November 2018 Clinical Advisor

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■■Screening for alcohol and depression ■■VVA management barriers ■■Sexual assault effects

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NOVEMBER 2018

MULTIPLE SYSTEM ATROPHY

A Common Form of Atypical Parkinsonism

FEATURE

Micronutrients for optimizing pregnancy outcomes ALT MEDS UPDATE

Wound care treatments LEGAL ADVISOR

A patient’s death following hospital discharge

DERMATOLOGY CLINIC

Painful, recurrent rash on the fingers

FREE CME COURSE

Minimally invasive total laparoscopic hysterectomy

| www.ClinicalAdvisor.com

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

Statement of Ownership, Management, and Circulation

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.

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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.

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.

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 infecPhysicians Dermatology University of Pennsylvania School 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 It p recurr•ent 44 THE ADVISOR AUGUST 2015 •on www.ClinicalAdvisor.com Castleton, severaCLINICAL l consideration urinary tract the male child who As it currently stands N.Y. , SGLT2 s that infections. for glycemic impede the receptor blocke There are control in ability to cleansenter into this decisio rs are FDA adults with n. Poor hygien should the e and quell -approved child have e may appro diet and exercise, but with type 2 diabetes phimosis, simpl infection potential. appropriate the in ved conjun FDA for use in patien Moreover, AdvisorForum_CA0815.indd urine 44 9/29/15ction 2:38 PM e cathet culture can ts with type has stated that they ketoacidosi steroid cream be a challenge. erization to obtain s, or those are not 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

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.

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

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

CONTENTS NOVEMBER 2018

NEWS AND COMMENT

23 Screen Time and Cognitive Development

23 Newsline ■■Screen Time, Sleep Duration Linked to Cognitive Development in Children ■■Assessment of Primary Care Screening for Alcohol Use and Depression ■■Barriers Hinder Effective Management of Vulvovaginal Atrophy ■■Sexual Harassment, Assault Affect Women’s Health 65 Conference Roundup: CHEST 2018 Meeting ■■Metered Dose Inhaler Errors Prevalent in COPD and Asthma ■■Montelukast Plus Levocetirizine in Asthma, Allergic Rhinitis ■■Benralizumab for Management of Severe Eosinophilic Asthma ■■Perfenidone for Improving Exercise Capacity, Dyspnea in Idiopathic Pulmonary Fibrosis

25 Micronutrients in Pregnancy

FEATURES 25 The Function of Micronutrients in Optimizing Pregnancy Outcomes Diet and lifestyle are important topics that should be discussed with all women who are capable of becoming pregnant.

57 Diffuse Bullous Skin Lesions

34 Multiple System Atrophy: A Common Form of Atypical Parkinsonism MSA is a rare disease process that is associated with significant morbidity and mortality.

Continues on page 14

71 Death After Hospital Discharge

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CONTENTS NOVEMBER 2018

FEATURES (cont’d) ■ Screening for alcohol and depression ■ VVA management barriers ■ Sexual assault effects FEATURE

Micronutrients for optimizing pregnancy outcomes ALT MEDS UPDATE

Wound care treatments

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

LEGAL ADVISOR

PAGE 60

Is clinician testimony hearsay?

Approximately 2% to 3% of the There is room global population for improvement of current T2D is affected by psoriasis. screening guidelines.

NEWSLINE

■ Meningococcal vaccine ■ Dairy consumption, CVD ■ Otitis media LEGAL ADVISOR

DERMATOLOGIC LOOK-ALIKES

NP faulted for patient care via fax

Erythematous annular lesions

DERMATOLOGY CLINIC

DERMATOLOGY CLINIC

Red-brown papules on the extremities

FEATURE

Current guidelines for management of low back pain

FREE CE COURSE

Laparoscopic sleeve gastrectomy

VOLUME 21, NUMBER 9

VOLUME 21, NUMBER 10

Minimally invasive total laparoscopic hysterectomy

■ Fidaxomicin for C difficile ■ Pediatric vaccine exemptions

contribute to effective and efficient healthcare utilization.

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

Painful, recurrent rash on the fingers

FREE CME COURSE

2018 SALARY SURVEY

See how your salary compares with your peers!

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16

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

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Dermatology Clinic ■ Painful, recurrent rash on the fingers ■ Painful penile lesions and groin swelling

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Dermatologic Look-Alikes Diffuse bullous skin lesions

67

Alternative Meds Update Update on both new and old treatments that could contribute to effective wound care Legal Advisor Could a patient’s death following hospital discharge have been avoided?

Correction: In the article titled, “A Zebra in the Emergency Department,” published in the October 2018 issue of The Clinical Advisor, the physician assistant title was misrepresented. A correction has been implemented in the online version of the article. The staff at The Clinical Advisor sincerely regrets this error.

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“You’re such a romantic.”

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NEWSLINE FASTING INSULIN VS HBA1C CME: CASE ■ Celiac diseaseCHALLENGE

A Common Form of Psoriasis andAssessment Hodgkin’s of current Atypical ParkinsonismLymphoma screening methods for predicting diabetes risk

A patient’s death following hospital discharge

VOLUME 21, NUMBER 11

DEPARTMENTS

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Community MULTIPLE SYSTEM ATROPHY paramedics

LEGAL ADVISOR

CME Feature Posttest

THE CLINICAL ADVISOR • SEPTEMBER 2018

Laparoscopic Hysterectomy Percutaneous surgical systems have emerged as a viable approach to gynecologic surgery.

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

THE CLINICAL ADVISOR • OCTOBER 2018

46

CME Case Clinic: Minimally Invasive Total

THE CLINICAL ADVISOR • NOVEMBER 2018

38

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com

NEWS ClinicalAdvisor.com/News

Monovalent Acellular Pertussis Vaccine Safe and Effective for Neonates With Mothers Unvaccinated for Tdap The monovalent acellular pertussis vaccine was found to be safe and effective in newborns whose mothers did not receive the tetanus toxoid, reduced diphtheria toxoid, and pertussis antigen vaccine.

Ketogenic Diet May Benefit Ovarian, Endometrial Cancer Patients Women with ovarian or endometrial cancer who adhere to a ketogenic diet may benefit from a selective loss of fat mass and a reduction in fasting serum insulin, while still retaining lean mass.

Diabetes Common in Patients With Ischemic, Hemorrhagic Stroke The prevalence of diabetes in stroke inpatients was estimated at 28%; the prevalence was higher in patients with ischemic stroke (33%) compared with hemorrhagic stroke (26%), as well as in studies that included both stroke types (24%).

Switching IV to Oral Antibiotics Noninferior for Some Endocarditis Events For certain patients with endocarditis on the left side of the heart who were in stable condition, switching from intravenous (IV) antibiotics to orally administered antibiotics was noninferior to staying on IV treatment.

THE WAITING ROOM

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Sharon M. O’Brien, MPAS, PA-C REM Sleep Behavior Disorder: A Clinical Challenge REM sleep behavior disorder is commonly seen in older men, and symptoms include violent muscle movements or fighting during the night.

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 clinician.

CASE STUDY Clinical Advisor.com/CaseStudy Brady Pregerson, MD Worsening Headache After Giving Birth A 32-year-old woman presents to the emergency department with gradually worsening generalized headache 8 days after giving birth to her second child.

Read the full case here: ClinicalAdvisor.com/CaseWorseningHeadache

MULTIMEDIA ClinicalAdvisor.com/Multimedia Put Your Stamp on the 2019 Salary Survey!

Don’t miss the opportunity to provide your feedback for our 2019 survey! View the results from this year’s Nurse Practitioner/Physician Assistant Survey, and tell us which topics you’d like to see repeated or omitted from next year’s results. See the results here: ClinicalAdvisor.com/2018SalarySurvey

16 THE CLINICAL ADVISOR • NOVEMBER 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. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

Check out some of our latest cases below!

DERM DX

Growth on the Left Index Finger A 58-year-old man presents for evaluation of a mass affecting his left index finger. The lesion has been gradually increasing in size over the past 3 years and has only recently become bothersome. He is currently taking medication to control hypertension and hyperlipidemia.

He denies arthritis, gout, or history of trauma to the affected area.

CAN YOU DIAGNOSE THIS CONDITION?

• Picker’s nodule • Ganglion cyst • Lipoma • Giant cell tumor of tendon sheath ● See the full case at ClinicalAdvisor.com/DermDx_Nov18

In partnership with

ORTHO DX

TheJopa.org

Journal of Orthopedics for Physician Assistants

Failed Hip Pinning An 82-year-old woman presents to the office 2 months after undergoing hip pinning for a nondisplaced femoral neck fracture.

Anteroposterior and lateral hip radiographs show collapse of the fracture with nonunion.

WHICH CHOICE MOST INFLUENCES FRACTURE HEALING?

• Number of screws used for fixation • Patient age • Patient gender • Amount of initial fracture displacement ● See the full case at ClinicalAdvisor.com/OrthoDx_Nov18

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

Newsline IN CHILDREN AGED 8 to 11 years, limiting recreational screen time to less than 2 hours per day as well as sustaining a minimum of 9 hours of sleep per night are associated with enhanced cognition, according to a study published in the Lancet Child and Adolescent Health.

A group of researchers analyzed data from 4520 children from 20 locations in the United States. Children and parents completed questionnaires to determine the number of hours spent per weekday and weekend watching recreational screenbased activities (ie, social media and television), as well as to define the number of hours of sleep a child gets on most nights.

Results from the study found that on average, children participated in physical activity for ≥60 minutes for a mean of 3.7 days per week, spent a mean of 3.6 hours per day engaging in recreational screen time, and slept for a mean of 9.1 hours per night. Overall, 2303 (51%) of participants met sleep recommendations, 1655 (37%) met screen time recommendations, and 793 (18%) met physical activity recommendations. Global cognition was positively associated with each additional recommendation met.

“We found that more than two hours of recreational screen time in children was associated with poorer cognitive

© OJO IMAGES / GETTY IMAGES

Screen Time, Sleep Duration Linked to Cognitive Development in Children

development,” the authors concluded.

“More research into the links between screen time and cognition is now needed, including studying the effect of different types of screen time, whether content is educational or entertainment, and whether it requires focus or involves multitasking.”

Assessment of Primary Care Screening for Alcohol Use and Depression FEW PATIENTS who are screened in primary care for hazardous alcohol use are also screened for depression, according to a study published in the Journal of the American Board of Family Medicine.

A group of investigators analyzed the frequency of depression screening according to the severity of alcohol use among primary care patients to determine if hazardous alcohol consumption is associated with significant depressive symptoms and if primary care patients are being screened properly.

Using cross-sectional information from 2,894,906 primary care patients (≥18 years of age), the researchers recorded patient alcohol use within the past 90 days, noting the typical number of drinking days per week and the typical number of drinks per day. They also noted whether the Patient Health Questionnaire 9 (PHQ-9), a standardized instrument recommended by the US Preventive Services Task Force for depression screening in primary care, was administered. If so, the

investigators further observed if patients’ total scores met the criteria for significant depression, which was defined as a total score of 10 or higher.

Within 30 days of the first screening for alcohol use, the PHQ-9 was administered to only 2.4% (n = 68,686) of the screened patients. The PHQ-9 was more likely to be administered to patients with the following characteristics: female sex (65.5%), age 18 to 39 years (47%), white race/ethnicity (56.8%), and abstinence from alcohol use (66.2%); of those who received PHQ-9 screening (n = 32,390), 47.2% endorsed significant depressive symptoms in the past 2 weeks.

“Only a small fraction of patients in this cohort were screened for depression,” the authors wrote. “These discrepancies between depression-screening rates and significant depressive symptoms suggest that screening for depression should be enhanced in these at-risk groups.”

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2018 23

Newsline Barriers Hinder Effective Management of Vulvovaginal Atrophy PRIMARY CARE providers (PCPs) and gynecologists differ in their confidence and knowledge regarding the management of patients presenting with vulvovaginal atrophy (VVA); however, both report similar barriers to effective care, according to a study published in Menopause.

A total of 360 participants were provided with multiple-choice and Likertscale questions that assessed knowledge and confidence, as well as a 12-item list that identified potential barriers to VVA care (eg, lack of time, complicated discussions regarding treatment options, lack of available information about treatment options, and patient embarrassment when asking questions). A total of 119 (33%) respondents completed the survey.

Respondents answered 66% of the knowledge-based multiple-choice questions correctly, with more gynecologists (77%) than PCPs (63%) identifying the correct answer. Compared with PCPs, gynecologists demonstrated greater

knowledge about VVA and estrogen therapy, as well as vaginal estrogen therapy for urinary symptoms.

In total, 39% of clinicians were highly likely or likely to assess for VVA during a well visit, 43% had high or very high confidence in advising patients aboutVVA

Lack of time (71%) was the most commonly identified barrier toVVA diagnosis and treatment, followed by lack of availability of educational materials for patients (44%); difficulty discussing sexual or urinary symptoms with patients was the least common barrier (2%). Gynecologists

As PCPs often manage gynecologic care of their post­ menopausal patients, addressing knowledge deficits and practice barriers may lead to improved management of VVA. symptoms, and 42% had high or very high confidence in their ability to advise patients about vaginal estrogen treatment.

Compared with PCPs, more gynecologists indicated being highly likely or likely to assess forVVA symptoms during a routine visit (72% vs 28%) and highly or very highly confident in their ability to counsel on VVA symptoms (72% vs 33%) and to advise on the risks/benefits of vaginal estrogen treatment (76% vs 30%).

identified 4 barriers more frequently than PCPs: estrogen as a high-risk medication among older women, the FDA black box warning for vaginal estrogen prescriptions, patient dissatisfaction with options for vaginal estrogen treatment, and lack of availability of educational materials for patients.The only difference between PCP and gynecologist barriers that was significant involved the cost of vaginal estrogen therapy.

FOR WOMEN IN midlife, exposure to sexual harassment and sexual assault is widespread and associated with higher blood pressure (BP, harassment), poorer mental health (assault), and poorer sleep (both), according to a study published in JAMA Internal Medicine.

A total of 304 nonsmoking women aged 40 to 60 years (mean age, 54 years) with no history of cardiovascular disease underwent physical examination and medical history assessment. A psychosocial questionnaire was included to record workplace sexual harassment, sexual assault, depression, anxiety, and sleep quality. Sexual harassment was identified as experiencing physical or verbal sexual harassment in the workplace, and

sexual assault was identified as unwanted sexual contact.

Of the cohort, 19% of women (n = 58) reported having experienced sexual harassment at work, and 22% of women (n = 67) reported a history of sexual assault.

For women who were not taking antihypertensive medications, the odds of

24 THE CLINICAL ADVISOR • NOVEMBER 2018 • www.ClinicalAdvisor.com

stage 1 or 2 hypertension were significantly greater for sexual harassment (odds ratio [OR], 2.36); odds of clinically poor sleep were also associated with sexual harassment (OR, 1.89).

Sexual assault was significantly associated with increased risk of clinically increased depressive symptoms, anxiety, and poor sleep.

“Future work should consider whether preventing or mitigating sexual harassment and sexual assault can improve women’s mental health and cardiovascular health,” the authors concluded. “Given the high prevalence of sexual harassment and assault, addressing these prevalent and potent social exposure may be critical to promoting health and preventing disease in women.” ■

© TOMAZL / GETTY IMAGES

Sexual Harassment, Assault Affect Women’s Health

FEATURE: JODI WESTFALL, FNP-C, DCNP, PMH-NP-C; JENNIFER RODE, PHD, ANP-C

The Function of Micronutrients in Optimizing Pregnancy Outcomes Understanding the function of essential nutrients on health would benefit family practitioners caring for women of childbearing age.

Micronutrients can have significant effects on pregnancy outcomes.

M

icronutrients are an often-overlooked consideration in primary care. Family practitioners caring for women of childbearing age must consider the effects of these essential nutrients on health and pregnancy outcomes.

Healthy levels of folic acid, iodine, magnesium, vitamin D, and iron all demonstrate improved outcomes in pregnancy.1 This article reviews the function of each of these micronutrients and their ensuing implications on pregnancy outcomes.

© IMAGE SOURCE / GETTY IMAGES

Case Examples

Case 1: A healthy 25-year old woman (gravida 0, para 0) presents to the office to undergo laboratory testing required for her employers “Healthy Employee” insurance discount. She is newly married and usually uses condoms for birth control.

She states that she is hoping to become pregnant in the next year and asks if there is anything she can do now to help her have a healthy pregnancy.

Case 2: A woman (gravida 1, para 1) presents for annual gynecologic care and reports that she takes “no daily medications.” Her provider asks if she plans to have more children, and the patient reports she is not sure when the timing will be right. Her provider then asks the patient about her nutritional status and if she takes any supplements on a regular basis. The patient responds, “I just need to start taking folic acid if I want to get pregnant, right?”

Case 3: A woman (gravida 0, para 0) presents to her gynecologist for annual care. She reports taking daily supplementation of magnesium, iron, and folic www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2018 25

OPTIMIZING PREGNANCY OUTCOMES WITH MICRONUTRIENTS

acid. “My friend told me I need to take these. I assume since they are available without a prescription they can’t do any harm.”

All of these case examples demonstrate scenarios in which a provider must understand micronutrients and how they can affect a patient’s current health. For women of childbearing age, these implications extend to potential future pregnancies.

More than half of all pregnancies are unintended; therefore, communication regarding diet and lifestyle should be directed to all women who are capable of becoming pregnant.2 Primary care providers are often the last to know about their patients’ plans for pregnancy. However, a woman’s nutritional status prior to conception can have serious implications on her health and birth outcomes. A focused history with direct questions about pregnancy intentions at every encounter with all women of childbearing age can help practitioners provide optimal preconception care. This care often begins with valuable guidance on smoking, alcohol consumption, vaccinations, and disease management.3 Importantly, it should also include a review of micronutrients — including folic acid, iodine, magnesium, vitamin D, and iron — which can have significant effects on pregnancy outcomes.A summary of recommendations for each of these micronutrients is provided in the accompanying Table.

Folic Acid

Folic acid, also known as folate or vitamin B9, is one of the 13 essential vitamins that are required for cell growth and function. It is not produced by the body, and therefore must be TABLE. Recommended Daily Micronutrient Supplementation Micronutrient

Prepregnancy Pregnancy Lactating

Folic acid, µg9 L-5-methyltetrahydrofolate may be appropriate to meet the needs of women with polymorphisms

400

400

400

Iodine, µg13 Also encourage acquisition through consumption of iodized salt

150

220-250

290

Magnesium, mg16 Magnesium aspartate, citrate, or lactate preferred; avoid magnesium oxide

300

300

300

Vitamin D, IU35

4000

4000

4000

18

30-40

18

obtained either from diet or supplementation. Folate occurs naturally in foods such as leafy green vegetables, black-eyed peas, lentils, rice, egg yolk, asparagus, and citrus fruit. Folic acid is a synthetic vitamin that is added to select foods, taken as a stand-alone supplement, or included in a multivitamin.

