned, with our current situation (at least in my state) NPs/PAs are expected to fall in line with their supervisor’s practice, in prescribing this medication or any other whether they are comfortable with it or not.—DEBRA FOLDOE, FNP-BC, Arlington, Tex. (210-2) Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. You may 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.

I worked as a primary care PA and first call to ER as well for over 2 decades, and I have always been happy to have the physician “umbrella” regarding opioids and their prescription.

For several years, my supervisor was very lenient, and I found myself caring for patients who had no motivation to stop using. The pattern of usage of the addicted patient was very different from that of the patient with chronic pain issues: the latter would vary the number of days a prescription lasted, and seasonal usage varied—far less in the summer during non-stormy times. The addicted patients invariably called the day before they were going to run out of their 45, 60, or 90 pills every month. The recent changes to the law in Texas encouraged me to undertake weaning many patients off their opioids and to use more “cocktail” combinations with a progression of several medications (including gabapentin pushed to the maximum dosage tolerated): NSAIDs, tramadol, acetaminophen, tricyclics + opioids to get the best result for patients. We, I feel, gave out too much pain medication without doing the hard work of getting patients on the least amount of medication and promoting activity that made the patients’ lives useful and satisfying.—MICHELE CSER, PA-C, Pecos, Tex. (210-3)

A NEED FOR EARLY AUTISM SCREENING I am floored [“USPSTF finds insufficient evidence for autism screening in all children,” March, p. 18]. As a pediatric nurse who works with children on the spectrum, I know that the

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.

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.

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earlier the intervention, the better the outcome. What this report is stating, in my humble opinion, is that we should wait for symptoms noticed by those who are not educated on what symptoms to look for. Most pediatricians take a “watchful waiting” attitude when the well-check screenings are abnormal; the longer one waits, the less effective the therapies will be. I would like to advocate for earlier diagnosis, before age 18 months. This is possible with the new technologies becoming available.—NANCY SEXTON, RN, Atlanta, Ga. (210-4)

healthy 18-year-old woman with no other explanation for her condition, the timing cannot be ignored, and a correlation should be suspected. Due to timing alone, these events should have been reported to the vaccine adverse event reporting system (www.vaers.hhs.gov). An explanation of Annabelle’s illness was never identified, and as the author concludes, “The precise mechanisms leading to tissue injury in the inflammatory myopathies are poorly defined in most cases.”—REBECCA LORD, CRNP, Richmond, Va. (210-6)

CANNABIDIOL AS MEDICINE In Sherril Sego’s review of Cannabis sativa [Alternative meds update, “Marijuana,” February, p. 98], she failed to mention anything about the substance of cannabidiol (CBD) from the plant. This is particularly important, because this substance is the one that does not tend to produce the euphoria and other psychotic effects of the substance tetrahydrocannabinol (THC). It is thought that CBD would be much more acceptable to patients and the community at large for accepting legalizing medical marijuana, since the abuse potential tends to occur with the TCH component. Strains of this plant can be grown that are high in the CBD content, but low in the TCH component. This is a very important fact to know when discussing marijuana, especially as a medical treatment.—LINDA WENDELL, FNP, Dryden, N.Y. (210-5)

YOUR QUESTIONS

TIMING OF MENINGOCOCCAL VACCINE In regards to the Clinical Challenge [“Markedly elevated serum transaminase levels,” February, p. 73] and the interesting but unfortunate case of Annabelle, there is only a brief mention of the fact that this young woman received a meningococcal vaccine just 4 to 6 weeks prior to the onset of her symptoms and eventual decline. In an otherwise perfectly

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.

NON-NARCOTIC ANALGESICS FOR MUSCULOSKELETAL PAIN Which non-narcotic analgesics are best for musculoskeletal pain (muscle strain, sprain, and fracture) and post-­operatively?— JACLYN LEITNER, PA-C, Glen Rock, N.J. (210-7) Non-opioid (non-narcotic) agents such as aspirin and acetaminophen are recognized as 2 of the most widely used analgesics and are effective for mild to moderate headache and pain of musculoskeletal origin. For acute adult musculoskeletal pain, the first-line choice can be paracetamol (acetaminophen) (500 mg to 1,000 mg) every 4 to 6 hours in patients with no hepatic impairment. A second-line agent can be conventional, as well as Cox-2 non-steroidal antiinflammatory drugs (NSAIDs) such as celecoxib or diclofenac, and using the lowest effective dose for the shortest course. (See National Prescribing Services Limited. Analgesics in acute musculoskeletal pain. 2003. Retrieved from http://www.nps.org.au/__data/ assets/pdf_ file/0015/22821/Analgesics2003ClinicalAuditPack. pdf.)—ABIMBOLA FARINDE, PhD, PharmD (See photo at bottom of this page for more information about Dr. Farinde.) (210-7) n

Claire O’Connell, MPH, PA-C,

Katherine Pereira, DNP, FNP,

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

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

Sherril Sego, FNP-C, DNP,

is an independent consultant in Kansas City, Mo.

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Indications and Usage NUEDEXTA is indicated for the treatment of pseudobulbar affect (PBA).

PBA occurs secondary to a variety of otherwise unrelated neurologic conditions, and is characterized by involuntary, sudden, and frequent episodes of laughing and/or crying. PBA episodes typically occur out of proportion or incongruent to the underlying emotional state.

PBA is a specific condition, distinct from other types of emotional lability that may occur in patients with neurological disease or injury.1 Important Safety Information NUEDEXTA (dextromethorphan hydrobromide and quinidine sulfate) 20mg/10mg capsules can interact with other medications causing significant changes in blood levels of those medications and/or NUEDEXTA which may lead to serious side effects. Adjust dose or use alternate treatment of the other medication when clinically indicated.

NUEDEXTA is contraindicated in patients concomitantly taking: QT-prolonging drugs metabolized

by CYP2D6 (e.g., thioridazine and pimozide); monoamine oxidase inhibitors (MAOIs) within the preceding or following 14 days; other drugs containing quinidine, quinine, or mefloquine and in patients with a known hypersensitivity to these drugs or any of NUEDEXTA’s components.

Discontinue use of NUEDEXTA if hepatitis, thrombocytopenia, serotonin syndrome or a hypersensitivity reaction occurs.

NUEDEXTA is contraindicated in patients with certain risk factors for arrhythmia: Prolonged QT interval; congenital long QT syndrome, history suggestive of torsades de pointes; heart failure; complete atrioventricular (AV) block or risk of AV block without an implanted pacemaker.

NUEDEXTA causes dose-dependent QTc prolongation. When initiating NUEDEXTA in patients at risk for QT prolongation and torsades de pointes, electrocardiographic (ECG) evaluation should

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Over 1,000,000 prescriptionsa

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IN PATIENTS WITH NEUROLOGIC CONDITIONS OR BRAIN INJURY

IMS Health data, 2015. 2

LOOK BELOW THE SURFACE: HE MAY HAVE PBA • An estimated 7 million people with neurologic conditions (eg, dementia, stroke, traumatic brain injury) have symptoms suggestive of pseudobulbar affect (PBA)b,c,3 • NUEDEXTA is the first—and only—FDA-approved treatment for PBA1 PBA is often mischaracterized as depression4-6

START SCREENING FOR PBA WITH THE SINGLE SCREENING QUESTION : d,7

Have you ever experienced involuntary episodes of crying and/or laughing that were exaggerated or even contrary to how you felt at the time?

A clinical diagnosis is required to determine if a patient has PBA.

d

Visit NUEDEXTA.com or call 1-855-4NUEDEX (468-3339). be conducted at baseline and 3-4 hours after the first dose. Risk factors include left ventricular hypertrophy or dystrophy or concomitant use of drugs that prolong QT interval or certain CYP3A4 inhibitors.

The most common adverse reactions are diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, urinary tract infection, influenza, increased gamma-glutamyltransferase, and flatulence.

NUEDEXTA may cause dizziness. Precautions to reduce the risk of falls should be taken, particularly for patients with motor impairment affecting gait or a history of falls.

These are not all the risks from use of NUEDEXTA. Please refer to the adjacent page for the brief summary of the Full Prescribing Information or useful prescribing information at www.NUEDEXTA.com.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch or call 1-800-FDA-1088. b

When considering patients with any of the 6 common neurologic conditions associated with PBA, it is estimated that PBA symptoms occur in 37% of patients, or an estimated 7.1 million Americans, with CNS-LS scores ≥13 and in 9.3% of patients, or an estimated 1.8 million Americans, with CNS-LS scores ≥21.8

c

In the PRISM study, the presence of PBA symptoms was defined as a CNS-LS score ≥13 and merits further diagnostic assessment. A more restrictive definition was also evaluated using a CNS-LS ≥21. The CNS-LS was validated as a PBA screening tool in ALS and MS populations.9-11

References: 1. NUEDEXTA Prescribing Information, Avanir Pharmaceuticals, Inc. 2. Data on file. Avanir Pharmaceuticals, Inc. 3. Work SS, et al. Adv Ther. 2011;28:586-601. 4. Crumpacker DW, et al. US Neurol. 2014;10:10-14. 5. Ahmed A, et al. Ther Clin Risk Manag. 2013;9:483-489. 6. Colamonico J, et al. Adv Ther. 2012;29:775-798. 7. Fonda JR, et al. J Rehabil Res Dev. 2015;52:839-850. 8. Brooks BR, et al. PLoS One. 2013;8:e72232. 9. Moore SR, et al. J Neurol Neurosurg Psychiatry. 1997;63:89-93. 10. Smith RA, et al. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004;5(suppl 1):99-102.

