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Cannabis Use Leads to Dismissal of Nursing Student CLINICAL CHALLENGE
Feeding Issues and Increased Fussiness in an Infant
Recognizing Signs and Symptoms of ADHD Across the Lifespan
Red, Swollen Finger With Fissure
Appropriate Treatment, Health Promotion for Black Women With HTN
FROM THE DIRECTOR
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Like many of you, I was counting the minutes until we could close the book on 2020. Although I know that time is just a human construct, this New Year’s Eve felt different. It felt like a new beginning, a chance to say goodbye to a truly horrible year. I am not going to recount all the painful statistics of the past year: all the unexpected deaths, surges, super-spreader events, and loss of milestones. Instead I want to focus on the future and what it may bring: the chance to reconnect with our colleagues at live medical meetings and celebrate milestones with our families; the chance for our frontline workers to take a break, a pause, a breath; and the chance for you to see your patients again, unmasked and in person. We also have a new administration in the White House and a change of leadership in the Senate. The Biden administration has vowed to value science, has developed a COVID-19 plan that is led by the federal government, and will provide billions of dollars of direct funding to the National Institutes of Health. These plans are poised to positively affect healthcare workers and researchers seeking grants. Although we have highly effective vaccines to fight the pandemic, researchers have not come to a firm conclusion as to what proportion of the population will need to be vaccinated to achieve herd immunity. We are also confronting new, more virulent variants of the virus that causes COVID-19. We currently believe that the existing vaccines will protect against these mutant strains, but we won’t know for sure until further research is conducted. So we also need to have patience. It is going to take a while before life returns to normal — whatever that new normal may look like. In this issue, we continue to examine how institutional racism has negatively influenced the health and wellbeing of people of color. Our cover story examines the stark difference in the incidence of hypertension between Black women and White women. We welcome your article submissions and look forward to a happier, healthier 2021. Nikki Kean, Director The Clinical Advisor
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 1
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Goodbye 2020, Hello 2021
Assistant editor Michelle Lampariello
CONTENTS JANUARY/FEBRUARY 2021
28 Botulinum toxins inhibit gut motility
Recognizing Signs and Symptoms of ADHD Across the Lifespan Primary care providers are increasingly called upon for the evaluation and treatment of patients with ADHD.
7 Appropriate Treatment, Health Promotion for 1 Black Women With Hypertension The high rate of hypertension among Black women stems from biological, genetic, environmental, and social factors. 28 Clinical Challenge: Feeding Issues and Increased Fussiness in an Infant A case of suspected Clostridium botulinum in a 3-month-old infant.
Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com.
Dermatology Clinic ■ Red Lesions on Buttocks and Legs ■ Red, Swollen Finger With Fissure
Dermatologic Look-Alikes Hyperpigmented Plaque on Trunk
Legal Advisor Cannabis Use Leads to Dismissal of Nursing Student
33 Lesions appear after respiratory infection
37 Many skin lesions may look like dirty skin
41 Student sues for disability discrimination
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CLINICAL CHALLENGE ClinicalAdvisor.com/CaseStudy
New Mammogram-Guided Measures Improve Breast Cancer Prediction Rates
Brady Pregerson, MD Pain and Swelling in the Left Knee A 56-year-old woman presents to the emergency department with a 3-day history of gradually worsening pain and swelling in her left knee. She denies injury, fever, or other complaints. She has never experienced this type of pain before, and she states that she is fairly active. See the full case at: ClinicalAdvisor.com/CaseJan_Feb21
New mammogram-based risk measures that rely on brightness and texture improve breast cancer risk prediction beyond an established measure of mammographic density.
Hepatitis B Virus Screening Recommended for At-Risk Teens, Adults In an updated recommendation for hepatitis B virus (HBV) screening, the USPSTF concluded that screening asymptomatic adults and adolescents at increased risk for HBV infection has moderate net benefit.
Low Rates of Bacterial Co-Infections Seen in COVID-19 Patients Bacterial and fungal co-infections in patients with COVID-19 are rare and mainly prevalent in critically ill patients, according to a cohort study.
Salt Intake Tied to Kidney Failure Risk in Older Adults In patients older than 65 years, higher salt intake (> 8 g/d) is associated with a reduced risk for end-stage kidney disease among patients with chronic kidney disease.