Prenatal and intrapartum folic acid supplementation is widely accepted as standard of care to prevent neural tube defects and structural malformations.4 Less well known is the impact of genetic polymorphisms that affect metabolism of folate and folic acid and its subsequent impact on pregnancy outcomes.

Both folate and folic acid are metabolically inactive and must be metabolically reduced to L-5-methyltetrahydrofolate (5MTHF) to be able to contribute to cellular metabolism.5 MTHFR genetic polymorphisms reduce metabolism of folate and folic acid.6 Two meta-analyses examining the MTHFR gene polymorphism, C677T, and risk for neural tube defects found a significant association, implying that women with a C677T polymorphism are at higher risk for delivering an infant with neural tube defects.7,8 In the United States, evidence suggests that up to 43% of American Indians and 34% of Americans of European descent have the most common MTHFR polymorphism (C677T). Asian populations were found to have up to 20% prevalence of the C677T polymorphism.8 The current folic acid recommendation is 0.4 to 0.8 mg/d for all women of childbearing age.9 With respect to estimates of the population carrying the MTHFR polymorphism, it may be beneficial to supplement with the bioavailable form of folate, L-5-MTHF.8 This form of folic acid does not require the metabolic activation that can be impaired with a genetic polymorphism. L-5-MTHF has been tested in healthy women and has been shown to be safe and at least as effective as folic acid.5,10 Individuals with known MTHFR mutations and a history of offspring with neural tube defects are clearly targeted for supplementation with the metabolically reduced, more bioavailable L-5-MTHF. However, recommending L-5-MTHF to all women of childbearing age may protect those not yet diagnosed with methylation polymorphisms.

Recommendation: 5MTHF, 400 µg/d, as tolerated for all women of childbearing age may be included in a routine prenatal vitamin or consumed as a stand-alone supplement.

Iodine

Iron, mg36,27

Iodine is a micronutrient that is necessary for thyroid function.

When a woman becomes pregnant, thyroid function increases dramatically to meet increasing metabolic demands.11 Lack of iodine in pregnancy has devastating, permanent consequences, and robust evidence links iodine insufficiency to multiple negative outcomes in pregnancy, including lower child IQ, child neural abnormalities, miscarriage, infant mortality, congenital iodine

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

Continues on page 30

OPTIMIZING PREGNANCY OUTCOMES WITH MICRONUTRIENTS

A woman’s nutritional status prior to conception can have serious implications on her health both during pregnancy and afterward. deficiency syndrome, and, most recently, autism.11,12 Foundational fetal neurologic formations initiated in the first trimester depend on thyroid hormones to develop correctly.The iodine recommendation for nonpregnant adult women is 150 µg/d; once a woman becomes pregnant, that recommendation increases to 220 to 250 µg, and increases to 290 µg/d while breastfeeding.13 The United States population is classified as having “more than adequate” iodine levels based on population urine iodine concentration (UIC) collected in 2009 and 2010; more recent evaluation of UICs in US women found a median UIC of 144 µg/L, which is lower than the recommended 150 µg/L.14 Black women had the lowest UIC, at 131 µg/L; the median UIC for pregnant women was even lower at 129 µg/L. A separate dataset found similarly low UICs: the median UIC for all adult women was 134 µg/L, the median UIC for women of childbearing age was 124 µg/L, and the median UIC for black women was 131 µg/L.These results are alarming, because the UIC of the US population has been considered more than adequate, and concerns of iodine deficiency are dismissed as a problem of other world regions. However, these results demonstrate that iodine deficiency is a condition that all providers need to address. Over the past several decades, the iodine status of the US population has declined from a median UIC of 320 μg/L to 145 μg/L (1 μg/L = 0.079 μmol/L), representing a 50% decrease, according to the National Health and Nutrition Examination Survey (NHANES I; 1971–1974) and NHANES III (1988–1994), respectively.14 One of the challenges in assessing and treating iodine deficiency is that there is no reliable clinical marker of individual iodine levels. Although UIC is often used as a marker for population iodine levels, it is less helpful as an individual indicator. Clinicians evaluating iodine levels in individual patients need to consider indirect indicators of iodine levels.

Providers should inquire and assess dietary intake of iodine.

Although the United States implemented iodized salt in 1942, many salts lack iodine. Estimates suggest that the US population obtains 60% of its iodine from dairy sources, both from feed given to dairy cows, and from iodine-containing processing methods, suggesting a reduced iodine intake in dairy-free diets.14 Approximately 70% of salt consumed in the United States comes from processed and restaurant foods that generally do not use iodized salt.14 The Institute of Medicine’s recommendation to reduce sodium intake for cardiovascular health many also contribute to low iodine intake.15 Recommendation: All women of childbearing age should take an iodine supplement of 150 µg/d.Although some prenatal vitamins include iodine, the assumption should not be made

that all do. Once a women becomes pregnant, recommended iodine intake increases to 220 to 250 µg/d. Providers may encourage iodized salt as a primary salt source, with instructions to the patient to check the labels carefully to ensure that the salt product is iodized.

Magnesium

Magnesium is a mineral essential to the human body. It is necessary for more than 300 enzymatic reactions and has an effect on basic physiology, including blood pressure, bone health, and cardiovascular health.16 Magnesium deficiency is associated with chronic fatigue, tetany, altered glucose metabolism, and electrolyte disturbances; during pregnancy, magnesium deficiency has been associated with preterm labor, pre-eclampsia, and maternal muscle cramps.17 The current recommended daily allowance (RDA) for magnesium in women is 310 to 320 mg/d; pregnant women are advised to consume 350 to 400 mg/d.16 The normal serum magnesium range is 0.65 mmol/L to 1.05 mmol/L; however, serum magnesium concentrations are poor predictors of intracellular/total body magnesium content.18 An estimated 68% of Americans do not consume the RDA of magnesium, whereas 19% fail to consume even half of the RDA of magnesium.19 Providers should consider the low levels of magnesium in the general population when advising women on preconception care. Providers can also rely on common

POLL POSITION Which of the following recommendations are endorsed by the Institute of Medicine regarding iodine supplementation?

■ Prenatal vitamins meet daily requirements for iodine.

16.97% ■ All women of childbearing age should take an iodine supplement of 150 µg/d.

15.15% ■ Iodized salt should not be considered a primary source of iodine.

18.8% ■ The recommended iodine intake for pregnant women is 200 µg/d.

49.7%

For more polls, visit ClinicalAdvisor.com/Polls.

30 THE CLINICAL ADVISOR • NOVEMBER 2018 • www.ClinicalAdvisor.com

As primary care providers lay the foundation of health for future pregnancies, their guidance in preparing women for healthy pregnancies is essential. clinical signs of hypomagnesemia, including loss of appetite, nausea, vomiting, fatigue, and weakness. Severe magnesium deficiency may present with symptoms including numbness, tingling, muscle contractions, cramps, seizures, and arrhythmias.18 Recommendation: Women of childbearing age may benefit from magnesium supplementation of 300 mg/d.

Magnesium received in the formulations of aspartate, citrate, or lactate appear to be better absorbed with improved bioavailability; magnesium oxide has demonstrated extremely low bioavailability.20 In addition to taking an oral supplement, magnesium status can also be improved with transdermal absorption via regular Epsom salt baths or foot soaks. Epsom salt is magnesium sulfate that is absorbed through the skin.

Vitamin D

Vitamin D is a fat-soluble vitamin that is produced endogenously with exposure of skin to ultraviolet radiation in sunshine. Naturally present in very few foods (primarily fish), vitamin D balances calcium levels and has protective roles in immune function and inflammation.21 An estimated 46% to 82% of US adults have vitamin D deficiency; the highest risk of deficiency is in dark-skinned individuals.22 Routine testing for vitamin D levels is not recommended.

Therefore, indirect measures of vitamin D levels can be estimated via an individual’s exposure to sunlight, latitude, clothing coverage, and skin pigmentation.23 Vitamin D deficiency has been linked to multiple adverse perinatal outcomes in pregnancy, including pre-eclampsia, gestational diabetes, low birth weight, bacterial vaginosis, and preterm delivery.24 In the general population, deficiency of vitamin D is also correlated with multiple chronic diseases, including cardiovascular disease and cancer.22 Recommendation: Vitamin D, 4000 IU/d, is recommended for childbearing-aged and pregnant women.25 Bioavailable forms include capsules and high-concentration drops.

Iron

Iron is an essential mineral necessary for transport of oxygen, as well as the production of hemoglobin and enzymes involved in many body functions. Physiologic iron requirements are 3 times greater in pregnant than in menstruating women.26 The increased need for iron in pregnancy is related to the growing placenta and fetus, and the expansion of blood volume by 50% increases demands for iron from 1.0 mg/dL at conception to 5.0 mg/dL by the second and third trimesters.27,28 The CDC defines anemia in pregnancy as hemoglobin concentration <11.0 g/dL in the

first and third trimesters and <10.5 g/dL in the second trimester.

An estimated 38% of pregnant women worldwide are anemic; in the United States, nearly 18% of pregnant women are anemic.28,29 In addition to the risk for anemia due to increased demand in pregnancy, the most common cause of iron deficiency is malnutrition, notably in those living in poverty or those consuming vegan or iron-poor diets. Other contributors include gastrointestinal absorption deficiencies and chronic blood loss.30 Iron supply in food comes in 2 forms: heme and nonheme.

Heme iron is highly bioavailable (15%-35%) and is found primarily in animal foods, including chicken liver, oysters, clams, beef liver, beef, tuna, eggs, shrimp, and lamb.26 Nonheme iron is found in nonanimal food and in iron-fortified foods, and has low bioavailability (2%-20%). Nonheme iron foods include bran, instant oatmeal, beans, molasses, spinach, brown rice, and peanut butter.

Although often attributed to symptoms of pregnancy, symptoms of iron deficiency can include fatigue, tachycardia, lightheaded and dizzy feelings, shortness of breath, and restless legs.31 In pregnancy, symptoms of anemia are also associated with preterm labor, low birthweight, and newborn and maternal mortality.30 Recommendation: Adequate but not too much is the goal with iron; the upper limit of iron intake is 45 mg/d.32 Women of childbearing age benefit from supplementation of 18 mg/d of iron, with adjustments based on dietary habits and menstrual losses. Pregnant women may require 30 to 40 mg to meet metabolic iron requirements.33 Although iron obtained via dietary intake is not likely to meet the demand of pregnant women, a diet that is iron abundant and highly bioavailable is recommended. Ascorbic acid may support the absorption of iron; foods that inhibit iron absorption include milk, coffee, and black tea. Iron supplementation at bedtime or between meals may also enhance its absorption.34 Because primary care providers lay the foundation of health for future pregnancies, their guidance in preparing women for healthy pregnancies is essential. A large part of this includes understanding the potential effects of micronutrients on pregnancy outcomes. Women of childbearing age may benefit from some supplementation. Discussion with women regarding their plans for pregnancy, diet, and lifestyle will help practitioners determine how to best direct patients in their decision to supplement with micronutrients. ■ Jodi Westfall, FNP-C, DCNP, PMH-NP-C, is an integrative medicine and nutrition specialist, and Jennifer Rode, PhD,ANP-C, is an associate professor in the Department of Nursing at Miami University in Hamilton, Ohio.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2018 31

right-hand column like this one does at the top

OPTIMIZING PREGNANCY OUTCOMES WITH MICRONUTRIENTS

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19. Rosanoff A, Weaver CM, Rude RK. Suboptimal magnesium status in the United

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2. Finer LB, Zolna MR. Shifts in intended and unintended pregnancies in the

20. Firoz M, Graber M. Bioavailability of US commercial magnesium prepara-

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3. Dunlop AL, Jack B, Frey K. National recommendations for preconcep-

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22. Forrest KY, Stuhldreher WL. Prevalence and correlated of vitamin D defi-

4. Cetin I, Berti C, Calabrese S. Role of micronutrients in the periconception

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23. Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: when to

5. Pietrzik K, Bailey L, Shane B. Folic acid and l-5-methyltetrahydrofolate:

test and how to treat. Mayo Clin Proc. 2010;85(8):752-758.

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24. Aghajafari F, Nagulesapillai T, Ronksley PE, Trough SC, O’Beirne M, Rabi

Pharmacokinet. 2010;49(8):535-548.

DM. Association between serum maternal 25-hydroxyvitamin D level and

6. Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms

pregnancy and neonatal outcomes: systemic review and meta-analysis of

and the associated diseases. Gene. 2014;533(1):11-20.

observational studies. BMJ. 2013;346:f1169.

7. Yan L, Zhao L, Long Y, et al. Association of the maternal MTHFR C677T

25. Hollis BJ, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supple-

polymorphism with susceptibility to neural tube defects in offsprings:

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evidence from 25 care-control studies. PLoS One. 2012;7(10):e41689.

and effectiveness. J Bone Miner Res. 2011;26(10):2341-2357.

8. Zhang T, Lou J, Zhong R, et al. Genetic variants in the folate pathway and

26. Abbaspour N, Hurrell R, Kelishadi R. Review on iron and its importance

the risk of neural tube defects: a meta-analysis of the published literature.

for human health. J Res Med Sci. 2014;19(2):164-174.

PLoS One. 2013;8(4):e595570.

27. Aranda N, Ribot B, Garcia E, Viteri FE, Arija V. Pre-pregnancy iron reserves,

9. Institute of Medicine (US) Standing Committee on the Scientific Evaluation

iron supplementation during pregnancy, and birth weight. Early Hum Dev.

of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and

2011;87(12):791-797.

Choline. Dietary Reference Intakes for Thiamine, Riboflavin, Niacin, Vitamin

28. Mei Z, Cogswell ME, Looker AC, et al. Assessment of iron status in US

B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC:

pregnant women from the National Health and Nutrition Examination

National Academies Press; 1998.

Survey (NHANES), 1999-2006. Am J Clin Nutr. 2011;93(6):1312-1320.

10. Lamers Y, Prinz-Langenohol R, Moser R, Pietrzik K. Supplementation with

29. Stevens GA, Finucane MM, De-Regil LM, et al; Nutrition Impact Model

[6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma homocys-

Study Group (Anaemia). Global, regional and national trends in haemoglobin

teine concentrations in health women. Am J Clin Nutr. 2004;79(3):473-478.

concentration and prevalence of total and severe anaemia in children and

11. Caron P. Neurocognitive outcomes of children secondary to mild iodine

pregnant and non-pregnant women for 1995-2011: a systematic analysis of

deficiency in pregnancy women. Ann Endocrinol (Paris). 2015;76(3):248-252.

population-representative data. Lancet Glob Health. 2013;1(1):e16-e25.

12. Román GC, Ghassabian A, Bongers-Schokking JJ, et al. Association of

30. Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015;373(5):485-486.

gesta­tion­al maternal hypothyroxinemia and increased autism risk. Ann Neurol.

31. Miller JL. Iron deficiency anemia: a common and curable disease. Cold Spring

2013;74(5):733-742.

Harb Perspect Med. 2013;3(7). pii: a011866. doi: 10.1101/cshperspect.a011866

13. World Health Organization. Assessment of Iodine Deficiency Disorders and

32. Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic,

Monitoring Their Elimination. A Guide for Programme Managers. 3rd ed. Geneva,

Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon,

Switzerland: World Health Organization; 2007.

Vanadium, and Zinc. Washington, DC: The National Academies Press; 2001.

14. Caldwell KL, Pan Y, Mortensen ME, Makhmudov A, Merrill L, Move J. Iodine

33. Milman N. Oral iron prophylaxis in pregnancy: not too little and not too

status in pregnant women in the National Children’s Study and in US women

much! J Pregnancy. 2012;2112:514345.

(15-44 years), National Health and Nutrition Examination Survey 2005-2010.

34. Milman N. Iron prophylaxis in pregnancy – general or individual and in

Thyroid. 2013;23(8):927-937.

which dose? Ann Hematol. 2006;85(12):821-828.

15. Institute of Medicine. Sodium Intake in Populations. Assessment of Evidence.

35. American College of Obstetricians and Gynecologists. Vitamin D:

Washington, DC: The National Academies Press; 2013.

screening and supplementation during pregnancy. Committee Opinion. 2011;

16. Institute of Medicine (US) Standing Committee on the Scientific

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Evaluation of Dietary Reference Intakes. Dietary Reference Intakes for Calcium,

36. National Institutes of Health Office of Dietary Supplements. Iron.

Phosphorous, Magne­­-sium, Vitamin D, and Fluoride. Washington, DC: The

Available at: https://ods.od.nih.gov/factsheets/Iron-HealthProfessional/.

National Academies Press; 1997.

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17. James MF. Magnesium in obstetrics. Best Pract Res Clin Obstet Gynaecol.

37. Centers for Disease Control and Prevention. Recommendations to prevent and

2009;24(3):327-337.

control iron deficiency in the United States. MMWR Recomm Rep. 1998;47:1-29.

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

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FEATURE: SUDHISHA JALA, PA-C; LISA DAITCH, PA-C

Multiple System Atrophy: A Common Form of Atypical Parkinsonism Multiple system atrophy is a rare, progressive neurodegenerative condition for which there is currently no cure.

© MOLLY BORMAN

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

34 THE CLINICAL ADVISOR • NOVEMBER 2018 • www.ClinicalAdvisor.com

M

ultiple system atrophy (MSA) is a progressive neurodegenerative disorder with an unknown cause. Previously known as Shy-Drager syndrome, MSA is a form of atypical parkinsonism that primarily affects the autonomic nervous system and movement. With onset in adulthood, the prevalence of MSA in the United States is estimated to be 2 to 5 cases per 100,000 people.1 Despite MSA being a rare disease process, it is important for healthcare providers to be aware of its presentation due to its significant morbidity and mortality.

