December 2018 Clinical Advisor by The Clinical Advisor

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■■Flu Vaccine in Pregnancy ■■HBV Guideline Adherence ■■Ovarian Cancer Screening ■■Cesarean Delivery Rates FEATURE

Guidance for Antibiotic Use in Myasthenia Gravis CASE STUDY: PEDIATRICS

A Case of Floppy Baby Syndrome LEGAL ADVISOR

Terminated for Taking FMLA?

DERMATOLOGY CLINIC

Pigmented Growth on the Upper Back

FEATURE

Effect of Artificial Sweeteners on Obesity Risk in Children

DECEMBER 2018

| www.ClinicalAdvisor.com

CME: CASE STUDY

ADPKD: Promising Treatment for a Rare, Inherited Disorder ADPKD can have a devastating effect on patients.

Vice president, content, medical communications, editor Kathleen Walsh Tulley editor@clinicaladvisor.com Associate editor Madeline Morr Assistant editor Rita Aghjayan Contributing editors Mark P. Brady, PA-C; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP; Sharon Dudley-Brown, PhD, FNP; Abimbola Farinde, PharmD; Laura A. Foster, CRNP, FNP; Abby A. Jacobson, PA; Maria Kidner, DNP, FNP; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Mary Newberry, CNM, MSN; Claire Babcock O’Connell, MPH, PA; Kathy Pereira, DNP, FNP; Sherril Sego, DNP, FNP; Ann Walsh, PA-C, SCT(ASCP); Kim Zuber, PA-C Production editor Kim Daigneau Group art director, Haymarket Medical Jennifer Dvoretz Senior production manager Krassi Varbanov Assistant manager, audience development Ashley Noelle Director of audience insights Paul Silver National accounts manager Alison McCauley, 973.224.6414 alison.mccauley @ haymarketmedical.com Publisher Kathleen Hiltz, 201.774.1078 kathleen.hiltz@haymarketmedia.com General manager, medical communications Jim Burke, RPh President, medical communications Michael Graziani CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 275 7th Avenue, 10th Floor, New York, NY 10001 For advertising sales, call 646.638.6085. For reprints, contact Wright’s Reprints at 877.652.5295. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Features” are not the actual individuals mentioned in the articles. They appear for illustrative purposes only. The Clinical Advisor ® (USPS 017-546, ISSN 1524-7317),Volume 21, Number 12, Published 12 times a year, monthly, by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, call (646) 638-6000 (M–F, 9am–5pm, ET). The Clinical Advisor is available on a paid subscription basis at the following annual rates: $75 USA, $85 Canada, $110 for all other foreign, in U.S. dollars, Single copy price: USA $20, Foreign $30. To order or update a paid subscription visit our website at www. ClinicalAdvisor.com or call (800) 436-9269. Periodicals postage rate paid at NewYork, NY, and additional mailing offices. Postmaster: Send changes of address to The Clinical Advisor, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2018

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

Advisor Forum 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.

CLINICAL PEARLS

It cannot be beat.—TERRI JORDAN, ARNP, Daytona Beach, Fla. (202-2)

NEUTROPHILS AND LYMPHOCYTES In interpreting a complete blood count with differential, anytime the neutrophils and lymphocytes are numerically close, it is a viral cause; when the neutrophils and lymphocytes are numerically distant, it is a bacterial cause. This is very helpful in determining treatment.—DONNA CARTER, FNP-C, Scottsburg, Ind. (202-1) GENERIC “CAINE” IS EFFECTIVE FOR WOUND CARE For pain relief, most pharmacies offer a “caine” at 2-510%, and basically nothing higher, for between $5 and $30 per tube. I work in wound care and use Walmart’s

INTRA-ARTICULAR INJECTIONS FOR SEVERE OSTEOARTHRITIS Patients with severe osteoarthritis in the knees seem to do better with intra-articular injections if you have them sit up and dangle their legs off the examination table and distract the knee slightly when administering the injection.—ROSEMARY LEDBETTER, PhD, PA, Troy, Ill. (202-3)

YOUR COMMENTS SLIPPED CAPITAL FEMORAL EPIPHYSIS IN OBESE ADOLESCENTS I just read the CME/CE article by Marilou Shreve, DNP, APRN, entitled, “Assessing and treating pediatric obesity” [ June 2015]. I was concerned regarding the oversight of a critical issue in obese adolescents: the increased risk of slipped capital femoral epiphysis (SCFE). This was not addressed in the article. The case study (p. 55) gave incomplete advice regarding the evaluation of an obese adolescent male with knee pain. The most common etiology of the insidious onset of knee pain in children is the hip, due to referred pain from the

Equate brand—vagicaine 20% benzocaine. When using this before debriding a wound, give it three minutes to sedate the nerves, then perform the procedure. I get good results, as patients say. It relieves pain and burning for $1.88.

Advisor F

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.

orum

These are lette and successe rs from practitioners s, observat around the below. We ions, and country who OUR CONSULTANTS pearls with invite you want to shar to participa their colle e their clinic agues. Resp te. al problems onding cons ultants are identified CON SULTAT IONS

TREATM ENT FOR INFECT URINAR ION SGLT2 REC MALE CHI S IN THE UNC Y TRACT IRCUMCI LD FOR DIA EPTOR BLOCKE If a male SED child conti Deborah L. Cross, MPH, CRNP, Laura A.BET Foster,ES CRNP, FNP, Abby A. Jacobson, PA-C, RS Abimbola Farinde, PhD, PharmD, With the nues toassociate ANP-BC, is practices family medicine is a physician assistant is a professor redevprogram adven t ofPrimary circu SGLT2 recep at Delaware Valley urinaryattract director, Gerontology NP elop Program, mcisi Columbia Southern moda litywith Palmetto on be perfo for type tor infecUniversity of Pennsylvania School Physicians Dermatology blockersGroup University 2 diabe rmed? regarding inCare as a treatm in Wilmington, Del. in Orange Beach, Ala. useCharleston, S.C. tes, is there ent urology is of Nursing, Philadelphia. any evide NATHAN in patients with to protect the is well advise nce or data type 1 diabe GARDNE d tes mellitus?— R, PA-C, continues to to recommend a circum upper tracts, the kidne CPAAPA, ys. develo cision•on It p recurr•ent 44 THE ADVISOR AUGUST 2015 www.ClinicalAdvisor.com Castleton, severaCLINICAL l consideration urinary tract the male child who As it currently stands N.Y. , SGLT2 s that enter infections. for glycemic impede the recept into There or blockers control in ability to cleans this decisio adults are FDA-appr n. Poor hygien are with diet and should the e and quell oved child have exercise, but with type 2 diabet e may appro phimosis, simpl infection potential. es appropriate the in ved for use in conjun 2:38 PM FDA has Moreover, AdvisorForum_CA0815.indd urine 44 e cathet patients with stated that 9/29/15ction culture can ketoacidosi steroid cream they are not type be a challenge. erization to obtain s, or those may tempo an FAR with severe 1 diabetes, patients with Having a short tion of the rarily solve renal functi diabetic steroid the trial of informINDE, PhD, Pharm these issues tenden , though after for infection D (See bottom on.—ABIMBOL ation about once again.—C cy redevelops, placin cessaA Dr. Farinde.) of this page Milwaukee g (203-2) for more , Wis. (203- OLEEN ROSEN, the child at risk 1) DNP, FNP -C, CLI Philip R. Cohen, MD,

is clinicaltions associate professor , shou ld of dermatology, University a of Texas Medical Center, The focus of Houston.

NICAL

Send us your letter Advisor Forum, The s with questions New York, and comm Clinical Advisor ents to: , 114 clinicaladvisoNY 10001. You may contacWest 26th Street , please indicatr.com. If you are writing in t us by e-mail at 4th Floor, each item. e so by including response editor@ to a the Letters are policy is edited for number in parent published letter, to heses at length and contribution print the author ’s name with clarity. The Clinicathe end of s will be accepted. l Advisor the letter. No anonym ’s ous

Write us today.

OUR CO

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PEARLS

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VAGINA L RESULT DISCHARGE AND ING FRO If a female M TAMPON ODOR patient has USE a ask if she uses tamp history of vaginal disch ons. If she the pelvic arge with says “yes,” exam when cond odor, that you woul , do not enter ucting the rotating of d to take a pap smea vagina in the same the specu way r. Instead, the cervix. lum Most retain from side to side start shallow until reach ed tampons ing are lodge d in the fold

Philip R.

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

SEND TO The Clinical Advisor 275 7th Avenue, 10th floor New York, NY 10001

62 THE CLINI

Deborah L. Cross, MPH, ANP-B

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

CAL ADVI

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, PhD,

is a profess PharmD, or at Columb ia Souther n Univers in Orange ity Beach, Ala.

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Laura A.

Foster,

practices familyCRNP, FNP, with Palmett medicine o Primary Care Physicia ns in Charles ton, S.C.

Abby A.

Jacobso

is a physicia n, PA-C, n at Delawa assistant re Dermatology Valley in Wilmington,Group Del.

.indd 62

9/29/15

2:44 PM

E-MAIL editor@clinicaladvisor.com

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2018 5

CONTENTS DECEMBER 2018

NEWS 13 Newsline ■■Effect of Vaccine on Flu Hospitalization During Pregnancy ■■Suboptimal Adherence to Chronic HBV Treatment Guidelines ■■Clinician Experience Influences Ovarian Cancer Screening Decisions ■■Significant Increase Seen in Cesarean Deliveries Worldwide 14 Adherence to Screening Guidelines

FEATURES 15 Effect of Artificial Sweeteners on Obesity Risk in Children Does drinking artificially sweetened beverages increase the risk of obesity compared with drinking other zero-calorie beverages? 26 Antibiotics in Myasthenia Gravis

43 Diffuse Erythematous Rash

26 Guidance for the Use of Antibiotics in Patients With Myasthenia Gravis The potential for antibiotics to unmask or worsen myasthenia gravis is significant given that patients with the condition may be predisposed to infectious diseases. 30 CME Case Study: A 27-Year-Old Man With Newly Diagnosed ADPKD In this case study, the journey of a patient navigating from diagnosis of autosomal-dominant polycystic kidney disease (ADPKD) through treatment is described. 37 CME Feature Posttest

53 Did FMLA Lead to Termination?

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MORE WAYS TO FIND US!

DEPARTMENTS ■ Flu Vaccine in Pregnancy ■ HBV Guideline Adherence ■ Ovarian Cancer Screening ■ Cesarean Delivery Rates FEATURE

Guidance for Antibiotic Use in Myasthenia Gravis CASE STUDY: PEDIATRICS

A Case of Floppy Baby Syndrome

THE CLINICAL ADVISOR • OCTOBER 2018

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

THE CLINICAL ADVISOR • NOVEMBER 2018

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

THE CLINICAL ADVISOR • DECEMBER 2018

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS | NOVEMBER 2018 | www.ClinicalAdvisor.com DECEMBER 2018 | www.ClinicalAdvisor.com A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS | OCTOBER 2018

NEWSLINE CME: CASE STUDY ■ Screening for alcohol

| www.ClinicalAdvisor.com

MULTIPLE SYSTEM ATROPHY Community CME: CASE CHALLENGE paramedics

of and Hodgkin’s ADPKD: Promising A Common Form Psoriasis Treatment for a Rare, Atypical Parkinsonism Lymphoma Inherited Disorder and depression ■ VVA management barriers ■ Sexual assault effects

contribute to effective and efficient healthcare utilization.

FEATURE

PAGE 60

Micronutrients for optimizing pregnancy outcomes

ADPKD can have a devastating effect on patients.

MSA is notable for accumulation NEWSLINE of α-synuclein Meningococcal in■glial cells.

vaccine ■ Dairy consumption, CVD ■ Otitis media

ALT MEDS UPDATE

Wound care treatments

Approximately 2% to 3% of the global population is affected by psoriasis.

LEGAL ADVISOR

Effect of Artificial Sweeteners on Obesity Risk in Children

FREE CME COURSE

Minimally invasive total laparoscopic hysterectomy

Red-brown papules on the extremities

VOLUME 21, NUMBER 10

FEATURE

DERMATOLOGY CLINIC

Painful, recurrent rash on the fingers

VOLUME 21, NUMBER 11

Dermatologic Look-Alikes Widespread Erythematous Rash

DERMATOLOGY CLINIC

Pigmented Growth on the Upper Back

VOLUME 21, NUMBER 12

Dermatology Clinic ■ Raised Pink Rash on the Lower Extremity ■ Pigmented Growth on the Upper Back

LEGAL ADVISOR

NP faulted for patient care via fax

FEATURE

Current guidelines for management of low back pain

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Case Study: Obstetrics and Gynecology Early Pregnancy and Painless Spotting

Case Study: Pediatrics A Case of Floppy Baby Syndrome

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“Have you tried icing it?”

A patient’s death following hospital discharge

LEGAL ADVISOR

Terminated for Taking FMLA?

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com

NEWS ClinicalAdvisor.com/News

HPV Screening Associated With Low Cervical Cancer Risk in Older Women

THE WAITING ROOM

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Tafari Mbadiwe Mistaking Legal Recourse for Evidence-Based Medical Practices in Surrogacy Paying a surrogate to carry a fetus shoehorns a fourth, and fifth, party into the already tight therapeutic triangle formed by the biological mom, fetus, and physician.

A woman with typical cytology screening adherence who stops screening at age 55 is predicted to have a risk of cervical cancer at 1 in 138, and a woman with typical cytology screening adherence who stops screening at age 70 years reduces her lifetime cervical cancer risk to 1 in 160.

Tissue-Selective Estrogen Complex May Benefit Postmenopausal Women With Vaginal Bleeding, Breast Discomfort For postmenopausal women who experience breast discomfort or persistent vaginal bleeding while receiving menopausal hormone therapy, switching to a tissue-selective estrogen complex may be beneficial.

Foster Care Reduces Risk for Psychopathology Associated With Institutionalized Care Children raised in institutions are at increased risk for general and externalizing psychopathology years after their removal from the institutions, but the risk for psychopathology is attenuated between ages 8 and 16 by early assignment to foster care.

Disagreements in Blood Pressure Guidelines Lead to Physician, Patient Confusion Discord among international, organizational blood pressure guidelines has led to confusion between physicians and patients alike.

CASE STUDY Clinical Advisor.com/CaseStudy David Kirsch, MD Trauma-Induced Pulmonary Embolism: A Clinical Case A 25-year-old man complaining of chest pain and with evidence of significant chest trauma presented to the emergency department after sustaining injuries while riding an all-terrain vehicle. Read the full case here: ClinicalAdvisor.com/CasePulmonaryEmbolism Brady Pregerson, MD Case Study: Abdominal Pain, Malaise, and a Bruise on the Leg A 44-year-old man presents to the hospital with generalized abdominal pain, malaise, subjective low-grade fever, and a bruise on his left shin. He has an extensive medical history including HIV, hypertension, diabetes, and GERD, but he denies vomiting or diarrhea. Read the full case here: ClinicalAdvisor.com/CasePainBruising

PRACTICE MANAGEMENT ClinicalAdvisor.com/PracticeManagement AHA, ADA, and Others Concerned Over Latest Trump Administration ACA Guidance More than 25 professional medical and patient advocacy organizations are in opposition to the Trump Administration’s latest effort to undermine the Affordable Care Act.

8 THE CLINICAL ADVISOR • DECEMBER 2018 • www.ClinicalAdvisor.com

Advisor Dx Interact with your peers by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/AdvisorDx. Check out some of our latest cases below!

DERM DX

Asymptomatic Lesion Above the Left Eye A 36-year-old Hispanic woman requests removal of a lesion above her left eye that has gradually increased in size over the past 8 months. She denies itching or bleeding. She does not take oral medications and states that recent blood work was reported as “normal.” No similar lesions are noted elsewhere. CAN YOU DIAGNOSE THIS CONDITION?

• Intradermal nevus • Xanthoma

• Sarcoid • Linear epithelial nevus

● See the full case at ClinicalAdvisor.com/DermDx_Dec18

In partnership with

ORTHO DX

TheJopa.org

Journal of Orthopedics for Physician Assistants

Persistent Left Knee Pain A 62-year-old woman presents to the office with left knee pain that has persisted for 2 years. The pain is located over the medial knee and is worse with activities. Radiographs show medial compartment arthritis of the left knee. The patient was told she was a candidate for a partial knee replacement, or unicompartmental knee arthroscopy (UKA), and she would like to learn more about this procedure. WHICH OF THE FOLLOWING STATEMENTS IS TRUE?

• Revision rates are higher for total knee arthroplasty (TKA) compared with UKA • TKA offers improved physiologic knee function • TKA has a higher rate of postoperative complications • UKA should not be performed in patients older than 60 years of age ● See the full case at ClinicalAdvisor.com/OrthoDx_Dec18

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2018 9

Newsline DURING PREGNANCY, the use of influenza vaccines moderately protected against laboratory-confirmed influenzalinked hospitalization over the course of 6 influenza seasons, according to research published in Clinical Infectious Diseases. The effectiveness of influenza vaccination against laboratory-confirmed influenza-associated hospitalization during pregnancy was assessed using data from the Pregnancy Influenza Vaccine Effectiveness Network (PREVENT), which was composed of public health or healthcare systems with incorporated laboratory, medical, and vaccination records. Data were taken from women whose pregnancies took place during the local

influenza seasons between 2010 and 2016. Study outcomes included acute respiratory or febrile illness (ARFI) and the confirmed presence of influenza viruses in real-time reverse transcription polymerase chain reaction (PCR). A total of 19,450 ARFI hospitalizations were reported, 6% of which had PCR influenza virus testing.The sample included 1030 hospitalizations, 25 of which were repeated hospitalizations. Results suggested that 79% of ARFI hospitalizations occurred in women younger than 35 years; 65% of ARFI incidents occurred in women in their third trimester, and 66% had no high-risk medical conditions. The researchers also noted that 58% of

Effect of Vaccination on Influenza-Related Hospitalization During Pregnancy

Flu vaccine was moderately protective against hospitalization.

ARFI hospitalizations with PCR testing were positive for influenza virus: 13% of influenza-positive and 22% of influenzanegative women had been vaccinated, which correlates to an unadjusted influenza vaccine effectiveness of 48% (40% adjusted) against influenza-associated hospitalization during pregnancy.