THE WAITING ROOM
Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Jim Anderson, MPAS, PA-C, DFAAPA Examining the Regulation Process for NPs, PAs State-by-state differences in regulation processes cause nurse practitioners (NPs) and physician assistants (PAs) to have different practice experiences across the United States.
MY PRACTICE ClinicalAdvisor.com/MyPractice
Psoriatic Arthritis, RA Have Similar Effect on Hand Function Both psoriatic arthritis and rheumatoid arthritis led to greater age-related loss of grip strength, fine motor skills, and self-reported hand function in patients compared with controls in a recent study.
4 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 • www.ClinicalAdvisor.com
Jean M. Bernhardt, PhD, CNP; Melissa Chittle, MBS, PA-C; Julie Marden, MSN, NP-BC; Darlene Sawicki, MSN, NP-BC COVID-19 Pandemic Creates New Roles for APPs When the pandemic first reached Boston in March 2020, Massachusetts General Hospital responded by redeploying advanced practice providers, including NPs and PAs.
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FEATURE: CAROL KOTTWITZ, DNP, PMHNP, PMHCNS
Recognizing Signs and Symptoms of ADHD Across the Lifespan Untreated ADHD in adults is associated with increased rates of unemployment and poor performance in educational and work settings.
© BSIP / WITT-DEGUILLAUME / MEDICALIMAGES.COM
ADHD is linked to the neurotransmitters norepinephrine and dopamine.
ttention-deficit/hyperactivity disorder (ADHD) is among the most commonly diagnosed mental health disorders in childhood worldwide, with an estimated prevalence of 7.2%.1 At least two-thirds of those diagnosed with ADHD as children will continue to experience symptoms into adulthood.2 In childhood and adolescence, boys are more than twice as likely as girls to be diagnosed with ADHD.This suggests there is both under-recognition and undertreatment of ADHD in girls.3 Untreated ADHD can cause significant consequences, such as impairments in school and work performance as well as relationship difficulties, with subsequent mental health sequelae.3 Adults with ADHD experience negative outcomes as well. Untreated ADHD in adults is associated with increased rates of unemployment and poor performance in educational and work settings. Other significant personal and social costs include a highter rate of traffic accidents, accidental injuries of all types, and criminal convictions and incarcerations (42% among ADHD patients compared with 14% among controls).4 Barbaresi et al found that adults with ADHD experience a mortality rate that is almost 2 times higher than the rate in those without ADHD, with an increased probability of dying by suicide and car accidents.5 Furthermore, adults with ADHD are more likely than those without ADHD to have substance use disorder (SUD), comorbid depression, and anxiety disorders.5 With the increasing prevalence of ADHD, patients or family members often approach www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 5
DIAGNOSING ADHD ACROSS THE LIFESPAN
The key neurotransmitters involved in the pathogenesis of ADHD are dopamine (attention, motivation) and norepinephrine (alertness). primary care providers (PCPs) for evaluation and treatment of ADHD. In 2015, the Centers for Disease Control and Prevention found that nearly half of all children with ADHD were first diagnosed by a PCP,6 making early identification and treatment crucial. PCPs build long-term trusting relationships with families and are uniquely positioned to manage conditions such as ADHD using the principles of chronic care and medical home models. Diagnostic Criteria
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) identifies the essential diagnostic feature of ADHD as a “persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with function or development.”7 Patients must meet 6 of 9 criteria for inattention and/or at least 6 of 9 criteria for hyperactivity/impulsivity. In addition, symptoms of the disorder must occur in more than 1 setting.7 Outside informants, such as parents, teachers, daycare providers, coaches, and religious leaders, are key to diagnostic accuracy and evaluation of social or occupational functioning across settings. Comorbidities
Patients with ADHD commonly have comorbid conditions with symptoms that obscure ADHD symptoms and complicate diagnosis and treatment. In a national parent survey, Danielson et al found that nearly two-thirds of children with a current ADHD diagnosis had at least one co-occurring condition. Behavioral or conduct problems were most common (51.5%), followed by anxiety (32.7%), depression (16.8%), autism spectrum disorder (13.7%), and Tourette syndrome (1.2%). In adolescents, SUD also was reported (1.2%).8 Adults with ADHD also experience comorbidities.The National Comorbidity Survey reported that adults with ADHD are 2.7 times more likely to develop major depressive disorder, 7.5 times more likely to develop dysthymia, and more than 5 times more likely to develop a mood disorder. In addition, substance use or dependence was twice as likely to occur in adults with ADHD.9 Neuroanatomy/Neurobiology/Genetics