MSA is thought to be associated with glial cytoplasmic inclusions with α-synuclein, as well as pathologic modifications in selected neurons.2 MSA cases are usually sporadic, and a distinguishing feature of the disease is the accumulation of α-synuclein in glial cells, which support neurons. α-Synuclein mainly deposits in oligodendrocytes, which are glial cells that produce myelin.3 Myelin is an insulating substance that wraps around the axons of most neurons and helps increase the speed at which a nerve impulse travels.A proposed mechanism posits that MSA involves “prion-like spreading of aberrant α-synuclein from neurons to glia through functionally connected networks, thereby leading to glial and myelin dysfunction and an inflammatory cascade that promotes secondary neurodegeneration.”1 This suggests that MSA is primarily a disorder of the glia and that myelin degeneration is characteristic of it.1 Symptoms of MSA result from loss of nerve cells in various areas of the brain and spinal cord, and

the loss of these nerve cells may be due to the accumulation of α-synuclein. Because MSA has this accumulation of α-synuclein, it is also known as a synucleinopathy.A possible risk factor for MSA is abnormalities in the synuclein gene SNCA, which is responsible for the instructions to create α-synuclein.3 A meta-analysis of 433 patients with a definitive diagnosis of MSA identified a mean age of onset at 54 years.4 This study showed that MSA affected both men and women about the same, with no gender differences in survival. MSA has been documented in white,Asian, and African populations with no preference for a particular race.1 Clinical Findings of MSA

The major clinical features of MSA are autonomic failure and motor dysfunction (Figure 1). Autonomic signs and symptoms can include “orthostatic hypotension, bowel and bladder disturbances, and sexual dysfunction.”5 The motor features classify MSA into 2 subtypes: MSA-P has predominant parkinsonism, and MSA-C has predominant cerebellar ataxia. Signs and symptoms that characterize MSA-P include postural instability, bradykinesia, irregular postural tremor, rigidity, and hypophonia. Signs and symptoms characterizing MSA-C include “gait ataxia, limb ataxia, ataxic dysarthria, and cerebellar disturbances of eye movements.”1 Another symptom that is common in MSA is anterocollis, which is anterior flexion of the neck. Dysphagia and dysautonomia are clinical features of both types of MSA. Urogenital dysfunction and orthostatic hypotension are the most common symptoms of dysautonomia in MSA. Urogenital dysfunction includes erectile dysfunction, urinary incontinence, frequency, and urgency. Sleep and breathing disorders common in MSA include REM sleep behavior disorder, nocturnal stridor, obstructive sleep apnea, restless leg syndrome, and excessive daytime sleepiness.

Although cognitive function in MSA remains fairly intact, it can be impaired. However, unimpaired cognitive function does not rule out MSA in patients with classic signs and symptoms.

Many patients with MSA tend to have depression and anxiety.1

of standing) or urinary incontinence. Poor responsiveness to levodopa when parkinsonism is present may be diagnostic for MSA, as may be the presence of a cerebellar syndrome.1 Neuroimaging lacks sufficient sensitivity or specificity to be used to diagnose MSA. Even so, there are diagnostic criteria that show “atrophy of putamen, middle cerebellar peduncle, or pons [on magnetic resonance imaging] as supportive features for possible MSA-P or MSA-C.”1 Hypometabolism of the cerebellum, putamen, or brainstem has been demonstrated on (18F)fluorodeoxyglucose-positron emission tomography (FDG-PET) in patients with MSA-P. In patients with MSAC, hypometabolism of the putamen has been demonstrated on FDG-PET, as has presynaptic dopaminergic denervation in the striatum on PET or single-photon emission computed tomography (SPECT).1 The “hot cross bun sign” is a nonspecific finding signifying T2 hypersensitivity that forms a cross through the pons as a result of degeneration of pontocerebellar fibers (Figure 2).This sign can be seen on imaging of patients with various causes of parkinsonism.1 A definitive diagnosis of MSA results from postmortem pathology “showing α-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures.”1 Striatonigral degeneration is indicative of MSA-P, and olivopontocerebellar atrophy is indicative of MSA-C.1

PARKINSONISM: • Stiffness • Slowness • Freezing

Basal ganglia

Work-up of MSA AUTONOMIC FEATURES: • • • • • •

Bladder symptoms Constipation Blood pressure regulation Snoring Sleep apnea Erectile dysfunction

Brainstem

Cerebellum

CEREBELLAR FEATURES: • Balance • Coordination

FIGURE 1. Origin of clinical features of multiple system atrophy.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2018 35

© TEFI / SHUTTERSTOCK

MSA is a clinical diagnosis; there are no imaging studies or laboratory tests that are diagnostic. Responsiveness to levodopa may be used to differentiate MSA-P from idiopathic Parkinson disease as there is usually a poor response to levodopa in patients with MSA-P; however, this may be ineffective in the early stages of MSA-P. Diagnostic criteria for MSA include a sporadic, progressive onset and age >30 years. Additional diagnostic criteria include autonomic failure with either orthostatic hypotension (as reflected by a reduction in blood pressure of ≥30 mm Hg systolic or ≥15 mm Hg diastolic within 3 minutes

sults from degeneration of pontocerebellar fibers.

MULTIPLE SYSTEM ATROPHY

Prognosis for MSA

FIGURE 2. Magnetic resonance imaging of the brain demonstrating the hot cross bun sign in a 60-year-old woman with MSA-C.

IMAGE COURTESY OF THE DEPARTMENT OF DIAGNOSTIC IMAGING, WARSAW, INSTITUTE OF MOTHER AND CHILD, WARSAW, POLAND.

Management of MSA

Currently no disease-modifying or neuroprotective treatments exist for MSA, nor are there effective medications to treat the cerebellar ataxia in MSA-C or the parkinsonian features in MSA-P. Physical therapy can be encouraged to enhance mobility and prevent falls. Occupational therapy can assist with activities of daily living, and speech therapy can also be beneficial if done in the early stages of MSA. Continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) can be used to treat obstructive sleep apnea or stridor.

The use of levodopa in MSA is primarily diagnostic.Although fludrocortisone acetate is the first-line medication for chronic orthostatic hypotension that results from autonomic failure, nonpharmacologic interventions are essential for managing chronic orthostatic hypotension.These include raising the head of the bed, removing medications that could be worsening the hypotension, instructing patients to rise slowly from supine to sitting, encouraging increased salt and water intake, and wearing elastic stockings that go up to the waist.6 Urinary symptoms associated with MSA can be treated with the muscarinic acetylcholine receptor antagonists oxybutynin or tolterodine. Multiple options are available for treatment of erectile dysfunction. Treatments for REM-sleep behavior disorder include tricyclic antidepressants, clonazepam, and melatonin. Depression can be treated with counseling and antidepressant medications. Support groups also provide benefit for individuals with MSA, as well as their families and caregivers.A number of treatment interventions are currently under investigation, including sertraline to reduce α-synuclein aggregation, infusing autologous mesenchymal stem cells for a possible neuroprotective effect, and intravenous immunoglobulins to stop the neuroinflammatory response.6

Progression of MSA can occur over 1 to 18 years, and the disease has a fatal course with 6 to 10 years as the median time from onset to death. Survival can be longer in some patients, and risk factors have been identified that predict shorter survival.These risk factors include early or severe autonomic failure, incomplete bladder emptying, and female gender.7 Causes of death include aspiration pneumonia or acute aspiration during sleep, sudden death due to cardiac arrest or unknown etiology, sudden death from laryngeal stridor and acute airway obstruction, or complications resulting from recurrent urinary tract infections.7 The effects of MSA subtype on prognosis were studied in the first prospective cohort study of MSA in the United States.2 No significant difference was identified between MSA-C and MSA-P in length of survival. Median survival was measured from onset of symptoms to death; median survival for MSA-C was 9.9 years and for MSA-P was 9.6 years.2 MSA-P has been found to predominate in Europe and North America, while MSA-C has been found to predominate in Japan.8 ■ Sudhisha Jala, PA-C, is employed by Gastroenterology Associates of Atlanta, Georgia, and Lisa Daitch, PA-C, is associate professor and director of admissions for the physician assistant program at Georgia Regents University, in Augusta, Georgia.

References 1. Factor S, Esper CD. Multiple system atrophy: clinical features and diagnosis. Available at: https://www.uptodate.com/contents/multiple-systematrophy-clinical-features-and-diagnosis. Updated June 8, 2018. Accessed October 14, 2018.

2. Low PA, Reich SG, Jankovic J, et al. Natural history of multiple system atrophy in the USA: a prospective cohort study. Lancet Neurol. 2015;14(7):710-719.

3. Multiple system atrophy fact sheet. Available at: https://www.ninds.nih.gov/ Disorders/Patient-Caregiver-Education/Fact-Sheets/Multiple-System-Atrophy.

Modified July 24, 2018. Accessed October 4, 2018.

4. Ben-Shlomo Y, Wenning GK, Tison F, Quinn NP. Survival of patients with pathologically proven multiple system atrophy: a meta-analysis. Neurology.

1997;48(2):384-393.

5. Coon EA, Sletten DM, Suarez MD, et al. Clinical features and autonomic testing predict survival in multiple system atrophy. Brain.

2015;138(Pt 12):3623-3631.

6. Factor SA, Esper CD. Multiple system atrophy: prognosis and treatment.

Available at: https://www.uptodate.com/contents/multiple-system-atrophyprognosis-and-treatment. Updated May 9, 2017. Accessed October 4, 2018.

7. Papapetropoulos S, Tuchman A, Laufer D, Papatsoris AG, Papapetropoulos N, Mash DC. Causes of death in multiple system atrophy. J Neurol Neurosurg Psychiatry. 2007;78(3):327-329.

8. Ozawa T, Onodera O. Multiple system atrophy: clinicopathological characteristics in Japanese patients. Proc Japan Acad. 2017;93(5):251-258.

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

CME CE FEATURED COURSE EDUCATIONAL OBJECTIVES After participating in this activity, clinicians should be better able to: • Discuss the evolution of laparoscopic surgery and the pros/ cons of various minimally invasive surgery (MIS) procedures • Describe the new category of percutaneous laparoscopic surgery made possible by sub–3 mm diameter instruments • Recognize the benefits of smaller incisions with minimization of tissue trauma and improved cosmesis • Appreciate the importance of decreased hospital stay, improved recovery time, and minimization of tissue trauma COMPLETE THE POSTTEST: Page 46

Reviewer Disclosures: Ruchit Parikh, PharmD, has ownership interest in Intercept Pharmaceuticals.

Release Date: May 16, 2018 Expiration Date: November 16, 2019 Estimated Time to Complete: 30 minutes Maximum Credits: 0.50 AMA PRA Category 1 CreditTM 0.50 CNE Contact Hour Accredited Provider: This activity is jointly provided by Haymarket Medical Education (HME) and AKH Inc., Advancing Knowledge in Healthcare.

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

Program Description: Just a few decades after the introduction of laparotomy, rapid developments in instrumentation and in the sophistication of optics led to development of laparoscopy and, ultimately, to the the near-universal adoption of minimally invasive surgery using endoscopic techniques for most gynecologic operations—with small incisions for access of surgical instruments, resulting in less pain, shorter hospital stays, and rapid recovery compared with conventional approaches. Further refinements in instrumentation then led to the development of minilaparoscopy, which quickly evolved into a cornerstone of gynecologic surgery, including diagnosis of pelvic pathologies and performance of a variety of therapeutic procedures.

Now, percutaneous surgical systems have emerged as a viable approach to gynecologic surgery that is expected to help further reduce tissue trauma and postoperative pain while improving cosmesis.

Intended Audience: Surgeons, gastroenterologists, physician assistants (PAs), nurses (RNs), and nurse practitioners (NPs) with a surgery specialty or interest in surgery.

Conflict of Interest Disclosure Policies: In accordance with the ACCME Standards for Commercial Support, HME requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational activities.

Faculty Erin T. Carey, MD, MSCR Assistant Professor Department of Obstetrics and Gynecology Division of Minimally Invasive Gynecologic Surgery University of North Carolina Chapel Hill, NC Dr. Carey receives consulting fees from and is on the speakers’ bureau of Teleflex Incorporated.

Accredited Provider Disclosures: The staff of Haymarket Medical Education and Dorothy Caputo, MA, BSN, RN, Lead Nurse Planner, of AKH Inc., Advancing Knowledge in Healthcare, have no relevant financial relationships to disclose.

Accreditation Statement: Haymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Designation Statement: Haymarket Medical Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Accreditation Statement: AKH Inc., Advancing Knowledge in Healthcare is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

Designation Statement: This activity is awarded 0.50 contact hours.

Disclosure of Unlabeled Use: This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed.

The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specific patient’s medical condition.

Disclaimer: The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Haymarket Medical Education, AKH Inc., Advancing Knowledge in Healthcare, or Teleflex Incorporated. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period May 16, 2018 through November 16, 2019, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the pre-assessment test; 3) respond to all polling questions online; 4) study the educational activity; and 5) complete the post-test and evaluation form and submit it online.

A statement of credit will be issued only upon receipt of the above elements and a post-test score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/Sept18feature.

If you have any questions relating to the CME accreditation of this activity, please contact HME at cmequestions@haymarketmedical.com.

If you have any questions relating to the CE accreditation of this activity, please contact AKH at jgoldman@akhcme.com.

If you have any questions relating to your certificate or other issues with this activity, please contact myCME. Support@haymarketmedical.com.

Jointly provided by

CME | CE FEATURED COURSE: ERIN T. CAREY, MD, MSCR

Case Clinic: Minimally Invasive Total Laparoscopic Hysterectomy Outcomes from minimally invasive surgery are equivalent to those of open laparotomy, but the procedure minimizes morbidity and complications.

S

© TETRA IMAGES / GETTY IMAGES

urgical procedures have evolved dramatically over the past century, with an increasingly rapid pace of change during the last 2 to 3 decades. Laparoscopy replaced open surgery as the preferred treatment option in most patients, providing benefits to patients in the form of reduced operative trauma.1 The tenet of minimally invasive surgery (MIS) is to safely perform surgery with equivalent outcomes compared with open surgery while minimizing the morbidity and complications associated with open laparotomy.

Less invasive surgery involves fewer and smaller incisions, with smaller and fewer (or no) ports.

Specific instruments that are structurally similar to the conventional instruments used in open surgeries have been redesigned to support the smaller incision.These smaller instruments reduce surgical trauma while maintaining adequate efficacy and safety standards.2 The results of these changes are less physical discomfort associated with traditional procedures, reduced recovery time, and virtually no visible scarring. Due to minimization of tissue trauma, the need for postoperative pain medication should also be reduced.

Smaller instruments reduce surgical trauma while maintaining adequate efficacy and safety standards.

Evolution of Minimally Invasive Surgery Instruments

During the mid-20th century, relatively few advances were made in surgical technology.

This changed radically with the introduction of laparoscopic surgery, leading to a reduction in wound complications and postoperative pain and www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2018 39

CME | CE FEATURED COURSE

Technology has evolved in an effort to provide less invasive techniques that decrease the morbidity associated with large incisions. improved cosmesis.The success of laparoscopic surgery laid the foundation for MIS.3 Over the past 2 decades, MIS has ushered in a number of fairly significant and widespread changes in general surgery, including the shift from relatively crude, cumbersome gadgets to sophisticated, controlled instruments, resulting in marked reductions in the size of surgical incisions as well as overall patient trauma induced by surgical procedures.

With the goal of performing ‘‘scar-less’’ surgery, surgeons continued to push the limits of MIS with natural orifice transluminal endoscopic surgery (NOTES) and single-incision laparoscopic surgery (SILS), also called single-site laparoscopy (SSL).3 These approaches, however, have proven to have important limitations. Several studies have compared SILS and NOTES with multiport surgery and found that they were not suitable for all surgical procedures because of difficulty with triangulation, poor visualization, limited access and working space, conflict between instruments, a steep learning curve, and restrictive patient selection criteria.4,5 Benefits of New Smaller Instruments With Minilaparoscopy

As MIS evolved toward minilaparoscopy, the expectation was that the benefits already realized for laparoscopy vs open surgery would be extended in terms of postoperative pain, recovery time, and cosmetic result, and that it would be possible to perform endoscopic procedures with the least invasive approach, resulting in gentler tissue handling, decreased need of retraction and dissection, and reduced operative trauma.

To this end, technology has continually evolved in an effort to provide increasingly less invasive techniques that decrease the morbidity associated with large incisions.6 The term “minilaparoscopy” encompasses all techniques for which smaller incisions are used, alone or in combination with smaller instruments. These smaller instruments were developed to reduce invasiveness by decreasing access tissue trauma, including postoperative pain and need for analgesia, and decreased hernia and wound infection.7 They also facilitated straightforward and efficient insertion, reducing blood loss and decreasing the time needed for closure of fascia and skin at the end of the procedure, thus reducing scarring/improving cosmesis and improving patient satisfaction.6-8 Different minilaparoscopic devices have been developed, including the 3-mm system by Storz, a completely reusable set with 36-cm–long instruments; the Sovereign mini-instruments, available in lengths of 20 cm and 29 cm; and the MiniSiteTM system that is available in a standard length of 18 cm.3 They

have been effectively used in a range of laparoscopic surgeries, including cholecystectomy, appendectomy, splenectomy, Nissen fundoplication, thyroidectomy, axillary lymph node dissections, and video-assisted thoracoscopic surgery.3,8 Use of some of these instruments is technically demanding, and many challenges remain.They are limited primarily by the instruments themselves. Their strength, length, and durability can restrict tissue manipulation. In addition, the required downsizing of the end-effector of 3-mm instruments do not offer the same range of end-effector options of functionality as do 5-mm instruments.9,10 The next step in the evolution of MIS was to minimize invasiveness of the procedures by decreasing the number and, more commonly, the size of the operating access ports, as well as decreasing the dimensions of trocars and the use of smallercaliber instruments.1,11 In 1998, Gagner and Garcia-Ruiz first described needlescopic surgery with instruments that were less than 3 mm in diameter.12 Theoretically, these instruments could reduce the risk of trocar-related injuries to both abdominal wall vessels and intra-abdominal organs: due to their decreased diameter, less force may be required to pierce the abdominal wall (reducing major vascular and organ injury). Furthermore, the smaller diameter may have a lower likelihood of injury to abdominal wall structures, such as the inferior epigastric vessels. However, the utilization of trocars increases the working diameter of the instruments, negating some of the benefit of minilaparoscopy.

On average, trocars add 0.5 mm to the diameter of an instrument, which represents a 25% increase in diameter and in abdominal wall trauma for a 2-mm instrument. Nonetheless, these trocar systems are more familiar to surgeons because they mimic current laparoscopy sets.

One of the more obvious advantages to the use of needlescopic instruments is the reduction in the size of the abdominal incisions, which results in nearly undetectable scars that require no closure other than simple bandages.10 Nevertheless, the utility of needlescopic instruments is hindered by their diminished shaft strength and small end-effector size. Some of the barriers to adoption of these needlescopic procedures include: 1) a steep learning curve, 2) prolonged operative time, 3) challenging technique, 4) compromised performance of devices, and 5) high costs associated with capital, service, and disposable technologies.8 Percutaneous Surgery

A further evolution of minilaparoscopy, the next step in the natural continuum of MIS, was achieved with the development

40 THE CLINICAL ADVISOR • NOVEMBER 2018 • www.ClinicalAdvisor.com

The Percuvance system provides the functionality found with traditional laparoscopic instruments while minimizing trauma with smaller incisions. of percutaneous laparoscopic instruments.These tools permit the performance of surgical procedures without the loss of triangulation, allowing the site of instrument insertion to be maintained. Unlike prior approaches, percutaneous devices are appropriate in a wide range of patients, including those who are obese (body mass index [BMI] ≥30 kg/m2).1,13 One such percutaneous instrument platform is the MiniLap® System by Teleflex. MiniLap is designed to enter through the skin while delivering essential surgical functions for routine laparoscopic procedures, minimizing trauma and incisions to leave nearly unnoticeable scars.