Suboptimal Adherence to Chronic HBV Treatment Guidelines THE PERCENTAGE of patients with chronic hepatitis B virus (HBV) infection undergoing evaluation and receiving treatment according to criteria established by the American Association for the Study of Liver Diseases (AASLD) has been found to be suboptimal, according to a study published in Clinical Gastroenterology and Hepatology. A retrospective, multicenter study was conducted to determine evaluation and treatment initiation practices in varying clinical settings and compare these findings with the AASLD guidelines. Patients with chronic HBV infection (N = 4130)

who visited community primary care physicians (n = 616), community gastroenterologists (n = 2251), or university hepatologists (n = 1263) were included in the analysis.Tests for chronic HBV infection included alanine aminotransferase, HBV e-antigen, and HBV DNA. The investigators reported that 36.69% of the primary care patients, 59.80% of the gastroenterologist care patients, and 79.97% of hepatology care patients underwent relevant testing within the first 6 months of receiving care. For primary care, gastroenterologist care, and hepatologist care, the proportion of

patients eligible for treatment in specialty practices was 12.76%, 24.96%, and 29.43%, respectively. For eligible patients receiving treatment from a gastroenterologist or a hepatologist, no significant difference was noted in the proportion beginning antiviral therapy (55.65% vs 57.90%, respectively): Of the 243 patients from the primary care cohort, 31 were eligible for treatment and only 12 received treatment. “Such findings suggest that there remains a lack of knowledge on the availability and effectiveness of [chronic HBV] treatment, likely both at provider and patient levels,” the authors noted.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2018 13

Newsline Experience Influences Ovarian Cancer Screening Decisions CLINICIANS WITH A nonprofessional experience with cancer — such as having cancer themselves or having family members, close friends, or coworkers with cancer — were found to offer nonrecommended ovarian cancer screening to low-risk patients more often than those without these nonprofessional experiences, according to a study published in the Journal of Women’s Health. Researchers surveyed 3200 US primary care clinicians to assess ovarian cancer screening, diagnosis, and management. The survey included 3 clinical vignettes that presented fictional patients (age 35 or 51 years,African American or white, and having public or private insurance).The case patients were identified as high risk (paternal grandmother had ovarian cancer, paternal first cousin had premenopausal breast cancer, woman had breast cancer at age 30), medium risk (mother had ovarian cancer at age 62), and low risk (mother

Clinicians in group practice were more likely to adhere to screening guidelines.

had breast cancer at age 70). The questionnaire also indicated whether the case patient requested ovarian cancer screening. The majority of clinicians included in the study were men (58.5%), white (71.1%), and practicing in an urban setting (82.0%).The final analysis included data from 497 clinicians who were presented

with an annual examination vignette of a woman at low risk for ovarian cancer. A total of 69.2% of clinicians with nonprofessional experience with cancer were found to adhere to ovarian cancer screening recommendations vs 86.0% of clinicians without similar cancer experience. Clinicians were more likely to follow screening guidelines for patients who did not specifically request ovarian cancer screening (79.7%) than for patients who requested ovarian cancer screening (63.9%). Clinicians in group practice were more likely to screen for ovarian cancer according to guidelines (75.8%) vs those in solo practice (57.4%). Physicians who adhered to other US Preventive Services Task Force (USPSTF) recommendations were more likely to adhere to guidelines for ovarian cancer screening vs those who were not strongly influenced by the USPSTF recommendations (79.6% vs 62.7%, respectively).

Significant Increase Seen in Cesarean Deliveries Worldwide intervene in this way when it is medically required.” Data from 169 countries were obtained to identify global disparities in cesarean delivery rates. Increased rates of cesarean delivery were attributed primarily to more births occurring in a healthcare

institution were more likely to undergo cesarean delivery compared with poor women and those using a public facility. The investigators cautioned against the use of cesarean delivery in the absence of a medical indication and outlined the risks associated with cesarean delivery,

Infants born via cesarean delivery may experience hormonal, physical, bacterial, and medical exposures, as well as immune system changes that can affect their health. setting, as well as increased frequency of cesarean delivery in these settings. Economic disparities were seen as a driver for the differences in cesarean delivery rates globally; wealthier women and those using a private healthcare

14 THE CLINICAL ADVISOR • DECEMBER 2018 • www.ClinicalAdvisor.com

including maternal death and disability, as well as scarring that can cause bleeding, abnormal development of the placenta, and in future pregnancies ectopic pregnancy, stillbirth, and preterm birth. ■

FROM 2000 TO 2015, the number of infants born via cesarean delivery increased from 12% to 21%, according to research published in The Lancet. An estimated 10% to 15% of all births require cesarean delivery due to pregnancy complications. However, the majority of countries report rates of cesarean delivery above these levels. According to lead author Marleen Temmerman, PhD, “…The large increases in [cesarean delivery] — mostly in richer settings for non-medical purposes — are concerning because of the associated risks for women and children. [Cesarean deliveries] can create complications and side effects for mothers and babies, and we call on healthcare professionals, hospitals, funders, women and families to only

FEATURE: MELISSA NOBLITT, RN, MSN-S; KINDRA L. SHEPARD, RN, MSN-S; SUSAN ELEY PHD, MS, FNP-BC

Effect of Artificial Sweeteners on Obesity Risk in Children Educating children and their families about healthy beverage choices is a crucial element for reducing the current pediatric obesity epidemic.

Long-term use of artificial sweeteners may increase body mass index in children.

besity is defined as a weight higher than normal for a given height.1 In the United States, healthcare providers are faced with a national obesity epidemic, as obesity rates have risen at an alarming pace since the middle of the 1970s.1 During this time period, obesity rates more than tripled for some pediatric age groups. According to the Centers for Disease Control and Prevention, an estimated 1 out of every 3 children aged 2 to 19 years is overweight or obese in the United States.2 Rates differ for various groups from state to state but remain high across the board nationally. Certain ethnic groups and low-income families have higher rates of obesity.2 Obesity is the most common nutrition disorder seen by healthcare providers among children and adolescents.3 If obesity rates continue to rise, today’s youth could possibly have shorter life spans than their parents due to poor health. Overweight and obese children have a greater risk for cardiovascular disease, hypertension, and type 2 diabetes, and are more likely to remain overweight or obese into adulthood.4 As children become adults, these obese individuals are at greater risk for the same conditions in addition to some forms of cancer, dementia, and other health concerns.4 In addition, childhood obesity has the potential to cause emotional and psychological issues such as behavior problems, depression, eating disorders, learning difficulties, low self-concept, and negative body image.5 Overall, obesity is not

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2018 15

ARTIFICIAL SWEETENERS AND OBESITY RISK IN CHILDREN

Obesity rates have risen at an alarming pace since the middle of the 1970s and have more than tripled for some pediatric age groups. a single condition but a complex disorder that affects the body in a multitude of ways. The development of obesity involves several elements such as dietary habits, environment, genetics, lifestyle, and metabolism.3 Although most overweight children have at least 1 obese parent, genetics and hormonal issues only account for <10% of all obesity cases.3 Weight gain occurs when caloric intake is greater than output; ie, eating too much without enough exercise. Obese children learn unhealthy familial patterns of food intake, exercise, and selection of leisure activities that encourage increased intake with decreased output from their parents and other family members.3 A common approach to children and families with obesity issues is to provide education on healthy diets, making better food choices, and decreasing sugar intake from items such as carbonated beverages. A popular substitution for sugary drinks has been artificially sweetened, zero-calorie beverages. However, new research indicates that artificial sweeteners may not be a healthy substitute, and studies have suggested a positive correlation between artificially sweetened beverages (ASBs) and weight gain in children.6 Laverty and colleagues suggest artificial sweeteners may be stimulating children’s appetites and leading to overconsumption of food.7 According to the Harvard School of Public Health, a study examining the relationship between ASBs and weight in 3682 participants over a 7- to

8-year period found an approximately 45% increase in body mass index (BMI) in participants consuming ASBs compared with those who did not consume ASBs.8 These data prompt the question: In the pediatric population, does drinking ASBs increase the risk of obesity compared with drinking other zero-calorie beverages? Purpose

Although current literature provides numerous potential causes behind obesity, effective solutions are limited. This literature review will examine the effects of zero-calorie beverages on weight in the pediatric population. In addition, it will support the need for further research on the relationship between artificial sweeteners and weight. Methodology

The literature review process began with developing inclusion criteria. Literature concentrating on the effects of sugar-free sweetened products on body weight in the pediatric population published between 2012 and 2017 was considered for inclusion.The next step in the process was the development of initial keywords and phrases. An array of keywords and phrases were used individually and in a variety of combinations to locate information relevant to the subject matter within selected databases and search engines. Initial keywords and

■ Obesity ■ Extreme obesity

20.6 Percentage

17.4

15 10 5 0

9.4

9.1 4.3 1.7

2-5 Years

6-11 Years

12-19 Years

FIGURE: Estimated percentage of US youth with obesity, ages 2-19, 2013-2014 NHANES data. 16 THE CLINICAL ADVISOR • DECEMBER 2018 • www.ClinicalAdvisor.com

Although most overweight children have at least 1 obese parent, genetics and hormonal issues only account for <10% of all obesity cases. phrases included weight loss, artificial sweetener, children, obesity, sugar-free, sugar-free beverages, non-nutritive sweeteners, water, weight gain, and pediatric.Appropriate databases and search engines were then selected. The initial search was initiated within the Cochrane Library with additional database searches of CINAHL, MEDLINE, SportDiscus, and PsycInfo completed with EBSCOhost. The Google Scholar search engine was used to find supplemental scholarly articles related to the topic. By using keywords and phrases with the inclusion criteria, a list of applicable nonduplicated literature was created for the review. Initially, the process began with a search for “artificial sweetener” in the Cochrane database that produced 60 study results. By adding “children” to the search criteria, the results were refined to 4 trials, of which only 3 studied artificial sweeteners in pediatric populations, with 2 addressing behavior issues and the third examining dental caries. After performing searches using keyword and phrase combinations, the Cochrane Library yielded 102 trial results and 0 Cochrane reviews. Only 1 trial could be applied to the topic literature review after applying inclusion criteria and removing duplicate findings. Searches of the remaining databases were performed using EBSCOhost with the same keywords and phrases to locate literature published in the past 5 years, yielding 407 results. Using the same criteria and time frame, Google Scholar provided the most results on the initial search, with 16,700 results.To refine the searches in both EBSCOhost and Google Scholar, more specific keywords and phrases were used to eliminate unrelated material for a total of 8 additional meta-analyses and trials for use in the literature review. In general, the databases provided a limited number of results, and Google Scholar delivered the most results pertaining to the effects of artificial sweeteners on weight loss in the pediatric population. The final review of literature consisted of 9 studies. Literature Review

Water provides a healthy alternative to an ASB.Water is a readily available, zero-calorie beverage that can be used for satiety and weight management without the adverse effects associated with consuming carbonated beverages.An interventional study conducted by Muckelbauer et al9 investigated whether body weight was influenced by replacing sugar-sweetened beverages (SSB) with increased water intake. A 24-hour self-recall survey along with body measurements of height and weight were conducted in 3220 school-age children (mean age, 8.3 years). The findings show that an increase of 1 glass of water

consumption daily resulted in decreased SSB consumption without any effects on overall BMI (P =.63). However, an increase in 1 glass of SSB increased BMI by 0.02 with an increase in the prevalence of obesity (P =.83). The results indicate that replacing SSBs with water does improve weight loss but does not result in overall BMI reduction. Sichieri et al10 indicated similar effects of water and weight loss in a study examining beverage choices of children and the resulting effects on BMI. By drinking more water, children potentially would drink less unhealthy beverages, thereby resulting in a change in BMI.The study included 1400 fourth-grade children who were given a survey to verify 24-hour beverage recall. Weight and height were measured on all children enrolled in the study.The intervention group received advice on healthy dietary plans and general health in a 2-hour session.The frequency of consumption of SSBs (soda and juice) was found to have a positive association with change in BMI when adjusted for age and gender; however, water intake results revealed an inverse association. Findings suggest weight gain may be prevented by consuming more water. The findings further indicate that children who drank more than 3 glasses of water at baseline had a smaller incremental change in BMI compared with those children who reported drinking less than 3 glasses of water. The control cohort was the only group to see a relationship between water consumption and a change in BMI from the beginning.This relationship could be an indicator of small changes within the intervention group concealing the possible relationship that led to drinking more water. A double-blind, randomized control trial (RCT) conducted by Katan et al11 replaced 1 SSB with a sugar-free beverage each day for 18 months in 477 children. Skin-fold thickness, predicted energy intake, fat mass, waist circumference, and armto-leg electrical impedance were calculated in all children at baseline and every 6 months through the end of the 18-month study.The type of beverage assigned to each child was hidden to complete the blind trial. Children who received the SSB had increased BMIs compared with those who received the sugar-free beverage. Some children with initially higher BMIs were switched to sugar-free beverages during the course of the treatment without their knowledge. The study showed a significant relationship in children with higher BMIs who consumed sugar-free beverages. Differences were seen in the effects of treatment with BMI measurements such as waist circumference. In the regression model, the treatment was more impactful in 91 overweight and obese children compared Continues on page 22

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2018 17

ARTIFICIAL SWEETENERS AND OBESITY RISK IN CHILDREN

Studies have suggested that artificially sweetened beverages may be stimulating children’s appetites and leading to overconsumption of food. with 386 children with healthy weight when using BMI as the continuous variable. Swithers12 completed a meta-analysis concerning artificial sweeteners and childhood obesity with inconsistent results. In a reviewed cross-sectional study, ASBs increased weight and body fat percentage in adolescents. Another study showed that replacing SSBs with ASBs in children was indicative of lower rates of weight gain. A meta-analysis by Foreyt et al13 of 9 observational studies examined the relationship between low-calorie sweetened beverages and SSBs on weight gain or obesity in more than 20,000 children. The majority of studies indicated a positive correlation between low-calorie sweetened beverages and weight gain, increased appetite, and obesity. Of 3 cross-sectional studies, two displayed positive relationships between low-calorie sweetened beverage consumption and BMI with the third study not showing any association. Four longitudinal studies indicated a positive association with increased weight and low-calorie sweetened beverage intake.Another study revealed increased low-calorie sweetened beverage consumption to be related to lower odds of obesity. One study of 3- to 6-yearolds could not establish any association between low-calorie sweetened beverages and BMI. Freswick14 found similar results with his meta-analysis of ASBs and children. His review of 9 cohort studies had inconsistent results. One study observed a positive relationship between ASB

POLL POSITION Genetics and hormonal issues account for what percentage of all pediatric obesity cases?

■ <10% ■ 25%

2.13% 7.23%

69.36%

■ 75% ■ >90%

21.28%

For more polls, visit ClinicalAdvisor.com/Polls.

consumption and weight gain or increased BMI in more than 11,000 children.Another study showed an inverse relationship between the consumption of ASB and BMIs.The study also noted a negative relationship with obesity and ASB consumption. A review of 4 RCTs resulted in different findings. In the first study, 38 obese girls were restricted to 1500 kcal/d with a “free” snack (unhealthy and SSB), while another group was restricted to healthy-only snacks and an ASB per day. No change in BMI was noted for the intervention group.Another study of 103 adolescents showed no weight change after an ASB was substituted for a SSB over a 25-week period. Lastly, a study of 224 adolescents involved random placement of participants within 2 groups.The intervention group substituted water or ASBs along with monthly phone calls encouraging water consumption. In non-Hispanic adolescents, no significant difference was seen in BMI at 1 year (P =.36) or 2 years (P =.68). However, in a subgroup analysis, Hispanic adolescents in the intervention group demonstrated a significant decrease in BMI at 1 year (P =.007) and 2 years (P = .01). Discussion

Findings reviewed in the last 5 years indicating that ASB consumption causes weight gain are inconclusive in the pediatric population. Although several studies showed positive relationships between consumption of ASBs and weight gain, others did not show any direct relationship. Most of the studies comparing SSBs with ASBs resulted in mixed conclusions. Seven studies showed statistical significance for ASBs and weight gain, whereas 5 studies were significant for weight loss or showed no association. None of the studies compared water, a noncaloric beverage, to drinking ASBs. A study replacing SSBs with water reported no statistical significance in weight loss but did report that participants did not gain weight throughout the study.10 Consequently, studies comparing SSBs with water had inconsistent findings as well. In the pediatric population, there are limited data about ASB consumption and its influence on weight. Most of the studies conducted on ASBs and the pediatric population are prior to a current report by Harvard School of Public Health that suggests avoidance of ASBs for the pediatric population.8 Although studies report that parents are concerned about allowing their children to consume ASBs, the consumption of ASBs is growing in the pediatric population as a dietary tool to reduce caloric intake.15 ASBs are readily available in schools, at sporting events, and within the community.Water Continues on page 24

22 THE CLINICAL ADVISOR • DECEMBER 2018 • www.ClinicalAdvisor.com

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ARTIFICIAL SWEETENERS AND OBESITY RISK IN CHILDREN

Obese children are at increased risk for cardiovascular comorbidities that persist into adulthood and result in increased healthcare-related costs. appears to have become the forgotten zero-calorie beverage that does not increase weight or BMI. SSBs and ASBs can easily be replaced with readily available water to increase hydration, decrease the risk of weight gain, and promote healthier dietary choices for all populations. The strengths of the reviewed literature originate from the methods used in a variety of studies reviewed. Many of the articles reviewed were RCTs, which are the “gold standard” for clinical research. Another strength to the review were the study samples ranging in size from 38 to 11,654 of children aged 2 to 18 years from the United States and various countries around the world, including Great Britain, Brazil, and the Netherlands.The use of larger sample sizes results in greater generalizability of the findings. The studies reviewed were conducted between 2001 and 2015, with the majority of the studies conducted within the last 8 years. Several of the studies were limited by participant dropout, study design, and validity of questionnaires used in the studies. The RCTs were limited by growth patterns in prepubertal children and overall dietary intake of the pediatric participants. In addition, gender differences in fat mass was a limiting factor as females exhibit a slightly higher body fat content than males throughout their lifespan.16 Limitations were created by the tools used to assess body fat such as BMI and skin-fold thickness. Although measurement of BMI is inexpensive and easy to implement, the test is not able to differentiate between lean BMI and body fat.17 Similarly, the skin-fold thickness test is safe and portable; however, it is not as accurate as other methods and is difficult to conduct in persons with a BMI of 35 or higher.17 Although some of the limitations can be easily addressed by selecting a more accurate body fat–assessment tool, growth patterns and differences in body composition are limitations that researchers must address in the design of the study.