11. Smith RA, et al. Mult Scler. 2004;10:679-685.

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NUEDEXTA® (dextromethorphan HBr and quinidine sulfate) Capsules 20mg/10mg Brief Summary of Prescribing Information See package insert for full Prescribing Information INDICATIONS AND USAGE NUEDEXTA is indicated for the treatment of pseudobulbar affect (PBA). PBA occurs secondary to a variety of otherwise unrelated neurologic conditions, and is characterized by involuntary, sudden, and frequent episodes of laughing and/or crying. PBA episodes typically occur out of proportion or incongruent to the underlying emotional state. PBA is a specific condition, distinct from other types of emotional lability that may occur in patients with neurological disease or injury.

DOSAGE AND ADMINISTRATION The recommended starting dose of NUEDEXTA (20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate) is one capsule daily by mouth for the initial seven days of therapy.

On the eighth day of therapy and thereafter, the daily dose should be a total of two capsules a day, given as one capsule every 12 hours. The need for continued treatment should be reassessed periodically, as spontaneous improvement of PBA occurs in some patients.

CONTRAINDICATIONS Quinidine and related drugs: NUEDEXTA contains quinidine, and should not be used concomitantly with other drugs containing quinidine, quinine, or mefloquine.

Hypersensitivity: NUEDEXTA is contraindicated in patients with a history of NUEDEXTA, quinine, mefloquine or quinidine-induced thrombocytopenia, hepatitis, bone marrow depression or lupus-like syndrome; also in patients with known hypersensitivity to dextromethorphan [see Warnings and Precautions (5.1 in full PI)]. MAOIs: NUEDEXTA is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. Allow at least 14 days after stopping NUEDEXTA before starting an MAOI [see Drug Interactions (7.1 in full PI)]. Cardiovascular: NUEDEXTA is contraindicated in patients with a prolonged QT interval, congenital long QT syndrome or a history suggestive of torsades de pointes, and in patients with heart failure [see Warnings and Precautions (5.3 in full PI)]. NUEDEXTA is contraindicated in patients receiving drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine and pimozide), as effects on QT interval may be increased [see Drug Interactions (7.2 in full PI)]. NUEDEXTA is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or in patients who are at high risk of complete AV block.

WARNINGS AND PRECAUTIONS Thrombocytopenia and Other Hypersensitivity Reactions: Quinidine can cause immune-mediated thrombocytopenia that can be severe or fatal. Non-specific symptoms, such as lightheadedness, chills, fever, nausea, and vomiting, can precede or occur with thrombocytopenia. NUEDEXTA should be discontinued immediately if thrombocytopenia occurs, unless the thrombocytopenia is not drug-related, as continued use increases the risk for fatal hemorrhage. Likewise, NUEDEXTA should not be restarted in sensitized patients, because of the risk of more rapid and more severe thrombocytopenia. NUEDEXTA should not be used if immune-mediated thrombocytopenia from structurally related drugs including quinine and mefloquine is suspected, as cross-sensitivity can occur. Quinidine-associated thrombocytopenia usually resolves within a few days of discontinuation of the sensitizing drug. Quinidine has also been associated with a lupus-like syndrome involving polyarthritis, sometimes with a positive ANA. Other associations include rash, bronchospasm, adenopathy, hemolytic anemia, vasculitis, uveitis, angioedema, agranulocytosis, the sicca syndrome, myalgia, elevated serum levels of skeletal muscle enzymes, and pneumonitis.

Hepatotoxicity: Hepatitis has been reported in patients receiving quinidine, generally during the first few weeks of therapy. Cardiac Effects: NUEDEXTA causes dose-dependent QTc prolongation [see Clinical Pharmacology (12.2 in full PI)]. QT prolongation can cause torsades de pointes-type ventricular tachycardia, with the risk increasing as prolongation increases.

When initiating NUEDEXTA in at risk patients, ECG evaluation of QT interval should be done at baseline and 3-4 hours after the first dose. This includes patients concomitantly taking drugs that prolong the QT interval or that are strong or moderate CYP3A4 inhibitors, and patients with left ventricular hypertrophy (LVH) or left ventricular dysfunction (LVD). LVH and LVD are more likely to be present in patients with chronic hypertension, known coronary artery disease, or history of stroke. LVH and LVD can be diagnosed utilizing echocardiography or another suitable cardiac imaging modality. Reevaluate ECG if risk factors for arrhythmia change during the course of treatment. Risk factors include concomitant use of drugs associated with QT prolongation, electrolyte abnormality (hypokalemia, hypomagnesemia), bradycardia, and family history of QT abnormality. Hypokalemia and hypomagnesemia should be corrected prior to initiation of therapy with NUEDEXTA, and should be monitored during treatment. If patients experience symptoms that could indicate cardiac arrhythmias, e.g., syncope or palpitations, NUEDEXTA should be discontinued and the patient further evaluated. Concomitant use of CYP2D6 Substrates: The quinidine in NUEDEXTA inhibits CYP2D6 in patients in whom CYP2D6 is not otherwise genetically absent or its activity otherwise pharmacologically inhibited [see CYP2D6 Poor Metabolizers (5.8 in full PI), Pharmacokinetics (12.3 in full PI), Pharmacogenomics (12.5 in full PI)]. Because of this effect on CYP2D6, accumulation of parent drug and/or failure of active metabolite formation may decrease the safety and/or the efficacy of drugs used concomitantly with NUEDEXTA that are metabolized by CYP2D6 [see Drug Interactions (7.5 in full PI)]. Dizziness: In a controlled trial of NUEDEXTA, 10% of patients on NUEDEXTA and 5% on placebo experienced dizziness.

Serotonin Syndrome: When used with SSRIs or tricyclic antidepressants, NUEDEXTA may cause serotonin syndrome, including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor [see Drug Interactions (7.4 in full PI), Overdosage (10 in full PI)]. Anticholinergic Effects of Quinidine: Monitor for worsening clinical condition in diseases that may be adversely affected by anticholinergic effects. CYP2D6 Poor Metabolizers: The quinidine component of NUEDEXTA is intended to inhibit CYP2D6 so that higher exposure to dextromethorphan can be achieved compared to when dextromethorphan is given alone [see Concomitant use of CYP2D6 substrates (5.4 in full PI), Pharmacokinetics (12.3 in full PI), Pharmacogenomics (12.5 in full PI)].

Approximately 7-10% of Caucasians and 3-8% of African Americans are poor metabolizers (PMs) lacking capacity to metabolize CYP2D6. In patients who may be at risk of significant toxicity due to quinidine, consider genotyping to determine if they are PMs prior to treating with NUEDEXTA.

ADVERSE REACTIONS A total of 946 patients participated in four Phase 3 controlled and uncontrolled PBA studies and received at least one dose of the combination product of dextromethorphan hydrobromide/quinidine sulfate in various strengths at the recommended or higher than the recommended dose. In a 12-week, placebo-controlled study (N=326), the most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) that led to discontinuation were muscle spasticity (3%), respiratory failure (1%), abdominal pain (2%), asthenia (2%), dizziness (2%), fall (1%), and muscle spasms (2%). The most common adverse reactions (≥ 3% and ≥ 2X placebo) were diarrhea (13%), dizziness (10%), cough (5%), vomiting (5%), asthenia (5%), edema (5%), urinary tract infection (4%), influenza (4%), flatulence (3%) and increased GGT (3%). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Safety Experience of Individual Components: Dextromethorphan: Drowsiness, dizziness, nervousness or restlessness, nausea, vomiting, and stomach pain. Quinidine: Cinchonism (nausea, vomiting, diarrhea, headache, tinnitus, hearing loss, vertigo, blurred vision, diplopia, photophobia, confusion, and delirium) is most often a sign of chronic quinidine toxicity, but it may appear in sensitive patients after a single moderate dose of several hundred milligrams. Other adverse reactions occasionally reported with quinidine therapy include depression, mydriasis, disturbed color perception, night blindness, scotomata, optic neuritis, visual field loss, photosensitivity, keratopathy, and abnormalities of skin pigmentation.

DRUG INTERACTIONS MAOIs: Do not use NUEDEXTA with monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding or following 14 days [see Contraindications (4.3 in full PI)].