A second system, Percuvance® (also by Teleflex), also enters directly through the skin without an insertion trocar; however, it then attaches extracorporeally to 1 of 7 interchangeable 5-mm tool tips to grasp, manipulate, cut, cauterize, and deliver Immediately after device removal

3-mm device

Hem-o-lok® ligating clips to soft tissue during laparoscopic surgery.Thus, the Percuvance platform combines streamlined access and 2.9-mm diameter instrumentation with larger, more robust tool tips into a single device, allowing for smaller incisions and less abdominal wall trauma.8,14 The Percuvance system can be used to perform a wide range of laparoscopic procedures, providing strength and functionality normally found with traditional laparoscopic instruments while minimizing trauma with smaller incisions in comparison to traditional laparoscopy. Operative time and length of hospital stay are similar to those of standard laparoscopic procedures.6 Figure 1 shows a comparison of skin, muscle, and peritoneal layer defects associated with use and removal of a 3-mm instrument with 5-mm and 11-mm to 12-mm trocars.7

5-mm trocar

11- to 12-mm trocar

SKIN DEFECT

MUSCLE DEFECT

PERITONEAL LAYER DEFECT

FIGURE 1. Skin, muscle, and peritoneal layer defects with a 3-mm percutaneous device vs 5-mm and 11-mm to 12-mm trocars.7 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2018 41

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CME | CE FEATURED COURSE

Evolution of Hysterectomy Procedure

The first total hysterectomy, including removal of the cervix in continuity with the body of the uterus, was performed in 1929.15 Laparoscopic surgery was widely adopted in the mid-20th century, although its use was largely limited to the diagnosis of gynecologic disorders and for relatively simple procedures. Rapid developments in the quality of instrumentation and sophistication in optics followed, and later the development of silicone chip cameras and high-resolution television monitors came. In a remarkably short time, these techniques were adopted universally, such that most gynecologic operations

CASE EXAMPLE:

Diagnostic Use of Percuvance Laura is a 35-year-old woman with painful and heavy periods, with cramping that she describes as “awful,” who misses 2 days of work each month because of menstrual pain. She also relates that she does not enjoy intercourse anymore due to discomfort with deep penetration. She tried oral contraceptive pills, with moderate improvement in her symptoms. A pelvic ultrasound was normal and there were no findings of pelvic floor muscle dysfunction on exam. Her doctor suspected endometriosis and advised Laura that laparoscopy was a way to both diagnose and treat disease unresponsive to medical therapy. She reported interest in future fertility.

After discussing risks and benefits, the decision was made to proceed with diagnostic laparoscopy.A 5-mm port was placed in the umbilicus and a uterine manipulator was inserted. A thorough evaluation of the pelvis was performed, and two 3-mm superficial lesions consistent with endometriosis were identified on the bilateral uterosacral ligaments, explaining her severe dysmenorrhea and pain with deep penetration during intercourse. The Percuvance system was employed with 2 additional percutaneous instruments placed in the bilateral lower quadrants; the 3-mm diameter shaft connected to the introducer tool with replacement of the necessary interchangeable 5-mm surgical tool tips (1 grasper and 1 monopolar scissor).

Removing the tissue through the umbilical port, the lesions were resected and then sent to pathology. Hemostasis was achieved with monopolar energy on the device scissor.The umbilical incision was closed with suture and the percutaneous entry sites were closed with glue. The patient was discharged home the same day.

Pathology confirmed endometriosis.When she was released to engage in sexual intercourse, she reported resolution of her sexual pain. She also noted that her menstrual pain was significantly improved and she was pleased with her postoperative recovery, cosmesis, and symptom relief.

were performed using endoscopic techniques, with several small incisions for access of surgical instruments, resulting in less pain, shorter hospital stay, and rapid recovery compared with conventional laparotomy.

Further refinements in instrumentation have been made in recent years. Minilaparoscopy has evolved into a viable alternative for diagnostic and small ablative procedures, providing all the benefits in the gynecological setting as for other types of surgery.16 Although there was concern that the reduced diameter of the instruments might impede certain needs, such as mechanical vessel sealing, minilaparoscopy is emerging as a new paradigm for gynecologic surgery.

Diagnostic accuracy of the minilaparoscope has been established, including diagnosis of pelvic pathologies and other therapeutic procedures such as salpingectomy, ligation with polymer clips, and hysterectomy.17 Percutaneous surgery is also being performed within the gynecological setting. Case studies have been reported for nerve-sparing laparoscopic colposacropexy,18 laparoscopic hysterectomy for fibroids,11 and for endometrial hyperplasia and endometrial cancer.14,19 The following case illustrates the use of the Percuvance system to perform total laparoscopic hysterectomy (TLH).

CASE PRESENTATION Social and Medical History

Fran is a premenopausal white female, age 45 years, who weighs 170 lb (BMI 29.2 kg/m2). She is multigravida 3; multiparas with 2 normal vaginal deliveries at ages 33 and 36; and 1 cesarean delivery at age 40.

• Presentation: She presents to her gynecologist with fatigue, significant lower back pain for the last 6 months, and pelvic pressure. She used to have regular 28-day menstrual cycles with 4 to 5 days of normal bleeding. In the last 8 months, her cycles have extended to 30 to 32 days in length and her menstrual bleeding lasts 8 to 9 days in each cycle. She experiences severe menorrhagia with heavy bleeding, flooding on days 2 through 5, passing of blood clots, and severe cramping and pain. Every month she has some intermenstrual spotting. She had no symptom improvement after a trial of oral contraceptive pills and a levonorgestrel-containing intrauterine device (IUD).

• Medical History: No previous irregular bleeding and no other gynecologic problems. No history of abnormal Pap smears. Iron-deficiency anemia secondary to chronic blood loss from menses.

• Surgical History: One cesarean delivery.

• Transvaginal Ultrasound: Uterus is approximately the size of a 12-week pregnancy, with multiple intramural and submucosal fibroids ranging in size from 1 cm (pea size) to 6 cm (plum size). Endometrial lining was of normal thickness

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and an endometrial biopsy was performed, showing benign histologic architecture of fibroids.

• Preoperative Diagnosis: Uterine leiomyomas Physical Exam at Time of Presentation

• General: 45-year-old overweight female looks to be her stated age • Eyes: sclera, white; conjunctiva, pink; fundoscopy shows normal-caliber vessels, no abnormal background pigmentation, hemorrhages, or exudates; visualized macula • Neuro: oriented to person, place, and time; normal motor tone, sensory, reflexes, and coordination; appears tired and processing time seems slightly slowed • HEENT: normal auditory canal and eardrum; no nasal discharge, normal midline septum; normal dentition, tongue, gums, mucosa, and pharynx • Neck: normal rotation and tilting; midline, mobile trachea; nonpalpable, normal-size thyroid • CV: BP, right arm/auscultation – 118/74; normal auscultation and palpation of carotid arteries and precordium; normal femoral pulse • Resp: normal resonant percussion and palpation of lung fields • GI: no tenderness or masses on palpation; liver size is normal

• Skin: no lesions • Lymph nodes: not palpable • GU: Bimanual exam reveals a bulky, 12–week size uterus, mildly tender, anteverted, and mobile – consistent with a fibroid uterus.

Fran’s steroid hormone levels are out of balance (normal estrogen on day 24: 350 pg/mL; normal progesterone: 6.8 ng/ mL), and she is moderately anemic as reflected by her hemoglobin and hematocrit values. All other values are within normal limits, with no metabolic abnormalities.

Diagnosis and Treatment Options

The diagnosis of abnormal uterine bleeding secondary to uterine leiomyomas is made. Treatment options for symptomatic fibroids include medical and surgical techniques.

Medical management treatment options include nonsteroidal anti-inflammatory drugs, combination oral contraceptive pills, progestin therapy (oral and IUD), anti-fibrinolytic agents, gonadotropin-releasing hormone (GnRH) analogues, and selective progesterone receptor modulators. Surgical management includes uterine artery embolization, myomectomy (hysteroscopic, laparoscopic/robotic, minilaparoscopic, or laparotomic), and definitive management with hysterectomy.20 POLLING QUESTION:

Which of the following approaches would you consider most appropriate in this case?

Laboratory Findings CHEMISTRIES

a. Medical management (eg, GnRH analogue therapy) b. Embolization c. Myomectomy d. Hysterectomy

Na 139 mEq/L

BUN 19 mg/dL

AST 21 IU/L (H)

T. Bili 0.7 mg/dL

K 4.4 mEq/L

Cr 1.1 mg/dL

ALT 25 IU/L (H)

Alb 2.4 mg/dL

CL 101 mmol/L

HbA1c = 6.0%

Alk Phos 107 IU/L

Calcium 9.6 mg/dL

CO2 26 mmol/L

Estrogen (day 24 of cycle) 97 pg/mL (L)

LDH 115 IU/L

Progesterone (day 24 of cycle) 10.4 ng/mL (H)

CBC AND DIFFERENTIAL RBC 3.9 million cells/µL

38% lymphocytes

HGB 10 g/dL (L) (normal: 12-16)

4% bands

HCT 3% (L) (normal 37%-47%)

2% myelocytes

Plt 200 × 103/mm3

1% basophils

WBC 9 × 103/mm3

1.5% eosinophils

45% neutrophils

CASE PRESENTATION, continued Management Decision for Symptomatic Uterine Fibroids

Fran’s gynecologist discussed pharmacologic intervention for her bleeding and bulk symptoms with a GnRH analogue as a treatment option, but she warned Fran that this approach has a high recurrence rate as she is premenopausal and treatment cycles are limited to 6 months. Fran said that she did not want to experience this amount of uterine bleeding again and she strongly desires definitive management. Together, through shared medical decision-making, they decided surgical intervention would meet Fran’s symptom goals. She has reservations about postoperative pain, as she has a close friend who became addicted to opioids after receiving them for pain management following laminectomy to treat spinal stenosis.

Options for surgical management were discussed. Her physician explained that the degree of postoperative pain is largely dependent on the invasiveness of the procedure—and that

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CME | CE FEATURED COURSE

TABLE 1. Percutaneous TLH: results of single-center 20-case series2 Baseline Characteristics Median age in years, (range)

50.5 (32-72)

Menopause, n (%)

15 (75%)

Nulliparous, n (%)

3 (15%)

Previous abdominal surgery, n (%)

10 (50%)

Indication for surgery, n (%) • Early-stage endometrial cancer • Endometrial hyperplasia • Risk-reducing surgery • In situ cervical cancer • Uterine fibroids

5 (25%) 2 (10%) 2 (10%) 1 (5%) 10 (50%)

Perioperative Outcomes Operative time (min), median (range)

67.5 (40-180)

Estimated blood loss (mL), median (range)

50 (10-100)

Uterus weight (g), median (range)

180 (30-1360)

Surgical procedure time (min), median (range) • Hysterectomy + BS, n (%) • Hysterectomy + BSO, n (%) • Hysterectomy + BSO + pLND , n (%)

5 (25) 13 (65) 2 (10)

Vaginal cuff closure time (min), median (range)

8.5 (4.5-14)

Drainage positioning, n (%)

5 (25)

Conversion to total laparoscopy

0 (0)

Conversion to laparotomy

0 (0)

Intraoperative complications

0 (0)

30-day complications

0 (0)

Discharge time (days), median (range)

2 (1-2)

BS, bilateral salpingectomy; BSO, bilateral salpingo-oophorectomy; pLND, pelvic lymph node dissection

the type of surgery depends on several factors: the number, topography, and size of fibroids, the age of the patient, her desire for fertility, her treatment history, and her desire to keep the uterus.20 Fran is 45 years of age and she and her husband have completed childbearing. She would like to minimize the risk of postoperative complications and recovery time so that she can care for her 3 young children, ages 12, 9, and 5 years, as well as her 72-year-old mother-in-law who was recently diagnosed with Alzheimer’s disease. Her goal is to be pain-free, back on her feet, and fully functional as soon as possible since she

is the primary caregiver in their family. She also stated that minimizing scarring would be preferable.

Fran has tried and failed medications to treat her pain and bleeding from the uterine fibroids. The possibility of embolization was considered, but Fran does not want the risk of a repeat interventional procedure if the embolization fails. Due to her enlarged uterus, bulk symptoms (likely contributing to her low back pain and pelvic pressure), bleeding profile, and desire to not require additional intervention in the future, definitive management with a hysterectomy was elected. Her gynecologist suggested TLH using a percutaneous laparoscopic approach to minimize tissue trauma and postoperative pain.

POLLING QUESTION:

What limitations would you anticipate with use of percutaneous laparoscopic instruments for gynecologic surgeries?

a. Difficult learning curve b. Technically challenging c. Compromised performance of instruments d. Disengagement of instrument tips e. Other Percutaneous Total Laparoscopic Hysterectomy

The safety and feasibility of a percutaneous surgical approach in hysterectomy was evaluated in a prospective case series of 20 patients with benign or early malignant gynecological diseases (May 2015 to February 2016). Table 1 shows the baseline characteristics of the study participants.2 Surgical procedures included total extrafascial hysterectomy with bilateral salpingectomy (25%), bilateral salpingooophorectomy (65%), and pelvic lymphadenectomy (15%).

The median operating time was 67.5 min (range 40-180), and the median estimated blood loss was 50 mL (range 50-100).

Median uterine weight was 180 g (range 30-1360). No conversions to standard laparoscopy or laparotomy were registered. Neither intraoperative nor postoperative complications occurred within 30 days post-surgery.The median discharge time was 1 day (range 1-2).2 This study demonstrated that the percutaneous approach was a safe and feasible option for hysterectomy for a variety of causes, including uterine fibroids, endometrial hyperplasia, and earlystage endometrial cancer. Good results in operative time, cosmesis, postoperative pain, recovery, and short hospitalization are advantageous compared to other ultra-minimally invasive techniques.2 Further published experience with percutaneous TLH comes from a single case study.The patient was a 52-year-old woman with heavy uterine bleeding.Transvaginal ultrasound revealed a 12–week size uterus with multiple fibroids.An endometrial biopsy demonstrated benign histologic architecture.TLH using

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• Discharge time: day of surgery • Follow-up: no postoperative complications on day 30 after surgery 5 mm

SUMMARY 2.9 mm

2.9 mm 5 mm

FIGURE 2. Schematic illustration of instrument placement for TLH with Percuvance.

minilaparoscopy in combination with percutaneous instruments was performed without any complications.11

Percutaneous laparoscopy is a new category of laparoscopic surgery that makes MIS even less invasive through smaller incisions, resulting in less abdominal wall trauma.The Percuvance system appears to have several advantages over more traditional approaches for gynecologic procedures such as TLH, as it combines streamlined access with highly functional instrumentation. Importantly, as this case illustrates, this system can be used to perform a wide range of laparoscopic procedures with the strength and functionality of traditional instruments while minimizing trauma because it requires substantially smaller incisions.

These instruments have an important place in the gynecological setting, both for diagnosis and performance of complete surgical procedures (see Case Example of Diagnostic Use of Percuvance).

In Fran’s case, the system made it possible to achieve her primary goals: to be pain-free and functional as quickly as possible in the postoperative setting so she could resume her duties as the primary caregiver for her multi-generational family.■ References 1. Ghezzi F, Cromi A, Siesto G, et al. Minilaparoscopic versus conventional

CASE PRESENTATION, continued Surgical Findings and Outcome

laparoscopic hysterectomy: results of a randomized trial. J Minim Invasive

The Percuvance system was used to confirm a diagnosis of uterine leiomyoma and to then perform TLH without complication. Minimal blood loss occurred, and same-day discharge home was achieved due to low postoperative pain. Fran was completely satisfied with the cosmetic result and postoperative pain control, which was achieved using primarily nonsteroidal analgesics and acetaminophen, with breakthrough-pain opioid therapy for only the day of surgery.

• Surgical procedure: TLH using the Percuvance instrument platform • Skin incision size: 5-mm umbilical port, 5-mm suprapubic port, Percuvance in the bilateral lower quadrants (see diagram, Figure 2) • Total access sites number: 4 • Median percutaneous device introduction time: 6 min • Intraoperative complications: none • Estimated blood loss: 25 mL • Operative time: 75 min • Uterine weight: 350 g • Closure: vaginal cuff closed laparoscopically with 0 V-Loc; skin, 4-0 Vicryl • Conversions: no conversions to standard laparoscopy or laparotomy

2. Gueli Alletti S, Rossitto C, Perrone E, et al. Percutaneous total laparoscopic

Gynecol. 2011;18(4):455-456. hysterectomy: results from a 20 case single-center experience. J Minim Invasive Gynecol. 2016;23(7 suppl):S214-S215. Abstract 695.

3. Krpata DM, Ponsky TA. Needlescopic surgery: what’s in the toolbox?

Surg Endosc. 2013;27:1040-1044.

4. Podolsky ER, Curcillo PG II. Single port access (SPA) surgery – a 24-month experience. J Gastrointest Surg. 2010;14(5):759-767.

5. Hosogi H, Strassel V, Martin C, et al. Single-port versus needlescopic versus conventional laparoscopic cholecystectomy: a comparative study. Asian J Endosc Surg. 2011;4(3):120-126.

6. Chang J, Boules M, Rodriguez J, Kroh M. Minilaparoscopy with interchangeable, full 5-mm end effectors: first human use of a new minimally invasive operating platform. J Laparoendosc Adv Surg Tech. 2016;26(1):1-5.

7. David G, Boni L, Rausei S, et al. Use of 3mm percutaneous instruments with 5mm end effectors during different laparoscopic procedures. Int J Surg.

2013;11(S1):S61-S63.

8. Tagaya N, Kubota K. Reevaluation of needlescopic surgery. Surg Endosc.

2012;26:137-143.

9. Lee PC, Lai IR, Yu SC. Minilaparoscopic (needlescopic) cholecystectomy: a study of 1,011 cases. Surg Endosc.2004;18(10):1480-1484.

10. Mamazza J, Schlachta CM, Seshadri PA, et al. Needlescopic surgery.

A logical evolution from conventional laparoscopic surgery. Surg Endosc.

2001;15(10):1208-1212.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2018 45

CME | CE FEATURED COURSE

11. Misirlioglu S, Arslan T, Urman B, Taskiran C. Percutaneous assisted-total

16. Berlit S, Tuschy B, Brade J, et al. Feasibility and perioperative morbidity of

laparoscopic hysterectomy using novel trocar configuration: 5-5-2. J Minim

mini-laparoscopic hysterectomy. In Vivo. 2014;28:263-266.