The brain regions and functions involved in ADHD are varied and fairly complex; a thorough explanation of the mechanisms is beyond the scope of this paper. Briefly, functional magnetic resonance imaging studies show that ADHD is correlated with dysfunction of frontal brain regions involving cognitive functions and sensorimotor processes.These are consistent with the classical model of ADHD as a disorder of deficient frontostriatal activation
and inefficient information processing in the dorsolateral prefrontal cortex. In addition, dysfunction in inter-relationships and inter-regulation among neural networks is the foundation for inconsistent symptom presentation of individuals with ADHD.10 The key neurotransmitters involved in the pathogenesis of ADHD are dopamine and norepinephrine.11 Dopamine is involved in attention, pleasure/reward, and motivation, whereas norepinephrine influences alertness. These neurotransmitters have important functional linkages to the anterior cingulate cortex, prefrontal cortex, and posterior parietal cortex. Dopamine enhances signal conduction and improves focus, on-task behavior, and on-task cognition. Norepinephrine acts on alpha2 receptors, which are found in the prefrontal cortex, by enhancing network connections.This allows the frontal cortex to increase inhibitions and enhance executive functioning. In ADHD, these neurotransmitters are either over- or underfunctioning, leading to decreased connectivity in the prefrontal cortex. These neurotransmitters are key to the psychopharmacological interventions that have been successful in treating ADHD.11 Family studies support a genetic heritability of 71% to 90%.A multitude of genetic variants affect dopamine and norepinephrine synthesis and metabolism in specific brain regions; these variants are influenced by environmental factors (ie, maternal smoking), which results in increased susceptibility to ADHD.12 Diagnosis, Evaluation, and Screening
In 2019, the American Academy of Pediatrics (AAP) produced evidence-based guidelines for the evaluation and treatment of ADHD.13 For evaluation and diagnosis, AAP recommends: • Any child or adolescent 4 to 18 years of age exhibiting academic or behavioral problems and symptoms of inattention, hyperactivity, or impulsivity should be evaluated for ADHD. • DSM-5 criteria must be met and an alternative etiology of symptoms must be ruled out for a diagnosis to be made. • Evaluation must include screening for comorbid conditions, such as emotional/behavioral conditions, developmental conditions, and physical conditions. Validated screening tools are recommended for assessment and ongoing monitoring of ADHD symptoms. To fully determine an ADHD diagnosis, multiple informants should administer these screening tools across environments (home, school, work).The tools evaluate DSM-5 subscales of inattention and hyperactivity-impulsivity, as well as some element of functional impairment in relationships with others, academic functioning, and behavioral functioning.
6 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 • www.ClinicalAdvisor.com
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DIAGNOSING ADHD ACROSS THE LIFESPAN
Studies have confirmed that typical ADHD behaviors in children negatively affect parenting styles and cause family stress. Although some behaviors are on a continuum and common in healthy children, in individuals with ADHD, these behaviors are noticeably more frequent than expected for their age. Screening tools are based on symptoms that have occurred over the previous 6 months. The tools recommended here are available in the public domain and often used in primary care settings. As with all screening tools and scales, professional judgment, including interviews and synthesis of data, is required to make a full diagnosis.
There are several general mental health screening tools available to assist in identifying comorbid conditions. Examples of these include the Weiss Symptom Record (WSR),17 Patient Health Questionnaire (PHQ-9),18 Generalized Anxiety Disorder Item-7 (GAD-7),19 Screen for Child Anxiety Related Disorder (SCARED),20 Alcohol Use Disorders Identification Test (AUDIT),21 and Suicide Assessment Five-Step Evaluation and Triage with the Columbia-Suicide Severity Rating Scale (SAFE-T with C-SSRS).22
Vanderbilt ADHD Parent Rating Scale (VADPRS) VADPRS is a time- and cost-efficient screening tool to identify ADHD symptoms and comorbidities.The scale includes the domains and symptoms of ADHD that are in alignment with DSM-5 criteria as well as an evaluation of academic performance and peer relationships. It specifically collects information about the emotional/behavioral conditions of oppositional defiant disorder (ODD), conduct disorder, anxiety, and depression.14 Moreover, the scale has a parent follow-up scale that is helpful and important for repeated measurement over time.A Spanish version of the parent scale also is available.