encourages families to eat 5 servings of fruits and vegetables daily, limit screen time to <2 hours per day, partake in >1 hour of physical activity per day, and restrict sugary drinks while increasing water consumption. Since this program has been implemented, Let’s Go! sites have seen a significant reduction in the amount of sugary beverages provided to children with an increase in water consumption. Children have reported feeling better and healthier since becoming aware of the program. The Alliance for a Healthier Generation assists schools, companies, community organizations, healthcare professionals, and families in improving circumstances and choices that lead to healthier children.20 According to the Alliance for a Healthier Generation, funding is provided by the American Heart Association and the Clinton Foundation with a goal to cut the prevalence of childhood obesity.The collaboration works to encourage children to create healthier lifestyles by improving access to healthier food and beverages.The organization works with food and beverage companies that provide food for schools. Since developing a nutrition guideline and collaborating with the beverage companies to help reduce obesity, a 90% decrease in beverage calories shipped to schools was realized between 2004 and 2010. Conclusion

Substituting ASBs for SSBs continues to be an acceptable way to reduce caloric intake in children. However, studies have not demonstrated a significant reduction in weight with the use of ASBs in the pediatric population.6 The elimination of sugar-laden soda and sports drinks in childcare facilities, schools, school events, and after-school programs would encourage better beverage choices. Increasing the availability of fresh water at school, in parks, and at recreational facilities would also encourage water consumption. Education on healthy beverage choices is a crucial element in reducing pediatric obesity. Healthcare providers need to be willing to converse with all children and families about Implications for Practice The pediatric obesity epidemic remains an issue of concern healthy diets, exercise, and making better food and beverin the United States, accounting for $14 billion in direct age choices. These conversations may require longer office medical costs.18 Obese children at increased risk for serious visits with pediatric weight management as a goal. Weight cardiovascular comorbidities that follow them into adulthood loss is seldom recommended in the pediatric population; and result in increased healthcare-related costs. Combating therefore, empowering children to make healthier food and childhood obesity needs to be not only a parental concern beverage choices will require education and awareness for the entire family. but a community and governmental concern. In conclusion, there are no easy answers to this dilemma. Let’s Go! is a nationally recognized childhood obesity– prevention program that has been put into action in Maine Limited data and research on the effects of ASBs on weight in and a few communities in surrounding states.19 This program the pediatric population indicate a need for further research. 24 THE CLINICAL ADVISOR • DECEMBER 2018 • www.ClinicalAdvisor.com

The pediatric obesity epidemic remains an issue of concern in the United States, accounting for approximately $14 billion in direct medical costs. Due to limitations such as the natural growth of children, it may be necessary to apply principles developed from adult studies to the pediatric population. Additional research is also needed to identify other contributing factors to the obesity epidemic in children. ■

12. Swithers SE. Not so sweet revenge: unanticipated consequences of high-intensity sweeteners. Behav Anal. 2015;38(1):1-17. 13. Foreyt J, Kleinman R, Brown RJ, Lindstrom R. The use of low-calorie sweeteners by children: implications for weight management. J Nutr. 2012;142(6):1155S-1162S. 14. Freswick PN. Artificial sweetened beverages and pediatric obesity:

Melissa Noblitt, RN, MSN-S, and Kindra L. Shepard, RN, MSN-S, are students and Susan Eley, PhD, MS, FNP-BC, is a professor at the College of Health & Human Services, School of Nursing, Indiana State University in Terre Haute.

the controversy continues. Children (Basel, Switzerland). 2014;1(1):31-39. 15. Sylvetsky A, Yichen J, Clark EJ, Welsh JA, Rother KI, Talegawkar SA. Consumption of low-calorie sweeteners among children and adults in the United States. J Acad Nutr Diet. 2017;117(3):441-448. 16. Kirchengast S. Gender differences in body composition from childhood to

References

old age: an evolutionary point of view. J Life Sci. 2010;2(1).

1. US Department of Health and Human Services. Overweight & obesity

17. Harvard School of Public Health. Measuring obesity. https://www.hsph.

statistics. https://www.niddk.nih.gov/health-information/health-statistics/

harvard.edu/obesity-prevention-source/obesity-definition/how-to-measure-

overweight-obesity. Updated August 2017. Accessed October 29, 2018.

body-fatness/. Accessed October 29, 2018.

2. Centers for Disease Control and Prevention. Childhood obesity facts.

18. National League of Cities. Economic cost of obesity. http://www.healthy-

https://www.cdc.gov/obesity/data/childhood.html. Updated August 13, 2018.

communitieshealthyfuture.org/learn-the-facts/economic-costs-of-obesity/.

Accessed October 29, 2018.

3. Schwarz SM. Obesity in children. https://emedicine.medscape.com/

19. Let’s Go! 5-2-1-0 Let’s Go! http://www.letsgo.org/. Accessed October 29, 2018.

article/985333-overview. Updated June 18, 2017. Accessed October 29, 2018.

20. Alliance for a Healthier Generation. About us. https://www.healthier

4. The State of Obesity. Obesity rates & trends overview. https://

generation.org/about_us/. Accessed October 29, 2018.

stateofobesity.org/obesity-rates-trends-overview/. Accessed October 29, 2018. 5. The Obesity Society. Childhood overweight. http://tosconnect.obesity.org/ obesity/resources/facts-about-obesity/childhood-overweight. Updated May 2014. Accessed October 29, 2018. 6. Sylvetsky A, Rother KI, Brown R. Artificial sweetener use among children: epidemiology, recommendations, metabolic outcomes, and future directions. Pediatr Clin North Am. 2011;58(6):1467-1480. 7. Laverty AA, Magee L, Monteiro CA, Saxena S, Millett C. Sugar and longitudinal study. Int J Behav Nutr Phys Act. 2015;12:137. 8. Harvard School of Public Health. Artificial sweeteners. https://www.hsph. harvard.edu/nutritionsource/healthy-drinks/artificial-sweeteners/. Accessed October 29, 2018. 9. Muckelbauer R, Gortmaker SL, Libuda L, et al. Changes in water and sugarcontaining beverage consumption and body weight outcomes in children. Br J Nutr. 2016;5(11):2057-2066. 10. Sichieri R, Yokoo E, Pereira R, Veiga G. Water and sugar-sweetened beverage consumption and changes in BMI among Brazilian fourth graders after 1-year follow-up. Public Health Nutr. 2012;16(1):73-77. 11. Katan MB, de Ruyter JC, Kuijper LJ, Chow CC, Hall KD, Olthof MR. Impact of masked replacement of sugar-sweetened with sugar-free beverages on body weight increases with initial BMI: secondary analysis of data from an 18 month double-blind trial in children. Plos One. 2016;11(7):e0159771.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2018 25

artificially sweetened beverage consumption and adiposity changes: national

FEATURE: CARRIE SMITH NOLD, MPA, PA-C

Guidance for the Use of Antibiotics in Patients With Myasthenia Gravis Clinicians must balance prompt and adequate treatment of infection with the risk that some antibiotics can aggravate myasthenia gravis.

Myasthenia gravis flares may be triggered by infection or surgery.

26 THE CLINICAL ADVISOR • DECEMBER 2018 • www.ClinicalAdvisor.com

ll prescribers should be aware of the range of possible adverse effects associated with antibiotics. Though perhaps less well recognized than other adverse effects, various neurotoxicities — including seizure, optic neuropathy, encephalopathy, peripheral neuropathy, and exacerbation of myasthenia gravis (MG) — may result from antibiotic use.1 This risk is increased in older patients, patients with impaired renal function, and patients with preexisting neurologic conditions.1 Safe prescribing practices can be particularly difficult in patients with MG due to myriad medications that can interfere with neuromuscular transmission. While the mechanism by which drugs affect the neuromuscular junction varies, medications commonly known to cause drug-induced neuromuscular blockade include certain antibiotics, anticonvulsants such as phenytoin, antirheumatic drugs such as penicillamine and chloroquine, cardiovascular drugs such as calcium channel blockers and β-blockers, and psychotropic drugs such as lithium.1,2 The relationship between antibiotic use and exacerbation of MG is particularly complicated as MG flares can also be triggered by infection and surgery.1 This requires clinicians to balance prompt and adequate treatment of infection with the risk that some antibiotics can aggravate the condition. This article is focused on a practical review of the relationship between MG, infection, and the possibility for certain antibiotics to cause clinical deterioration in patients with the condition.

antibiotics, to exacerbate or unmask MG.

Infection and Myasthenia Gravis

The potential for antibiotics to unmask or worsen MG is particularly significant given that patients with MG may be predisposed to acquiring infectious diseases. Possible factors that could contribute to an increased risk for infection include an autoimmune disease process, muscle weakness, and possible immunosuppressive treatments.3 Most patients with MG require immunosuppressive medication such as prednisone, azathioprine, mycophenolate mofetil, or rituximab.4 Additionally, approximately 15% of patients with MG have a second autoimmune disease such as lupus or rheumatoid arthritis, which may also require immunosuppressive medications.4 Currently available immunosuppressive medications used in MG broadly suppress immune reactivity, including the ability to react against microbes.3 While the exact increase in rate of infection is not known, it is estimated that the risk for infection while on corticosteroids increases 20% to 50%.3 Baseline respiratory muscle weakness from MG can predispose patients to infection in the lower respiratory tract.3 Conversely, infection is a common cause of exacerbation of MG that may lead to complications such as respiratory weakness and failure.3 This underscores the importance of adequate disease control and treatment of infection in patients with MG. Neurology and primary care providers should educate patients about the risk of infection leading to possible worsening of their MG. Although vaccines are generally recommended for patients with MG, live-attenuated vaccines should be avoided in those who are immunosuppressed, and vaccination should be avoided during an acute exacerbation.3 If vaccination with live-attenuated doses is necessary, it is ideal to do so before immunosuppressive therapy is started.3 Antibiotics and Myasthenia Gravis

As infection can cause a myasthenic exacerbation or crisis, it should be treated swiftly while taking care to avoid additional patient harm. Certain antibiotic agents should be avoided, if possible, in patients with MG. Antibiotics can impede neuromuscular transmission by blocking the release of acetylcholine presynaptically, competitively binding with the acetylcholine receptors postsynaptically, or acting at both sites in combination.2,5 Most notably, aminoglycosides, fluoroquinolones, macrolides, and telithromycin may interfere with neuromuscular transmission and lead to worsening muscle weakness. When this occurs, clinical deterioration typically begins within 24 to 48 hours after the new antibiotic is begun; however, there have been cases in which clinical decline occurs within minutes.2,5,6 The severity of the reaction also varies, with patients experiencing mild to severe weakness requiring differing levels of clinical intervention.2,6 Additionally, patients with no known history of MG have been reported to first experience myasthenic weakness after antibiotic use.2,6 Therefore, all

providers should be aware that in addition to the potential for antibiotics to aggravate existing MG, antibiotics may also unmask undiagnosed MG. Aminoglycosides

Aminoglycosides affect neuromuscular transmission by both inhibiting acetylcholine release presynaptically and blocking the acetylcholine receptor postsynaptically.2 This class of antibiotics has been associated with aggravating pre-existing MG and postoperative respiratory distress.2 Though this association was originally reported in streptomycin, further studies have led neuromuscular blockade by aminoglycosides to be considered a class effect.7 There have been documented cases of aminoglycosides precipitating a myasthenic reaction in the absence of concomitant infection, as well as cases implicating aminoglycosides in causing intensive care unit-related weakness in patients who do not have MG.5 In addition to neuromuscular blockade, aminoglycosides are also associated with other neurotoxic effects including ototoxicity, peripheral neuropathy, and encephalopathy.7 Fluoroquinolones

Fluoroquinolones have been associated with unmasking and worsening MG.2 In 2011, the US Food and Drug Administration (FDA) added a boxed warning to fluoroquinolones related to the risk of worsening symptoms for patients with MG.8 The same year, a review of case reports and FDA adverse event reports concluded that fluoroquinolones may result in significant MG exacerbations as a class effect.9 The exact mechanism by which fluoroquinolones affect neuromuscular transmission is not known; however, theories include inhibition of acetylcholine release presynaptically and a direct toxic effect on the acetylcholine channel.5,9 Fluoroquinolones do share structural similarities with other medications that impair neuromuscular transmission such as quinine.9 Other neurotoxicities associated with fluoroquinolones include seizures, encephalopathy, myoclonus, and psychosis.7 Macrolides and Telithromycin

Macrolides should also be avoided, if possible, in patients with MG.There have been cases of erythromycin both aggravating and unmasking MG.2,5 Similar reports exist for clarithromycin and azithromycin.5,10 Telithromycin, a ketolide antibiotic closely related to erythromycin, carries an FDA black box warning stating it should not be used in patients with MG as it has been associated with respiratory failure.5,6 It is believed that telithromycin affects the neuromuscular junction peripherally, and while the exact target is unknown, cases of worsening myasthenic weakness related to telithromycin use have been described in patients with acetylcholine and muscle-specificreceptor tyrosine kinase antibodies.6 In an article examining cases in which telithromycin was implicated in exacerbating or

www.ClinicalAdvisor.com â&#x20AC;˘ THE CLINICAL ADVISOR â&#x20AC;˘ DECEMBER 2018 27

right-hand column like this one does at the top

ANTIBIOTIC USE IN MYASTHENIA GRAVIS

unmasking MG, although patients had concomitant respiratory infection, the temporal relationship between administering the medication and symptom worsening seemed to support telithromycin use as the main causative factor in patient deterioration.6 Of note, telithromycin was discontinued in the United States in 2016.11

Case reports exist of the β-lactam class of antibiotics possibly causing worsening of myasthenic symptoms.1,5 Furthermore, polymyxin has been associated with neuromuscular blockade.7 As there are multiple factors that have an impact on the clinical course of a patient with MG and infection, these patients should be closely monitored when any new antibiotics are initiated.

Other Antibiotics

Other antibiotics have been associated with unmasking MG or precipitating a worsening of myasthenic symptoms. Clindamycin and tetracycline have been linked to cases of aggravated MG, but less data exist about these relationships.1,2,5

Patient Management Considerations

Given the possible interactions and adverse effects described above, treating infection in patients with MG without causing further harm can be difficult. For example, while typical

TABLE. Medications That Exacerbate or Unmask Myasthenia Gravis Class of Drug

Drug Name(s)

Class of Drug

Drug Name(s)

Aminoglycosides

• Amikacin • Gentamycin • Kanamycin • Neomycin

• Netilmicin • Streptomycin • Tobramycin

H-2 receptor agonists

• Cimetidine • Ranitidine • Roxatidine

Antiarrhythmic agents

• Etafenone • Peruvoside

• Procainamide • Propafenone

Heavy metal antagonists

• D-penicillamine

Antiepileptics

• Carbamazepine • Gabapentin

• Phenytoin • Trimethadione

Hydantoins

• Nitrofurantoin

Antihelmintics

• Pyrantel pamoate

Interferons

• Interferon alfa

ß-blockers

• Atenolol • Propranolol • Nadolol • Sotalol • Oxprenolol • Timolol ophthalmic • Practolol solution

Macrolides

• Azithromycin • Erythromycin • Telithromycin

Calcium channel blockers

• Amlodipine • Felodipine

Monobasic amino acid antibiotics

• Clindamycin • Lincomycin

• Vancomycin

Carbapenems

• Imipenem

Penicillins

• Ampicillin

• Penicillin

Chemotherapeutic agents

• Cisplatin • Doxorubicin

Polymyxins

• Colistin • Colistinmethate

• Polymyxin B

Corticosteroids

• Hydrocortisone • Prednisolone • Methylprednisolone • Prednisone

Psychotropic medications

• Chlorpromazine • Lithium • Haloperidol • Tricyclic antidepressants

Dehydropeptidase inhibitors

• Cilastatin

Quinolone derivatives

• Chloroquine • Quinidine

Fluoroquinolones

• Ciprofloxacin Gemifloxacin Levofloxacin Lomefloxacin Moxifloxacin

Sulfonamides

• Sulfamethoxazole/trimethoprim

Glycopeptide antibiotics

• Vancomycin

Tetracyclines

• Doxycycline • Minocycline

• Nifedipine • Verapamil

• Etoposide

• Norfloxacin • Ofloxacin • Perfloxacin • Trovafloxacin

• ß interferon

• Quinine

• Tigecycline

From Ahmed A, Simmons Z. Drugs which exacerbate or induce myasthenia gravis: a clinician’s guide. Internet J Neurol. 2008;10(2); and Pascuzzi RM. Medications and myasthenia gravis: a reference for health care professionals. Myasthenia Gravis Foundation of America. http://www.myasthenia.org/LinkClick.aspx?fileticket=JuFvZPPq2vg%3D. October 2000. Accessed November 8, 2018.

28 THE CLINICAL ADVISOR • DECEMBER 2018 • www.ClinicalAdvisor.com

undesirable outcomes in patients with MG.

first-line treatment for a patient with community-acquired pneumonia (CAP) may consist of a fluoroquinolone or a β-lactam plus a macrolide, both fluoroquinolones and macrolides can be especially problematic for patients with MG. One case study reported success using tigecycline to treat a patient with MG, CAP, penicillin allergy, and previous MG exacerbation following moxifloxacin use.5 Providers need to obtain a thorough history, including allergies and any previous MG flares with antibiotic use, and consider the full clinical picture before selecting an antibiotic. Medications used around the time of surgery should be given careful consideration as patients with MG may be sensitive to certain types of anesthesia and muscle relaxants; aminoglycosides should be avoided as they are associated with postoperative respiratory depression.2 If a patient with MG being treated with antibiotics begins to decompensate, it may be difficult to determine whether the worsening is caused by the MG, acute infection, or medication. In the event the antibiotic is implicated as the causative factor for the deterioration, it may be necessary to discontinue the treatment and begin a non-neurotoxic antibiotic.7 Symptoms typically resolve hours to days after the antibiotic is discontinued, but additional therapy may be required, particularly in the case of bulbar or respiratory weakness.2,5 Patients may respond to anticholinesterase drugs such as neostigmine or pyridostigmine; however, resulting cholinergic side effects may include increased secretions, which can complicate clinical management.2 Treatment with intravenous immunoglobulin and plasma exchange should be considered for severe exacerbations of MG. Respiratory function should be closely monitored, and hospital admission may be required.