Invasive Gynecol. 2016;24(7 suppl):S164.

17. Ng YW, Lim LM, Fong YF. Minilaparoscopic hysterectomy made easy: first

12. Gagner M, Garcia-Ruiz A. Technical aspects of minimally invasive abdomi-

report on alternative instrumentation and new integrated energy platform.

nal surgery performed with needlescopic instruments. Surg Laparosc Endosc.

J Obstet Gynaecol Res. 2014;40(5):1436-1440.

1998;8(3):171-179.

18. Romano F, Legge F, Scambia G, Guido M. Nerve-sparing laparoscopic

13. McCloy R, Randall D, Schug SA, et al. Is smaller necessarily better? A systematic

colposacropexy using a percutaneous surgical system: a case report. J Minim

review comparing the effects of minilaparoscopic and conventional laparoscopic

Invasive Gynecol. 2016;24(4):536-537.

cholecystectomy on patient outcomes. Surg Endosc. 2008;22(12):2541-2553.

19. Rossitto C, Cianci S, Gueli Alletti S, et al. Laparoscopic, minilaparo­scopic,

14. Rossitto C, Gueli Alletti S, Costantini B, et al. Total laparoscopic hysterec-

single-port and percutaneous hysterectomy: comparison of perioperative

tomy with percutaneous (Percuvance) instruments: new frontier of minimally

outcomes of minimally invasive approaches in gynecologic surgery. Eur J

invasive gynecological surgery. J Minim Invasive Gynecol. 2016;23(1):14-15.

Obstet Gynecol Reprod Biol. 2017;216:125-129.

15. Sutton C, Chir B. Past, present and future of hysterectomy. J Minim Invasive

20. Puchar A, Feyeux C, Luton D, Koskas M. Therapeutic management of

Gynecol. 2010;17(4):421-435.

uterine fibroid tumors. Minerva Ginecol. 2016;68(4):466-476.

CME CE

POSTTEST

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/Nov18feature.

CREDITS: 0.50 | Case Clinic: Minimally Invasive Total Laparoscopic Hysterectomy

Expiration date: November 16, 2019 1. Which of the following statements regarding minimally invasive surgery (MIS) is correct? a. The only major limitation to single-incision laparo­ scopic surgery (SILS) is restrictive patient-selection criteria. b. Natural orifice transluminal endoscopic surgery (NOTES) overcomes the difficulties with triangulation and poor visualization associated with SILS. c. MIS techniques are superior to conventional laparoscopic surgery in virtually every application in which they have been assessed. d. Compared with older MIS techniques, newer mini­ laparoscopic instruments reduce tissue trauma and offer improved patient outcomes.

2. Which of the following statements regarding needlescopic surgery is correct? a. This approach results in nearly undetectable scars that require no closure other than simple bandages. b. It is associated with a greater risk of trocar-related injuries. c. Surgeons find this technique easy to master. d. This approach typically decreases operative time.

3. Which of the following statements regarding the Percuvance percutaneous instrument platform is correct? a. Similar to earlier MIS techniques, percutaneous laparoscopic surgery is not appropriate in obese patients (eg, those with a body mass index of ≥30 kg/m2). b. The 2.9-mm shaft system requires use of a 10-mm insertion trocar. c. Different end effectors are attached extracorporeally through a ≥5-mm trocar. d. Operative time and length of stay clock in at less than half of what is typically needed with standard laparoscopic procedures. e. The most common limitations include disengagement of instrument tips and loss of pneumoperitoneum.

4. Use of percutaneous laparascopic instruments in the gynecologic setting : a. Has largely been limited to the diagnosis of pelvic pathologies and minor ablative procedures. b. Has been used successfully to perform colposacropexy and hysterectomy, as well as to treat endometrial hyperplasia and endometrial cancer. c. Has not been reported in the medical literature except in one single-case report. d. Is unlikely to rival conventional MIS due to the limited strength and functionality of sub–3 mm instruments.

TO TAKE THE POSTTEST please go to: ClinicalAdvisor.com/Nov18feature

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

Dermatology Clinic CASE #1

Painful, Recurrent Rash on the Fingers CLAIRE WIGGINS, BS;TALIA NOORILY, BA; CHRISTOPHER RIZK, MD

A 51-year-old white man presents to the clinic with a 2-year history of a painful, recurrent rash on his fingers. He initially noticed redness, irritation, and pustules around his nails that he thought were caused by an infection. However, the rash progressed to affect the nail bed, eventually destroying his nails. On examination, well-demarcated, scaly plaques with associated pustules and nail atrophy are present on the right second and third distal digits. He is otherwise healthy.

What is your diagnosis? Turn to page 48

CASE #2

© DR M.A. ANSARY / SCIENCE SOURCE; NOT ACTUAL PATIENT

Painful Penile Lesions and Groin Swelling ALICE O. MWANDA, DNP, FNP-C; RHONDA CONNER-WARREN, PHD, RN, PNP-PC

A 22-year-old man presented with complaints of painful lesions on his penis and swelling in the left groin that started 10 days ago. He denied fever, chills, night sweats, rashes, dysuria, discharge, testicular pain, or proctitis. His female partner had been diagnosed with chlamydia one year earlier but he has not undergone evaluation. Multiple small, nontender scabbed lesions are identified in the bilateral scrotal area and on the shaft of penis. The right inguinal lymph node was tender and swollen.

What is your diagnosis? Turn to page 49 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2018 47

Dermatology Clinic CASE #1

Acrodermatitis Continua of Hallopeau

Acrodermatitis continua of Hallopeau (ACH) is a chronic eruption of painful, sterile pustules on the distal fingers or toes. Named after the French dermatologist Francois Hallopeau, who was one of the first to characterize the disease in 1890, ACH has been identified by several other names including dermatitis repens, acrodermatitis perstans, and acropustulosis.1,2 Although infectious, neural, and inflammatory etiologies were initially proposed, ACH was only first associated with pustular psoriasis in 1925.3 Since that time, it has been definitively shown that ACH is a rare acropustular variant of pustular psoriasis.3 ACH is an uncommon form of pustular psoriasis, which makes robust epidemiologic studies difficult to conduct.

Typically, the disease initially presents in a single digit rather than multiple and in the fingers more often than the toes.4 ACH is most often seen in middle-aged women and is associated with other varieties of psoriasis and autoimmune conditions.Additional risk factors are difficult to describe due to the low number of reported cases; however, risk factors for pustular psoriasis in general include smoking, psychological stress, trauma, medications, and infection.5 Clinical presentation of ACH is characterized by acute episodes of progressive, painful pustule formation under and surrounding the nail plate associated with erythematous and scaly skin.6 Initially, a painful psoriasiform plaque develops around the nail fold. Small pustules then develop from the site of inflammation, and with time these often coalesce into larger lakes of pus. When these lesions burst, a shiny, erythematous bed is revealed, following which the cycle of pustule formation begins again. The lesions usually arise from the distal digit and tend to slowly spread proximally; depending on the phase of the disease, the lesions may appear moist and erythematous or crusted with small pustules underneath.

ACH can also remain distally in 1 or more digits for many years without spreading.The nail fold and nail bed are often involved, leading to nail matrix destruction. In persistent cases, these eruptions may lead to severe atrophy, onychodystrophy, or osteolysis. Mucous membranes such as the oral mucosa, tongue, conjunctiva, and urethra have been reported to be affected in ACH as well.6-8 Histologically, ACH is distinguished by the presence of subcorneal spongiform pustules with neutrophilic infiltration,

which is typical for pustular psoriasis.These features are present on biopsy of the epidermis and nail bed, where marked acanthosis is often noted. Dermal changes are notable for lymphocytic inflammatory infiltrate and dilated vessels. In severe, chronic cases, there can be extreme thinning of the dermis and epidermis. Cultures of pustular fluid are typically sterile; however, secondary infection can occur and a positive culture should not rule out the diagnosis of ACH.9 The differential diagnosis of ACH can be quite broad depending on the time of diagnosis. In early stages, ACH can be easily confused for herpetic whitlow, paronychia, or acute contact dermatitis (ACD). Unlike ACH, paronychia does not typically have a relapsing course. ACH may be distinguished from ACD because ACD lesions are usually vesicular, not

ACH is an uncommon form of pustular psoriasis, which makes robust epidemiologic studies difficult to conduct. pustular.6 In children with evidence of subungual hyperkeratosis and inflammatory rash, parakeratosis pustulosa should be considered.5 Although in an atypical location, squamous cell carcinoma may appear similar to later lesions of ACH; the two can be differentiated by histopathology. Other lesions within this spectrum of pustular psoriasis include palmoplantar pustular psoriasis, generalized pustular psoriasis, and drug-induced acute exanthematous generalized pustular eruption. All of these conditions may be differentiated from ACH based on the location of the lesions.10 Diagnosis of ACH is largely based on the acute clinical presentation, reported progression of disease, and biopsy results. Gram stain smear, potassium hydroxide preparation, and culture of the pustules are necessary for diagnosis.8 When differentiating varieties of pustular psoriasis, genetic testing may play a role in diagnostics.10 Evidence-based treatment guidelines have been limited due to the rare nature of this disease; however, a variety of therapies have been attempted. Topical treatments such as vitamin A and D derivatives, tacrolimus ointment, corticosteroids, and 5-fluorouracil cream have been used with mixed results.8 There has been documented success with corticosteroid injections into the lateral or proximal nail folds for nail bed and nail matrix disease, respectively.6 There have also been multiple reports of successful ACH treatment with phototherapy. Systemic therapy with methotrexate, cyclosporine, and photochemotherapy as well as

48 THE CLINICAL ADVISOR â&#x20AC;˘ NOVEMBER 2018 â&#x20AC;˘ www.ClinicalAdvisor.com

tumor necrosis factor blockers, infliximab, adalimumab, and etanercept have also been reported to be successful.8 Further investigation is required in order to define standard recommendation for treatment. However, ACH is often refractory to treatment and may eventually destroy the nail bed and underlying bone.

The patient described in this case was initiated on a treatment regimen of combination calcipotriol and betamethasone dipropionate ointment applied twice daily for 1 month. At follow-up examination, the erythema and pustules were noted to be resolved, but there were no improvements to the dystrophic nails.

Claire Wiggins, BS, is a medical student; Talia Noorily, BA, is a medical student; and Christopher Rizk, MD, is a dermatology fellow, Baylor College of Medicine, Houston,Texas.

References 1. Richardson LJ, Kratochvil FJ, Zieper MB. Unusual palatal presentation of oral psoriasis. J Can Dent Assoc. 2000;66:80-82.

2. Saunier J, Debarbieux S, Jullien D, Garnier L, Dalle S, Thomas L. Acrodermatitis continua of Hallopeau treated successfully with ustekinumab and acitretin after failure of tumour necrosis factor blockade

CASE #2

Lymphogranuloma Venereum

The differential diagnoses for the presentation of the primary lesions in this case included lymphogranuloma venereum (LGV), herpes, chancroid, syphilis, pyoderma, and trauma.1 Since there was no scarring or history of ulceration(s), rashes, or trauma, LGV was suspected. Clinical guidelines recommend that clinicians consider LGV in the differential diagnosis when sexually active patients present with inguinal or femoral lymphadenopathy, buboes, or proctitis.2 The name “lymphogranuloma venereum” comes from Latin words that mean swelling of granular tissue in the lymph nodes resulting from sexual intercourse with an infected partner.3 LGV was considered rare before 2003; however, since that time large outbreaks have been reported in Western Europe and North America primarily in men having sex with men.4 LGV is acquired through sexual contact with contaminated exudates that contain an invasive form of

and anakinra. Dermatology. 2015;230(2):97-100.

3. Mobini N, Toussaint S, Kamino H. Noninfectious erythematous, papular, and squamous diseases. In: Elder DE, Elenitsas R, Johnson B, Murphy G, eds. Lever’s Histopathology of the Skin. 9th edition. Philadelphia: Lippincott,Williams & Wilkins; 2005:174-210.

4. Yerushalmi J, Grunwald MH, Hallel-Halevy D, et al. Chronic pustular

Lymphogranuloma venereum is caused by C trachomatis bacteria that penetrate tiny skin abrasions and mucous membrane tears.

eruption of the thumbs. Diagnosis: acrodermatitis continua of Hallopeau (ACH). Arch Dermatol. 2000;136:925-930.

5. Benjegerdes KE, Hyde K, Kivelevitch D, Mansouri B. Pustular psoriasis: pathophysiology and current treatment perspectives. Psoriasis (Auckland, NZ). 2016;6:131-144.

6. Tosti A, Piraccini B. Nail disorders. In: Bolognia J, Schaffer JV, Cerroni L. Dermatology. 4th ed. Philadelphia: Elsevier Saunders; 2018:1203-1219.

7. Barron JA. Acrodermatitis of Hallopeau and erosive oral mucositis successfully treated with secukinumab. JAAD Case Rep. 2017;3:215-218.

8. Sehgal VN, Verma P, Sharma S, et al. Acrodermatitis continua of Hallopeau: evolution of treatment options. Int J Dermatol.

2011;50(10):1195-1211.

9. Piraccini BM, Fanti PA, Morelli R, Tosti A. Hallopeau’s acrodermatitis continua of the nail apparatus: a clinical and pathological study of 20 patients. Acta Derm Venereol. 1994;74:65-67.

10. Twelves S, Mostafa A, Dand N, et al. Clinical and genetic differences between pustular psoriasis subtypes (published July 21, 2018). J Allergy Clin Immunol. doi: 10.1016/j.jaci.2018.06.038

Chlamydia trachomatis serovars L1, L2, and L3 from a person with active lesion(s).1 From an epidemiologic perspective, LGV has been seen in warm climates in parts of Africa, Asia, South America, and the Caribbean.5 HIV is recognized as a risk factor for LGV.6,7 Testing for HIV and other sexually transmitted infections (STIs) is essential for individuals with a diagnosis of LGV. LGV is caused by C trachomatis bacteria penetrating tiny skin abrasions and mucous membrane tears.8 The bacteria spread to genital and rectal lymphatic tissue, causing marked inflammation, necrosis, buboes, abscesses on inguinal lymph nodes, and infection of surrounding tissues. After several weeks or months, healing and fibrosis results in scarring, which damages the lymph nodes and disrupts their function.The permanent lymphatic disruption can cause genital deformity and the lymph nodes can develop chronic swelling, hardening, and enlargement. C trachomatis can also spread systemically through the bloodstream and enter the central Continues on page 54

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2018 49

Dermatology Clinic nervous system, thereby resulting in urogenital infections, trachoma, conjunctivitis, and pneumonia.

The incubation period of LGV is approximately 5 to 21 days. LGV occurs in 3 stages. The first stage, which is often unrecognized, involves the development of rapidly healing, painless genital papules or pustules.9 The genital lesions disappear while the infection spreads to lymph channels and lymph nodes of the genital and rectal areas.1 Lesions of LGV can be herpetiform ulcers with other various forms possible; the ulcer is usually asymptomatic, inconspicuous, and rapidly healing and leaves no scarring.8 The patient’s history may reveal a chancroid or ulcer at the site of inoculation.

However, by the time the patient seeks medical attention the lesion has usually disappeared.10 The secondary or inguinal stage of LGV begins 2 to 6 weeks after onset of the primary lesion. It involves the inguinal syndrome, which manifests with constitutional symptoms (fever, malaise) associated with inguinal buboes.11 Severe local pain in buboes, as well as lower abdominal and back pain may be present.

Goals of treatment of LGV are to cure the disease and to prevent ongoing tissue scarring that may cause complications.

The third stage of LGV manifests as anogenitorectal syndrome with anal pruritus, rectal discharge, fever, rectal pain, tenesmus, constipation,“pencil” stools, and weight loss.10,12 In both women and men, the tertiary stage of LGV can result in degeneration of the genitalia resulting in a condition called esthiomene (from the Greek, “eating away”); the area becomes swollen with ulceration.11 Esthiomene occurs 1 to 20 years after primary infection with LGV.13 In men, lesions occur most commonly on the penis or scrotum; in women, lesions are found on the vaginal wall, cervix, or labia.8 A large, tender lymphatic nodule or bubo, urethritis, and cervicitis are other signs of primary LGV. It has been observed that the most common clinical manifestation of LGV among heterosexuals is tender inguinal and/or regional lymphadenopathy that is typically unilateral.2 Bubo formation is most common in men and results in a distinctive inguinal swelling known as the “groove sign.”5 Since the path of pelvic lymph drainage is different in women, inguinal lymph node involvement characterize fewer than one-third of cases.8 In addition, approximately 30% of women typically have deep iliac or perirectal nodes and may present with

nonspecific back and/or abdominal pain. In stages 2 and 3 of the disease, most women are not diagnosed because of the lack of inguinal lymphadenopathy.

Inflammation of the lymph nodes characterizes the secondary stage of untreated LGV in men. Initially the inguinal bubo is a firm, somewhat painful mass; as it steadily enlarges it becomes very painful, restricts mobility, and takes on a deep blue color.8 The color change is a signal of impending rupture of the bubo through the skin, although in some cases the bubo does not rupture but involutes and becomes firm. Thick yellow pus may drain from the site for weeks or months. Healing can be slow, resulting in scar formation.

Systemic manifestation of secondary LGV may include meningitis, pneumonitis, and other major infections. Other reported conditions include arthritis, hepatitis, and ocular inflammatory disease.

Anorectal LGV can be caused by direct inoculation or it may be a chronic or late manifestation of lymphatic spread from the inguinal area.8 Clinical manifestations of anorectal LGV include multiple ulcerations or chronic inflammation of the rectal mucosa, mucopurulent rectal discharge, and rectovaginal fistulae in women.8 Fever, rectal pain, and tenesmus may also be present.

Rectal strictures, perirectal abscesses, and fistulas represent the severe morbidity associated with LGV.8 In female patients or men who have sex with men, signs and symptoms of more invasive infection are typically present; these include proctolitis (including mucoid and/or hemorrhagic rectal discharge), anal pain, constipation or painful bowel movements, fever, and/or ulcers and lymphadenopathy without proctitis.10,12 The fibrosis caused by chronic inflammation in the tertiary stage can lead to lymphatic obstruction and elephantitis of the genital area; this finding is usually seen in women.11 Case Patient Treatment and Follow-Up

Goals of treatment of LGV are to cure the disease and to prevent ongoing tissue scarring that may cause additional complications. It is also important to prevent further transmission of the disease in the community.

During the initial visit, the patient in the case presentation was treated with azithromycin 1 g coverage for the known exposure to chlamydia.Treatment for the probable herpetic lesions was not initiated as the lesions had been present for 10 days and were resolving. Laboratory assessment that was conducted during the visit included gonorrhea, chlamydia, herpes simplex virus type 1 (HSV-1), HSV-2, urinalysis, syphilis, HIV, and complete blood count. Patient education was initiated to identify and counsel on risky behaviors that are associated with STI exposure and transmission.