Drugs that Prolong QT and are Metabolized by CYP2D6: Do not use with drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine or pimozide) [see Contraindications (4.4 in full PI)]. Drugs that Prolong QT and Concomitant CYP3A4 Inhibitors: Recommend ECG in these patients who are taking NUEDEXTA [see Warnings and Precautions (5.3 in full PI)]. SSRIs and Tricyclic Antidepressants: Use of NUEDEXTA with SSRIs or tricyclic antidepressants increases the risk of serotonin syndrome [see Warnings and Precautions (5.6 in full PI)]. CYP2D6 Substrate: The co-administration of NUEDEXTA with drugs that undergo extensive CYP2D6 metabolism may result in altered drug effects [see Warnings and Precautions (5.4 in full PI)]. Desipramine (CYP2D6 substrate): This tricyclic antidepressant is metabolized primarily by CYP2D6. A drug interaction study was conducted between a higher combination dose of dextromethorphan (dextromethorphan hydrobromide 30 mg/quinidine sulfate 30 mg) and desipramine 25 mg. This dose increased steady state desipramine levels approximately 8-fold. If NUEDEXTA and desipramine are prescribed concomitantly, the initial dose of desipramine should be markedly reduced. The dose of desipramine can then be adjusted based on response, but a dose above 40 mg/day is not recommended. Paroxetine (CYP2D6 inhibitor and substrate): When the combination dose of dextromethorphan hydrobromide 30 mg/ quinidine sulfate 30 mg was added to paroxetine at steady state, paroxetine exposure (AUC0-24) increased by 1.7 fold and Cmax increased by 1.5 fold. Consider initiating treatment with a lower dose of paroxetine if given with NUEDEXTA. The dose of paroxetine can then be adjusted based on response, but dosage above 35 mg/day is not recommended. Digoxin: Quinidine is an inhibitor of P-glycoprotein. Prescribing quinidine with digoxin, a P-glycoprotein substrate, results in serum digoxin levels that may be as much as doubled. Alcohol: As with any other CNS drug, caution should be used when NUEDEXTA is taken in combination with other centrally acting drugs and alcohol.

USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate studies of NUEDEXTA in pregnant women [see Pregnancy (8.1 in full PI)]. Labor and Delivery: The effects of NUEDEXTA on labor and delivery are unknown. Nursing Mothers: It is not known whether dextromethorphan and/ or quinidine are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NUEDEXTA is given to a nursing mother. Pediatric and Geriatric Use: The safety and effectiveness of NUEDEXTA in these populations has not been determined. Renal and Hepatic Impairment: Dose adjustment of NUEDEXTA is not required in patients with mild to moderate renal or hepatic impairment. Increases in dextromethorphan and/or quinidine levels are likely to be observed in patients with severe renal or hepatic impairment.

DRUG ABUSE AND DEPENDENCE NUEDEXTA contains dextromethorphan, and dextromethorphan abuse has been reported, predominately in adolescents. These observations were not systematic and it is not possible to predict on the basis of this experience the extent to which NUEDEXTA will be misused once marketed. Therefore, patients with a history of drug abuse should be observed closely.

OVERDOSAGE Evaluation and treatment of NUEDEXTA overdose is based on experience with the individual components. Treatment of dextromethorphan overdosage should be directed at symptomatic and supportive measures. Treatment of quinidine overdosage requires monitoring the QTc interval and should involve a healthcare provider experienced in cardiac arrhythmia prevention and treatment and α-blockade-induced hypotension. Because of the theoretical possibility of QT prolongation that might be additive to those of quinidine, antiarrhythmics with Class I (procainamide) or Class III activities should (if possible) be avoided.

PATIENT COUNSELING INFORMATION Physicians should discuss the following topics with patients when prescribing NUEDEXTA: Hypersensitivity: [see Contraindications (4.2 in full PI), Warnings and Precautions (5.1 in full PI)].

Cardiac effects: Consult their healthcare provider immediately if they feel faint or lose consciousness. Inform their healthcare provider if they have any personal or family history of QTc prolongation [see Contraindications (4.4 in full PI), Warnings and Precautions (5.3 in full PI) Drug Interactions (7 in full PI)]. Dizziness: [see Warnings and Precautions (5.5 in full PI), Adverse Reactions (6.1 in full PI)]. Drug Interactions: [see Drug Interactions (7 in full PI)]. Dosing: Instruct patients to take NUEDEXTA exactly as prescribed, not to take more than 2 capsules in a 24-hour period, to be sure that there is an approximate 12-hour interval between doses, and not to take a double dose after a missed dose. General: Contact their healthcare provider if their PBA symptoms persist or worsen. Advise patients to keep this and all medications out of reach of children and pets.

Marketed by Avanir Pharmaceuticals, Inc., Aliso Viejo, CA 92656 1-855-4NUEDEX (468-3339) www.NUEDEXTA.com © 2015 Avanir Pharmaceuticals, Inc. NUE-0016(1)-OTH-0715

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Dermatology Clinic CASE #1

An exophytic, brown, and mildly tender nodule EMAN BAHRANI, BA, AND MAURA HOLCOMB, MD

A 26-year-old African American man with no significant past medical history presents with a growth on his left foot that had been increasing in size for 1 year. He initially thought it was a wart but had concerns when it continued to grow and became painful. Examination reveals an exophytic, brown, and mildly tender nodule, 3 cm in diameter, on his left medial heel and instep. The overlying skin is crusted and friable. His nails and hair show no abnormalities. There is no associated lymphadenopathy. The remainder of the examination is unremarkable.

What is your diagnosis? Turn to page 56.

CASE #2

Purpuric macules on a man with sepsis ANNA GREGOIRE, BS, AND TIFFANY SHIH, MD

A 55-year-old man with a past medical history of intravenous drug abuse presents to the emergency room with sepsis; he develops purpuric macules on the upper and lower extremities and the lower abdomen on the second day of admission.

They are asymptomatic lesions that started on the lower extremities and spread as the patient became more edematous. Examination shows purpuric macules that coalesce into patches over these dependent areas. Blood cultures show growth of methicillin-sensitive Staphylococcus aureus, and an echocardiogram finds vegetations on the tricuspid valve.

What is your diagnosis? Turn to page 57. www.clinicaladvisor.com • THE CLINICAL ADVISOR • APRIL 2016 55

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Dermatology Clinic CASE #1

Acral lentiginous melanoma

Melanoma is a mucocutaneous malignant tumor arising from melanocytes and the sixth leading cause of malignancy in the United States.1 It causes more than 75% of all skin cancer deaths. One subtype, acral lentiginous melanoma (ALM), accounts for less than 5% of all melanoma cases and presents on the palms, soles, and subungual sites.

The mean age of diagnosis for this condition is in the 60s.

It begins with lentiginous (radial) growth and evolves into dermal (vertical) invasion after months or years.2 Although the exact etiology remains unknown, melanoma is postulated to be a disease caused partially by ultraviolet (UV) radiation, with a higher incidence in whites and on sun-exposed sites. ALM, however, appears disproportionately in African Americans, Asians, and Hispanics, and no consistent results show a correlation with UV exposure.1-3 ALM exhibits increased expression of KIT, a tyrosine kinase receptor, and fewer BRAF kinase mutations than are seen in other cutaneous melanomas, indicating genetic risk factors.4 Compared with other subtypes, a higher proportion of ALMs are diagnosed at a later stage due to their unusual locations and visual similarity to benign lesions. This may explain the increased mortality associated with this cancer subtype.3 One-third1 to one-half 3 of ALM cases are initially misdiagnosed as benign lesions, such as verrucae, ulcers, hematomas, or fungal infections. Some may present as chronic wounds or dysplastic nevi, and dermoscopy is helpful for differentiation.5,6 Like other melanomas, ALM can present classically as pigmented or mottled macules, or papules with irregular borders. Benign acral nevi share some features with ALM but are usually symmetric, light brown, and uniform, with clear borders. Some ALMs become amelanotic, with red-pink coloration and are easily missed, especially on plantar surfaces. Advanced tumors can form large, exophytic, friable nodules. Many lesions are associated with pain, bleeding, or itching.7 Melanonychia, a black-brown pigmentation in the nail plate, is an important characteristic seen in two-thirds of subungual melanomas but is also seen in benign conditions (eg, trauma, onychomycosis, paronychia). If the streak extends onto the nail fold, it is called Hutchinson sign.

Important diagnoses to consider include Bowen disease and drug-induced nail pigmentation, which can be ruled out based on patient history, dermoscopy, or biopsy, if necessary.1,3,7 Early diagnosis is essential for survival. Educating patients about the “ABCDEs” of melanoma (asymmetrical shape, border, color, diameter, evolution) is as important as looking for changes in color, shape, or size of skin lesions on sunexposed and protected skin. Another mnemonic, “EFG,” stands for elevated, firm, or growing, and accounts for amelanotic or nodular melanomas. Surrounding erythema or inflammation should also increase suspicion, as well as individual nevi that are distinct from surrounding ones.1

One-third to one-half of acral lentiginous melanoma cases are initially misdiagnosed as benign lesions.