References 1. Bhattacharyya S, Darby R, Berkowitz AL. Antibiotic-induced neurotoxicity. Curr Infect Dis Rep. 2014;16(12):448. 2. Barrons RW. Drug-induced neuromuscular blockade and myasthenia gravis. Pharmacotherapy. 1997;17(6):1220-1232. 3. Gilhus NE, Romi F, Hong Y, Skeie GO. Myasthenia gravis and infectious disease. J Neurol. 2018;265(6):1251-1258. 4. Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;375(26):2570-2581. 5. Vak Berkel MA, Twilla JD, England BS. Emergency department management of a myasthenia gravis patient with community-acquired pneumonia: does initial antibiotic choice lead to cure or crisis? J Emerg Med. 2016;50(2): 281-285. 6. Perrot X, Bernard N, Vial C, et al. Myasthenia gravis exacerbation or unmasking associated with telithromycin treatment. Neurology. 2006;67(12):2256-2258. 7. Grill MF, Maganti RK. Neurotoxic effects associated with antibiotic use: management considerations. Br J Clin Pharmacol. 2011;72(3):381-393. 8. FDA updates warning for fluoroquinolone antibiotics [news release]. US Food and Drug Administration website. https://www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm513183.htm. Updated August 15, 2016. Accessed November 7, 2018. 9. Jones SC, Sorbello A, Boucher RM. Fluoroquinolone-associated myasthenia gravis exacerbation: evaluation of postmarketing reports from the US FDA adverse event reporting system and a literature review. Drug Saf. 2011;34(10): 839-847. 10. Pradhan S, Pardasani V, Ramteke K. Azithromycin-induced myasthenic crisis: reversibility with calcium gluconate [letter]. Neurol India. 2009;57(3):352-353. 11. Ernst D. Antibiotic with history of safety issues discontinued. Monthly Prescribing Reference website. https://www.empr.com/news/antibioticwith-history-of-safety-issues-discontinued/article/482628. March 11, 2016. Accessed November 7, 2018.

Certain classes of antibiotics have been associated with aggravating or unmasking MG and should ideally be avoided in patients with the condition. Primary care and emergency room providers are often the first line of care when treating patients with MG and infection. Given the complex relationship between infection and MG, all providers should be aware of the possible effects of antibiotic treatment on MG and promptly treat infection while avoiding patient harm. Proper patient education and counseling before starting medications that may affect the neuromuscular junction are essential. As many medications can affect neuromuscular transmission and it may be impractical to avoid use of all of these medications, clinicians should closely monitor patients with MG who are started on new medications. ■ Carrie Smith Nold, MPA, PA-C, is assistant professor and didactic coordinator in the Physician Assistant Program at the Philadelphia College of Osteopathic Medicine, Georgia Campus. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2018 29

Conclusion

CME CE FEATURED COURSE EDUCATIONAL OBJECTIVES After completing the activity, the participant should be better able to: • Identify patients with autosomal-dominant polycystic kidney disease (ADPKD) by recognizing the signs and symptoms of the disease and instituting a complete diagnostic workup • Plan a clinical strategy that aims to mitigate progression of ADPKD as much as possible with available, evidencebased modalities • Anticipate emerging therapies with vasopressin type 2 (V2) receptor antagonists that can delay progression in ADPKD through an understanding of ADPKD pathobiology, therapeutic targets, and recent clinical trials COMPLETE THE POSTTEST: Page 37

Release Date: October 9, 2018 Expiration Date: October 9, 2019 Estimated Time to Complete: 30 minutes Maximum Credits: 0.50 AMA PRA Category 1 Credit(s)TM Accredited Provider: This activity is provided by the National Kidney Foundation and produced by Haymarket Medical Education. Commercial Supporter: This activity is supported by an educational grant from Otsuka America Pharmaceutical, Inc. Program Description: Although autosomal-dominant polycystic kidney disease (ADPKD) is a rare disorder, it can have a devastating effect on patients. As morphological disorganization of renal tissue progresses, large, fluid-filled cysts develop, increasing kidney size and ultimately compromising kidney function. In this Case Clinic, a leading expert illustrates the gamut of ADPKD management, from recognition of the disorder, which typically begins insidiously, through current treatment protocols.Topics include screening and genetic counseling, laboratory testing and imaging studies for diagnosis and disease monitoring, development of a treatment plan that addresses concomitant cardiovascular risk factors, and implementation of tolvaptan therapy, a novel vasopressin receptor antagonist that can slow ADPKD progression but requires close monitoring of liver function. Intended Audience: Nephrologists, pediatric nephrologists, internists, family physicians, physician assistants, and nurse practictioners Conflict of Interest Disclosure Policies: It is the policy of the National Kidney Foundation and Haymarket Medical Education to ensure balance, independence, objectivity, and scientific rigor in all CME/CE activities. Any individual who has control over CME/CE content is required to disclose to learners prior to the activity any relevant financial relationship(s) they may have with commercial interests supporting this activity or whose products or devices are discussed in this activity. If, on the basis of information disclosed, a perceived conflict exists, resolution will be achieved based on the National Kidney Foundation’s Disclosure and Conflict of Interest Policy. Faculty Simin O. Goral, MD Director, Polycystic Kidney Disease Clinic Transplant Nephrology Fellowship Director Professor of Medicine Hospital of the University of Pennsylvania Philadelphia, PA Dr. Goral receives grant support from Astellas, AstraZeneca, Kadmon Corporation, and Otsuka America Pharmaceutical, Inc. Planning Committee Disclosures: Jessica Joseph, MBA Vice President, Scientific Activities National Kidney Foundation New York, NY Ms. Joseph has no financial relationships with commercial interest(s). Danielle Nathan, MA Senior Director, Professional Education National Kidney Foundation New York, NY Ms. Nathan has no financial relationships with commercial interest(s). Margot Embree Fisher Director, Grant and Content Development Haymarket Medical Education Paramus, NJ Ms. Embree Fisher has no financial relationships with commercial interest(s). Priya Wanchoo, MD, CHCP Vice President and Medical Director Haymarket Medical Education Paramus, NJ Dr.Wanchoo has no financial relationships with commercial interest(s). Accreditation Statement: In support of improving patient care, the National Kidney Foundation is jointly accredited by the Accreditation Council for Continuing Medical Education

(ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education to the healthcare team. Designation Statement: The National Kidney Foundation designates this enduring activity 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. Additional Credit Information Physician Assistant Continuing Education AAPA accepts certificates of participation for educational activities certified for AMA PRA Category 1 CreditTM from organizations accredited by ACCME or a recognized state medical society. PAs may receive a maximum of 0.50 Category 1 Credits for completing this activity. Nurse Practitioner Continuing Education The American Academy of Nurse Practitioners Certification Program (AANPCP) accepts certificates of participation for educational activities certified for AMA PRA Category 1 CreditTM from organizations accredited by ACCME. Individuals are responsible for checking with the AANPCP for further guidelines. Disclosure of Unlabeled Use: During their presentations, faculty may discuss an unlabeled use or an investigational use not approved for a commercial product. Each faculty member is required to disclose this information to the audience when referring to an unlabeled or investigational use. Disclaimer: The faculty, the National Kidney Foundation, and Haymarket Medical Education do not recommend the use of any pharmaceutical, diagnostic test, or device outside of the labeled indications as approved by the FDA. Please refer to the official prescribing information for each product for approved indications, contraindications, and warnings. Information contained in this educational resource is based upon current data available at the time of publication. Information is intended to help clinicians become aware of new scientific findings and developments.This National Kidney Foundation/Haymarket Medical Education resource is not intended to set out a preferred standard of care and should not be construed as one, neither should the information be interpreted as prescribing an exclusive course of management. Variations in practice will inevitably and appropriately occur when clinicians take into account the needs of individual patients, available resources, and limitations unique to an institution or type of practice. Every healthcare professional making use of information in this educational resource is responsible for interpreting the data as it pertains to clinical decision-making in each individual patient. Instructions: Learners will review the materials on accreditation information, target audience, learning objectives, and disclosure information; complete the pre-test; review the content; and complete the post-test (minimum score of 70% required; learners will only have 3 attempts to pass the posttest) and evaluation to successfully earn credit. For any questions concerning the accreditation of this activity, please send an email to CMEinfo@kidney.org. If you have any other questions relating to your certificate or other issues with the activity, please contact myCME. Support@haymarketmedical.com. Privacy Policy To view the National Kidney Foundation privacy and confidentiality policy as it relates to this CME/CE activity, please visit http://www.kidney.org/. For additional professional education resources, contact the National Kidney Foundation at 1-800-622-9010 or visit https://www.kidney.org/professionals.

Provided by

Produced by

CME | CE FEATURED COURSE: SIMIN O. GORAL, MD

Case Study: A 27-Year-Old Man With Newly Diagnosed ADPKD A detailed family and patient history elicits information resulting in a diagnosis of autosomal-dominant polycystic kidney disease.

T, a 27-year-old man, visits a primary care physician (PCP) for a physical examination required for employment with the fire department. KT estimates it has been nearly 10 years since his last physical. His history is remarkable for the report of an estranged father who died young because of “bad kidneys.” KT smokes 1 pack of cigarettes daily. When asked about any changes in urination, he mentions that his urine looked dark lately, which he attributed to poor hydration during his workouts. He also mentions back pain that he has been experiencing recently. On examination, KT’s blood pressure (BP) is 145/94 mm Hg. He has a late systolic murmur, and fullness is noted in the left upper quadrant. Urinalysis reveals hematuria with innumerable red blood cells (RBCs) per high-powered field (HPF). Serum creatinine is 1.55 mg/dL (normal for adult men: 0.9-1.3 mg/dL). KT is referred for a nephrology consultation.

Differential Diagnosis of ADPKD

Computed tomographic angiography revealing multiple hypodensities in the kidney.

Upon patient identification and referral, a consulting nephrologist should perform urine protein to creatinine ratio (UPCR) along with imaging of kidney size, cyst quantity, and total kidney volume (TKV) calculation via renal ultrasonography, magnetic resonance imaging (MRI), or computed tomography (CT).1,2 Imaging findings help to distinguish polycystic disease from other renal conditions that can decrease

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Preferred first-line antihypertensive therapies for use in autosomal-dominant polycystic kidney disease include ACE inhibitors and ARBs. estimated glomerular filtration rate (eGFR). Increased TKV is a valuable diagnostic feature of autosomal-dominant polycystic kidney disease (ADPKD) and may also be a prognostic biomarker of renal function decline and disease progression.3-5 UPCR (or urine albumin to creatinine ratio [UACR]) plus eGFR should be conducted at baseline for longitudinal monitoring.1,6-8 The nephrologist conducts a detailed family and patient history, which elicits KT’s report that his father had cysts in his kidneys. KT also describes chronic back pain that he dismisses as “probably just muscle strain.” A urine sample taken during the visit shows a UPCR of 405 mg/g. Ultrasonography reveals at least 20 cysts in the left kidney and more than 30 cysts in the right kidney. The left kidney is 18 cm long; the right kidney is 20 cm long. On follow-up MRI, TKV is 1254 mL. The patient is diagnosed with ADPKD. Additional Assessments

KT returns to the office to learn the diagnosis and to receive additional evaluations: eGFR and other assessments of renal function, serum metabolic profile, and the presence or absence

of any infectious complications (urinary tract infection [UTI] or cyst infection). At this visit, KT’s BP is 158/98 mm Hg. KT recalls urinary frequency and a slow urine stream a few weeks ago, but these symptoms have resolved. He reports no changes in his back pain and no new pain, and he does not present with fever. During the visit, the nephrologist discusses scheduling of cardiovascular and cerebrovascular screening, including an echocardiogram and cranial magnetic resonance angiography. Since KT is planning to start a family, he is referred for genetic testing and counseling. Laboratory results, returned following KT’s visit, include an eGFR of 57.0 mL/min/1.73 m2, total cholesterol of 230 mg/dL (low-density lipoprotein [LDL] of 150 mg/dL), and a negative urine culture. Echocardiography shows mild left ventricular hypertrophy (LVH) and mitral valve prolapse. Genetic testing reveals truncating PKD1 mutation. This finding, along with KT’s male sex and hypertension and his history of gross hematuria before age 35 years, puts him at higher risk for early disease progression, which the nephrologist notes in KT’s chart. Treatment Plan

Considerations in Tolvaptan Treatment Candidates for therapy • High-risk patients with rapid progressive disease (by Mayo Classification or Predicting Renal Outcomes in ADPKD [PROPKD] score) Recommended initial dosage • 60 mg/d (45 mg on waking; 15 mg 8 hours later) • May titrate up at >1-week intervals to 60+30 mg, then 90+30 mg/d, based on tolerability • Encourage patients to drink enough water to avoid thirst or dehydration Warning: risk of serious liver injury • Prescribers and patients must enroll in a REMS program* • Mandated hepatic testing at baseline; monitoring at 2 and 4 weeks after initiation, then monthly for 18 months and every 3 months thereafter during treatment *US Food and Drug Administration. Approved Risk Evaluation and Mitigation Strategies (REMS). Available at REMS@FDA.

BP control to a low target, statin therapy, and the novel agent tolvaptan are valuable interventions in this patient. Rigorous BP control to a target of 110/75 mm Hg is essential in ADPKD, as confirmed by the results of the HALTPKD trial.9 Preferred first-line antihypertensive therapies are renin-angiotensin-aldosterone system (RAAS) inhibitors: angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs).1 Statins appear to have favorable effects on the kidney and can be a useful addition to the regimen.1,10,11 The use of tolvaptan is appropriate for an adult patient with ADPKD and an eGFR >45 mL/ min/1.73 m2 who most likely has rapidly progressing disease.12 Neither a cyst infection nor a UTI are present at this time, so no antimicrobial therapy is needed. The nephrologist, in consultation with the multidisciplinary care team, develops an initial treatment plan for KT. The plan includes: • Strict BP control (target: 110/75 mm Hg) with lisinopril 2.5 mg daily (starting dose) • Atorvastatin 10 mg daily • Lifestyle changes: dietary sodium restriction; increased fluid intake to ≥3 L/d to achieve urine osmolarity <280 mOsm/ kg; smoking cessation

32 THE CLINICAL ADVISOR • DECEMBER 2018 • www.ClinicalAdvisor.com

Although family history indicates genetic inheritance of ADPKD in most cases, 10% of patients have no known family history. • Tolvaptan: 45 mg first dose, 15 mg second dose (8 hours later); with planned titration to a target dosage of 120 mg daily • Rest and physical therapy if needed to manage back pain Treatment Initiation and Monitoring

Regular reevaluation of the patient with ADPKD enables the assessment of hypertension, kidney function, and disease progression during the course of treatment.1 As this patient had an elevation in lipids, a repeat metabolic profile is warranted. Tolvaptan-treated patients, as part of the Risk Evaluation and Mitigation Strategy (REMS) program for use of this agent, must also undergo alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin testing prior to initiation of tolvaptan, at 2 weeks and 4 weeks after initiation, then monthly for 18 months and every 3 months thereafter. Current expert guidelines, which were published prior to the availability of approved treatment to slow the progression of ADPKD, do not provide recommendations for follow-up imaging to assess TKV. However, it may be instructive for the patient to undergo MRI or CT to measure TKV every 3 to 5 years to assess whether the rate of TKV growth compares with that anticipated from the initial imaging assessment.13 KT meets with a nurse to go over the treatment plan and to develop a schedule for monitoring, including office visits for BP and laboratory testing for renal function; he is also advised about the need for liver-function monitoring, as mandated by the REMS for tolvaptan-treated patients (see sidebar, Considerations in Tolvaptan Treatment). The nurse educates KT on medication dosing, possible adverse events associated with treatment, and the use of a home BP monitoring system. Over the next 3 months, home BP monitoring suggests a drop in BP to 130/85 mm Hg on average.At the 3-month visit, KT undergoes BP check, UPCR, urinalysis for blood, serum creatinine/eGFR, and lipid panels; aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin testing are also conducted. Blood pressure at the office is 135/90 mm Hg, prompting the nephrologist to uptitrate lisinopril. UPCR is 360 mg/g; urine shows 18 to 20 RBCs/HPF; eGFR is 56.0 mL/min/1.73m2; LDL cholesterol is 136 mg/ dL. Liver function tests remain within normal limits, as they have since the first REMS-mandated check 2 weeks after tolvaptan initiation. KT reports that, at the start of therapy, he was constipated and felt thirsty, but these effects, potentially related to tolvaptan

treatment, diminished over time. He also expresses anxiety over the effect of his diagnosis on long-term employment, since he is no longer an eligible candidate for the fire department. The nephrologist refers KT to a social worker on the multidisciplinary care team. Evidence-Based Management of ADPKD

ADPKD is a heritable disorder affecting 1 to 2 people per 1000.14,15 The disease arises overwhelmingly from mutations to the PKD1 gene (~85% of cases) or PKD2 gene (~15% of cases); recently, other genes, such as GANAB, have been implicated in a small number of cases.16-18 In most cases, family history indicates genetic inheritance, but 10% of patients have no known family history, suggesting the possibility of de novo mutation.16 PKD mutations lead to protein expression localized to the primary cilia of renal cells, resulting in the classification of ADPKD as a ciliopathy.18 The result is morphologic disorganization of renal tissue.16 These mutation-driven renal changes produce the hallmark disease process of ADPKD: development of large, fluid-filled cysts in the kidney, which over time increase kidney size and compromise kidney function.12,15,18 Patients with ADPKD exhibit symptom patterns that include hypertension, pain, kidney stones, hematuria, and cyst infections.12,15 Long-term complications decrease life expectancy and include end-stage renal disease (ESRD) with the need for dialysis and/or transplantation and cardiovascular/cerebrovascular disease, including heart-valve abnormalities and intracranial aneurysm.2,10,12,15 Risk factors for a more severe, rapid disease course include PKD1 mutation (especially truncating PKD1 mutation), male sex, early onset of hypertension, early gross hematuria or other early urologic event, high TKV, significant decreases in GFR, overt proteinuria, and macroalbuminuria.6,12,19,20 Although 3 or more pregnancies is considered a risk factor in women, this is as yet unproven.20 Relative values of key risk factors have been incorporated into a prognostic scoring system, the PROPKD (Table 1).12,21 The Mayo Classification for prediction of disease progression in ADPKD by height-adjusted TKV and age also allows quantification of risk.22 Identification, differential diagnosis, and management of ADPKD have been impeded by the historical absence of clinical practice guidelines and a lack of strategies to delay progression of disease.23 In the last 5 years, however, the nephrology community has made progress in remedying these deficits.