54 THE CLINICAL ADVISOR • NOVEMBER 2018 • www.ClinicalAdvisor.com

Further direction included abstinence from sexual intercourse until follow-up evaluation and treatment were completed.

Anticipatory guidance regarding potential future exacerbations or flare-ups that would require medical evaluation and treatment at the onset of lesion eruption was provided.The patient was advised to return to the clinic in 1 week for follow-up examination and discussion of the laboratory results.

At the 1-week follow-up appointment, the patient stated that the previous genital lesions had resolved, but a new painful lesion was now on his penis. He denied fever or chills.

Physical examination revealed continued tender swelling in the right groin area with a palpable lymph node that had increased in size without erythema or warmth. Multiple healing lesions were noted on inspection of the genitals. One new erythemic ulceration was now located on the dorsal area of his penis. The penis was not swollen.

Laboratory results that were reviewed and discussed with the patient during the 1-week follow-up evaluation indicated positive chlamydia and HSV-1 tests. Complete blood count was negative for leukocytosis. Other negative laboratory testing included urinalysis, gonorrhea, syphilis, HIV, and HSV-2. The patient was diagnosed with LGV due to the clinical presentation and the positive chlamydial infection.

The patient was started on a treatment regimen of doxycyline 100 mg twice daily for 21 days (the recommended treatment for LGV) and acyclovir 400 mg 3 times a day for 5 days (for the new HSV-1 lesion).2 The patient was provided with discharge instructions from the Centers for Disease Control and Prevention on STIs including LGV, herpes, and chlamydia; he was instructed to notify his partner of the multiple diagnoses.The patient was informed of mandatory reporting of STIs by health care providers to the state’s health department.The patient was instructed to return in 3 weeks for re-evaluation.

On his third and final visit after completion of treatment, the patient reported that he informed his partner and she had sought treatment. He denied sexual activity since his last visit to the clinic. Physical examination revealed that the genital lesions and the swollen right inguinal lymph node bubo had now resolved.The patient was instructed to delay sexual activity until his partner had finished her treatment.

To exclude reinfections, a follow-up visit 3 months after the initial diagnosis with LGV was recommended.

LGV in men and women, and recognize that assessment of sexual practices is crucial. As in this case description, treatment guidelines indicate that patients with clinical symptoms consistent with LGV including inguinal lymphadenopathy and genital ulcers need to be presumptively treated for LGV.2 Persons who have had sexual contact with an individual with LGV who is within 60 days of onset of symptoms should be examined and tested at the anatomic site of exposure.They should be presumptively treated with a chlamydia regimen (azithromycin 1 g orally single dose or doxycycline 100 mg orally twice a day for 7 days). Parra-Sánchez et al documented

Large outbreaks of LGV have been reported in Western Europe and North America, primarily in men having sex with men. successful treatment of LGV with a single dose of azithromycin in 11 of 13 (84.6%) patients who received it.15 On the contrary, Oud et al found that azithromycin 1 g seemed insufficient to manage established infections with some cases of inguinal LGV requiring prolonged courses of doxycycline exceeding the currently advised 21-day regimen.16 Clinicians are to stress the importance of follow-up visits to reassess for complex comorbidities and/or until resolution of symptoms.

Further teaching is needed to educate patients on the potential for reinfection, risky behaviors, and potential complications due to delayed treatment. Although the infection is rare in industrialized countries, primary care clinicians should be aware of the clinical presentation of LGV and current treatment guidelines. ■ Alice O. Mwanda, DNP, FNP-C, and Rhonda Conner-Warren, PhD, RN, PNP-PC, are both assistant professors of health programs at Michigan State University College of Nursing, East Lansing, Michigan.

References 1. Papadakis MA, McPhee SJ, Rabow MW. Current Medical Diagnosis & Treatment. 55th ed. New York: McGraw-Hill Medical; 2017.

2. Workowski KA, Bolan GA. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):33-34.

3. Ceovic R, Gulin SJ. Lymphogranuloma venereum: diagnostic and treatment

Conclusion

challenges. Infect Drug Resist. 2015;8:39-47.

Patients with LGV present with a wide range of symptoms indicative of other conditions and are frequently coinfected with other STIs.14 Clinicians presented with this situation in primary care need to be cognizant of the presentation of

4. White JA. Manifestations and management of lymphogranuloma venereum.

Curr Opin Infect Dis. 2009;22(1):57-66.

5. Mabey D, Peeling RW. Lymphogranuloma venereum. Sex Transm Infect.

2002;78:90-92.

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

© The New Yorker Collection 2018 from cartoonbank.com. All Rights Reserved.

Dermatology Clinic 6. Macdonald N, Sullivan AK, French P, et al. Risk factors for rectal lympho-

guideline on the management of lymphogranuloma venereum. J Eur Acad

granuloma venereum in gay men: results of a multicentre case-control study

Dermatol Venereol. 2015;29(1):1-6.

in the UK. Sex Transm Infect. 2014;90(4):262-268.

12. Ward H Martin I, Alexander S, et al. Lymphogranuloma venereum

7. Petrovay F, Balla E, Erdősi T. Emergence of the lymphogranuloma venereum

in the United Kingdom. Clin Infect Dis. 2007;44(1):26-32.

L2c genovariant, Hungary, 2012 to 2016. Euro Surveill. 2017;22(5).

13. Gross G, Tyring SK. Sexually Transmitted Infections and Sexually Transmitted

8. McCance KL, Huether SE, Brashers VL, Rote NS, eds. (2014). Pathophysiology:

Diseases. Berlin, Heidelberg: Springer Berlin Heidelberg; 2011.

The Biologic Basis for Diseases in Adults and Children. 7th edition. St. Louis, MO:

14. Pallawela SNS, Sullivan AK, Macdonald N, et al. Clinical predictors

Elsevier Mosby; 2014.

of rectal lymphogranuloma venereum infection: results from a multicentre

9. Arsove P. Lymphogranuloma venereum (LGV). Available at:

case–control study in the UK. Sex Transm Infect. 2014;90(4):269-274.

http://emedicine.medscape.com/article/220869-overview. Updated

15. Parra-Sánchez M, García-Rey S, Rodríguez IP, Fernández PV, Sánchez MJT, Folía

September 7, 2018. Accessed October 13, 2018.

JCP. Clinical and epidemiological characterisation of lymphogranuloma venereum

10. Centers for Disease Control and Prevention. Lymphogranuloma venereum

in southwest Spain, 2013–2015. Sex Transm Infect. 2016;92(8):629-631.

(LGV). Available at: https://www.cdc.gov/std/tg2015/lgv.htm. Updated June 4,

16. Oud EV, de Vrieze NHN, de Meij A, de Vries HJC. Pitfalls in the diagnosis

2015. Accessed October 13, 2018.

and management of inguinal lymphogranuloma venereum: important lessons

11. De Vries HJ, Zingon A, Kreuter A, Moi H, White JA. 2013 European

from a case series. Sex Transm Infect. 2014;90(4):279-282.

“And then they literally have a parade.”

56 THE CLINICAL ADVISOR • NOVEMBER 2018 • www.ClinicalAdvisor.com

Dermatologic Look-Alikes Diffuse Bullous Skin Lesions JESSICA SHEU, BA; JOAN FERNANDEZ, BS; CHRISTOPHER RIZK, MD

CASE #1

CASE #2

A 55-year-old man presents to the clinic with multiple tense bullae diffusely involving his trunk and extremities that overlie urticarial plaques. The patient states that for the past 4 weeks, his skin has been intensely itchy, and he has noticed areas of redness that he describes as “hives.”

He has tried over-the-counter anti-itch creams and moisturizers without relief. He states that besides having a viral respiratory illness last month, he is otherwise in good health.

A 40-year-old African American man presented to the clinic with a few small flaccid blisters as well as multiple crusted erosions and some areas of post-inflammatory hyperpigmentation on his back and in the creases of his elbows. He stated that he also experienced painful mouth blisters approximately 1 to 2 months earlier and occasionally still experiences these blisters. He reports that he has never had anything like this before, and aside from an occasional outbreak of herpetic mouth ulcers, he is otherwise healthy.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2018 57

Dermatologic Look-Alikes CASE #1

Bullous Pemphigoid

Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease.1 The term “pemphigoids” refers to a group of autoimmune bullous diseases characterized by subepidermal blistering.1 Lever first described the histopathologic subepidermal split and acantholysis characteristic of pemphigoid diseases in 1953.2,3 The mean age of presentation is between 75 and 85 years, and the risk of developing BP increases with age.4,5 In Europe, the estimated incidence of BP is between 4.5 and 14.0 new cases per million per year.1,2 BP is an autoimmune disorder in which immunoglobulin G (IgG) autoantibodies attack BP180 (BPAG2, type XVIII collagen) and BP230 (BPAG1-e) antigens found on hemidesmosomes, which are responsible for the tight barrier between the epidermis and dermis.5-7 Many triggers are associated with BP, some of which include medications and viral infections.

Certain drugs, such as loop diuretics and neuroleptics, are thought to alter the immune response to specific antigens or, conversely, modify the antigenic properties of the epidermal basement membrane leading to the development of BP.1,2,8 Infections such as human herpesvirus, hepatitis B and C viruses, Helicobacter pylori, and Toxoplasma gondii have also been associated with the development of BP.1 Other triggers linked to the development of this disease include trauma, burns, radiotherapy, ultraviolent radiation, various autoimmune disorders, psoriasis, and certain neurologic disorders.2 Patients with BP often present with an intensely pruritic eruption of tense vesicles/bullae and annular urticarial plaques that overlie either normal or inflamed, erythematous skin.2,9 The bullae tend to develop on the trunk and flexural surfaces, often in a symmetrical distribution.8 As many as 10% to 20% of patients have mucosal involvement, with the oral mucosa most commonly affected.8 BP bullae are usually preceded by a prodromal nonbullous phase characterized by intense pruritus and eczematous patches and/or fixed urticarial-like lesions.1,2 This prodromal phase can sometimes persist for months to years prior to bullae development.8 The gold standard in establishing a diagnosis of BP is by lesional fixed tissue histopathology and perilesional direct immunofluorescence (DIF) analysis.10 Light microscopy usually shows subepidermal blister formation with a superficial dermal eosinophilic infiltrate.1 DIF analysis shows linear IgG and/or complement C3 deposition at the epithelial basement

membrane zone.1-3,8 Enzyme-linked immunosorbent assay (ELISA) has recently become more widely used for the detection of recombinant BP180 circulating antibodies, given its high sensitivity (~92%) and specificity (~98%).3 At present, there are no generally accepted criteria for the diagnosis of BP; however, according toVaillant et al, diagnosis of BP can be made when 3 of the 4 clinical criteria are present: (1) age >70 years, (2) absence of atrophic scars, (3) absence of mucosal involvement, and (4) absence of predominant bullous lesions on the neck and head.3,8 BP can bear close resemblance to a variety of dermatoses including localized or generalized drug reactions, contact and allergic dermatitis, urticarial vasculitis, arthropod reactions,

The term “pemphigoids” refers to a group of autoimmune bullous diseases characterized by subepidermal blistering. scabies, ecthyma, or even pityriasis lichenoides. In addition, several other autoimmune blistering diseases can mimic BP, including linear IgA dermatosis, pemphigoid gestationis, and epidermolysis bullosa acquisita.Therefore, a detailed patient history, clinical evaluation, histopathologic examination displaying the characteristic findings of BP, and DIF studies are crucial components necessary to distinguish BP from other similarly presenting disorders.2 Linear IgA dermatosis and BP both present with subepidermal splitting; therefore, DIF must be used to distinguish between these 2 diseases. In BP, DIF shows C3 and IgG deposition, whereas C3 and IgA deposits are present in linear IgA dermatosis.11,12 Furthermore, bullous pemphigoid has a predominantly eosinophilic infiltrate, while linear IgA dermatosis has a largely neutrophilic infiltrate.3 Pemphigoid gestationis is an autoimmune bullous dermatosis that occurs in the second or third trimester of pregnancy.13 BP cannot be differentiated from pemphigoid gestationis in the urticarial or bullous stage of the disease, and the histopathology of pemphigoid gestationis is similar to cell-rich BP.12 However, the diseases can be distinguished clinically as BP usually affects the thighs and lower legs of the elderly and has not been reported in pregnancy.13 Epidermolysis bullosa acquisita can be distinguished from BP by the detection of IgG autoantibodies to typeVII collagen at the cutaneous basement membrane zone.14 Because bullous pemphigoid is a chronic fluctuating disease, the primary goal of treatment is to reduce the symptomatic blister burden and to improve the patient’s quality of life.The standard of care for the treatment of disease involves either

58 THE CLINICAL ADVISOR • NOVEMBER 2018 • www.ClinicalAdvisor.com

high-potency topical corticosteroids or systemic corticosteroids, both of which have been found to lead to a significant reduction in BP180 and BP230 autoantibodies.8 Due to the poor tolerability and side effects of systemic corticosteroids, especially in elderly patients, more dermatologists are preferring highpotency topical corticosteroids, such as clobetasol propionate, for the management of patients with moderate disease.4,8 However, if topical steroids fail to provide adequate relief, systemic corticosteroids are an appropriate option.15 Systemic antibiotics, such as tetracyclines, and adjunctive immunosuppressants, such as azathioprine, are also used as adjunctive treatment.15,16 A few cases have even reported benefits with therapy targeting anti-BP180 IG3 through omalizumab use. This method of immunoadsorption resulted in rapid decreases of circulating antibodies; however, this method is not widely used.8 In the case presented here, the patient underwent biopsy of one of his lesions, the findings of which were consistent with a diagnosis of BP. The patient was initiated on oral prednisone. At his follow-up appointment 3 weeks later, the patient’s blister burden had substantially decreased and his pruritus had diminished. He was instructed to continue the prednisone with an extended-taper dosing schedule in place.

CASE #2

Pemphigus Vulgaris

Pemphigus vulgaris (PV) is the most common of the group of autoimmune bullous diseases characterized by intraepithelial blister formation.17,18 PV is a rare autoimmune disease with an incidence of approximately 0.42 per 100,000 people in the United States.The incidence is much higher in some Ashkenazi Jewish populations and in Eastern countries, such as China, Japan, Malaysia, and India.The disease affects men and women equally and has a mean age of onset of 50 to 60 years; however, it has also been reported in children and the elderly.17,19 PV is a potentially life-threatening disease with a high mortality rate if untreated (50% at 2 years, 100% at 5 years).20 PV is characterized by the deposition of IgG antibodies against desmoglein 3 (Dsg3, a 130kDa protein) and desmoglein 1 (Dsg1) found in the mucous epithelium and in skin desmosomes, causing loss of cell-cell adhesion as well as keratinocyte acantholysis, both of which combine to form the blisters that are observed clinically.2,3,20,21

The onset and course of PV depend on the interaction between predisposing and inducing factors.17 Medications, pesticides, malignancies, ultraviolet radiation, and stress have all been associated with the development of PV.18 Viral infections, especially of herpetic origin, may trigger a PV outbreak or complicate its clinical course.17 Physical agents (ultraviolet or ionizing radiation, thermal or electrical burns, surgery, and cosmetic procedures), contact allergens (organophosphate pesticides), dietary factors (foods that contain allyl compounds), and emotional stress are less commonly associated but still have been reported to cause PV.17

The onset and course of pemphigus vulgaris depend on the interaction between predisposing and inducing factors.

Clinically, patients present with small flaccid blisters that almost immediately rupture leaving crusted erosions.3 Mucous membranes are usually affected first and present with painful, nonhealing oral erosions and fragile blisters.13,20,22 Evaluation of patients with only oral involvement may be difficult, as intact bullae are difficult to find due to mastication or trauma. Oral lesions often precede skin findings by several months. Skin involvement is characterized by a diffuse eruption of flaccid blisters and erosions localized to the face, scalp, extremities, and flexural surfaces.22 Traditionally, patients with PV will have a positive Nikolsky sign. If left untreated, PV can be fatal secondary to complications associated with the disruption of the protective skin barrier, which results in uncontrolled protein and fluid loss as well as the development of opportunistic infections.13 The diagnosis of PV is accomplished through a combination of clinical findings, histopathology, and immunohistochemistry.

Diagnosis is confirmed by DIF assay, indirect immunofluorescence (IIF) assay, or ELISA to Dsg1 and Dsg3 recombinant fusion proteins.22 DIF reveals deposition of IgG and C3 binding to the keratinocyte cell surface in the mid and lower or entire epidermis of the perilesional skin or mucosa.An ELISA kit for detection and titration of circulating anti-Dsg3 and anti-Dsg1 antibodies has recently become available to aid in diagnosis.2,23 Additionally, recent studies looking at the human leukocyte antigen typing of affected individuals have identified pemphigus-prone genes in the patient’s genotype.23 However, despite the multiple tools available, there are currently no uniformly accepted criteria for the diagnosis of PV.3 The differential diagnosis for PV includes BP, pemphigus foliaceus, pemphigus herpetiformis, dermatitis herpetiformis, Continues on page 62

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2018 59

Dermatologic Look-Alikes TABLE. Bullous Pemphigoid vs Pemphigus Vulgaris Bullous Pemphigoid2-8, 9-15

Pemphigus Vulgaris18-25,27-30

Clinical Presentation

• Blisters: pruritic, tense • Urticarial, prurigo-like, or eczematous plaques • Erosions and crusts

• Blisters: fragile, flaccid, possibly painful • Mucous membrane involvement • Erosions and crusts

Age Affected

Affects elderly patients aged 75 to 81 years

Affects patients aged 50 to 60 years

Histopathology

Subepidermal blister

Intraepidermal blister

DIF

C3 and IgG BMZ staining

IgG and C3 ICS

Autoantigen

BP180, BP230

Dsg3, Dsg1

Prognosis

Favorable

Nikolsky Sign

Negative

Diagnosis

• Clinical presentation • Histopathologic features • DIF • IIF • ELISA

• Clinical presentation • Histopathologic features • DIF • IIF • ELISA

Common Treatment

Systemic and topical corticosteroids, immunosuppressive agents

Systemic corticosteroids, immunosuppressive agents

Derm callout goes in this space right in Poor here in three lines to highlight an Positive important point in this article right here

BMZ = basal membrane zone; DIF = direct immunofluorescence microscopy; Dsg = desmoglein; ELISA = enzyme-linked immunosorbent assay; ICS = intercellular staining; IIF = indirect immunofluorescence microscopy

and IgA pemphigus. BP is characterized by pruritic, tense blisters localized to the flexural aspects of the extremities and the trunk. Unlike that seen in PV, most patients with BP do not suffer from oral involvement and they will have a negative Nikolsky sign.3 More information regarding the differentiation between BP and PV is included in the Table.