Dermoscopy aids the diagnosis of melanoma and involves a two-step algorithm. First, a lesion is considered melanotic in origin if it contains a pigment network, streaks, aggregated globules, homogeneous blue pigment, or parallel pattern (seen in acral lesions). Once the lesion is deemed melanocytic, it must be determined if it is benign nevi or melanoma.1,5 Accentuated pigmentation on the ridges in a parallel pattern is a finding specific to ALM.5 Other dermoscopic signs of ALM are irregular diffuse pigmentation or irregular lines within pigmented nail lesions. Amelanotic ALM exhibits remnants of pigmentation and heterogeneous vascular patterns. Recognition of these dermoscopic patterns can help identify early disease.6 Excisional biopsy is the gold standard for diagnosis.

Incisional biopsies are acceptable with lesions in the facial or acral regions, those with low clinical suspicion, or those that are very large but may not show the full Breslow depth.7,8 Histologically, ALM possesses an asymmetric proliferation of single melanocytes at the dermal-epidermal junction and atypical melanocytes in the hyperplastic epidermis.

Single, pleomorphic melanocytes with enlarged nuclei and dendritic processes predominate. In contrast, benign nevi are composed mainly of nested melanocytes. In late stages of disease, pagetoid migration is visible. Deep dermal mitoses and frequent skip areas within the tumor are also features of ALM.1,7 Prognostic markers include Breslow thickness, Clark level, ulceration, dermal mitoses, sentinel

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lymph node positivity, and signs of intravascular or neural involvement.2,4,7 Surgical excision of the primary neoplasm is the only curative procedure. The goals are to achieve histologically negative margins and prevent local recurrence. For tumors <1 mm thick, 1-cm surgical margins are sufficient. Tumors that are 1 to 2 mm thick require surgical margins of 1 to 2 cm. For tumors >2 mm, 2-cm margins are recommended with sentinel lymph node biopsy (SLNB) in all tumors >1 mm thick.4,8 Amputation of the toes or fingers may be indicated in cases of subungual ALM. Lesions >4 mm thick are difficult to manage and often require adjuvant high-dose interferon therapy. Other adjuvant therapies for patients at high risk of recurrence or metastases include radiation and tyrosine kinase inhibitors. Once diagnosis has been confirmed, a full staging workup is necessary.8 In our case, an incisional biopsy of the patient’s neoplasm confirmed the diagnosis of ALM >4 mm thick. The lesion was surgically removed with clean margins down to the muscle, necessitating a graft. SLNB results came back positive, and the patient was referred to oncology for further treatment.

Eman Bahrani, BA, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston.

References 1. Garbe C, Bauer J. Melanoma. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds.

Dermatology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012:1885-1894.

2. Bradford PT, Goldstein AM, McMaster ML, Tucker MA. Acral lentiginous melanoma: incidence and survival patterns in the United States, 19862005. Arch Dermatol. 2009;145(4):427-434.

3. Stubblefield J, Kelly B. Melanoma in non-Caucasian populations. Surg Clin North Am. 2014;94(5):1115-1126.

4. Bello DM, Chou JF, Panageas KS, et al. Prognosis of acral melanoma: a series of 281 patients. Ann Surg Oncol. 2013;20(11):3618-3625.

5. Oh TS, Bae EJ, Ro KW, et al. Acral lentiginous melanoma developing during long-standing atypical melanosis: usefulness of dermoscopy for detection of early acral melanoma. Ann Dermatol. 2011;23(3):400-404.

6. Phan A, Dalle S, Touzet S, et al. Dermoscopic features of acral lentiginous melanoma in a large series of 110 cases in a white population. Br J Dermatol. 2010;162(4):765-771.

7. Piliang MP. Acral lentiginous melanoma. Clin Lab Med. 2011;31(2): 281-288.

8. Bichakjian CK, Halpern AC, Johnson TM, et al; American Academy of Dermatology. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol. 2011;65(5):1032-1047.

CASE #2

Leukocytoclastic vasculitis secondary to infective endocarditis

Leukocytoclastic vasculitis (LCV) is classified as a cutaneous small-vessel vasculitis; it is often idiopathic, or follows an acute infection or exposure to a new medication.1 LCV occurs in both sexes equally and at all ages, but it is more common in adults. Only 10% of cases are reported in children.1,2 Approximately 50% of cases are idiopathic, whereas infectious causes constitute 15% to 20% and drug exposure causes 10% to 15% of cases. Infectious causes include ß-hemolytic Streptococcus group A, Mycoplasma, and Mycobacterium leprae, which represent the most common bacterial sources. Septic vasculitis is another infectious cause of LCV, most commonly caused by infective endocarditis.3 Endocarditis should remain on the differential diagnosis of those presenting with LCV-appearing lesions because of the known association and similarities in certain clinical signs and laboratory values.3 Viruses with known association include those resulting in upper respiratory infection (URI) and hepatitis C and B, including hepatitis vaccines. Cases of LCV have been reported with use of almost every class of medication.

Some of the most common medications include allopurinol, cephalosporins, hydralazine, methotrexate, minocycline, nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives, penicillin, phenytoin, propylthiouracil, quinolones, sulfonamides, and thiazides.1 Taking multiple medications is an uncommon or rare cause of LCV. However, cases have been reported; for example, with anti-tuberculosis agents.4 Inflammatory disorders cause 15% to 20% LCV cases.

Common associated diseases include autoimmune connective tissue diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and Sjögren syndrome.1 Lymphoproliferative neoplasms and solid tumors, especially lung, colon, genitourinary, and breast cancers (2-5%), are related to development of cutaneous small-vessel vasculitis. Recurrence of LCV suggests the need for evaluation of recurrence of the malignancy.1,5 Clinical presentation includes palpable purpura as the hallmark of LCV; diameter varies from pinpoint to several centimeters.

Lesions typically develop as a single crop that begins as a purpuric macule or partially blanching urticarial papule. Annular, vesicular, bullous, or pustular lesions also appear. Lesions usually

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Dermatology Clinic develop 7 to 10 days following exposure; however, cases of hours to years between exposure and eruption have been reported.1,5 Lesions typically predominate on the ankles and lower legs, especially dependent areas, or pressure points. In patients with limited mobility, the buttocks and posterior thighs may present as the primary site of involvement.5 Systemic symptoms occur in 5% to 25% of patients and commonly include ankle edema, mild pruritis, pain or burning, fever, and malaise.1,2,5 Arthralgias occur in 15% to 65% of patients, genitourinary symptoms in 3% to 7%, and gastrointestinal involvement in 3% to 5%.1 Involvement of other organ systems is rare and should lead to consideration of alternative diagnoses; however, serious systemic disease can accompany LCV and needs to be investigated, especially gastrointestinal, renal, or neurologic involvement. Lesions typically resolve in 3 to 4 weeks; however, residual postinflammatory hyperpigmentation remains.

Recurrence or chronic disease occurs in 10% of cases.1,5 LCV is thought to be caused by circulating immune complexes that lodge in vessels walls, leading to complement activation. Diverse inflammatory mediators lead to endothelial injury and swelling.5 Histologic examination reveals angiocentric segmental inflammation of the postcapillary venule. Expansion of vessel wall, fibrin deposition, and infiltration by neutrophils that show fragmented nuclei is also seen.5 Tissue eosinophilia on histologic examination suggests medication as the cause.

Separating cases of benign cutaneous vasculitis (after infection or induced by a drug) from those associated with underlying disease requires careful clinical evaluation. The patient’s medical history represents an opportunity to discuss infectious disorders, prior associated disease, medication usage, and a review of systems. Screening laboratory tests include urinalysis when the history suggests recent drug ingestion. A complete blood count, urinalysis, strep throat culture or antistreptolysin O titer, hepatitis B and C serologies, and antinuclear antibody and rheumatoid factors all represent initial screening test options based on clinical interpretation in patients with no obvious cause. Serum protein electrophoresis and serum complement tests, along with antineutrophil cytoplasmic antibody and cryoglobulin measurements, are additional laboratory tests to consider.5 Skin biopsies are performed to confirm the diagnosis of LCV. Biopsy results also identify patients at higher risk of systemic complications.2 Within the first 24 hours, biopsies with immunofluorescence and ultrastructural studies demonstrate the presence of immunoglobulins, complement components, and fibrin deposits within postcapillary venules. Repeat biopsies reveal prominence of fibrin with destruction of immunoglobulin deposits.5

Initial treatment of LCV in patients who are clinically well and have normal urinalysis results consists of nonaggressive therapy because most cases are acute and self-limited and affect only the skin.5 Nonaggressive measures include rest, elevation of legs, analgesics, and avoidance of trauma and cold. If LCV results from medication, the offending drug should be discontinued; any infectious disease or neoplasm then requires separate treatment.1,5 Arthralgias associated with LCV may be treated with NSAIDs. Oral antihistamines block the vasodilation caused by histamine and reduce immune complex trapping, thereby improving LCV. With severe, intractable, or recurrent disease, systemic treatments are utilized.