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Consensus opinion has been promulgated, including conference recommendations published in 2015 by Kidney Disease: Improving Global Outcomes (KDIGO).1,24,25 Tolvaptan, a novel vasopressin receptor antagonist therapy that can slow ADPKD progression,26,27 has been approved in Europe and the United States, and recommendations for tolvaptan use have been published by the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA).12 Other therapies are in development for ADPKD, including additional vasopressin receptor antagonists, somatostatin analogues, and tyrosine kinase inhibitors.17 TABLE 1. Predicting Renal Outcomes in ADPKD (PROPKD) Scoring12,21 Risk Factor

Points*

Male sex

Hypertension before the age of 35 years

At least 1 urologic event† before the age of 35 years

Nontruncating PKD1 mutation

Truncating PKD1 mutation

* Total score ≤3 eliminates risk of evolution to ESRD before 60 years of age (negative predictive value, 81.4%); total score >6 predicts ESRD onset before 60 years of age (positive predictive value, 90.9%). †Examples include gross hematuria, flank pain, and cyst infection.

TABLE 2. Diagnostic Approaches in ADPKD1,12,28,30 Renal ultrasonography* MRI*, especially to rule out simple cysts in patients with <5 cysts CT* Physical examination, laboratory, and relevant imaging for ESRD, cardiovascular complications (LVH, mitral valve prolapse), intracranial aneurysm, etc Direct mutation screening by Sanger sequencing of PKD1 and PKD2 (genetic screen of choice); recommended for selected patients only (eg, equivocal physical findings; family genetic counseling needed) *Can be used to measure TKV.

Identifying and Diagnosing ADPKD

In the presence of ADPKD-associated symptoms, a family history of kidney cysts or early kidney-related mortality raises the suspicion of cystic disease.2 It is challenging, however, to identify ADPKD in the younger patient who reports no family history of renal disease. Clinicians must be alert to subtle clinical or laboratory features in any patient, such as BP elevation, hematuria, kidney stones, UTI history, pain, and serum-creatinine elevation.1,17,24 Palpation of an enlarged kidney supports the identification of disease.28 A significant portion of patients, however, remain asymptomatic for many years.1,17,24 Upon identification, a consulting nephrologist should perform a complete diagnostic workup, along the lines of this case presentation. Elements of the workup are shown in Table 2. ADPKD can be diagnosed by elevated UPCR along with imaging of kidney size, cyst quantity, and TKV calculation via renal ultrasonography, MRI, or CT.1,2 Imaging findings help to distinguish polycystic disease from other renal conditions that can decrease eGFR. Markedly increased TKV is a valuable diagnostic feature of ADPKD and may also be a prognostic biomarker of renal function decline and progression to ESRD.3-5,29 As ADPKD is associated with serious complications, the workup should include an assessment of the degree of chronic kidney disease as well as the quantitation of proteinuria, in addition to an assessment of cardiovascular and cerebrovascular health.1,6-8 Cardiovascular complications are a major cause of death in patients with ADPKD; LVH and cardiac valvular abnormalities are among the cardiovascular manifestations of the disease.30 Intracranial aneurysm is especially dangerous; rupture of the aneurysm causes intracranial hemorrhage and death in 8% to 11% of patients.28 Diverticular disease and extrarenal cyst development also may occur.1,28 Extrarenal cysts are found most often in the liver, but they may affect the pancreas, thyroid, and subarachnoid and seminal vesicles.28 Signs and symptoms of cyst infection and UTIs should be assessed and, if present, followed up with cultures. Genetic screening for PKD1 and PKD2 gene mutation is generally not recommended for all patients with ADPKD.1,12 According to KDIGO consensus, testing is limited to patients with equivocal or atypical renal imaging findings; marked discordant disease within a family; very mild ADPKD; sporadic disease with no family history; early and severe disease; ADPKD with syndromic features; or a need for reproductive counseling.1 In the case presented here, KT needed reproductive counseling following an early disease onset and so was referred for genetic testing. When conducting the workup, it is valuable to document findings that help to quantify the risk of progression in ADPKD;

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documentation of risk is more important than ever now that there is an approved drug, tolvaptan, that can delay progression.6 If genetic testing has been conducted, the PROPKD score can be used with maximal accuracy; a score greater than 6 on the PROPKD (Table 1) is a predictor of ESRD before the age of 60 years. In the case presented, KT had a PROPKD score of 9.12,21 Additional factors that may forecast early progression are larger kidney size, higher TKV, and early decrease in eGFR,3,6,12 all of which occurred in KT’s case.

Statin therapy is advisable in ADPKD. Statins appear to have favorable effects on kidney weight, kidney volume, cyst volume, renal function, and renal hemodynamics.10 Results of statin use, however, are not conclusive,10,32,33 and a post hoc analysis in the HALT-PKD trial did not demonstrate a benefit for statins.11 Larger randomized trials are needed, but at this time, statins are thought to be a useful addition to the regimen.10,11 A novel treatment for ADPKD, tolvaptan, has been approved in the European Union and the United States. Pivotal trials of tolvaptan, TEMPO and REPRISE, have shown the efficacy Developing the Treatment Plan KT’s initial treatment plan accords with current KDIGO of tolvaptan in delaying cardinal signs of progression.26,27 consensus for overall care in ADPKD; it is also congruent with In the 3-year, phase 3 TEMPO trial (N=1445),26 the rate of 1,12 ERA-EDTA recommendations for the use of tolvaptan. increase in TKV for the tolvaptan group was 2.8% per year vs Rigorous BP control to a target of 110/75 mm Hg is essential 5.5% per year for the placebo group (P <.001).Tolvaptan also in ADPKD. The HALT-PKD trial established that BP control yielded significantly lower rates of kidney pain along with a to a low target (95/60 mm Hg to 110/75 mm Hg) vs a stan- slower decline in kidney function. Adverse events associated dard target (120/70 mm Hg to 130/80 mm Hg) significantly with tolvaptan included thirst, polyuria, nocturia, urinary slowed the rise in TKV (Figure), decreased urinary albumin frequency, polydipsia, renal pain, hematuria, and abnormalities excretion, decreased LV mass, and slowed the increase in renal in liver-function testing. In the 12-month, phase 3 REPRISE trial (N=1370),27 there vascular resistance.9 Preferred first-line antihypertensive therapies are RAAS was a significant difference in change from baseline in eGFR inhibitors—ACEIs and ARBs.1 Blood pressure control with with tolvaptan treatment (P <.001).This finding indicated a medication should be accompanied by lifestyle management delay in decline of renal function with tolvaptan vs placebo. The ERA-EDTA recommends tolvaptan for adult ADPKD that includes sodium restriction, increased fluid intake (eg, to 2 increase in T Significant, 14.2% lower increase Numerically smaller patients agedannual <50 years with an eGFR >45 mL/min/1.73 m ≥3 L/d), and smoking cessation.1, 28,31 in TKV with low BP target*

from baseline with low BP target*

2000

P=.006

5 4 3 2

5.6

Annual Increase in TKV (%)

6 5

6.6 5.6

1000

500

95%BP, Cl: 1639-1938 mL. Low target Standard BP, target ‡ 95% Cl: 1498-1782 95/60-110/75 mm120/70-130/80 HgmL. mm Hg (n=275) (n=284) †

1500

1788† 1636‡

1000

500

Low BP, target 95/60-110/75 mm Hg (n=275)

*60 months (50years) of follow-up.

Low Standard BP, target BP, target 95/60-110/75 120/70-130/80 mmmm Hg Hg (n=275) (n=284)

*60 months (5 years) of follow-up. † 95% Cl: 1639-1938 mL. ‡ 95% Cl: 1498-1782 mL.

1788†

Standard BP, target 120/70-130/80 mm Hg (n=284)

6.61500

5.6

P=.006 5

2000

TKV at 60 Months (mL)

P=.006

2000

TKV at 60 Months (mL)

Annual Increase in TKV (%)

Significant, 14.2% lower Significant, annual increase 14.2% lower annualNumerically increase smallerNumerically increase in TKV smaller increase in TKV † 1788 in TKV with low BP in target* TKV with low BP 6target* from baseline with low from BP baseline target* with low BP target* 1500 6.6

1000

1636‡ 500

Standard BP, target 120/70-130/80 mm Hg (n=284)

Standard Low BP, target BP, target 95/60-110/75 120/70-130/80 mm mm HgHg (n=275) (n=284)

1636‡

Low BP, target 95/60-110/75 mm Hg (n=275)

*60 months (5 years) of follow-up. † 95% Cl: 1639-1938 mL. ‡ 95% Cl: 1498-1782 mL.

FIGURE. Effect of rigorous vs standard blood pressure (BP) reduction on total kidney volume (TKV) in the HALT-PKD trial.9 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2018 35

Low BP, target 95/60-110/75 mm H (n=275)

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CME | CE FEATURED COURSE

who have demonstrated or who are likely to have rapidly progressing disease. The ERA-EDTA also recommends not starting tolvaptan in patients aged 30 to 40 years with an eGFR >90 mL/min/1.73 m2 or those aged 40 to 50 years with an eGFR >60 mL/min/1.73 m2.12 Alleviating pain and infection are important aspects of ADPKD care. Multidisciplinary management of chronic pain is recommended; pain control with nonsteroidal anti- inflammatory drugs, which can cause renal injury, should be avoided in patients taking RAAS-blocking agents or in those with an eGFR <60 mL/min/1.73 m2.1 Cyst infections and UTIs should be treated with antimicrobials. Lipid-permeable antibiotics, notably fluoroquinolones and sulfamethoxazole/ trimethoprim, remain the standard treatment for cyst infections, provided the organisms are susceptible.1,34,35 Cyst infection can recur despite treatment and so requires vigilance.1

of symptomatic polycystic kidney disease. In: Li X (ed). Polycystic Kidney Disease. Brisbane, Australia: Codon Publications; 2015:75-94. 3. Perrone RD, Mouksassi MS, Romero K, et al. A drug development tool for trial enrichment in patients with autosomal dominant polycystic kidney disease. Kidney Int Rep. 2017;2:451-460. 4. Grantham JJ, Torres VE. The importance of total kidney volume in evaluating progression of polycystic kidney disease. Nat Rev Nephrol. 2016;12(11):667-677. 5. PKD Foundation. Kidney 101. https://pkdcure.org/what-is-pkd/adpkd/ kidney-101/. Accessed July 11, 2018. 6. Müller RU, Haas CS, Sayer JA. Practical approaches to the management of autosomal dominant polycystic kidney disease patients in the era of tolvaptan. Clin Kidney J. 2018;11(1):62-69. 7. Kidney Disease Improving Global Outcomes. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013;3(1):1-150. 8. Methven S, MacGregor MS, Traynor JP, et al. Assessing proteinuria in

Monitoring the Patient With ADPKD

chronic kidney disease: protein-creatinine ratio versus albumin-creatinine

It is crucial to monitor patients with ADPKD regularly in terms of blood pressure control, structural kidney changes (eg, cyst development, TKV), kidney function, and disease progression.1 In the case presented, the nephrologist scheduled periodic monitoring of BP, renal function, and lipids—all of which should be assessed at regular intervals in this patient. Timely follow-up also allows for detection of signs of infection and the cardiovascular, cerebrovascular, and other extrarenal complications of ADPKD. Psychosocial evaluation should be a part of monitoring by the multidisciplinary care team. Anxiety and depression are reported by more than 60% of patients with ADPKD, and patients may need professional support for employment issues, family planning, and life quality.1

ratio. Nephrol Dial Transplant. 2010;25:2991-2996. 9. Schrier RW, Abebe KZ, Perrone RD, et al. Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med. 2014;371(24):2255-2266. 10. Ecder T. Statins in the treatment of autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 2016;31(8):1194-1196. 11. Brosnahan GM, Abebe KZ, Rahbari-Oskoui FF, et al. Effect of statin therapy on the progression of autosomal dominant polycystic kidney disease: a secondary analysis of the HALT PKD trials. Curr Hypertens Rev. 2017;13(2):109-120. 12. Ganesvoort RT, Arici M, Benzing T, et al. Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice. Nephrol Dial Transplant. 2016;31:337-348.

Conclusion

13. Chebib FT, Perrone RD, Chapman AB, et al. A practical guide for

This case presentation illustrates the paradigm of care for a younger patient with ADPKD. In this case, following identification and differential diagnosis, the nephrologist intervenes aggressively, prescribing rigorous BP control, statin therapy, and tolvaptan, with the goal of managing symptoms, controlling the rise in TKV, and delaying disease progression.This kind of early, optimized therapy, combined with regular monitoring, represents current, evidence-based practice in ADPKD. ■

treatment of rapidly progressive ADPKD with tolvaptan. J Am Soc Nephrol.

References

1202-1212.

1. Chapman AB, Devuyst O, Eckardt KU, et al. Autosomal-dominant poly-

17. Mao Z, Chong J, Ong AC. Autosomal dominant polycystic

cystic kidney disease (ADPKD): executive summary from a Kidney Disease:

kidney disease: recent advances in clinical management. F1000Res.

Improving Global Outcomes (KDIGO) Controversies Conference. Kidney

2016;5:2029.

Int. 2015;88(1):17-27.

18. Bergmann C. Genetics of autosomal recessive polycystic kidney

2. Guler S, Cimen S, Hurton S, Molinari M. Diagnosis and treatment modalities

disease and its differential diagnoses. Frontiers Pediatr. 2018;5:221.

2018;29(10):2458-2470. 14. Porath B, Gainullin VG, Cornec-Le Gall E, et al. Mutations in GANAB, encoding the glucosidase IIa subunit, cause autosomal-dominant polycystic kidney and liver disease. Am J Human Genet. 2016;98: 1193-1207. 15. Takiar V, Caplan MJ. Polycystic kidney disease: pathogenesis and potential therapies. Biochim Biophys Acta. 2011;1812(10):1337-1343. 16. Tan YC, Blumenfeld J, Rennert H. Autosomal polycystic kidney disease: genetics, mutations, microRNAs. Biochim Biophys Acta. 2011;1812(10):

36 THE CLINICAL ADVISOR • DECEMBER 2018 • www.ClinicalAdvisor.com

right-hand column like this one does at the top

19. Cornec-Le Gall E, Audrézet MP, Chen JM, et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013;24:1006-1013. 20. Schrier RW, Brosnahan G, Cadnapaphornchai MA, et al. Predictors of autosomal dominant polycystic kidney disease progression. J Am Soc Nephrol. 2014;25(11):2399-2418. 21. Cornec-Le Gall E, Audrézet MP, Rousseau A, et al. The PROPKD score: a new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2016;27:942-951. 22. Irazabal MV, Rangel LJ, Bergstralh EJ, et al. Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials. J Am Soc Nephrol. 2015;26(1):160-172. 23. European ADPKF Forum. The Brussels Declaration on ADPKD. https://web.era-edta.org/uploads/eaf-brussels-declaration-march-2016.pdf. Published September 7, 2016. Accessed July 3, 2018. 24. Horie S, Mochizuki T, Muto S, et al. Evidence-based clinical practice guidelines for polycystic kidney disease 2014. Clin Exp Nephrol. 2016;20(4): 493-509. 25. Rangan GK, Alexander SI, Campbell K, et al. KHA-CARI guideline recommendations for the diagnosis and management of autosomal dominant polycystic kidney disease. Nephrology. 2016;21:705-716. 26. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012; 367(25):2407-2418. 27. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in laterstage autosomal dominant polycystic kidney disease. N Engl J Med. 2017;377(20):1930-1942. 28. Halvorson CR, Bremmer MS, Jacobs SC. Polycystic kidney disease: inheritance, pathophysiology, prognosis, and treatment. Int J Nephrol Renovasc Dis. 2010;3:69-83. 29. Cheong B, Muthupillai R, Rubin MF, Flamm SD. Normal values for renal length and volume as measured by magnetic resonance imaging. Clin J Am Soc Nephrol. 2007;2(1):38-45. 30. Ecder T. Cardiovascular complications in autosomal dominant polycystic kidney disease. Curr Hypertens Rev. 2013;9(1):2-11. 31. Wong ATY, Mannix C, Grantham JJ, et al. Randomised controlled trial to determine the efficacy and safety of prescribed water intake to prevent kidney failure due to autosomal dominant polycystic kidney disease (PREVENT-ADPKD). BMJ Open. 2018;8:e018794. 32. Zand L, Torres VE, Larson TS, et al. Renal hemodynamic effects of the HMG-CoA reductase inhibitors in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 2016;31(8):1290-1295. 33. van Dijk, Kamper AM, van Veen S, et al. Effect of simvastatin on renal function in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 2001;16(11):2152-2157. 34. Alam A, Perrone RD. Managing cyst infections in ADPKD: an old problem looking for new answers. Clin J Am Soc Nephrol. 2009;4(7): 1154-1155. 35. Sallée M, Rafat C, Zahar JR, et al. Cyst infections in patients with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2009;4(7):1183-1189.