Pemphigus foliaceus, an acquired autoimmune blistering disease, can be differentiated from PV by the lack of mucosal lesions and the absence of anti-Dsg3 antibodies.3,24,25 Pemphigus herpetiformis can be differentiated from PV histologically by the presence of spongiosis and microabscesses in the mid or subcorneal epidermis, mostly without acantholysis.

Pemphigus herpetiformis typically presents as gyrate or annular erythematous lesions with clusters of small or abortive vesicles and/or pustules, frequently in herpetiform patterns.11,26 Dermatitis herpetiformis presents as pruritic, excoriated papulovesicles, often in a grouped pattern. Unlike PV, DIF assay in dermatitis herpetiformis shows granular IgA and C3 in the tips of the dermal papillae, and IIF assay shows IgA antibodies against endomysium.11

IgA pemphigus is a vesiculopustular disease in which the skin lesions initially appear as tense bullae but typically evolve into translucent, fluid-filled blisters, which may be confused for PV.27 However, patients with IgA pemphigus usually present with annular plaques that have collarette-like scaling.11 First-line treatment for patients with PV includes systemic corticosteroids, either alone or in combination with corticosteroid-sparing immunosuppressive agents.28 Prednisone or deflazacort are initially given at a high dosage (100-200 mg/d) and can be used with azathioprine (2.5 mg/kg/d), cyclophosphamide (1-3 mg/kg/d), or mycophenolate mofetil (1 g twice per day).As the patient begins to improve clinically, the steroid dose can be gradually tapered as tolerated.23 Additionally, topical preparations of epidermal growth factor or pimecrolimus seem to decrease the time required for healing of erosions.29 Treatment should be continued for several years; thus, the side effects of the steroid and immunosuppressive therapy are more likely to affect mortality and morbidity than the disease itself.23 In general, any therapy strategy should weigh the benefits vs the risks of the treatment protocol for each patient.29 For

62 THE CLINICAL ADVISOR • NOVEMBER 2018 • www.ClinicalAdvisor.com

patients in remission, the ingestion of any unnecessary drugs and sun exposure are discouraged as they may increase the risk of a pemphigus relapse.20 Following presentation to the clinic, the patient presented in this case underwent biopsy of his lesions, the findings of which were consistent with a diagnosis of PV. Treatment with highdose prednisone and azathioprine was initiated; as the patient’s blisters subsided, the doses of each were tapered.The patient’s symptoms are currently well controlled with no recent flares. ■

15. Hofmann S. Doxycycline in the treatment of bullous pemphigoid: as good as systemic corticosteroids? Br J Dermatol. 2015;173(1):17-18.

16. Meijer JM, Jonkman MF, Wojnarowska F, Wiliams HC, Kirtschig G. Current practice in treatment approach for bullous pemphigoid: comparison between national surveys from the Netherlands and the UK. Clin Exp Dermatol. 2016;41(5):506-509.

17. Ruocco V, Ruocco E Schiavo AL, Brunetti G, Guerrera LP, Wolf R. Pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies. Clin Dermatol. 2013;31(4):374-381.

18. Venugopal SS, Murrell DF. Diagnosis and clinical features of pemphigus vulgaris. Dermatol Clin. 2011;29(3):373-380.

Jessica Sheu, BA, is a medical student; Joan Fernandez, BS, is a medical student; and Christopher Rizk, MD, is a dermatology resident at the Baylor College of Medicine, Houston,Texas.

19. Yeh SW, Sami N, Ahmet RA. Treatment of pemphigus vulgaris: current and emerging options. Am J Clin Dermatol. 2005;6(5):327-342.

20. Ruocco E, Baroni A, Wolf R, Ruocco V. Life-threatening bullous dermatoses: pemphigus vulgaris. Clin Dermatol. 2005;23(3):223-226.

References

21. Bystryn J, Rudolph JL. Pemphigus. Lancet. 2005;366(9479):61-73.

1. Schiavo AL, Ruocco E, Brancaccio G, Caccavale S, Ruocco, V, Wolf R. Bullous

22. Joly P, Litrowski N. Pemphigus group (vulgaris, vegetans, foliaceus, herpeti-

pemphigoid: etiology, pathogenesis, and inducing factors: facts and controver-

formis, brasiliensis). Clin Dermatol. 2011;29(4):432-436.

sies. Clin Dermatol. 2013;31(4):391-399.

23. Baroni A, Lanza A, Cirillo N, Brunetti G, Ruocco E, Ruocco V. Vesicular and

2. Schmidt E, Torre RD, Borradori L. Clinical features and practical diagnosis of

bullous disorders: pemphigus. Dermatol Clin. 2007;25(4):597-603.

bullous pemphigoid. Dermatol Clin. 2011;29(3):427-438.

24. Junior JV, Maruta CW, Sousa JX, et al. Clinical and immunological profile in

3. Kershenovich R, Hodak E, Mimouni D. Diagnosis and classification of pem-

pemphigus vulgaris and pemphigus foliaceus. Clin Exp Dermatol. 2012;38(1):20-24.

phigus and bullous pemphigoid. Autoimmunity Rev. 2014;13(4-5):477-481.

25. Ohata C, Ishii N, Furumura M. Locations of acantholysis in pemphigus

4. Joly P, Roujeau J, Benichou J, et al. A comparison of oral and topical corticoste-

vulgaris and pemphigus foliaceus. J Cutan Pathol. 2014;41(11):880-889.

roids in patients with bullous pemphigoid. N Engl J Med. 2002;346(5):321-327.

26. Porro AM, Caetano LD, Maehara LD, Enokihara MM. Non-classical forms

5. Daniel BS, Borradori L, Hall RP, Murrell DF. Evidence-based management of

of pemphigus: pemphigus herpetiformis, IgA pemphigus, paraneoplastic pem-

bullous pemphigoid. Dermatol Clin. 2011;29(4):613-620.

phigus and IgG/IgA pemphigus. An Bras Dermatol. 2014;89I(1):96-106.

6. Saniklidou AH, Tighe PJ, Fairclough LC, Todd I. IgE autoantibodies and their

27. Tsurata D, Hashimoto T. IgA pemphigus. In: Murrell DF, ed. Blistering

association with the disease activity and phenotype in bullous pemphigoid: a

Diseases. Berlin; Springer-Verlag: 2015:299-305.

systemic review. Arch Dermatol Res. 2018;310(1):11-28.

28. Kasperkiewcz M, Schmidt E, Zillikens D. Current therapy of the pemphigus

7. Naldi L, Cazzaniga S, Borradori L. Bullous pemphigoid: simple measures for

group. Clin Dermatol. 2012;30(1):84-94.

a complex disease. J Invest Dermatol. 2012;132(8):1948-1950.

29. Frew JW, Martin LK, Murrell DF. Evidence-based treatments in pemphigus

8. Amber KT, Murrell DF, Schmidt E, Joly P, Borradori L. Autoimmune subepi-

vulgaris and pemphigus foliceus. Dermatol Clin. 2011;29(4):599-606.

dermal bullous diseases of the skin and mucosae: clinical features, diagnosis, 9. Tran JT, Mutasim DF. Localized bullous pemphigoid: a commonly delayed diagnosis. Int J Dermatol. 2005;44(11):942-945.

10. Venning V, Taghiour K, Mustapa MM, Highet A, Kirtschig G. British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012. Br J Dermatol. 2012;167(6):1200-1214.

11. Kasperkiewicz M, Kowalewski C, Jablonska S. Pemphigus herpetiformis: from first description until now. J Am Acad Dermatol. 2014;70(4):780-787.

12. Venning VA. Linear IgA disease: clinical presentation, diagnosis, and pathogenesis. Dermatol Clin. 2011;29(3):453-458.

13. Rados J. Autoimmune blistering diseases: histologic meaning. Clin Dermatol.

2011;29(4):377-388.

14. Yamase A, Kono T, Ishii N, Hashimoto T, Saeki H. An autoimmune bullous dermatosis with clinical, histopathological and immunological features of bullous pemphigoid and epidermolysis bullosa acquisita in an adult. Br J Dermatol.

2016;175(4):790-793.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2018 63

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and management. Clin Rev Allergy Immunol. 2018;54(1):26-51.

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.

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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.

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Conference Roundup CHEST 2018 Meeting The American College of Chest Physicians San Antonio, Texas

© BSIP / GETTY IMAGES

METERED DOSE INHALER ERRORS PREVALENT IN COPD AND ASTHMA In the United States, two-thirds of adults diagnosed with chronic obstructive pulmonary disease (COPD) or asthma reported metered dose inhaler errors, indicating the importance of educating patients on inhaler technique and selecting the right device.

The authors of this meta-analysis sought to estimate overall and step-bystep errors related to the use of metered dose inhalers in US adult populations with COPD or asthma.They performed a systematic review of studies accessed from relevant databases (PubMed,

This review highlights the importance of educating patients on inhaler technique.

EMBASE, PsycINFO, Cochrane, and Google Scholar) that mentioned inhalerrelated errors reported in patients diagnosed with COPD or asthma.

Independent reviewers graded the quality of each study and extracted data on sociodemographic and clinical characteristics, as well as overall and step-bystep metered dose inhaler errors. The researchers calculated the proportion of patients who experienced overall device errors (defined as error in ≥20% of the inhaler steps), as well as step-by-step errors. A meta-analysis estimated mean effect size for overall and step-by-step errors across all studies, and randomeffects models were used to calculate weighted or pooled estimates.

A total of 8 studies with 1198 participants were identified in which the weighted mean error rate for metered dose inhalers overall was 66.5%. In addition, 5 studies (n = 857) provided stepby-step errors and attributed the most common as failure to attach the inhaler to a spacer (73.8%), failure to exhale fully and away before using the inhaler (68.7%), failure to inhale slowly and deeply (47.8%), failure to hold breath for 5 to 10 seconds (40.1%), and failure to shake the inhaler before use (37.9%).

In adults with COPD or asthma, twothirds reported errors related to metered dose inhaler use. In reported step-by-step errors, ≥40% of patients failed to exhale fully and away prior to inhalation, to inhale slowly and deeply, or to hold their breath for a full 5 to 10 seconds.

The findings of this review indicate the importance of educating patients on inhaler technique. Many of the stepby-step errors are preventable by using nebulized therapy instead of a metered dose inhaler device.

MONTELUKAST PLUS LEVOCETIRIZINE IN ASTHMA, ALLERGIC RHINITIS A fixed-dose combination of montelukast plus levocetirizine was found to be safe and effective for the treatment of perennial allergic rhinitis and asthma compared with montelukast alone.

A 4-week double-blind, randomized, multicenter phase 3 study was conducted to compare montelukast monotherapy vs combination therapy with montelukast plus levocetirizine in a cohort of patients with perennial allergic rhinitis and mild to moderate asthma.

Following a 1-week placebo runin period, participants were randomly assigned to receive montelukast 10 mg/d (n = 112) or montelukast 10 mg/d plus levocetirizine 5 mg/d (n = 116) for 4 weeks. The primary efficacy end point was mean daytime nasal symptom score (MDNSS).

Additional efficacy end points included mean nighttime nasal symptom score, mean composite symptom score, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, overall assessment of allergic rhinitis by both participants and physicians, asthma

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Conference Roundup

PIRFENIDONE FOR IMPROVING EXERCISE CAPACITY, DYSPNEA IN IDIOPATHIC PULMONARY FIBROSIS Pirfenidone was found to be superior to placebo in improving exercise capacity and dyspnea in patients with idiopathic pulmonary fibrosis (IPF) and advanced impairment of lung function.

Investigators conducted a post hoc analysis of the ASCEND (ClinicalTrials. gov Identifier : NCT01366209) and CAPACITY (ClinicalTr ials. gov Identifiers: NCT00287716; NCT00287729) clinical trials. Patients with IPF were randomly assigned to either a total daily dose of pirfenidone 2403 mg/d (n = 90) or placebo (n = 80).

Changes from baseline in the 6-minute walk distance (6MWD) and University

Chest radiograph showing diffuse lesions associated with pulmonary fibrosis.

of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) total score as well as changes in the composite outcome of a 6MWD decline of ≥50 m or death and an increase in UCSD SOBQ total score of ≥20 points or death were assessed at 52-week follow-up.

At baseline, the median 6MWD in the treatment and placebo groups were 385.5 m and 375.5 m, respectively, and baseline median UCSD SOBQ total scores were 42.0 and 43.8. The median change in 6MWD from baseline to the 52-week follow-up was –34.0 m with pirfenidone vs –81.5 m with placebo. A significantly lower proportion of patients with 6MWD decline ≥50 m or who had died were in the pirfenidone group (43.3% vs 61.5%; P =.0279).

The median change in the UCSD SOBQ total score from baseline to 52 weeks also favored pirfenidone (+17.0 [pirfenidone] vs +21.5 [placebo]). In addition, a significantly lower proportion of patients who experienced an increase in the UCSD SOBQ total score of ≥20 points or death by 52-week follow-up were randomly assigned to pirfenidone (43.8% vs 57.5%; P =.0081).

66 THE CLINICAL ADVISOR • NOVEMBER 2018 • www.ClinicalAdvisor.com

BENRALIZUMAB FOR MANAGEMENT OF SEVERE EOSINOPHILIC ASTHMA Benralizumab was found to significantly improve asthma exacerbation rate, asthma control, asthma-related quality of life, and prebronchodilator forced expiratory volume in 1 second (FEV1) in patients with severe eosinophilic asthma.

Researchers conducted a literature search via PubMed, CENTRAL, CINAHL Plus, EMBASE, IPA, and ClinicalTrials.gov databases for double-blinded, randomized, placebocontrolled, phase 3 clinical trials that measured the effects of benralizumab as add-on treatment in patients with severe eosinophilic asthma. Outcomes of interest were Asthma Control Questionnaire scores, Asthma Quality of Life Questionnaire scores, and prebronchodilator FEV1 values.

Of the 1211 articles that were initial hits in the search, 3 — totaling 2730 participants — met inclusion and exclusion criteria and were included in the analysis. Benralizumab was associated with a significant reduction in annual exacerbation rates. In addition, Asthma Control Questionnaire scores, Quality of Life Questionnaire scores, and FEV1 were significantly improved in patients who received benralizumab. Adverse event rates were not statistically different than with placebo.

“This study provides evidence-based recommendations for use of benralizumab in asthmatic patients with eosinophilia and [can] help direct current treatment guidelines,” the researchers wrote. ■

These articles were originally published on Pulmonology Advisor.com

© ZEPHYR/SCIENCE SOURCE

control test (ACT) score, and frequency of rescue medication use during the study period.

Of the 333 patients who were screened to participate in this study, a total of 228 eligible participants were randomly assigned to treatment. Mean patient age was 43.32±15.02 years; 66.7% of the participants were women. Demographic characteristics were similar between the 2 groups.

Compared with montelukast monotherapy, montelukast plus levocetirizine demonstrated a significant reduction in MDNSS. Regarding all other allergic rhinitis efficacy end points, the combination therapy group experienced greater improvements compared with the montelukast monotherapy group. Similar results were reported with respect to overall assessment scores, as well as FEV1, FVC, FEV1/FVC, and ACT score changes from baseline in the 2 treatment arms.

Montelukast plus levocetirizine was well tolerated, with a safety profile similar to that reported for montelukast monotherapy.

ALTERNATIVE MEDS UPDATE

What you should know about the herbs and supplements patients use Bethany Helm, MPAS, PA-C Christopher Howell, DSc, MPAS, PA-C, MBA

Essentials of Wound Care: Alternative Treatments

established regimens in danger of becoming less effective to common pathogens.5 Ultimately the rise in pathogenic opposition, the burden to the healthcare community, and patient welfare could be insurmountable.6,7 While not often easy to quantify, a salient example is the rising cost of methicillinresistant Staphylococcus aureus (MRSA), with treatment in the United States alone well in excess of $34 billion each year.5 Yet, this is not limited to financial capital, as mortality from MRSA has been attributed to 75% of inpatient burn cases alone.6,8 Therefore, it becomes evident that alternative treatments need to be entertained as potential adjuncts to contemporary pharmacotherapeutic regimens. Although complementary therapies such as acupuncture, massage, and relaxation have been proposed, these may be impractical for most clinical scenarios.3,9 With this in mind, we present treatment options (and the evidence supporting paradigm shifts) that suggest prompt adaptation into conventional practice with the greatest applicability to improve patient outcomes in wound management.9

Essential Oils Essential oils are derived from distillation of leaves, bark, or flowers of certain organic materials that are believed to possess inherent antimicrobial properties with limited risk of progression in emerging microbial resistance. 1,5,6,­10-12 Recent literature supports the use of various essential oils to decrease virulence, particularly multidrug resis10 tance. Promotion of antimicrobial properties and improvement in wound healing have been linked to those oils with phenols, alcohols, and terpenic ketones.4-6 Although numerous agents have been proposed for use as potential antimicrobials, only a few have been consistently studied for their reliability and mechanism of action.5,6,10 Yet, the studies that have been performed have shown destruction of the microbial cell membrane leading to lysis and expulsion

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Complications in wound healing — coupled with increasing multidrug resistance — is an emerging threat to patient morbidity and mortality, presenting challenges to infectious disease and contemporary wound care managers.1-4 The accelerated rate at which microorganisms are becoming increasingly resistant to established pharmacotherapeutic agents is staggering, with

ALTERNATIVE MEDS UPDATE

Vapor Organism-targeted therapies can be affected by the route of essential oil exposure. As a vapor, essential oils have consistently revealed an affinity for some of the most virulent organisms, such as MRSA, but also vancomycinresistant Enterococci and Clostridium difficile.12 In vitro studies of essential oil vapor have revealed promising results in reducing numerous “antibiotic-resistant, healthcare-associated” pathogens.12 Most of the focus in this research aims to reduce air contamination during procedures and in environments where airborne pathogens pose risk. A study performed by Doran et al reported a reduction in airborne bacteria by 89% when essential oil vapor was used for as little as 15 hours.12 With limited established toxicity profiles when delivered as an aerosolized instrument, essential oils present the greatest benefit in areas where decontamination places a significant burden on medical and treatment staff. 12 The value of vapor transmission is therefore that of prophylactic management as a means of disease reduction.