Chronic vasculitis treatment includes colchicine, 0.6 mg twice or three times daily, or dapsone, 50 to 200 mg/d for 2 to 3 weeks.

Low doses of each may be combined if monotherapy is unsuccessful or intolerances develop.1,5 Systemic corticosteroids (60–80 mg/d) are recommended for use in serious systemic manifestations of LCV or in those with necrotic lesions.5 However, due to adverse effects of long-term oral corticosteroids, a taper over 4 to 6 weeks should be attempted.1 In patients with refractory LCV, immunosuppressive agents including mycophenolate mofetil (2-3 g/d), methotrexate (5–25 mg/wk), or azathioprine (50-200 mg/d) can be considered. Other options in difficult cases include cyclophosphamide, monthly or intravenous pulses of steroids, cyclophosphamide, cyclosporine (3–5 mg/kg/d), and tumor necrosis factor blockers, particularly infliximab.5 Because the patient was thought to have LCV secondary to infective endocarditis, treating the underlying infection was expected to clear his lesions. Empiric antibiotics was initiated on admission. When his blood culture results returned positive for MSSA, his antibiotics were narrowed. When his infection cleared, his purpura resolved within the next few weeks. n Anna Gregoire, BS, is a medical student and Tiffany Shih, MD, is a resident physician at the University of Minnesota in Minneapolis.

References 1. Shinkai K, Fox JP. Cutaneous vasculitis. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, PA: Elsevier Saunders; 2012:385-393.

2. Micheletti RG, Werth VP. Small vessel vasculitis of the skin. Rheum Dis Clin North Am. 2015;41(1):21-32.

3. Salahuddin H, Luni FK, Siddiqui N, et al. Bacterial endocarditis complicated by leukocytoclastic vasculitis. Am J Med Sci. 2015;350(6):500.

4. Avcu G, Sensoy G, Çeliksoy MH, et al. Cutaneous leukocytoclastic vasculitis associated with anti-tuberculosis drugs. Pediatr Int. 2015;57(1):155-179.

5. Cutaneous vascular diseases. In: James WD, Berger TG, Elston DM, eds.

Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, PA: Saunders Elsevier; 2011:801-845.

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Dermatologic Look-Alikes Light spots on the back KYLE FLORES, BS, AND JULIA R. NUNLEY, MD

CASE #1

CASE #2

An 18-year-old man of Mediterranean descent comes in for evaluation of the skin across his upper back and neck, which he says has lost its normal color; a friend initially noticed this while they were surfing earlier in the summer. Although he has no associated symptoms, he is very worried about what is happening to his skin, as well as his appearance, because his fellow surfers tease him about the color change. He has no remarkable past medical history. Physical examination reveals coalescent, hypopigmented, scaly macules with minimal erythema, symmetrically distributed over his upper back.

A 27-year-old African American woman presents with color changes that she noted on her lower back while showering 1 week ago. She says nothing is different in her bathing regimen and reports no recent travel, outdoor activities, illness, or underlying medical conditions. Although asymptomatic, she thought she had a fungal infection; however, topical antifungal creams have failed to improve the rash. Physical examination reveals nonscaly, hypopigmented, symmetrically distributed macules convalescing into patches over the midline of the lower back.

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Dermatologic Look-Alikes CASE #1

Tinea versicolor

Tinea versicolor (TV), also known as pityriasis versicolor, is an innocuous superficial skin infection caused by the commensal yeast Malassezia.

Well known to clinicians in lower-latitude regions of the United States, the prevalence of TV is estimated to be as high as 50% in tropical regions such as West Samoa and as low as 11.1% in northern areas such as Sweden.1 In 1801, TV was identified as a distinct dermatologic entity; 45 years later, a yeast was discovered as its cause.2 The exact genus was debated until 1963, when both Malassezia and Pityrosporum were found to have identical antigens and turned out to be the same organism.2 Although it has been traditionally taught that M furfur is the most common causative organism, molecular studies recently revealed M globosa to be the most common isolate.3 Malassezia resides in the outermost layer of the epidermis, the stratum corneum, where it breaks down host lipids to synthesize its own cell wall. This cell wall provides mechanical stability, a structure for keratinocyte adherence, and a defense mechanism against host immune attacks.4 Ubiquitously present, Malassezia is part of the natural human flora; excessive overgrowth is required for the development of TV. This becomes possible when the host provides excessive lipids via sebaceous secretions and/or the host immune system cannot suppress the growth, and it is promoted by a warm, humid environment.

Individuals with oily skin or immune deficiency have a predilection to develop TV. Thus, postpubescent young adults with hormonally active sebaceous glands are the most commonly affected age group. Transplant patients who take chronic immunosuppressive medications are also commonly affected. TV is most apparent in hot, humid weather due to increased sweat production and normal tanning of unaffected skin, which emphasizes the color changes. Other predisposing factors include pregnancy, use of oral contraceptives, and malnutrition. There is no predilection for race or sex.1 Sun-exposed areas of the upper back and neck are most commonly affected. Classically, TV develops with hypopigmented, confetti-like, scaly macules with a subtle erythematous rim; however, some cases are inversely hyperpigmented.

Pigment variability is likely due to a combination of pigmentary effects specific to the causative Malassezia species, as well as host immune responses4; scale represents fungal overgrowth and the inflammatory response. Although the eruption is sometimes mildly pruritic, patients are more often concerned with the esthetic effects.

The differential diagnosis for TV is extensive and includes vitiligo, postinflammatory hypopigmentation (or hyperpigmentation), pityriasis alba, hypomelanosis of Ito, discoid lupus erythematosus, secondary syphilis, progressive macular hypomelanosis (PMH), tinea corporis, seborrheic dermatitis, and mycosis fungoides. Clinical subtleties may help the provider distinguish TV from many of these other entities. For example, vitiligo presents with depigmentation, not hypopigmentation, produces white hairs in the affected areas, and does not have scale. Postinflammatory hypopigmentation is usually preceded by an inflammatory and/or symptomatic process. Pityriasis alba is more commonly seen in children, is often on the face, and is associated with atopy. Mycosis fungoides, a type of cutaneous T-cell lymphoma, can mimic many eruptions. However, it is more common in sun-protected areas, such as across the hips and buttocks, fails to respond to typical treatments for TV, and ultimately requires a biopsy for diagnosis. If any of these clinical parameters are present, patients should be referred to

The prevalence of tinea versicolor is estimated to be as high as 50% in tropical regions such as West Samoa. a dermatologist. The dermatophyte causing tinea corporis can be identified by culture or distinct characteristics upon the examination of skin scrapings prepared with potassium hydroxide. Clinical clues to aid in the diagnosis of TV include age, humid climate, oily skin, scale, a prior history of a similar rash, as well as exacerbation in the summer months with resolution in the winter. Laboratory studies can be used to confirm the diagnosis.

The Wood’s lamp may be a useful bedside diagnostic tool. Although the sensitivity is suboptimal, Wood’s lamp fluorescence of TV should reveal a diffuse yellow-white or copper-orange sheen or a folliculocentric bluish-white fluorescence.5 A better diagnostic test is microscopic examination of skin scrapings after preparation with potassium hydroxide

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(KOH). Although they are taught as a straightforward procedure, KOH preparations can be challenging; however, if one develops technical expertise, many fungal diagnoses can be made at the bedside. To perform this test, the area must first be wiped with alcohol; scale should be gently scraped with a number 15 blade and placed on a glass microscope slide. The examiner should then apply 1 to 2 drops of a 10% to 20% KOH solution, cover it with a coverslip, and view it under 10× to 40× magnification to reveal the ­classic

Patients diagnosed with TV should be educated that Malassezia is not contagious because it is part of the normal flora. “spaghetti” (hyphae) and “meatballs” (spores) findings of TV; if a dermatophyte is the cause, as in tinea corporis, branching, septate hyphae will be seen instead. Chemicals such as Chicago Sky Blue and chlorazole black are added to some commercially available KOH products to increase diagnostic accuracy because these chemicals adhere to and stain the fungal wall, thereby improving visualization.6 Routine fungal cultures will yield false-negative results for TV because standard media does not contain the nutrients necessary to grow the lipophilic Malassezia.