CME CE

POSTTEST Expiration date: October 9, 2019

A statement of credit will be issued only upon receipt of a completed preassessment test, activity evaluation form, and posttest with a score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/Dec18feature. CREDITS: 0.50 Case Study: A 27-Year-Old Man With Newly Diagnosed ADPKD

1. Which of the following is a risk factor for more rapid, severe disease progression in autosomal-dominant poly cystic kidney disease (ADPKD)? a. Early gross hematuria b. Low total kidney volume (TKV) c. Older age at diagnosis d. PKD2 mutation 2. What diagnostic finding distinguishes ADPKD from other renal cystic diseases that could reduce the kidney function? a. Urine protein to creatinine ratio (UPCR) b. Estimated glomerular filtration rate (eGFR) c. Imaging study with TKV calculation d. Urinalysis for blood 3. What should the blood pressure (BP) target be in a patient 18 to 25 years of age with ADPKD and a GFR >60 mL/min? a. 110/75 mm Hg b. 120/70 mm Hg c. 130/80 mm Hg d. 140/90 mm Hg 4. According to the European Renal Association - European Dialysis and Transplant Association, which of the following patients is a candidate for tolvaptan therapy? a. One aged 30-40 years with an eGFR >90 mL/min/1.73 m2 b. One aged 40-50 years with an eGFR >60 mL/min/1.73 m2 c. One with a Predicting Renal Outcomes in ADPKD (PROPKD) score >6 d. One aged <50 years with an eGFR >45 mL/min/1.73 m2 who has demonstrated or who is likely to have rapidly progressing disease 5. Which of these antibiotic classes is preferred for cyst infection in ADPKD? a. Beta-lactams b. Fluoroquinolones a. Cephalosporins b. Aminoglycosides TO TAKE THE POSTTEST please go to: ClinicalAdvisor.com/Dec18feature

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2018 37

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. 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. We are available to assist you in crafting both short clinical pearls or an indepth review of a topic that is of interest to you. CLINICAL FEATURES update our readers on the latest information about conditions seen in everyday practice. Running approximately 2500 to 5000 words, including 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 1500 words, and accompanying images are encouraged. Please include your title and affiliation. Dermatology Clinic CASE #1

Fingernail dystrophy in a young child SIMO HUANG, BS, CHRISTOPHER RIZK, MD

The patient is a 12-year-old Hispanic girl who presents with a 6-month history of nail dystrophy involving all of her fingernails. On examination, all 10 of her fingernails exhibit longitudinal ridging, pitting, fragility, thinning, and distal notching. The patient’s mother is very concerned about the cosmesis of her daughter’s nails. The patient has no systemic symptoms. On review of systems, the patient’s mother noted that her daughter has started to develop circular patches of hair loss that appear to resolve on their own. The patient has no relevant social or family history and does not take any medications. What is your diagnosis? Turn to page 54

CASE #2

Headache, malaise, and a rash ZACHARY SOLOMON, BS, DAVID RIZK, BA, CONNIE WANG, MD

A 42-year-old man presents with a four-day history of experiencing headache, malaise, and stabbing right-sided headache. Two days after his initial symptoms appeared, he developed a rash over the area of pain. He reports that he went hiking through the Texas hill country prior to becoming ill. The patient is otherwise in good health and has an unremarkable medical history. Physical examination reveals unilateral erythematous, thin, raised plaques over the right forehead. In addition, he has no relevant social or family history. What is your diagnosis? Turn to page 55 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2017 53

DERMATOLOGY CLINIC is a department that presents photos of actual cases and asks readers to identify the condition. Each case opens with 1 or 2 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 1000-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 s ubmission. 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 c olleagues 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 646.576.4912; by e-mail to editor@ClinicalAdvisor.com; or by mail to The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001.

38 THE CLINICAL ADVISOR • DECEMBER 2018 • www.ClinicalAdvisor.com

Dermatology Clinic CASE #1

Raised Pink Rash on the Lower Extremity JESSICA SHEU, BS; TALIA NOORILY, BA; CHRISTOPHER RIZK, MD

A 30-year-old woman presents to the clinic with a raised pink rash on her right lower leg. She says that she first noticed bumps on her shin approximately 2 months earlier.The rash is neither pruritic nor painful, and she has no other skin lesions elsewhere on her body. On examination, a waxy erythematous plaque is visualized on the anterior lower leg. On review of systems, the patient describes palpitations and unplanned weight loss over the past 4 months. She is otherwise healthy and has no family history of skin conditions. What is your diagnosis? Turn to page 40

CASE #2

Pigmented Growth on the Upper Back GAIL TAN, BS; ARIELLA NOORILY, BA; CHRISTOPHER RIZK, MD

A 39-year-old man presents to the clinic with a pigmented growth on his left upper back.The patient reports that the lesion has been present since childhood and claims that it grew and became darker when he was 14 years old. It has been stable and asymptomatic since then, but the patient dislikes its appearance. On examination, the lesion is a brown, linear, verrucous plaque.The surrounding skin tissue is unaffected. A biopsy of the plaque reveals hyperkeratosis, acanthosis, and papillomatosis. What is your diagnosis? Turn to page 41 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2018 39

Dermatology Clinic CASE #1

Pretibial Myxedema

Pretibial myxedema (PTM) is an uncommon manifestation of autoimmune thyroid disease, occurring in 4% of patients with Graves disease (GD) and in 15% of patients with Graves-related ophthalmic disease.1 From 1% to 10% of individuals with hyperthyroidism experience PTM; it may also occur in euthyroid patients, as well as those with chronic stasis dermatitis.2 PTM is an infiltrative lesion of the dermis and the subcutaneous tissue.1,3 The first well-documented association of a localized myxedema with Hashimoto thyroiditis was described in 1987.4 It classically presents with thickening of the skin most frequently localized to the pretibial region, earning this disorder its common name.5 PTM has also been described in other areas of the limbs, such as the toes or radial skin.5 In general, these lesions can be morphologically variable; however, they are most commonly pink and waxy with peau d’orange appearance.2 PTM has a gradual onset, typically developing 12 to 24 months after a diagnosis of thyrotoxicosis.5 This condition predominantly affects older adults, especially those in their 60s. Women are 3.5-times more likely to be affected than men.5 The prevalence of PTM is approximately 0.5% to 4% in patients with GD and as high as 15% in patients with severe Graves orbitopathy and markedly increased serum levels of thyrotropin receptor antibodies.5 To date, the exact pathogenesis of this condition is unknown, but it is widely understood that both mechanical and immunologic factors may be involved.6 Trauma to soft tissues or a lengthened duration of standing may induce PTM. For instance, edema, smoking, and arterial or venous insufficiency often lead to local hypoxia that may cause PTM.5 The pathophysiology of PTM is thought to involve the release of inflammatory cells and cytokines. Specifically, when the immune reaction is triggered, infiltrating T lymphocytes begin a cascade that leads to release of cytokines.6 This release causes cell proliferation and synthesis of glycosaminoglycans, particularly chondroitin sulfate and hyaluronic acid, from which PTM arises.7 Another possible trigger for PTM development is radioactive iodine.8 Light microscopic analysis of a localized myxedema biopsy specimen demonstrates abundant mucin in the reticular dermis but usually not in the papillary dermis.5 There may be a few lymphocytes in the perivascular spaces, but extensive infiltration with lymphocytes is not common.6 Compared

with normal skin, PTM is associated with increased mast cells, and the amount of collagen fibers is relatively reduced with marked edema; acanthosis, papillomatosis, and hyperkeratosis are occasionally noted.5 Ultrastructural studies may demonstrate fibroblasts with dilated endoplasmic reticulum, which is a marker for active glycosaminoglycan synthesis and secretion.5 Clinically, PTM is classified into 3 forms: diffuse PTM, which is characterized by nonpitting edema and/or hyperpigmentation of the skin with dilated follicular openings; plaque-like or nodular myxedema, which is characterized by sharply circumscribed dermal lesions; and elephantiasic PTM, which is characterized by a combination of edema and nodules.5 Skin changes that appear in patients with PTM can look similar to those in patients with simple edema from venous insufficiency or fluid retention, chronic or lichenified dermatitis, hypertrophic lichen planus, generalized myxedema, or urticarial phases of certain blistering episodes.5 Accumulation of mucin in the dermis is also a prominent feature in several cutaneous mucinoses including scleromyxedema, reticular erythematous mucinosis, and follicular mucinosis.5 The location of these mucinoses in the upper extremities helps to differentiate them from PTM. Also, patients with cutaneous mucinoses usually lack thyroid dysfunction and ophthalmopathy.5 The diagnosis of PTM is usually readily apparent due to the typical pretibial lesions, but biopsy may be necessary in some situations9; in a recent report, diagnosis was confirmed by biopsy in 58% of 178 cases.9 Imaging studies, such as radiography, may also aid in diagnosis.5 In the majority of cases, PTM is mild with symptoms limited to aesthetics.5 In rare occasions, the lesions may be painful or pruritic.9 Generally, no treatment is required as up to 50% of patients report experiencing complete spontaneous remission after several years, with an average time to resolution of nearly 9 years.5 In cases with significant discomfort and deformity, a number of therapies have been proposed, including hyaluronidase or glucocorticoid injections, compressive dressings, and topical corticosteroids.10 While the administration of hypodermal triamcinolone injections has not yet been extensively studied, adverse reactions including hypopigmentation and skin atrophy may hinder its use.10 Mesotherapy, also known as intradermotherapy, is a method of steroid administration originally used in chronic pain management with lower risk of skin atrophy than hypodermal injections.10 Although preliminary, one study demonstrated that mesotherapy in PTM is well tolerated and effective; however, future studies of greater scale are warranted.10 The patient in the case described above was diagnosed with Graves disease and treated by an endocrinologist. She elected not to treat her PTM.

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Jessica Sheu, BS, is a medical student;Talia Noorily, BA, is a medical student; and Christopher Rizk, MD, is a dermatology fellow at Baylor College of Medicine, Houston,Texas. References 1. Kriss JP. Pathogenesis and treatment of pretibial myxedema. Endocrinol Metab Clin North Am. 1987;16:409-415. 2. Rojanametin K, Masaru T. Dermoscopy of pretibial myxedema. J Am Acad Dermatol. 2015;73:e195-e196. 3. Smith TJ, Bahn RS, Gorman CA. Hormonal regulation of hyaluronate synthesis in cultured human fibroblasts: evidence for differences between retroocular and dermal fibroblasts. J Clin Endocrinol Metab. 1989;69:1019-1023. 4. Humbert P, Dupond JL, Carbillet JP. Pretibial myxedema: an overlapping clinical manifestation of autoimmune thyroid disease. Am J Med. 1987;83:1170-1171. 5. Fatourechi V. Pretibial myxedema: pathophysiology and treatment options. Am J Clin Dermatol. 2005;6:295-309. 6. Bahn RS. Clinical review 157: pathophysiology of Graves’ ophthalmopathy: the cycle of disease. J Clin Endocrinol Metab. 2003;88:1939-1946. 7. Bull RH, Coburn PR, Mortimer PS. Pretibial myxoedema: a manifestation of lymphoedema? Lancet. 1993;341:403-404. 8. Harvey RD, Metcalfe RA, Morteo C, et al. Acute pre-tibial myxoedema following radioiodine therapy for thyrotoxic Graves’ disease. Clin Endocrinol (Oxf). 1995;42:657-660; discussion 661. 9. Schwartz KM, Fatourechi V, Ahmed DDF, Pond GR. Dermopathy of Graves’ disease (pretibial myxedema): long-term outcome. J Clin Endocrinol Metab. 2002;87:438-446. 10. Vannucchi G, Campi I, Covelli D, et al. Treatment of pretibial myxedema with dexamethazone injected subcutaneously by mesotherapy needles. Thyroid. 2013;23:626-632.

CASE #2

Epidermal Nevus

Epidermal nevi are congenital hamartomatous proliferations of the epithelium. A hamartoma is a disordered overgrowth of benign tissue in its area of origin. Epidermal nevi are classified based on the predominant epidermal cell involved: keratinocytic (verrucous [wart-like] epidermal nevus), sebaceous (nevus sebaceous), pilosebaceous (nevus comedonicus), eccrine gland (eccrine nevus), or apocrine gland (apocrine nevus).1 Epidermal nevi are uncommon, occurring in approximately 1 in 1000 live births, and equally affect males and females. They are typically seen at birth or develop in early childhood.

Most cases are sporadic, occurring as an isolated finding and remaining quiescent after adolescence. However, a group of rare epidermal nevus syndromes have been associated with additional neurocutaneous abnormalities, most often affecting the brain, eyes, and skeletal system. Epidermal nevus syndrome is often termed Solomon syndrome.1 Epidermal nevi originate from pluripotent stem cells in the basal layer of the embryonic epidermis. The etiology of most epidermal nevi is thought to be due to the mosaicism of FGFR3 and PIK3CA mutations during embryologic development. These mosaics are only present in the cells of the nevus. However, if mutations occur very early in development, they lead to more extensive epidermal nevi and affect other organ systems.2 Ten different histologic patterns of epidermal nevus have been described. The most common type is linear epidermal nevus, also known as keratinocytic, or verrucous epidermal nevus. Histologically, it displays hyperkeratosis, papillomatosis, and acanthosis and appears similar to seborrheic keratosis.3 Linear epidermal nevi are typically found on the torso or limbs as linear, round, or oblong patches with pigmentation varying in color from yellow-tan to brown.They can be flattopped, velvety, or verrucous.With age — particularly around puberty — nevi can become thicker, darker, and more verrucous. Linear epidermal nevi often follow relaxed skin tension lines or develop in a linear configuration known as the lines of Blaschko, which are thought to follow the paths that cells travel during fetal skin development.The differential diagnosis of linear epidermal nevus includes other linear dermatoses such as lichen planus, lichen striatus, linear porokeratosis, linear Darier disease, and linear psoriasis.3 Although the malignant potential of epidermal nevus is low, there have been rare cases of squamous cell carcinoma and basal cell carcinoma arising within epidermal nevi that warrant complete excision. This malignant transformation is most common in middle-aged or elderly individuals.4 Nevus sebaceous usually presents as a solitary, smooth, and waxy plaque with yellow-orange discoloration and surrounding alopecia.These nevi are found most frequently on the scalp at birth and can sometimes involve the neck, trunk, and proximal extremities. Like most epidermal nevi, they may also become more verrucous with age. Though rare, tumors may arise within nevus sebaceous. The most common benign tumors are syringocystadenoma and trichoblastoma. Malignant tumors are less common but include apocrine carcinoma, squamous cell carcinoma, and eccrine poromas. Differential diagnosis includes aplasia cutis, congenital nevi, and seborrheic keratosis.4 Nevus comedonicus lesions are hamartomas of the pilosebaceous unit. Clinically, they resemble comedones and are

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Dermatology Clinic characterized by dilated follicular pores that contain keratinaceous plugs instead of hair shafts. They are usually asymptomatic and commonly affect the face and neck area. Differential diagnosis includes acne vulgaris, milia, acne neonatorum, nevus sebaceous, and linear Darier disease. The non-inflammatory variant is asymptomatic while the inflammatory variant might require surgical or medical intervention to alleviate significant pain.5 Eccrine nevus shows an increased number of eccrine glands on histology without any other abnormalities. These nevi are distributed on the trunk, arms, or legs and are often associated

Skin biopsy with histopathologic confirmation provides the most definitive diagnosis of epidermal nevus. with hyperhidrosis. The morphology varies from tan to skin-colored papules. Therapy is focused on symptomatically treating the hyperhidrosis with surgery, iontophoresis, or sympathectomy, or with agents such as aluminum chloride solution, anticholinergics, or botulinum toxin.6 Apocrine nevi are hamartomatous proliferations of the apocrine glands.They can present as nodules on the axilla or upper chest and also as a solitary nodule on the scalp. Histology of apocrine nevus shows apocrine glands that extend from the epidermis to the subcutaneous fat.3 Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare variant presenting with pruritus, erythema, and scaling, often on the buttocks and lower extremities. Psoriasiform papules form linear plaques that follow the lines of Blaschko. Histopathology shows a dermal infiltrate of inflammatory cells as well as psoriasiform epidermal hyperplasia with alternating columns of orthokeratosis and parakeratosis.7 ILVEN appears similar to linear psoriasis clinically, but it is more resistant to therapy; glucocorticoids, cryotherapy, laser therapy, and surgical excision have shown variable success.8 In most cases, the diagnosis of epidermal nevi can be made clinically. However, skin biopsy with histopathologic confirmation provides the most definitive diagnosis. Children with small isolated epidermal nevi and normal physical examination are not at risk for complications. However, patients with extensive epidermal nevi or systemic abnormalities require further workup for epidermal nevus syndrome. Diagnosis in these patients requires a thorough developmental history, careful physical examination (especially neurologic and skeletal assessments), and individualized imaging based on the suspected system involved.9

Most epidermal nevi occur sporadically due to a postzygotic gene mutation and are present in only some of the cells in the body (mosaic). However, patients with the epidermolytic histologic variant of epidermal nevus may have gonadal mosaicism for the KRT1 or KRT10 (keratin 1 and 10) genes. Patients with this variant carry the genetic mutation for epidermolytic hyperkeratosis and are at risk of passing this gene on to children. Genetic counseling may be warranted for these patients.4 Treatment of epidermal nevus is challenging.There are no proven topical methods for treatment, and destructive modalities often only lead to temporary improvements.Topical retinoids, electrodessication, cryotherapy, and laser therapy may be marginally beneficial. Surgical modalities with full-thickness excision have better success in providing definitive treatment. However, significant scarring can complicate the excision of larger lesions, and recurrence is still possible.10 The patient in the case described above elected to have the nevus removed for cosmetic reasons.A full-thickness excision was performed and he healed well. ■ Gail Tan, BS, is a medical student;Ariella Noorily, BA, is a medical student; and Christopher Rizk, MD, is a dermatology fellow at Baylor College of Medicine, in Houston,Texas. References 1. Brandling-Bennett HA, Morel KD. Epidermal nevi. Pediatr Clin North Am. 2010;57(5):1177-1198. 2. Hafner C, Lopez-Knowles E, Luis NM, et al. Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern. Proceed Natl Acad Sci U S A. 2007;104(33):13450-13454. 3. Thomas VD, Valencia D, et al. Benign epithelial tumors, hamartomas, and hyperplasias. In Goldsmith AL, ed. Fitzpatrick’s Dermatology in General Medicine. 8th edition. New York, NY: McGraw-Hill; 2012. 4. Jaqueti G, Requena L, Sánchez Yus E. Trichoblastoma is the most common neoplasm developed in nevus sebaceus of Jadassohn: a clinicopathologic study of a series of 155 cases. Am J Dermatopathol. 2000;22(2):108-118. 5. Tchernev G, Ananiev J, Semkova K, Dourmishev LA, Schönlebe J, Wollina U. Nevus comedonicus: an updated review. Dermatol Ther (Heidelb). 2013;3(1):33-40. 6. Kawaoka JC, Gray J, Schappell D, Robinson-Bostom L. Eccrine nevus. J Am Acad Dermatol. 2004;51(2):301-304. 7. Meibodi NT, Nahidi Y, Javidi Z. Epidermolytic hyperkeratosis in inflammatory linear verrucous epidermal nevus. Indian J Dermatol. 2011;56(3):309-312. 8. Abdullah L, Abbas O. Answer: Can you identify this condition? Canadian Fam Physician. 2012;58(3):286. 9. Solomon LM, Fretzin DF, Dewald RL. The epidermal nevus syndrome. Arch Dermatol. 1968;97(3):273-285. 10. Lee BJ, Mancini AJ, Renucci J, Paller AS, Bauer BS. Full-thickness surgical excision for the treatment of inflammatory linear verrucous epidermal nevus. Ann Plastic Surg. 2001;47(3):285-292.