Swanson, Nolan and Pelham Teacher and Parent Rating Scale (SNAP-IV) This questionnaire has been revised to include items evaluating the inattention and hyperactivity/impulsivity domains, as well as symptoms of ODD.15 The SNAP-IV evaluates functioning as it relates to classroom behavior; it provides both parent and teacher rating scales and has shown reliable psychometric properties. A clinical interview is needed to determine onset, progression, and functional impairment.15 Adult ADHD Self Report Screening Scale for DSM 5(ASRS-5) The ASRS-5 is a short screening tool to determine the presence of ADHD symptoms in individuals older than 18 years.16 It is used in combination with the ASRS symptom checklist. A clinical interview to evaluate symptoms and review of differential diagnosis and comorbid conditions are recommended. When evaluating patients for ADHD, clinicians should evaluate for the presence of comorbidities and consider the patient’s overall mental health. The significant prevalence of depression, anxiety, SUD, and suicide among patients with ADHD requires repeated, ongoing assessment and measurement of these conditions (preferably monthly) to facilitate early recognition and treatment and to track progress.16
The 2019 AAP report recommends the following guidelines for treatment: • ADHD is a chronic condition, and as such, PCPs should follow the management principles of the chronic care and medical home models. • First-line treatment for preschool children should be parent training in behavior management and classroom behavioral interventions. • Elementary and middle school-aged children should receive US Food and Drug Administration (FDA)-approved medications, parent training, and classroom interventions, as well as an evaluation for an Individualized Education Program (IEP). • Adolescents should receive FDA-approved medications (with adolescent’s consent), as well as behavioral training and classroom interventions/instructional supports. • Medications for ADHD should be titrated to achieve maximal benefits with minimal side effects. • If the PCP is trained or experienced in the diagnosed comorbid disorders, they should initiate treatment; otherwise, they should refer the patient to an appropriate specialist.13 Behavioral and Psychological Interventions Studies have confirmed that typical ADHD behaviors in children negatively affect parenting styles and cause family stress. These behaviors affect school performance, work, and social aspects of life. Impulsivity and poor emotional regulation lead to difficulty following rules, aggression, tantrums, and general noncompliance.23 Though the evidence is mixed, a multimodal approach to treatment of ADHD continues to be recommended. In younger children, group-based behavioral interventions (based on social learning theory), positive parenting, and parent behavioral training are recommended before the initiation of FDA-approved medications.13
8 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 • www.ClinicalAdvisor.com
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DIAGNOSING ADHD ACROSS THE LIFESPAN
Because ADHD is a chronic disorder, PCPs must recognize its presentation across the lifespan and target treatment appropriately. Behavioral parent training involves 8 to 12 group or individual sessions focusing on learning styles, developing a reward and consequence system, understanding the antecedents to behaviors, and teaching children to better communicate their needs. Behavioral parent training results in less severe episodes of noncompliance around chores, mealtimes, homework, and peer interactions.23 Although behavioral parent training is associated with a reduction in ADHD symptoms, challenges with childcare and transportation can make it difficult for working patients to complete traditional face to face sessions.24 Online parent training has proven effective and provides additional options for parents.24 Adults with ADHD also benefit from a multimodal approach to therapy. The Canadian ADHD Resource Alliance Practice Guidelines indicate that it is critical to set individuals up for success in work environments.25 The guidelines recommend cognitive behavioral therapy and mindfulness training. With foundations based on the relationships among cognition, emotion, and behavior, cognitive behavioral therapy has shown efficacy when specific focus is placed on time management and organizational skills. Mindfulness training, including meditation, teaches skills of focusing on the present and inhibiting distractions and intrusive thoughts. Mindfulness also has been shown to improve mood and anxiety in children, adolescents, and adults with ADHD, with improvements maintained over time.25