On biopsy, histologically, hyphae and spores in the stratum corneum are seen, sometimes with mild epidermal or dermal inflammation.7 Patients diagnosed with TV should be educated that Malassezia is not contagious because it is part of the normal flora and that the color change is caused, in part, by the body’s reaction to the yeast. Therefore, there will be a delay in resolution of the color change despite effective therapy. Because epidermal regeneration requires 4 weeks, it may take up to 1 month for the skin to return to normal color. Continued treatment should be encouraged to assure complete resolution, as results are not immediate. The treatment course is 4 weeks. In 60% to 80% of patients, the condition recurs within 2 years; patients should be educated to anticipate this.7 Topical antifungal treatments were recently proven to be equally as effective as oral azoles.8 Although the duration of topical treatment may result in suboptimal patient compliance, the safety profile of topical therapy may outweigh this limitiation.8,9 Topical treatments contain antifungal agents such as selenium sulfide, zinc pyrithione, an azole, or an

allylamine. Shampoos containing selenium sulfide or zinc pyrithione should be applied to affected areas for 10 minutes daily before washing off; topical azoles or allylamines should be applied twice daily.

Although highly effective, oral azole and allylamine medications are more expensive, are associated with hepatotoxicity, and have numerous drug-drug interactions through inhibition of the cytochrome P450 system. Systemic therapy should be used only in special occasions, such as extensive disease or when topical therapy is not practical in an otherwise healthy patient.8,9 Preventive treatments are theoretical; some authors suggest that monthly use of topical agents or shampoos may be beneficial.9 If the rash persists after 4 weeks of compliant treatment, an alternative diagnosis should be considered.

In our case, the patient was treated with 1% terbinafine cream; resolution was noted after 3 weeks of therapy. He continues to surf with his friends who stopped teasing him once they discovered his rash was not contagious.

CASE #2

Progressive macular hypomelanosis

Progressive macular hypomelanosis (PMH) is a newly described, poorly understood, and largely underdiagnosed dermatologic condition.10 It was first described in 1983

by Guillet et al.11 on darkskinned young women as a “bizarre,” hypopigmented macular rash that did not respond to antifungal therapy. Over the next two decades, numerous reports surfaced describing the same condition by other names, including Creole dyschromia, nummular and confluent hypomelanosis of the trunk, cutis trunci variata, and idiopathic multiple large macule melanosis. As with tinea versicolor (TV), PMH is an innocuous condition that may be cosmetically distressing to the individual affected.

The cause of PMH was unknown until 2001, when Westerhof et al. observed a curious red fluorescence at the base of hair follicles using a Wood’s lamp; red, glowing dots were present within lesional skin and were notably absent on unaffected skin.12,13 Knowing that Propionibacterium acnes, the bacteria associated with acne vulgaris, fluoresces red under Wood’s light due its coproporphyrin molecules, Westerhof thought this was the

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Dermatologic Look-Alikes causative organism. Data from other investigators supported his hypothesis.14 However, in 2010, Westerhof reported the results from molecular analyses of organisms cultured from PMH and suggested that a novel species of Propionibacterium was likely instrumental in this new condition.13 Exactly how Propionibacterium causes PMH remains speculative; the leading theory is that this organism secretes an unidentified factor that, in some way, interferes with melanogenesis.10,12-14 One can surmise a possible pathogenesis from the clinical findings. Because Propionibacterium bacteria reside within pilosebaceous units, the hypothetical factor associated with

Suggested topical treatments for patients with PMH include benzoyl peroxide and antibiotics such as clindamycin. skin lightening may diffuse radially from the ducts into the surrounding tissue, causing hypopigmented macules around each affected hair follicle, identified as glowing red by Wood’s light.13 These macules are more prevalent in the midline of the torso due to the higher concentration of sebaceous glands and typically coalesce into larger patches. This is a key clinical feature of PMH that suggests a functional role for glandular activity, because it corresponds to the anatomic sites noted to sweat more during exertion. PMH is asymptomatic and clinically lacks scale, erythema, or other secondary changes.

The prevalence of PMH is unknown. Researchers in the Netherlands report PMH to be more common than either TV or pityriasis alba, suggesting that PMH is generally more common than it is recognized.10 Although controversial, current literature suggests a slight predominance in women.10,15 The increased reporting in dark-skinned individuals may simply reflect heightened recognition because the adjacent darker normal skin highlights the lighter affected skin.

Most patients are young adults and no person older than age 50 years has been diagnosed with PMH, suggesting disease regression over time.15 Hence, the term “progressive” may be somewhat inaccurate, although Guillet et al.11 initially reported that the disease worsened over a 4-year period before regressing. The lack of an association with acne vulgaris may support causation by a newly discovered Propionibacterium species.12,13 Diagnosis of PMH requires a high index of suspicion. To the untrained eye, PMH and TV can appear indistinguishable. Both consist of asymptomatic, hypopigmented macules coalescing

over the back, more often in young adults during the summer months. However, some clinical features can provide clues; PMH does not have scale or an erythematous rim, which are characteristic of TV. However, one should suspect the diagnosis of PMH in cases of presumed—but unconfirmed—TV that fail an appropriate course of antifungal medication.

As previously described, hypopigmented macules on the trunk can be caused by other conditions, including pityriasis alba, leprosy, mycosis fungoides, hypomelanosis of Ito, and postinflammatory hypopigmentation.

Use of Wood’s lamp can help distinguish PMH from TV, as well as from several other similar conditions, but proper Wood’s lamp technique is crucial. The examination room should be completely dark, and the investigator should allow 1 minute for the lamp to warm and 3 minutes for his or her eyes to acclimate. The skin of interest should be cleaned with an alcohol wipe to remove any soap or lotion residue that may fluoresce.5 When illuminating the skin with Wood’s light, the investigator should compare lesional to nonlesional skin, noting the specific characteristics. If the diagnosis remains in question, other studies can help ensure a proper diagnosis.

If a biopsy is performed, the histologic findings of PMH include a paucity of epidermal melanin and a mild, perifollicular, lymphoid dermal infiltrate; a gram stain will demonstrate Propionibacterium, a gram-positive bacteria, within the pilosebaceous units.12,13 Successful treatment of PMH remains largely anecdotal.

In theory, the goal is to inhibit sebum production, eliminate the causative bacteria, and stimulate melanin production.

Suggested topical treatments include benzoyl peroxide and antibiotics such as clindamycin. Oral antibiotics may also be effective. Some studies report efficacy with phototherapy, but recurrence is common because phototherapy does not treat the presumed infectious cause.10,14,15 Low-dose isotretinoin may be successful, presumptively due to inhibition of sebum production.16 However, the patient and clinician must both be registered in the US Food and Drug Administration-regulated iPledge™ program, which monitors pregnancy risk in women.

The patient described in our case was effectively treated with a 2-month course of oral minocycline, 100 mg twice daily.

She has not returned to the clinic for long-term follow-up. n Kyle Flores, 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.

Continues on page 68

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Dermatologic Look-Alikes References

10. Relyveld GN, Menke HE, Westerhof W. Progressive macular hypomel-

1. Muhammad M, Kamai M, Islam T, et al. A study to evaluate the safety

anosis: An overview. Am J Clin Dermatol. 2007;8(1):13-19.

and efficacy of oral fluconazole in the treatment of tinea versicolor.

11. Guillet G, Helanon R, Gauthier Y, et al. Progressive macular hypomela-

Mymensingh Med J. 2009;18(1):31-35.

nosis of the trunk: Primary acquired hypopigmentation. J Cutan Pathol.

2. Negroni R. Historical aspects of dermatomycoses. Clin in Dermatol.

1988; 15(5):286-289.

2010;28(2):125-132.

12. Westerhof W, Relyveld GN, Kingswijk MM, et al. Propionibacterium

3. Crespo Erchiga V, Delgado Florencio V. Malassezia species in skin dis-

acnes and the pathogenesis of progressive macular hypomelanosis. Arch

eases. Curr Opin Infect Dis. 2002;15(2):133-142.

Dermatol. 2004;140(2):210-214.

4. Hort W, Meyser P. Malassezia virulence determinants. Curr Opin Infect

13. Relyveld GN, Westerhof W, Woudenberg J, et al. Progressive macular

Dis. 2011;24(2):100-105.

hypomelanosis is associated with a putative Propionibacterium species. J Inv

5. Asawanonda P, Taylor CR. Wood’s light in dermatology. Int J Dermatol.

Dermatol. 2010;130(4):1182-1184.

1999;38(11):801-807.

14. Hassan A, El-Badawi MA, Abd-Rabbou FA, et al. Progressive macular

6. Lim SL, Lim CS. New contrast stain for the rapid diagnosis of pityriasis

hypomelanosis pathogenesis and treatment: A randomized clinical trial.

versicolor. Arch Dermatol. 2008;144(8):1058-1059.

Journal of Microscopy and Ultrastructure. 2014;2(4):205-216.