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Dermatologic Look-Alikes Widespread Erythematous Rash SIRUS JESUDASEN, BA; JOAN FERNANDEZ, BA; CHRISTOPHER RIZK, MD

CASE #1

CASE #2

A 24-year-old man presents to his primary care physician with complaints of new-onset sore throat and fatigue. He is diagnosed with acute pharyngitis and given a prescription for ampicillin as empiric treatment. Five days later he presents to a local hospital emergency department complaining of a new rash that began on his trunk and spread to his arms and legs. On examination, he is found to have widespread erythematous macules and papules, some of which coalesce, that are located diffusely across his trunk and extremities.

A 50-year-old man presents to an urgent care clinic complaining of a fast-developing pruritic rash after being stung by a wasp. On examination, he is found to have wheals, some of which have become confluent, spread diffusely across his body.The wheals are noted to be surrounded by erythema that blanches under pressure. A single punctate white lesion is visible within one of the wheals.The patient has no difficulty breathing and is normotensive with a blood pressure of 120/70 mm Hg.

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Dermatologic Look-Alikes CASE #1

Morbilliform Drug Rash

Morbilliform — or exanthematous — drug eruptions are among the most common type of drug reactions and may present after administration of a wide variety of medications. In fact, they make up approximately 40% of drug reactions and have been described to occur in as many as 2% to 3% of hospitalized patients.1,2 An estimated 1 in 1000 hospitalized patients are reported to experience a serious cutaneous drug reaction.1 Such drug reactions are thought to emerge after medication administration via the presence of haptens, or drug components binding to endogenous proteins to produce an antigen. These haptens may then be presented by antigenpresenting cells to naive T cells, leading to subsequent T-cell activation; this results in cell proliferation and the release of cytokines and other inflammatory mediators.3 Infiltration of these activated T cells into the skin along with the release of their inflammatory mediators result in rash development.3 Certain medications have been identified that have a greater propensity to cause morbilliform drug eruptions; these include certain antibiotics (penicillins, cephalosporins, amphotericin B, etc), as well as nonsteroidal anti-inflammatory drugs (NSAIDs), allopurinol, and barbiturates, among others.4 In general, cutaneous administration of drugs has been associated with increased risk of sensitization and subsequent rash emergence compared with oral or parenteral administration of the same medication.2 Specific risk factors that increase the likelihood of rash formation include a variety of disorders and genetic factors that alter a patient’s immune response. Certain HLA alleles have been shown to increase the risk of hypersensitivity reactions, such as that seen with HLA-A*3101 and carbamazepine.3 A higher risk of rash development has also been noted in patients with HIV infections and in those who have received bone marrow transplants. Additionally, patients with certain infections who are treated with particular medications have a greater likelihood of developing a morbilliform rash; for example, an exanthematous rash often occurs in patients with infectious mononucleosis who take antibiotics such as ampicillin.3 Presentation of a morbilliform drug rash typically occurs 1 to 2 weeks following the initial administration of a medication, and it is very unlikely to occur within 3 days after initial administration; however, with re-exposure to a causative drug, a rash may emerge within a few days of administration.3,5 The rash is usually first identified on the trunk, especially in areas

of pressure or trauma foci, with subsequent spread distally to the limbs and neck in a bilateral and symmetrical manner.4,5 Typical presentation of the rash consists of erythematous, pinkto-red papules or macules that are more likely to blanch with pressure and may coalesce; involvement of mucous membranes is not expected.3,5 On histologic examination, a superficial perivascular infiltrate with admixed eosinophils is suggestive of the diagnosis; dermal edema may also be present.1,4 The differential diagnosis for a morbilliform drug rash primarily includes various infectious rashes. Measles is one consideration, as it also causes a morbilliform (or “measles-like”) rash, although measles tends to start at the head and spread downward and is associated with symptoms such as cough, conjunctivitis, coryza, and buccal Koplik spots.3 Rubella may also be considered; it is typically associated with fever as well as lymphadenopathy and possible arthralgias.3 In the case of recent organ transplant (2-4 weeks prior to manifestation of rash), acute graft-vs-host disease should also be considered. HIV seroconversion can also lead to an exanthematous rash approximately 1 to 6 weeks after transmission; this rash typically involves the palms and soles and may also present with genital and/or oral aphthous ulcers. StevensJohnson syndrome and toxic epidermal necrolysis syndrome should also be considered, especially in cases with widespread cutaneous involvement and additional mucosal involvement. Diagnosis of a morbilliform drug rash is clinical and based on the abrupt presentation of an exanthematous rash in the setting of a newly introduced medication.5 Building a drug calendar of all prescribed or over-the-counter medications for the several weeks preceding rash onset can be helpful in identifying suspect medications.5 Although laboratory tests

Presentation of a morbilliform drug rash typically occurs 1 to 2 weeks following the initial administration of a medication. are not necessary for diagnosis of a morbilliform drug rash, serologic assessment can be useful for ruling out infectious etiologies. Eosinophilia as determined by a complete blood count with differential may also be supportive of the diagnosis of a morbilliform drug rash, albeit not diagnostic.5 The first step in the treatment of a morbilliform drug rash is identification and subsequent discontinuation of the causative drug; however, in the case of a mild reaction to an essential and irreplaceable medication, the medication may be continued while the patient seeks specialist care.5 Medical treatment of the rash may include the application of emollients and topical steroid

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creams to the affected areas, although topical glucocorticoid use should be avoided on the face and in intertriginous areas.3,5 The prescription of an antihistamine such as diphenhydramine or hydroxyzine may also be considered, especially for patients presenting with associated pruritus.3 In the case of a severe reaction, hospitalization or specialist care may be advisable. In the case scenario provided, the patient was diagnosed with a morbilliform drug reaction secondary to the use of ampicillin in a case of missed acute mononucleosis. The ampicillin was discontinued and the patient was given a prescription for topical steroids. He was also directed to take the oral antihistamine diphenhydramine. The patient was counseled about the benign nature of the rash and after a few days, the rash resolved with no associated complications.

CASE #2

Urticaria

Urticaria, also referred to as hives or wheals, is a relatively common skin rash that often occurs in the setting of exposure to an allergen but may also present secondary to a specific physical trigger. Urticarial rashes have been recognized for an extremely long time, with initial descriptions made by Hippocrates as early as the 400s BC.Today, approximately 20% of the population experience urticaria at some point in their lives.6 The initial presentation of acute urticaria often occurs in children, especially after exposure to a new potential allergen. In the case of chronic urticaria, a number of comorbidities have been described, particularly in children, including atopy, low vitamin D levels, and psychiatric disorders.7 The development of urticaria is primarily thought to occur via an allergic or autoimmune pathway. Allergens or recognition of self-antigens by IgE results in the activation of mast cells and basophils. The activation of these cells, as well as subsequent degranulation of mast cells, leads to massive histamine release.8 Histamine release in the dermis results in urticarial lesions, while release in the deeper dermis and subcutaneous tissue leads to angioedema.9 Multiple ideas have been proposed to describe the etiology of urticaria; the most common involves exposure to allergens, such as pollen and peanuts, which then stimulates the allergic pathway resulting in urticaria.9 Additionally, food pseudoallergens, or substances that either contain histamine-like

molecules or directly release endogenous histamine, have also been identified as possible causal agents for urticaria.9 Infections caused by a broad range of common viruses and bacteria have been known to cause urticaria as well, particularly in children.9 Similarly, allergic drug reactions may cause urticaria, such as seen with beta-lactam antibiotics and NSAIDs. It has also been noted that physical stimuli such as mechanical pressure or heat may reliably produce urticaria in some susceptible patients.10 Urticaria typically presents as a wheal with characteristic features including central swelling, surrounding reflex erythema, and associated burning or pruritus.11 The skin rash can be accompanied by angioedema, or swelling of the underlying dermis and/or mucosal tissue; associated signs and symptoms such as flushing or wheezing may also be present.10 Urticaria typically resolves within a few hours of onset and almost always within 24 hours.11 Urticaria is classified as either acute or chronic based on whether episodes of the rash have occurred continuously for less than 6 weeks or more than 6 weeks, respectively.11 Urticaria can also be subdivided into inducible and spontaneous based on whether a specific trigger or precipitating factor can be identified. Examples of inducible urticaria include urticaria that occurs in response to temperature changes or to specific substance exposure (contact urticaria).10,11

A complete review of systems is important for identifying any signs and symptoms that may be associated with urticaria. The time frame of presentation is important when establishing a differential diagnosis for urticaria, as it may provide clues to a specific trigger or exposure to an allergen that leads to the rash, such as with new drug exposures or physical precipitants like mechanical pressure or heat.10 Autoimmune diseases including bullous pemphigoid and systemic lupus erythematosus should also be considered, especially in the setting of a positive family history or rheumatologic findings such as uveitis or joint pain.10 A viral exanthem is another potential diagnosis to consider when a patient presents with new-onset rash in addition to other clinical signs of infection.10 Due to its life-threatening nature, anaphylaxis must be immediately considered and ruled out; a lack of involvement of other organ systems can help to quickly remove this possibility from the differential diagnosis.9 Insect bites may also produce urticarial-like lesions, although the diagnosis of urticaria is much less likely when the lesions continue to persist beyond a day or a history of insect bites is present.9

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Dermatologic Look-Alikes TABLE. Morbilliform Drug Rash vs Urticaria Morbilliform Drug Rash3-5

Urticaria8,9,11

Presentation

• Erythematous papules and macules, with possible coalescence • Spread from trunk to extremities

Wheals with central swelling, reflex erythema, and burning or pruritus

Associations

Recent introduction of a new medication

• Specific reliable trigger • Often allergen associated

Etiology

• Activation of naive T cells by haptens • Subsequent T-cell proliferation and inflammatory release

• Activation of mast cells and basophils by IgE • Subsequent histamine release

Diagnosis

• History and physical examination • Timing and progression of the rash

Treatment

• Antihistamines • Topical steroids and emollients • Possible hospitalization or specialist care

• Avoidance of triggers • Antihistamines • Oral steroids or additional antihistamines in severe cases • Omalizumab in recalcitrant cases

Important to consider or rule out

Stevens-Johnson syndrome (widespread cutaneous rash, mucosal involvement)

Anaphylaxis (hypotension, angioedema of the airway)

Diagnosis of an urticarial rash is primarily clinical, with a detailed exposure history, timing of the onset of the rash, and rash progression being the most helpful historical elements.9 A complete review of systems is important for identifying any signs and symptoms that may be associated with urticaria, as well as to rule out other potential infectious or systemic causes of rash. The primary method for treating urticaria is to eliminate or avoid the trigger, if it is known, to as great of a degree as is possible.9 The first-line agent for the medical management of acute urticaria is a second-generation H1 blocker or an antihistamine, such as loratadine or cetirizine.9 In cases of severe or prolonged urticaria, a brief course of oral corticosteroids, such as prednisone at a dosage of 0.5 to 1 mg/kg for 3 to 10 days, may also be considered.9 Prescribing an epinephrine autoinjector may also be prudent for patients who have a history of severe allergic reactions involving anaphylaxis or angioedema of the airways.9 The first-line management approach to chronic urticaria is also second-generation H1 blockers and antihistamines; however, if these agents fail to control symptoms, a trial of a leukotriene receptor antagonist should be considered.9 For cases of recalcitrant urticaria, a high-potency antihistamine such as hydroxyzine or doxepin, or immunomodulatory therapy such as the anti-IgE antibody omalizumab may be required.9 In the case scenario provided, the patient had no symptoms beyond the itchy wheals. The rash fully resolved within the next few hours. He was discharged with instructions for antihistamine use in the event of a recurrence, and he was counseled to avoid areas with wasps and to use insect repellent when he is outdoors. ■

Sirus Jesudasen, BA, is a medical student; Joan Fernandez, BA, is a medical student; and Christopher Rizk, MD, is a dermatology resident at Baylor College of Medicine, in Houston,Texas. References 1. Gerson D, Sriganeshan V, Alexis JB. Cutaneous drug eruptions: a 5-year experience. J Am Acad Dermatol. 2008;59(6):995-999. 2. Pichler WJ, Adam J, Daubner B, Gentinetta T, Keller M, Yerly D. Drug hypersensitivity reactions: pathomechanism and clinical symptoms. Med Clin North Am. 2010;94(4):645-664. 3. Stern RS. Exanthematous drug eruptions. N Engl J Med. 2012;366:2492-2501. 4. Ramdial PK, Naidoo DK. Drug-induced cutaneous pathology. J Clin Pathol. 2009;62(6):493-504. 5. Dyall-Smith D. Morbilliform drug reaction. DermNet NZ website. www. dermnetnz.org/topics/morbilliform-drug-reaction/. Updated January 2016. Accessed November 5, 2018. 6. Jafilan L, James C. Urticaria and allergy-mediated conditions. Prim Care. 2015;42(4):473-483. 7. Cornillier H, Giraudeau B, Munck S, et al. Chronic spontaneous urticaria in children - a systematic review on interventions and comorbidities. Pediatr Allergy Immunol. 2018;29(3):303-310. 8. Church MK, Kolkhir P, Metz M, Maurer M. The role and relevance of mast cells in urticaria. Immunol Rev. 2018;282(1):232-247. 9. Schaefer P. Acute and chronic urticaria: evaluation and treatment. Am Fam Physician. 2017;95(11):717-724. 10. Radonjic-Hoesli S, Hofmeier KS, Micaletto S, Schmid-Grendelmeier P, Bircher A, Simon D. Urticaria and angioedema: an update on classification and pathogenesis. Clin Rev Allergy Immunol. 2018;54(1,):88-101. 11. Godse K, Abhishek D, Zawar V, et al. Consensus statement for the diagnosis and treatment of urticaria: a 2017 update. Indian J Dermatol. 2018;63(1):2-15.

46 THE CLINICAL ADVISOR • DECEMBER 2018 • www.ClinicalAdvisor.com

AND Case Study | OBSTETRICS GYNECOLOGY EXAMINATION

Early Pregnancy and Painless Spotting A 30-year-old woman who is 6 weeks pregnant calls in to the after-hours Ob/Gyn line over the weekend with reported spotting. AMBER MURPHY, PA-C

THE CASE A 30-year-old woman (gravida G3, para 1) who is approximately 6 weeks pregnant called in to the after-hours Ob/Gyn line over the weekend with reported spotting. She stated that she had bright red spotting for 24 hours that has now stopped. She denied any pain, dizziness, gastrointestinal symptoms, change in activity, or trauma. She had a miscarriage at 6 weeks’ gestation 3 months prior and is concerned for another miscarriage. She also denied any history of sexually transmitted infections, drug use, or smoking.

The patient presented on April 24th for examination, 24 hours after the bleeding stopped, at which time human chorionic gonadotropin (hCG) levels were obtained for comparison with previous levels. The patient was sent home, but she was directed to call if bleeding started again or if she experienced any pain. A review of the β-hCG levels is as follows:April 15th, 674 mIU/ mL; April 20th, 4934 mIU/mL; and April 24th, 9014 mIU/mL. Progesterone level recorded on April 15th was 15.0 ng/mL (expected firsttrimester progesterone range, 11.2-90.0 ng/mL). The results were discussed with the patient’s obstetrician/gynecologist and were determined to be increasing appropriately. The hCG levels should increase by at least 53% in 48 hours or double in 72 hours (Table).The patient was still concerned for miscarriage and was scheduled for an ultrasound at the hospital that week to confirm the pregnancy.

IMAGING AND TREATMENT The ultrasound was scheduled for 3 days after the last hCG level was taken, and no further spotting was noted. On the morning of the ultrasound, the patient experienced sharp, shooting lower pelvic/vaginal pain that went away after a few minutes. She presented for her ultrasound, which did not show any products of conception within the uterus. A transvaginal ultrasound was then performed, which revealed a left ectopic pregnancy with a fetal pole and positive cardiac activity. Free fluid was noted suggesting rupture. The patient was stable and sent immediately for direct admit and scheduled for an emergent laparoscopy. The patient was taken to the operating room for laparoscopy to remove the ectopic pregnancy and repair the possible rupture. Once visualized, a left cornual ectopic pregnancy was identified and was noted to be bulging from the side of the uterus (Figure).The decision was made to convert

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Case Study TABLE. Normal Range for Human Chorionic Gonadotropin (hCG) Levels During Pregnancy Approximate Gestational Age

hCG Value (mIU/mL)

1 week

5-50

2 weeks

40-1000

3 weeks

100-5000

4 weeks

600-10,000

5-6 weeks

1500-100,000

7-8 weeks

16,000-200,000

2-3 months

12,000-300,000

20% to 50% of cases in this location.2 Although the maternal mortality rate associated with ectopic pregnancies is decreasing, the maternal mortality rate associated with cornual ectopic pregnancies remains at 2.5% because of misdiagnosis of these gestations.2

CONCLUSION The classic presentation of delayed menstruation, pain, and vaginal bleeding or spotting is not always representative of miscarriage. Some degree of vaginal bleeding is reported in 60% to 80% of women with ectopic pregnancy prior to rupture.2 Routine prenatal care does not include serial hCG levels or early transvaginal ultrasound assessment. It is important to have a high degree of suspicion for ectopic pregnancy in a woman with painless first-trimester bleeding. Relying on serial hCG levels alone will not identify all ectopic pregnancies. Clinical judgment is key in screening and identifying women with an ectopic pregnancy before rupture occurs. ■

to an open laparotomy, which was successful in removing the ectopic pregnancy. The patient was hemodynamically stable during the entire procedure and fully recovered.