an effective agent is found. Central nervous system stimulants are associated with appetite suppression, weight reduction, and growth delay in children and adolescents.28 Therefore, height and weight must be routinely monitored. Implementing drug holidays during weekends and school breaks as well as encouraging high-calorie snacks and timing dosing with or after meals/ snacks may be effective strategies to prevent weight loss.28 Although amphetamines are the first-choice medication for treatment of ADHD in adults,26 comorbidities and contraindications may alter initial treatment decisions. A history of heart attack, and electrical/structural abnormalities or arrhythmia, hypertension, stimulant use disorder, angle closure glaucoma, and pregnancy are contraindications for treatment with stimulants. Significant comorbidities such as psychosis, SUD, severe mood disorder, and bipolar disorders affect the overall risk assessment and are given priority in treatment decisions.25 Although it is common for some depressive symptoms or anxiety to occur secondary to ADHD, these conditions usually will improve with ADHD treatment and may not need additional pharmacologic strategies. When stimulants are contraindicated, it is common for providers to prescribe bupropion, a dopamine and norepinephrine reuptake inhibitor, to treat ADHD in adults.25 ADHD Across the Lifespan
Pharmacological Interventions When choosing a pharmacological treatment, clinicians are faced with multiple and conflicting treatment guidelines and algorithms. Providers are expected to synthesize and evaluate multiple factors: efficacy of the drug in reducing the target symptoms and improving global clinical functioning, effects on comorbidities, tolerability, formulation, long-acting vs shortacting agents, effects on weight and blood pressure, safety, and cost. A table of FDA-approved medications for ADHD can be found at https://www.empr.com/home/clinical-charts/ adhd-treatments/. Although the FDA has approved both stimulant and nonstimulant medications for the treatment of ADHD in children and adolescents, psychostimulants are recommended as first-line treatment.13 A 2018 meta-analysis supported the use of methylphenidate as a first-line treatment of ADHD in children and adolescents.26 In a 2020 meta-analysis, the authors reported that discontinuation of medications in children and adolescents was associated with a decrease in quality of life.27 It should be noted that not all stimulants work the same way, and several different medications may need to be tried before
Because ADHD is a chronic disorder that requires lifelong monitoring and treatment, PCPs must recognize its presentation across the lifespan and target treatment appropriately. Preschoolers Although DSM-5 diagnostic criteria apply to preschool-aged children, evaluation and treatment are challenging. First-line treatment for children 4 to 6 years of age is behavioral parent training and classroom interventions. If behavioral interventions do not promote significant improvement, methylphenidate may be prescribed for children with severe symptoms.13 Preschoolers with ADHD are less likely to be ready for school than children without ADHD, underscoring the need for early identification and treatment.29 Adolescents Special considerations associated with this age group are related to the neurodevelopmental delay and impulsivity that come with ADHD. With academic promotion to high school or college, there are increasing demands for time management, longer-range planning toward future goals, and organization
10 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 • www.ClinicalAdvisor.com
It is the role of the PCP to manage mild to moderate ADHD with co-occurring anxiety, depression, and substance use. of multiple tasks. Therefore, functional difficulties related to executive functioning that may not have been apparent earlier become apparent, leading to a previously missed diagnosis of ADHD. The complexity of learning to drive may pose serious challenges to patients with ADHD, who are at higher risk for traffic accidents. In addition, adolescents often begin to experience issues with substance abuse and diversion of stimulant medications.25 The following established clinic practices should be implemented in the management of adolescents and adults with ADHD. Initial stimulant prescriptions should be delayed until a diagnosis is established. If prescribed, patients must agree to implementation of a Schedule II patient agreement, regular appointments, not asking for prescriptions outside of regular appointments, periodic urine drug screens (UDS), and stated actions for positive UDS for illicit drugs. In addition, before prescribing a stimulant, the PCP should check the prescription monitoring program for any red flags.These precautions can improve care and manage provider risk related to long-term prescriptions for CNS stimulants in adolescents and adults.30 The use of nonstimulants or extended-release stimulants is preferred when substance use or misuse is a concern.16 Adults Adults with ADHD present differently than their younger counterparts and, therefore, may go undiagnosed.A recent review of the literature supports the importance of emotional dysregulation as a significant element of adult ADHD that is not reflected in the DSM-5 criteria.31 To improve identification of ADHD, some clinicians may wish to include neuropsychological tests; however, because of the inconsistent cognitive deficits of ADHD, no distinct psychometric test or profile for ADHD exists.32 The PCP must review the screening items carefully with the patient during a diagnostic interview to clarify and expand on selected answers. Further inquiry related to impairment in functioning, such as time management difficulties, erratic work/academic performance, anger control issues, family or marital problems, difficulty managing finances, frequent accidents related to recklessness or inattention, or frequent loss of cell phones or keys, may provide important information to clarify the overall diagnostic picture. A thorough substance use history, including stimulant, energy drink, caffeine, and cigarette use, may present the possibility of the individual treating their symptoms to enhance attention or to manage psychiatric comorbidities. Implementation of substance use monitoring strategies is