Topical Although vapor is the most prevalent essential oil route, topical antimicrobial therapy is regarded as an important component of wound care to prevent wound deterioration and infection.4,8 The skin plays a significant role in protecting the internal body environment from external hazards, and any intrusion into or destruction of this barrier can disrupt the body’s essential systemic structures and biomechanical function.13 Burns from heat, chemicals, electricity, sunlight, and radiation are just a few examples of trauma that can expose the body to denaturing compromise. Accidental thermal burns alone are considered the leading cause of mortality and disability with an estimated 2 million people afflicted each year, and wound healing is essential for barrier restoration.13,14 The aim of wound healing is to facilitate a short time for repair with few side effects and reducing incidence of infections, which is why there is a growing tendency toward pharmaceutical herb usage.15,16 The 4 phases of wound healing — hemostasis, inflammation, proliferation, and remodeling — are each influenced by the migration of specific types of cells into the wound; each phase is dependent on the acceleration or deceleration of certain components in that process, which when fostered allow for improved healing.11,14,17,18 The primary treatment goal of topical agents is to promote multidimensional wound healing by inhibiting the proliferation of infection-causing microbes.13,15 Inhibition of microbe proliferation may lead some to entertain applying essential oils to wound dressings.6,8 Of those noted agents, tea tree oil from Melaleuca alternifolia lends itself as one of the most effective agents against prominent skin flora — especially Staphylococcal species, namely MRSA and methicillin-susceptible S aureus — when topically applied.5,9 Predominating in chronic wound management, tea tree oil has the advantage of possessing both bacteriostatic and bactericidal properties, while also increasing monocytic differentiation and decreasing inflammation and overall time spent healing.5,9 Although tea tree oil has been reported

by Shea et al as the most efficacious essential oil monotherapy for topical wound management, geranium and citricidal oils can also be used as a combination agent with similar results.8 Lavender has been proposed to possess similar antimicrobial, anti-inflammatory, and even analgesic properties.6 However, the evidence for its proposed benefits, including wound healing and scar reduction, remains largely anecdotal.6,12 Studies have revealed some agents with a proclivity toward improved deep tissue wound healing derived from their phytochemical ingredients. L augustifolia and L nobilis are noted

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of cellular ions.9 The most common agents proposed with a propensity for wound healing effectiveness are Aloe vera, echinacea, thyme, peppermint, mimosa, cinnamon, tea tree, rosemary, ginseng, jojoba, eucalyptus, lemongrass, garlic, and gingko.3,9,10 As with existing pharmacotherapeutic agents, the efficacy of an essential oil is dependent on the target organism, its concentration, and its dispersion properties.10 For example, Foeniculum vulgare fruits are known to possess broad-spectrum antimicrobial properties — with activity against both Grampositive and Gram-negative microbes — and antifungal properties, while other agents have proven more selective when used appropriately.10 Rosemary and clary sage oils are known to inhibit only Gram-positive bacteria, while basil oil may inhibit both Gram-positive and Gram-negative bacteria.

Although evidence supports the effectiveness of rosemary, clary sage, and basil against S aureus, rosemary has also been associated with synergistic and inhibitory properties against E faecalis when added to antibiogram-directed treatments (even when the organism had proven resistant to such agents as gentamycin and ciprofloxacin).1 It is important to note that routes of administration and associated efficacy are contingent on the agent being examined, and what works for some essential oils will not apply to all agents and illnesses being considered.

for improved tensile strength of a wound following incision, which can be beneficial for those who are prone to poor wound healing and atrophy.6,19

Oral Studies have supported the use of essential oils as oral therapies. For example, while a naturally occurring spice compound, the bioactive component of turmeric is proposed to possess anti-inflammatory, analgesic, and healing properties.3 At this time, however, the ideal dosage of the agent and route of optimal delivery remain uncertain.3 Although toxicity, allergic reactions, and complications from topical and vapor agents remain low, the safety of oral therapies cannot be substantiated reliably. Therefore, oral administration of essential oils is not endorsed.9,12

Specific Agents Aloe and Honey

Conventional strategies of wound management have included Aloe in both simple and complex wound care regimens, including dressings. Such dressings, historically composed of pectin and gelatin with success, were recently studied using Aloe vera as part of their matrix. The results supported Aloe’s strong antiinflammatory effect, enhanced cell migration, and scar prevention, as well as orderly collagen formation and neovascularization.21 Further studies of the effect of Aloe vera gel on wound healing continue to support significant acceleration in the healing process due to increased proliferation of fibroblasts and keratin, increased collagen synthesis, and reduction of inflammation.15,18 While higher-potency applications have demonstrated impressive findings in healing time, these outcomes were consistently observed across all spectra of wound management and potency of gel, including low-potency aloin vehicles.18 Overall, clinical research has supported that aloin solution, especially that of Aloe gel, promotes faster rate of wound closure and inhibited scar tissue formation and should be considered an essential component within the continuum of topical wound management.

Honey

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Aloe

Aloe vera extract has shown impressive effects in cutaneous injury and wound healing, especially those associated with burn and frostbite.13,17,20,21 Since antiquity, Aloe has been known by many as “the healing plant,”16 and it is ultimately the most studied species of the Aloe genus.15-18,20,21 Recent research has revealed that in addition to its hypoglycemic, gastroprotective and “antimalignancy properties, it has been shown to exhibit antiinflammatory, antifungal, and antimicrobial properties.”15-18,20,21 It is through these essential properties that Aloe is able to exert its skin protective activities, including stimulating primary epidermal keratinocyte proliferation that is crucial in the first hours of wound healing.14,20 The gel formulation of Aloe is derived from the succulent leaves of the plant, whereas Aloe juice is obtained from the peripheral bundle sheath cells.20 Aloe gel, the active ingredient of which is an organically active compound known as aloin, increases Aloe’s stability, basic structure, and water solubility, making it attractive to study in wound healing.18 Consisting of 99% water with long-chain polysaccharides, Aloe gel prevents skin dryness and bacterial growth, largely due to its high osmotic composition.15 Furthermore, Aloe gel has been found to increase epithelialization, thereby shortening the duration of wound healing; this has been most prominently studied in first- and second-degree burns.17

The use of honey for wounds, burns, and skin ulcers dates back many centuries. In the wake of progressive medical breakthroughs, including antibiotics and advanced surgical techniques, the use of honey as a foundational intervention has all but ceased.22 However, renewed interest has been observed, due largely to rising antibiotic resistance and desire for favorable adjuncts to topical wound therapy, of which honey has anecdotal and historical evidence of benefit.22 Beyond its low cost and availability, honey has properties that make it an attractive topical treatment option, including: improved tolerance of the patient to dressing changes; wound odor, swelling, hypertrophy, and contracture reduction; as well as prohibitive microbial growth properties.23 These properties would be particularly beneficial for burn injuries for which necrotic tissue can result in complex infections.23 As a vehicle, topical honey has proven anti-inflammatory and antimicrobial to both bacterial and fungal elements due mainly to its acidic viscosity, which not only allows a “moist healing environment that absorbs exudates [and accelerates] healing, but also improves patient tolerance and comfort.”22,23 Studies have compared honey with contemporary wound therapies with promising success. In several studies comparing the use of pure undiluted honey vs conventional silver sulfadiazine (SSD), honey was found to have superior healing effects.23

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ALTERNATIVE MEDS UPDATE Healing time was significantly lower (18.1 vs 32.6 days), swab cultures became negative in less than 7 days whereas none in the SSD group became negative, and a majority of the honey group recovered completely (81% vs 45%).23 However, in additional clinical trials, it was demonstrated that burn severity contributed to the effectiveness of honey and SSD. When considering superficial and partial-thickness burn wounds, it was noted that the honey group had better healing rates and properties; however, when studying mixed partial-thickness and full-thickness burn wounds, honey did not seem to improve healing. As few studies have been conducted, more trials are needed to elucidate the benefit of honey for burn wound healing.22

Conclusion

6. Süntar I, Akkol EK, Tosun A, Keleş H. Comparative pharmacological and phytochemical investigation on the wound healing effects of the frequently used essential oils. J Essential Oil Res. 2014;26(1):41-49.

7. Andreau V, Mendoza G, Arruebo M, Irusta S. Smart dressings based on nanostructured fibers containing natural origin antimicrobial, anti-inflammatory, and regenerative compounds. Materials. 2015;8(8):5154-5193.

8. Edwards-Jones V, Buck R, Shawcross SG, Dawson MM, Dunn K. The effect of essential oils on methicillin-resistant Staphylococcus aureus using a dressing model. Burns. 2004;30(8):772-777.

9. Stea S, Beraudi A, De Pasquale D. Essential oils for complementary treatment of surgical patients: state of the art. Evid Based Complement Alternat Med. 2014;2014:726341.

10. Liakos I, Rizzello L, Scurr DJ, et al. All-natural composite wound dressing films of essential oils encapsulated in sodium alginate with antimicrobial properties. Int J of Pharm. 2014;463(2):137-145.

Complications of wound healing coupled with multidrug resistance and cost effectiveness beg the idea of researching new and perhaps even past methods of care that could contribute to effective wound care. Essential oils, Aloe, and honey have demonstrated efficacy when used independently and synergistically with pharmacotherapy. The broad availability and low risk of side effects make such alternatives an attractive solution to wound care. Further trials to explore efficacy and consistency with specific essential oils and susceptible organisms would be beneficial, as would deeper exploration of Aloe and honey for burns and more expansive wound management. ■

11. Wu JG, MA L, Zhang SY, et al. Essential oil from rhizomes of Ligusticum chuanxiong induces apoptosis in hypertrophic scar fibroblasts. Pharm Biol.

2011;49(1):86-93.

12. Doran AL, Morden WE, Dunn K, Edwards-Jones V. Vapour-phase activities of essential oils against antibiotic sensitive and resistant bacteria including MRSA. Lett Appl Microbiol. 2009;48(4):387-392.

13. Hashemi SA, Madani SA, Abediankenari S. The review on properties of aloe vera in healing of cutaneous wounds. BioMed Res Int. 2015;2015:714216.

14. Moriyama M, Moriyama H, Uda J, et al. Beneficial effects of the genus aloe on wound healing, cell proliferation, and differentiation of epidermal keratinocytes. PLoS ONE. 2016;11(10):e0164799.

15. Takzare N, Hosseini M-J, Hasanzadeh G, et al. Influence of aloe vera gel on

Bethany Helm, MPAS, PA-C, is a PA and is employed by the Guam Seventh-day Adventist Clinic. At the time of this writing she was a graduate student at Kettering College Master of Physician Assistant Studies program. Christopher Howell, DSc, MPAS, PA-C, MBA, is associate professor at Kettering College Master of Physician Assistant Studies, in Dayton, Ohio. Dr Howell is also a staff clinician in the Emergency Department withTeam Health; North Dayton Addiction Recovery; and East Indiana Addiction Recovery.

dermal wound healing process in rat. Toxicol Mech Methods. 2009;19(1):73-77.

16. Jahandideh M, Hajimehdipoor H, Mortazavi SA, Dehpour A, Hassanzadeh G. Evaluation of the wound healing activity of a traditional compound herbal product using rat excision wound model. Iranian J Pharm Res. 2017;16(Suppl):153-163.

17. Fox LT, Mazumder A, Dwivedi A, et al. In vitro wound healing and cytotoxic activity of the gel and whole-leaf materials from selected aloe species.

J Ethnopharmacol. 2017;200:1-7.

18. Li L-J, Gao S-Q, Peng L-H, et al. Evaluation of efficacy of aloin in treating acute trauma in vitra and in vivo. Biomed & Pharmacother. 2017; 88:1211-1219

References

19. Cheung C. Older adults, falls, and skin integrity. Adv Skin Wound Care.

1. Sienkiewicz M, Łysakowska M, Kowalcyzk E, et al. The ability of selected

2017;30(1):40-46.

plant essential oils to enhance the action of recommended antibiotics against

20. Akaberi M, Sobhani Z, Javadi B, Sahebkar A, Emami SA. Therapeutic

pathogenic wound bacteria. Burns. 2017;43(2):310-317.

effects of Aloe spp. in traditional and modern medicine: a review. Biomed

2. Beitz JM, Goldberg E, Yoder LH. The lived experience of having a chronic

Pharmacother. 2016;84:759-772.

wound: a phenomenologic study. Medsurg Nurs. 2005;14(1):51-82.

21. Tummalapalli M, Berthet M, Verrier B, et al. Composite wound dressings of

3. Levine, J. The effect of oral medication on wound healing. Adv Skin Wound

pectin and gelatin with aloe vera and curcumin as bioactive agents. Int J Biol

Care. 2017;30(3):137-142.

Macromol. 2016;82:104-113.

4. Barreto RS, Albuquerque-Júnior RL, Araújo AA, et al. A systematic review of

22. Dorai AA. Wound care with traditional, complementary and alternative

the wound-healing effects of monoterpens and iridoid derivatives. Molecules.

medicine. Indian J Plast Surg. 2012;45(2):418-424.

2014;19(1):846-862.

23. Gupta SS, Singh O, Bhagel PS, et al. Honey dressing versus silver sulfadia-

5. Chin K, Cordell B. The effect of tea tree oil (Melaleuca alternifolia) on wound

zene dressing for wound healing in burn patients: a retrospective study.

healing using a dressing model. J Altern Complement Med. 2013;19(12):942-945.

J Cutan Aesthetic Surgery. 2011;4(3);183-187.

70 THE CLINICAL ADVISOR • NOVEMBER 2018 • www.ClinicalAdvisor.com

LEGAL ADVISOR CASE

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Death After Hospital Discharge A recently discharged patient dies in a fire, and the hospital is sued.

BY ANN W. LATNER, JD

When Mr N, a 37-year-old nurse practitioner, learned that his former patient had died recently in a house fire, he was shocked and saddened. He had last seen Mr P only 2 days prior, when he was being discharged from the hospital. There had been so much positive change in the patient during his 2-month stay that Mr N was optimistic that the patient would continue to improve.

The patient had been brought to the hospital 2 months earlier by his ex-wife and daughter.

They had found Mr P, who was 63 years of age, severely intoxicated in his home and were very concerned about his living conditions.The family told hospital staff that Mr P lived alone in a trailer home with no running water. They described the home as unsanitary with fire hazards. They pointed out burns on Mr P’s hands and suggested he had gotten them when items in his home caught fire.

Mr P was examined by emergency department staff and subsequently admitted to the hospital with diagnoses that included hepatic encephalopathy, possible alcohol withdrawal, deterioration of functional status, and a neglected state. Mr N was one of the hospital staff assigned to Mr P’s

A guardianship order that stated guardians could act only as necessitated by the patient’s actual mental and adaptive limitations was found to be limited in scope.

care. An emergency psychiatric evaluation conducted by a psychiatrist on the day after admission concluded that Mr P’s alcohol addiction was potentially lethal and that he likely suffered from significant cognitive impairment that would be slow to resolve.

One week after he was admitted, Mr P was examined by a neuropsychologist who was unable to complete the entire testing process because of Mr P’s poor motivation and lack of effort; nevertheless, the neuropsychologist concluded that Mr P did not have the capacity to manage his finances or make informed decisions regarding his health.

The patient’s daughter and ex-wife were appointed guardians after a hearing. The guardianship order stated that they could act “only as necessitated by Mr P’s actual mental and adaptive limitations.”

Cases presented are based on actual occurrences.

Names of participants and details have been changed.

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

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2018 71

LEGAL ADVISOR Meanwhile, Mr P wanted to leave the hospital, and an aide had to be assigned to ensure he did not. Over the next 6 weeks, Mr P’s condition improved. His hepatic encephalopathy was being treated, he was not drinking alcohol, and he was eating well and resting. Mr N, who spoke with the patient every day, noticed a marked change in Mr P’s mental status and coherence. Based on this improvement, the neuropsychologist who had examined him 6 weeks earlier was asked to conduct a follow-up assessment. This time, his findings about the patient were strikingly different. He described the patient as alert, friendly, pleasant, and very cooperative. Mr P told the physician that he was looking forward to returning home and planned to quit drinking (although without therapy or group support). After completing the examination, the doctor concluded that Mr P did have the capacity to manage his finances independently and make better informed decisions regarding his health.

Based on this evaluation, the hospital decided to discharge the patient; however, his guardians objected. The issue was referred to the hospital’s attorney, who concluded that the guardianship was limited in that the guardians could only make decisions for Mr P when he was not capable of making them himself. As it was determined that he was now capable, Mr P should be allowed to decide whether he could return home independently. Mr P wanted to go home.

Mr N was asked to assess whether Mr P should be discharged.

Based on his own assessment and after reviewing the medical record, including the neuropsychologist’s second report, and conferring with the other treating clinicians, Mr N concluded that Mr P had sufficient capacity to manage his own affairs and decided to discharge him. As part of the discharge plan, Mr N scheduled appointments for Mr P with his primary care provider, an outpatient pain clinic, and a community case manager. He also recommended that Mr P participate in alcohol abuse treatment and gave him a list of community resources that were available. Mr P’s daughter was notified that he was being discharged. She objected to the discharge, but when Mr N offered to arrange for a taxi to take Mr P to her home, the daughter declined. Mr P left the hospital that day with a friend.

Mr P’s daughter and ex-wife went to see him the next day and found him intoxicated. One day later he died as a result of a fire that destroyed his entire home.

Mr N was stunned at the news, and a few months later was stunned again after being informed that the hospital was being sued. The patient’s former guardians were alleging that the hospital was negligent for discharging Mr P over the objections of the guardians, and that the discharge plan failed to meet the standard of care. The case went to trial.

Legal Background

After a 5-day trial during which Mr N, the neuropsychologist, and the physicians involved in Mr P’s care all testified, the court ultimately found in favor of the hospital.The court found that based on the neuropsychologist’s second examination, and the fact that he had a first exam to compare it to, the patient had regained capacity prior to his discharge from the hospital.The court held that the guardianship order of the daughter and ex-wife was very limited in scope and that they were authorized to make healthcare decisions for him “ONLY to the extent necessitated by Mr P’s actual and adaptive limitations.” Because he was not found to be limited in mental capacity at the time of his discharge, the guardians had no authority to make decisions for him.

The patient was determined to have had regained capacity prior to his discharge from the hospital.

Finally, the court looked at Mr P’s discharge to determine whether Mr P was provided with a safe and reasonable discharge plan. The court listened carefully to Mr N’s testimony about the appointments he made for follow-up treatment for the patient, as well as his strong recommendation that the patient stop drinking and attend group meetings. He testified that at the time of his discharge, Mr P admitted that he was an alcoholic and that he was going to try to stop drinking.

The court found this acknowledgment showed insight and significant progress, and because Mr P was medically stable and had capacity and an appropriate discharge plan, he was entitled to make the decision to leave.

Protecting Yourself

The court noted that before the patient was discharged, Mr N reviewed the entire discharge plan with him and made sure he understood. This encounter was noted in the patient’s file.

Mr N also conferred with the other treating clinicians, reviewed the medical record, and created an appropriate discharge plan, which included making follow-up appointments. As with most cases, good record keeping, noting changes in mental status of a patient, and making decisions in consultation with the patient’s other clinicians will always stand you in good stead in the event of a lawsuit. ■ Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, NY.

72 THE CLINICAL ADVISOR • NOVEMBER 2018 • www.ClinicalAdvisor.com

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