Amber Murphy, PA-C, works in obstetrics at Beaumont Hospital in Royal Oak, Michigan.

DISCUSSION

References 1. Cunningham F, Leveno KJ, Bloom SL, et al. Ectopic pregnancy. In: Williams

In a normal pregnancy, following fertilization the blastocyst implants in the endometrial lining of the uterine cavity. Implantation elsewhere is considered an ectopic pregnancy. In the United States, ectopic pregnancies comprise 1% to 2% of all first-trimester pregnancies.1 Ectopic pregnancies account for 6% of all pregnancy-related maternal deaths1; this number has dramatically decreased over the past decades with early urine and serum beta-hCG levels, transvaginal ultrasounds, and early diagnosis through assessment of symptoms by medical providers. Nearly 95% of ectopic pregnancies are implanted into the fallopian tube.1 The remaining 5% involve a cornual ectopic pregnancy, which is also known as an interstitial ectopic pregnancy.1 In a cornual ectopic pregnancy, the blastocyst implants where the proximal segment of the fallopian tube connects with the muscular wall of the uterus. In this case study, as the embryo grew at the junction of the fallopian tube and uterus, it eroded the tissue, ultimately attaching to the outside of the uterus. An interstitial pregnancy can be difficult to distinguish on ultrasound from an intrauterine pregnancy that is eccentrically placed.The hCG levels will rise appropriately, which in this case caused a delay in diagnosis. Due to delay in diagnosis, rupture occurs in approximately

Obstetrics. 24th edition. New York, NY: McGraw-Hill; 2013. 2. Surette A, Dunham SM. Early pregnancy risks. In: CURRENT Diagnosis & Treatment Obstetrics & Gynecology. 11th edition. New York, NY: McGraw-Hill; 2013.

FIGURE. Left cornual ectopic pregnancy.

48 THE CLINICAL ADVISOR • DECEMBER 2018 • www.ClinicalAdvisor.com

Case Study | PEDIATRICS believed Grace was having a seizure. The baby was brought to the hospital by emergency services. Once in the trauma bay, Grace went into respiratory arrest twice. After she was stabilized, she was admitted to the pediatric intensive care unit for further workup and observation.

EXAMINATION

A Case of Floppy Baby Syndrome A previously healthy 4-month-old infant presents with weak cry, inability to feed, and having the appearance of a “floppy rag doll.” VICTORIA ARASI HAUFF, PA-C; JUDITH STALLINGS, EDD, MHE, PA-C

THE CASE The parents of a previously healthy 4-month-old infant, Grace, were alarmed when she suddenly became extremely cranky and her cry sounded weaker than usual. That night while breastfeeding the baby had a weak latch. Her parents were concerned with her stark change in behavior and decided they would bring her to her pediatrician the next day if she skipped another feeding. The following morning, Grace’s condition had worsened. Her cry was even weaker, she was unable to feed, and her parents noted she had the appearance of a “floppy rag doll.” When the parents called her name, Grace did not respond, and her mother described Grace as “looking right through me.” The parents called 911 because they

50 THE CLINICAL ADVISOR • DECEMBER 2018 • www.ClinicalAdvisor.com

On physical examination, Grace exhibited hypotonia with loss of deep tendon reflexes in the upper extremities and later progressing to the lower extremities. In addition, Grace’s examination displayed ptosis, impairment in extraocular movements, a mottled skin appearance, and drooling that required frequent suctioning. All other portions of the physical examination were normal, including her vital signs. Her history was positive for constipation, but otherwise she had been completely healthy and had been delivered vaginally at 38 weeks without complications. Cerebrospinal fluid analysis ruled out meningitis. Blood cultures, complete blood count, and comprehensive metabolic panel were all within normal limits. Electroencephalography was performed and ruled out seizure. Computed tomographic examination of the head was negative for any signs of trauma. Urinalysis showed increased white cells. Based on these findings, the working diagnosis was either a urinary tract infection or a metabolic disease. However, the medical team was stumped by Grace’s continuing physical deterioration.They could not determine an obvious cause of her hypotonia (referred to as “floppy baby syndrome”).

DIAGNOSIS AND TREATMENT Grace’s mother noticed that her baby attempted to feed but could not swallow and asked the clinician to further examine the pharynx. Upon examination there was noted to be loss of the patient’s gag and swallow reflex. Although having had no personal experience with such a case, the clinician believed that Grace might be demonstrating signs

DISCUSSION Infant botulism is a paralytic disease caused by ingestion of Clostridium botulinum, an organism found in soil that releases a neurotoxin after colonizing the gastrointestinal tract.1 In a global study by Koepke et al, the United States was found to have the highest number of infant botulism cases with a total of 2419 from 1976-2006, resulting in an incidence of 2.1 cases per 100,000 live births.2 Approximately 98% of cases of infant botulism occur in patients between 1 and 6 months of age.3 While foodborne botulism occurs after ingestion of toxin, infant botulism differs in that the organisms in the intestines are continually making toxin.3 As botulinum spores can be widely found in the environment, ingestion of the organisms may be a relatively common occurrence in humans; however, normal flora in intestines of adults are able to compete against the botulinum organisms. Babies are more susceptible to the disease, as their intestinal flora may not be able to clear the organism from their body.4 Once the toxin travels through the bloodstream, it binds to the neuromuscular junction, blocking acetylcholine.1,5 Without acetylcholine in the presynaptic junction, muscle excitation cannot occur, causing “symmetric, descending motor weakness and flaccid paralysis with autonomic dysfunction progressing over the course of hours to a few days, proceeding from cranial nerves to the trunk, extremities, and finally the diaphragm.”6 The main risk factor that has been implicated in infant botulism is honey exposure in children younger than one year of age, as honey has been found to contain botulinum spores.Therefore, honey consumption among infants younger than one year of age is not recommended.1 Although this is the most well-known risk factor, 85% of patients with infant

botulism have no known honey exposure. Honey consumption among infants has declined, yet the incidence of the disease has remained at approximately the same rate in the United States.3 Living in rural areas near construction sites is another risk factor for the disease, as microscopic spores can be ingested from dirt and dust from the environment.2,7 Additionally, constipation is a risk factor because “with fewer bowel movements per day, the gut flora may be disrupted, which could encourage spore growth and colonization.”7 Typical clinical findings of infant botulism include progressive hypotonia, flaccid paralysis extending from the cranial nerves to the extremities, and constipation. Parents of infants with the condition often note that their babies have a weak latch while trying to breastfeed or are unable to feed at all. Other signs are a weak “sheep-like” cry, drooling, decreased head control, loss of facial expression, and diminished deep tendon reflexes. Ptosis, fixed pupils, mydriasis, impaired extraocular movements, and inability to follow may be ophthalmic physical examination findings. Apnea can occur, as well.1,8 There are several clinical mimics of infant botulism that all present as “floppy baby syndrome”: spinal muscular atrophy, metabolic diseases like mitochondrial disease, Guillain-Barré syndrome, and other neurologic infections. Therefore, it is important to know the appropriate diagnostic studies to

of infant botulism. Electrophysiology studies were performed and exhibited findings characteristic of infant botulism.A stool sample was collected and sent for confirmation. After the clinical diagnosis of infant botulism was made, botulinum immune globulin (BabyBIG®) was ordered from the Centers for Disease Control and Prevention (CDC) and flown in from California where it is produced. Once it arrived, the medication was infused intravenously for 1 hour. BabyBIG immune globulin was curative for Grace. Fortunately, during the course of her 2-week hospital stay she did not require intubation despite her serious symptoms. Occupational therapy, physical therapy, and speech therapy were consulted. Following appropriate treatment, Grace made a full recovery and is now a healthy toddler who has reached all of her milestones.

Photomicrograph revealing Clostridium botulinum.

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Case Study perform to lead to an accurate diagnosis.8 Botulinum toxin can be found in stool, gastric aspirate, vomit, and blood; however, these tests have a low sensitivity. The confirmatory and most sensitive diagnostic test for botulism is toxin neutralization mouse bioassay of stool samples, conducted at either the CDC or state health departments.6 Electrophysiology studies can be helpful for diagnosis, as well. The typical triad of electromyographic findings for infant botulism are low-amplitude compound muscle action potentials, tetanic or post-tetanic facilitation, and absence of post-tetanic exhaustion.9 To rule out other causes of paralysis, muscle and nerve biopsies can be performed.10 Other testing that can be performed to rule out other differentials includes cerebrospinal fluid analysis and culture, metabolic panels, and hepatic panels. However, the results of these studies are typically unremarkable.6,7 Since symptoms may progress before confirmatory diagnostic results are returned, all treatment should start as soon as a clinical diagnosis is made. Infants should be hospitalized so they can receive respiratory support and parenteral nutrition, if necessary. Treatment for infant botulism approved by the US Food and Drug Administration is intravenous human botulism immune globulin, referred to as BabyBIG. A 5-year, double-blind, randomized control trial performed in California found that infants treated with BabyBIG had a reduced mean duration of hospital stay from 5.7 weeks to 2.6 weeks. Additionally, duration of time spent in the intensive care unit was reduced by a mean of 3.2 weeks, mechanical ventilation was reduced by 2.6 weeks, and tube feeding was reduced by 6.4 weeks. Although the immune globulin is an expensive treatment, the study also found that its use results in an $88,600 reduction in mean hospital charges per patient.5 Acquiring the drug as soon as possible after clinical diagnosis is crucial to decrease the morbidity of the disease.7 Although infant botulism causes severe symptoms, the prognosis for the disease has greatly improved and the mortality rate has declined to 3% to 6%.1,6 As regeneration of motor end plates occurs, patients progressively improve. Peripheral muscles typically take longer than the diaphragm to recover.7 The most worrisome complication of the disease is respiratory failure, and studies have found that “approximately half of all infants with infantile botulism require mechanical ventilation at some point during the course of infection.”7 Fortunately,“neurologic sequelae are rarely seen as a result of infantile botulism,” and no permanent deficits occur.7 Speech, occupational, and physical therapy may be needed during the recovery process to ensure that the infants are able to catch up to milestones they have missed and get back on track developmentally.

SUMMARY The etiology of Grace’s case of infant botulism cannot be attributed to honey, as she had no exposure. Although there is no way to definitively determine what caused her disease, a possible etiology is ingestion of spores from a local park, where another infant acquired infant botulism after exposure there, as well.Additionally, Grace had a history of constipation, which could have put her at increased risk for the disease. This case demonstrates the significance of maintaining a broad differential diagnosis, which should include consideration of diseases that are less prevalent. Lack of clinical awareness of rare conditions can lead practitioners down the wrong path. As a primary care provider, it is crucial to consider infant botulism in infants presenting with “floppy baby syndrome,” even if they do not have a history of honey consumption. Early recognition prevents delays in diagnosis so that the highly effective immune globulin treatment can be started as soon as possible. ■ Victoria Hauff, PA-C, currently works in dermatology in Woodstock, Georgia. Judith Stallings, EdD, MHE, PA-C, is PA program director at Augusta University. References 1. Hay WW, Deterding RR, Levin MJ, Azbug MJ. Current Diagnosis and Treatment: Pediatrics. 22nd Edition. New York: McGraw-Hill Education; 2014. 2. Koepke R, Sobel J, Arnon SS. Global occurrence of infant botulism, 19762006. Pediatrics. 2008;122(1):e73-e82. 3. Tseng-Ong L, Mitchell WG. Infant botulism: 20 years’ experience at a single institution. J Child Neurol. 2007;22(12):1333-1337. 4. Grant KA, McLauchlin J, Amar C. Infant botulism: advice on avoiding feeding honey to babies and other possible risk factors. Community Pract. 2013;86(7):44-46. 5. Arnon SS, Schechter R, Maslanka SE, Jewell NP, Hatheway CL. Human botulism immune globulin for the treatment of infant botulism. N Engl J Med. 2006;354(5):462-471. 6. Fox CK, Keet CA, Strober JB. Recent advances in infant botulism. Pediatr Neurol. 2005;32(3):149-154. 7. Brown N, Desai S. Infantile botulism: a case report and review. J Emerg Med. 2013;45(6):842-845. 8. Francisco AM, Arnon SS. Clinical mimics of infant botulism. Pediatrics. 2007;119(4):826-828. 9. Smith JK, Burns S, Cunningham S, Freeman J, McLellan A, McWilliam K. The hazards of honey: infantile botulism. BMJ Case Rep. 2010. doi: 10.1136/ bcr.05.2010.3038,2010 10. Keet CA, Fox CK, Margeta M, et al. Infant botulism, type F, presenting at 54 hours of life. Pediatr Neurol. 2005;32(3):193-196.

52 THE CLINICAL ADVISOR • DECEMBER 2018 • www.ClinicalAdvisor.com

LEGAL ADVISOR CASE

Terminated for Taking FMLA? Was an alleged HIPPA violation just a pretext to fire a nurse for taking family leave? BY ANN W. LATNER, JD

In this month’s case, a court must choose whether to accept a hospital’s explanation that a nurse was fired for violating the Health Insurance Portability and Accountability Act (HIPPA) or let a jury decide whether the hospital’s action was merely a pretext for firing the nurse for taking advantage of the Family and Medical Leave Act (FMLA). Ms N had been experiencing increasing personal and professional difficulties over the past 2 years. Although life had never been easy for the 53-year-old nurse, in the 2 years since a new supervisor was brought on in the hospital emergency department (ED) where she worked, things had taken a definite turn for the worse. Ms N had been working at the hospital for close to 13 years. Shortly after she began, her toddler son was diagnosed with autism. His condition turned out to be severe, and he required constant care.After a few years, the stress of the situation became too much for the marriage, and Ms N’s husband left. Although Ms N’s mother was able to help to some extent, caring for her son was difficult. He would go through periods of insomnia and have gastrointestinal problems, but his inability to communicate

FMLA allows employees to take up to 12 weeks of leave per year for various purposes, including caring for a family member.

made helping him challenging. Over the past 7 years, Ms N had been using FMLA leave intermittently to care for her son when he was having an episode. She was always careful to request the FMLA time properly, and she was glad to have that option to take time off when her son needed care. Two years ago, a new supervisor, Ms S, was hired to manage the ED nursing team. Ms S was in her early 30s, single, and career-driven. Ms S had strong feelings about how the ED should be run, including a belief that it should be staffed by “younger, energetic” nurses. Ms N, in her 50s and one of the oldest nurses in the ED, felt uncomfortable about comments she heard Ms S make to others, and she began documenting these occurrences. “The ED is a place for young nurses, not old nurses, and this taking of family leave is not going to be tolerated,” was one comment Ms N heard Continues on page 55

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 her supervisor make to another employee. Ms S also clearly had a problem with Ms N’s use of FMLA time and began referring to FMLA leave as “mental health breaks.” Ms S told Ms N that she may have “gotten away with” using FMLA time with her previous supervisor, but “you won’t get away with it with me.”When speaking to other younger nurses, the supervisor referred to older nurses like Ms N as “old farts” and “old women” and even said to Ms N,“I know you’re getting older and you have problems with your memory, so you may need to write this down.” Work began to feel oppressive to Ms N, yet she continued to work and use FMLA as needed.That fall, her son was having significant difficulties that required Ms N to take FMLA time intermittently in September, October, and November. When Ms N returned after the November FMLA leave, Ms S loudly announced,“Anybody with family leave, you’re going.”

FMLA prohibits an employer from discriminating against or discharging an employee for using such leave. Two weeks later, Ms N was approached by the sister of a patient who was asking for information on her sibling’s condition. The patient’s nurse was not available, so Ms N spoke to the patient and requested permission to access the medical record and share some information with the patient’s sister. The patient, an elderly woman, agreed. Ms N, however, neglected to note this in the patient’s chart. She filled the sister in on the patient’s condition and finished her shift. Ms N was fired two weeks later. She was told that the patient complained that private information about her condition had been shared by Ms N without the patient’s permission, which constituted a HIPPA violation. Ms N tried to protest that she had received permission from the patient, but because she hadn’t noted this in the chart, she was terminated from her position. Ms N hired an attorney and explained the situation, including showing the attorney the list of comments the supervisor had been making. “I believe that the alleged HIPPA violation was just a pretext to fire you,” said the attorney. “It sounds as though you were really fired for your age and for your use of FMLA.” The attorney filed a lawsuit against the hospital, alleging wrongful termination.The hospital made a motion for summary judgment, asking the court to dismiss the case against it. After looking at all the evidence before it in the light most

favorable to the nonmoving party (Ms N), the court agreed with Ms N that there was sufficient evidence for a jury to be able to decide if the HIPPA violation was really a pretext for firing Ms N due to her age or use of FMLA time.The court sent the case for a jury trial on this issue. Legal Background

FMLA was established as a way for working Americans to balance work responsibilities with personal and family needs. Signed into law in 1993, FMLA was intended to encourage businesses to adopt flexible practices that would have the potential to increase productivity and improve employee morale. Summary judgment is when one side asks the court to dismiss the case, claiming that there is no dispute about facts, and that the law clearly entitles the moving party to win. FMLA allows employees to take up to 12 weeks of leave per year for various purposes, including caring for a family member with a serious medical condition. The Act prohibits an employer from preventing or interfering with an employee taking FMLA time and from discriminating against or discharging an employee for using such leave. After looking at all the evidence, the court concluded that, based on the facts, a jury could reject the hospital’s claim of a HIPPA violation and find that the hospital intentionally discriminated against Ms N based on her age and her use of FMLA. Thus, the court could not dismiss the case and had to send it to a jury where Ms N will be able to make her claim against the hospital. Protecting Yourself

While Ms N was proactive in terms of taking notes about the comments and remarks that were made toward her and about older nurses and family leave, she should have been equally proactive in noting that she had gotten permission from the patient to share personal information. By not making that note, Ms N made it easy for the hospital to establish a pretext to fire her. She essentially gave the hospital the ammunition it was using. However, her careful documentation of the comments made by her supervisor will be crucial in trying to convince the jury that she was fired due to her age and her use of FMLA rather than for a HIPPA violation. As with most cases, taking good notes is the best legal protection in almost all circumstances. ■ Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, NY. Reference US Department of Labor. FMLA e-tools. Wage and Hour Division. https:// www.dol.gov/whd/fmla/etools.htm. Accessed November 15, 2018.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2018 55