indicated if substance use or medication diversion/misuse is suspected. An adult treatment algorithm is being developed by the American Psychiatric Association and can be found at www.psychopharm.mobi/algo_live/. Older Adults The lack of age-appropriate diagnostic criteria and the complexity of differential diagnosis (mild cognitive impairment, increased polypharmacy, sleep disturbances, chronic pain, and physical conditions) make an ADHD diagnosis difficult in older patients. In a systematic review,Torgersen et al found that the prevalence of ADHD symptoms declines to 1% to 2.8% in adults older than 50 years.33 However, there is reason to believe that ADHD symptoms persist into late adulthood in a large number of patients. Older adults are likely to have comorbid mental health disorders that require treatment, including depression (36%-54%) and anxiety (26%-42%), as well as mild cognitive impairment.33 Fischer et al found that approximately 50% of memory clinics in the United States reported seeing ADHD patients; 20% of clinics reported screening regularly for ADHD.34 However, they concluded that ADHD in older adults may not have been considered to be a premorbid condition affecting cognitive functioning.34 In general, older adults have a reduced capacity to metabolize drugs and have an increased sensitivity to medication-associated side effects. In addition, there are increased concerns about polypharmacy and drug-drug interactions in this population. Despite a lack of controlled studies, a “start low, go slow” titration approach is recommended when using central nervous system stimulants. Patients reported improvements in variables of attention, such as being more organized, more focused, and being able to understand written text better. In addition to stimulants as first-line treatment, psychological treatments using metacognitive therapy and cognitive behavioral therapy have shown promise.34 When to Refer
It is the role of the PCP to manage mild to moderate ADHD with co-occurring anxiety and depression. When medical or psychiatric comorbidities contribute to the complexity of treatment and uncertainty of diagnosis, it may be time to refer the patient to psychiatric clinicians or therapists. Referral also is recommended for patients who fail to respond to algorithm-recommended treatments, as well as for those in whom drug-seeking behavior is suspected or there is a patient/ family reluctance to accept the diagnosis and/or treatment.25 ■ Continues on page 16
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 11
DIAGNOSING ADHD ACROSS THE LIFESPAN
Carol Kottwitz, DNP, PMHNP, PMHCNS, is a psychiatric nurse practitioner and owner of CK Therapeutics LLC, and assistant professor in the School of Nursing and Human Physiology at Gonzaga University in Spokane,Washington.
comorbid disorders: clinical implications of a dimensional approach. BMC Psychiatr. 2017;17(1):302. 17. Weiss MD. Diagnosis of childhood-onset condition in adult psychiatry. Prim Psychiatry. 2010;17(8):21-28. 18. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depres-
sion severity measure. J Gen Intern Med. 2001;16(9):606-613.
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27. Tsujii N, Okada T, Usami M, et al. Effect of continuing and discontinuing
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Replication. Am J Psychiatry. 2006;163(4):716-723.
J Clin Psychiatry. 2020;81(3):19r13015.
10. Cortese S, Kelly C, Chabernaud C, et al. Toward systems neuroscience of
28. Waxonsky JG, Pelham WE 3rd, Campa A, et al. A randomized controlled
ADHD: a meta-analysis of 55 fMRI studies. Am J Psychiatry. 2012;169(10):1038-1055.
trial of interventions for growth suppression in children with attention-deficit/
11. Stahl SM. Attention deficit hyperactivity disorder and its treatment. In:
hyperactivity disorder treated with central nervous system stimulants.
Stahl SM, ed. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and
J Am Acad Child Adolesc Psychiatry. 2020;59(12):1330-1341.
Practical Applications. 4th ed. Cambridge University Press; 2016:471-502.
29. Perrin HT, Heller NA, Loe IM. School readiness in preschoolers with symptoms
12. Pliszka SR. Attention-deficit hyperactivity disorder across the lifespan.
of attention-deficit/hyperactivity disorder. Pediatrics. 2019;144(2):e20190038.
30. Downey E, Pan W, Harrison J, Posa-Juncal E, Tanabe P. Implementation of a
13. Wolraich ML, Hagan JF, Allan C, et al. Clinical practice guideline for the
Schedule II patient agreement for opioids and stimulants in an adult primary
diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder
care practice. J Family Med Prim Care. 2017;6(1):52-57.
in children and adolescents. Pediatrics. 2019;144(4):e20192528.