7. Faergemann J. Pityrosporum species as a cause of allergy and infection.

15. Duarte I, Nina BI, Gordiano MC, et al. Progressive macular hypomela-

Allergy. 1999;54(5):413-419.

nosis: An epidemiological study and therapeutic response to photothera-

8. Gupta AK, Kogan N, Batra R. Pityriasis versicolor: A review of pharma-

py. An Bras Dermatol. 2010;85(5):621-624.

cological treatment options. Expert Opin Pharmacother. 2005;6(2):165-178.

16. Kim YJ, Lee DY, Lee JY, Yoon TY. Progressive macular hypomela-

9. Gupta AK, Lyons DC. Pityriasis versicolor: An update on pharmacologi-

nosis showing excellent response to oral isotretinoin. J Dermatol.

cal treatment options. Expert Opin Pharmacother. 2014;15(12):1707-1713.

2012;39(11):937-938.

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Writers’ Guidelines The Clinical Advisor welcomes submissions from its readers. Writing for us is an opportunity to share your knowledge and experience with your colleagues — and to collect a fee in the bargain! We pay an honorarium for every submission we accept.

We’ll be glad to work with you to develop your ideas into compelling articles. As for length, that depends on which kind of article you submit.

CLINICAL FEATURES update our readers on the latest information about conditions seen in everyday practice. Running approximately 2,500 to 5,000 words, including the references, features can be written either as regular narratives or as a series of questions and answers. Topics should be selected with the busy primary-care clinician in mind; specialists should review specialty topics from the primary-care point of view.

If at all possible, articles should be accompanied by clinical photos.

Charts, tables, and algorithms are also encouraged. Please include your title and affiliation.

CLINICAL CHALLENGE is our popular department comprising histories of difficult cases. Each case is presented as a step-by-step, chronological account, revealing the author’s thought processes along the way. It is divided into sections in this order: the patient presentation; the patient history; the twists and turns eventually leading to a diagnosis; the treatment and outcome; and a discussion of the lessons learned or of the condition in general.

The length should be about 1,500 words, and accompanying images are encouraged. Please include your title and affiliation.

DERMATOLOGY CLINIC is a department that presents photos of actual cases and asks readers to identify the condition. Each case opens with one or two color photos and a 75-to-100-word description of the patient presentation, without giving away the diagnosis.

This is followed by a 750-to-1,000-word summary that includes a fuller description of the ailment, an explanation of how the correct diagnosis was reached, a general review of the condition along with a differential diagnosis, and a description of the patient’s treatment and outcome. Topics must be approved by the editor prior to submission. Please include your title and affiliation.

COMMENTARY is our guest editorial page. It gives you the opportunity to sound off on an issue of importance to your colleagues nationwide. A typical Commentary runs about 600 words in length. Please include your title and affiliation.

To discuss your editorial ideas, contact us by phone at 646.638.6078; by e-mail to editor@ClinicalAdvisor.com; or by mail to The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2016 69

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LEGAL ADVISOR CASE

Collaborative practice agreements

BY ANN W. LATNER, JD

Ms. B, a 36-year-old nurse practitioner (NP), had known Dr. C, a 45-year-old family practice physician, for several years before she asked him to enter into a collaborative practice agreement with her. The two clinicians had once worked together and were friends.

Ms. B knew that the physician, in addition to having his own busy practice, had collaborative practice agreements with several other NPs. Ms. B wanted to start her own practice but needed a physician to sign a collaborative practice agreement to do so. Dr. C quickly agreed to Ms. B’s request, telling her that he was already in collaborative practice agreements with 8 other NPs. The clinicians signed the agreement, and Ms. B opened her practice and began treating and writing prescriptions for her patients.

According to the law of the state in which they practiced, as part of the collaborative practice agreement, Dr. C was required to review at least 5% of Ms. B’s charts each week to evaluate her prescriptive practices. Although both clinicians were aware of this, neither was particularly concerned about the requirement, and Dr. C did

© THINKSTOCK

Duty of care owed to a nurse practitioner’s patient by a collaborative practice partner comes into question.

An NP enters into a collaborative practice agreement with a family physician, but the clinicians do not adhere to all of the requirements.

not review any of the charts of Ms. B’s patients, although he did occasionally review her notes.

At one point after reviewing Ms. B’s notes, the physician expressed some concern about Ms. B’s prescribing practices and suggested that she attend a narcotic-prescribing seminar. However, he never followed up, and Ms. B never took the suggestion.

One of Ms. B’s patients was high-risk, with a history of pain, depression, suicide attempts, and polysubstance abuse. During the 3-month period, from January to March, in which Ms. B was treating the patient, she prescribed multiple medications, including hydrocodone/acetaminophen, methadone, bupropion, lithium, and alprazolam. In late March, the patient died, and an autopsy revealed the cause of death to be acute bronchopneumonia complicated by a mixed-drug interaction.

Continues on page 72

Cases presented are based on actual occurrences.

Names of participants and details have been changed.

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

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LEGAL ADVISOR The patient’s widow consulted with a plaintiff’s attorney.

After a discussion with the attorney and examination of the patient’s records by an expert, the widow decided to sue.

Although Dr. C never examined the patient or looked at his file, both he and Ms. B were named in the lawsuit.

The lawsuit caused terrible tension between the two clinicians. Their working relationship swiftly turned hostile and fell apart. Dr. C was angry and resentful at being drawn into a lawsuit that he felt was none of his business. He hired a defense attorney and filed a motion to dismiss the case, based on his assertion that he owed no duty of care, which is a required element for a medical malpractice case, because he never saw or treated the patient.

The trial court ruled that Dr. C did indeed owe a duty of care to the patient. Dr. C appealed to the state’s Court of Appeals. During the appeal, Dr. C argued that he had never even seen the patient’s file, that the patient was not his patient, and that the only one who owed a duty of care to the patient was Ms. B. The Court of Appeals disagreed and held that Dr. C did have a duty to the patient.

Legal background

Dr. C’s main argument was that since he had no doctorpatient relationship with the patient, then he owed no duty to the patient. However, healthcare practitioners can still sometimes owe a duty to a third party to whom they have not provided care. In analyzing whether a duty existed, the

This case shows how important it is to comply with all requirements of a collaborative practice agreement.

Court of Appeals looked at 3 factors: 1) the relationship of the parties; 2) the reasonable foreseeability of harm to the person who was injured; and 3) public policy concerns.

While there was no direct relationship between Dr. C and the patient, the court held that when a physician voluntarily enters into a contract with a nurse practitioner pursuant to which he agrees to provide oversight of her prescriptive practices, the purpose is for the protection of the NP’s patients.

The court found this to weigh in favor of a duty.

When looking at the second factor—foreseeable harm—the court noted that Dr. C admitted that his failure to adequately supervise and review Ms. B’s charts, as required by their collaborative practice agreement, could result in harm to

her patients. This also pointed toward a duty by the physician, because he knew his action or inaction could affect Ms. B’s patients.

Finally, the court looked at public policy and noted that the legislature had created a detailed list of requirements that a collaborative practice agreement must fulfill. The reason, the court noted, is to protect and ensure the safety of the public.

Based on this, the court rejected Dr. C’s argument that he did not owe a duty to the patients of Ms. B with whom he had a collaborative practice agreement, and it ruled that the case could proceed against him.

The lawsuit is not over, however. The case has been sent back to trial court where a jury will decide the remaining issues: whether the clinicians breached their duty to the patient, and whether the breach was the cause of the patient’s death.

Protecting yourself

Collaborative practice agreements vary widely from state to state. In some states, nurse practitioners need a written agreement with a physician to diagnose, treat, and prescribe.

In other states, physician collaboration is only needed for NPs to prescribe. Some states do not require collaborative practice agreements at all.

If you have a collaborative practice agreement with a physician, be sure you understand and follow the requirements, for the benefit of yourself, your patients, and your collaborative practice partner. Both Ms. B and Dr. C were aware that the agreement into which they entered required the physician to review a random 5% of Ms. B’s patient charts each week.

Yet neither clinician took this seriously.

Had Ms. B pushed the physician to look at the charts, he might have spotted a dangerous prescribing behavior that could have better protected Ms. B’s patient and thus, protected Ms. B from a lawsuit. In the case of Dr. C, it is even clearer why he should have complied. The Court of Appeals held that, had he fulfilled his legal obligation to review the required number of charts and found nothing wrong, he would not be liable for malpractice committed by Ms. B in the care of a patient whose chart was not reviewed.

Although malpractice in this case has not yet been established, nor may it ever be established, this case is an example of how necessary it is for both parties to comply with all requirements of a collaborative practice agreement. n Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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ALTERNATIVE MEDS UPDATE

What you should know about the herbs and supplements patients use

By Sherril Sego, FNP-C, DNP Ms. Sego is an independent consultant in Kansas City, Mo.

Color therapy

© BSIP / PHOTOTAKE

We all use colors to describe certain moods, thoughts, and even weather conditions. “Feeling blue,” “green with envy,” and “cowardly yellow” are commonly used phrases in our English language. But where do these sayings come from?

Some of the earliest writings we have about color come from the ancient Greek philosopher Aristotle. Aristotle wrote an entire treatise about color, aptly named, On Color.1 He is credited with creating the first known color wheel, attributing four main colors to four main domains: earth, wind, fire, and water.1

Background Chromotherapy is defined as “the use of light of specific colors to treat health problems.”2 There are many reports in the literature about the possible benefits of color therapy. The basis for most of the studies and theories is the understanding that light (and colors) are composed of electromagnetic energy.

Each color represents a different intensity, or pulse, of energy.3 The body comprises varying energy fields called chakras, depending on the system and body part. Chromotherapy assumes that illness is caused by or causes an imbalance in these chakras. True chromotherapy is intended to rebalance using specific colors, thus healing the ailment.4

Science Much more recent than Aristotle, the modern equivalent of the founder of color therapy could easily be Max Luscher.5 Luscher developed “Luscher’s Color Test,” which is

a psychological test using the premise that sensory perception of color, as well as internal reactions to color, are combinations of not only objective preference but subconscious as well.

Luscher’s test, however, has been largely criticized by much of the psychology world after a comparison study against the well-established Minnesota Mental Personality Index when it failed to correspond to established benchmarks of accuracy.6 In one randomized clinical trial, researchers explored the effect of color therapy on people who had a stroke more than 6 months previously.7 The study enrolled both the patient and the closest caregiver to show the impact of color therapy on perceived quality of life, or in this instance, purpose in life, as measured by a standardized questionnaire.7 Participants were split into 2 groups. The treatment group received 2 hours/week of color-based therapy for 16 weeks, and the control group received routine therapy. The questionnaire was administered before the study began and at the end of the trial. Results showed an average 50% improvement in purpose in life for patients in the treatment group and more

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ALTERNATIVE MEDS UPDATE than 25% improvement in purpose in life for caregivers in the treatment group.

In another small study, 64 college students were randomly exposed to scenarios suggesting anxiety, calm, or neutrality.8 Participants were then instructed to use their choice of colors to complete a standardized pre-drawn mandala, similar to a color wheel. The results were evaluated for use of colors considered warm (anxious) and cool (calm) and found no statistical difference in the choice of colors used by the participants.8 Our body perceives light rays through the retina of the eye.9 The subsequent chain of events involves complex mechanisms of the autonomic nervous system. In a study to evaluate chromotherapy in healthy people, more than 110 participants were randomly assigned to 1 of 3 groups: those exposed to specific colors, those exposed to specific modulations in light frequency, and a placebo group of those exposed to non-modulated white light. Measurements of autonomic function (heart rate, heart rate variability, skin conductance) were noted before and after the study. Results revealed significant changes in these measures in the treatment groups compared with the placebo group.10 Another uncontrolled study from 2000, viewed by some as purely anecdotal, showed that in Glasgow, where blue light street lamps were installed in several neighborhoods, the crime rate had decreased significantly after several months.11

of chromotherapy. Insurance coverage and outof-pocket costs vary widely.

Summary

Cost of chromotherapy depends on the discipline of the therapist.

Behavioral health providers and rehabilitation professionals are the most common practitioners of chromotherapy.

Safety, interactions

Many practices, including the use of therapeutic touch, craniosacral therapy, and magnet therapy, are based on concepts similar to those of chromotherapy. As healthcare professionals, we must provide the basics of safety and efficacy for our patients. These decisions are usually based on the presenting condition and the potential financial burden for the patient; however, it would not hurt to make sure that the waiting and examination rooms are painted in calming colors. n References 1. Shields C. Aristotle’s Psychology. In: Zalta EN, Nodelman U, Allen C, Oppenheimer P, eds. Stanford Encyclopedia of Philosophy. (Spring 2016 edition). http://plato.stanford.edu/ entries/aristotle-psychology.

2. Miller BF, Keane CB, O’Toole MT. Miller-Keane Encyclopedia & Dictionary of Medicine, Nursing, and Allied Health. 7th ed. Philadelphia, PA: Saunders; 2003.

3. How does chromotherapy work? WebMD answers. http://answers.webmd.com/answers/1189420/how-doeschromotherapy-work. Posted April 14, 2010.

4. Samina T, Azeemi Y, Raza SM. A critical analysis of chromotherapy and its scientific evolution. Evid Based Complement Alternat Med. 2005;2(4):481-488.

5. Luscher M. Luscher Color Diagnostic. Available at: http:// www.luscher-color.com.

6. Holmes CB. Relationship between the Luscher Color Test and the MMPI. J Clin Psychol. 1984;40(1):126-128.

7. Kim MK, Kang SD. Effects of art therapy using color on

Although there are no documented safety concerns, the impact of color therapy on mood and autonomic function indicates a need for caution in those with known behavioral health conditions. There are no reported interactions of chromotherapy with other therapies.

Cost, how supplied

purpose in life in patients with stroke and their caregivers.

Yonsei Med J. 2013;54(1):15-20.

8. Kersten A, van der Vennet R. The impact of anxious and calm emotional states on color usage in pre-drawn mandalas. Art Ther: J Am Art Ther Assoc. 2010;27(4):184-189.

9. Conway BR, Chatterjee S, Field GD, et al. Advances in color science: from retina to behavior. J Neurosci.

2010;30(45):14955-14963. lated, colored light on the autonomic nervous system. Adv Mind Body Med. 2013;27(4):7-16.

11. Simbun TY. Blue street lights believed to prevent suicides, street crime. The Seattle Times. December 11, 2008.

© THINKSTOCK

10. Ross MJ, Guthrie P, Dumont JC. The impact of modu-

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COMMENTARY Sharon O’Brien is a practicing physician assistant and health coach in Asheville, N.C.

A dietary plan for better sleep I have often been asked by patients about the relationship between food and sleep. Various articles are available on the Internet suggesting that eating foods such as bananas and cherries before going to bed can help promote better slumber. I even have a co-worker who swears that her glass of cherry juice puts her right to sleep. Can I say for sure that these things are helpful? Well, it may depend on the patient. However, research suggests that what you eat in the evening can influence your sleep.

We probably have all experienced eating a high-carbohydrate meal and then feeling sleepy afterward.

So we know that food has an effect on our bodies. Researchers now have evidence that fiber and

A diet rich in fiber, with reduced intake of sugar and non-fiber carbs, may help a patient sleep better.

sugar eaten before bed can affect the different stages of sleep (St-Onge MP, Roberts A, Shechter A, Choudhury AR. Fiber and saturated fat are associated with sleep arousals and slow wave sleep. J Clin Sleep Med. 2016;12[1]:19–24.)

In this study, meals were provided to research participants 3 times daily, with the evening meal at 7:00 p.m. The controlled diet contained 31% of energy from fat, 53% from carbohydrates, and 17% of energy from protein. Sleep was assessed each night with use of polysomnography. The participants also had an opportunity to eat whatever they wanted for 2 days for comparison.

The findings of the study showed that fiber intake was associated with decreased time in stage 1 sleep, our lightest stage of sleep, and an increased time in slow-wave sleep, which is our most restorative sleep. Saturated fat was associated with decreased time in slow-wave sleep. Both sugar and non-sugar/non-fiber carbohydrates were associated with more nocturnal arousals.

A diet rich in fiber, with reduced intake of sugar and non-fiber carbohydrates, may help a patient sleep better. Bananas and cherries have fiber, but they also have a considerable amount of sugar. Although it may not sound as appealing, cauliflower, broccoli, and cabbage are great sources of fiber. These might be a better suggestion to your patients if they want to sleep better.

Other foods can influence sleep, including those that are rich in tyramine and tyrosine.

These are naturally occurring amino acids that increase the production of norepinephrine. So eating these foods before going to bed could stimulate a patient. Foods rich in tyramine include eggplant, potatoes, spinach, and sugar.

Tyrosine is found in avocados, turkey, chicken, milk, almonds, and cheese.

Any food could potentially be problematic if a large quantity is consumed too close to bedtime. Digestion is an active process. It is best to consume your evening meal 3 to 4 hours before bedtime to allow for healthy digestion. I suggest eating your lightest meal in the evening, and save heavier meals for breakfast or lunch.

We also have to remind our patients that spicy, acidic foods before bedtime can cause gastroesophageal reflux (GERD). Alcohol consumption before bedtime can also add to GERD symptoms. Again, eating earlier in the evening can be beneficial for your patients with GERD, in addition to raising the head of their bed.

Avoid foods such as chocolate, citrus, and fatty or greasy foods.

Furthermore, remind patients that caffeine should be avoided. For some, caffeine can linger in the body for as long as 12 hours. So if they are drinking caffeinated substances after lunch, it could affect their sleep later in the evening.

Most know the usual suspects such as coffee, tea, and soda. However, some cookies, puddings, and yogurt also contain caffeine. n

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