31. Reimherr F, Roesler M, Marchant BK, et al. Types of adult attention-deficit/
14. Becker SP, Langberg JM, Vaughn AJ, Epstein JN. Clinical utility of the
hyperactivity disorder: a replication analysis. J Clin Psychiatry. 2020;81(2):19m13077.
Vanderbilt ADHD Diagnostic Parent Rating Scale comorbidity rating scales.
32. Lange KW, Hauser J, Lange KM, et al. Utility of cognitive neuropsychologi-
J Dev Behav Pediatr. 2012;33(3):221-228.
cal assessment in attention-deficit/hyperactivity disorder. Atten Defic Hyperact
15. Costa DS, de Paula JJ, Malloy-Diniz LF, Romano-Silva MA, Miranda DM.
Parent SNAP-IV rating of attention-deficit/hyperactivity disorder: accuracy in
33. Torgersen T, Gjervan B, Lensing MB, Rasmussen K. Optimal management of
a clinical sample of ADHD, validity, and reliability in a Brazilian sample.
ADHD in older adults. Neuropsychiatr Dis Treat. 2016;12:79-87.
J Pediatr. 2019;95(6):736-743.
34. Fischer BL, Gunter-Hunt G, Steinhafel CH, Howell T. The identification and
16. Katzman MA, Bilkey TS, Chokka PR, Fallu A, Klassen LJ. Adult ADHD and
assessment of late-life ADHD in memory clinics. J Atten Disord. 2012;16(4):333-338.
16 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 • www.ClinicalAdvisor.com
FEATURE: THERESA CAPRIOTTI, DO, MSN, CRNP, RN; ALAINA ROMAN, BSN; MOLLIANA SCHWARZ, BSN
Appropriate Treatment, Health Promotion for Black Women With HTN Black women are more likely than White women to have high blood pressure and die earlier from complications related to hypertension.
© MICHELE GRAHAM
ypertension is a common health condition that affects 1 in 3 adults (32.6%) in the US.1 However, hypertension is not evenly distributed in the US population; the incidence of hypertension is disproportionately higher among Black Americans than White Americans, affecting 42% of Black men and 44% of Black women.2 The prevalence of hypertension and cardiovascular disease among Black women is particularly high.3 Compared with White women, Black women are 60% more likely to have high blood pressure.4 Black women also are more likely to be diagnosed with hypertension at a younger age, have higher blood pressure readings, and die earlier from complications related to hypertension compared with White women.5,6 In 2017, Black men and women were 20% more likely to die from heart disease than non-Hispanic White patients.4 Despite the availability of effective medications and tailored therapies for Black patients, disease management is less effective among Black patients than White patients, yielding higher mortality rates.1-7 In a study by Jamerson et al, Black women were less likely than White women to achieve blood pressure control. After 5 years, 59% of Black women and 65% of White women had a blood pressure level of less than 140/90 mm Hg.7 Risk Factors in Black Women
The high rate of hypertension among Black women stems from biological, genetic, environmental, and social factors. Biological factors associated www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 17
The high rate of hypertension among Black women stems from biological, genetic, social, and environmental factors. with higher risk of hypertension include aortic stiffness, vascular remodeling, and endothelial dysfunction.8 One biological factor of note involves response to stress. Hypertension in Black women arises, in part, from augmented adrenergic vascular reactivity and reduced vasodilator responses to stress. The body activates its hypertensive stress response more often and keeps the vessels constricted for longer periods of time in Black women than in non-Black women.8 Patients may have a genetic predisposition to this biological response. Several genes implicated in activation of the reninangiotensin-aldosterone system (RAAS) have been studied in Black populations and have revealed a surprising number of novel variants and pathways possibly implicated in the pathogenesis of hypertension. Among them, a variant of the armadillo repeat containing 5 (ARMC5) gene appears to be a rare inherited cause of primary aldosteronism and, consequently, low-renin hypertension in Black individuals.9 Environmental factors that contribute to hypertension include limited physical activity, smoking, alcohol use, and institutional racism.4 Other causes of hypertension among Black men and women include diet, specifically a Southern diet, defined in the REGARDS study as a high intake of fried foods, organ meats, processed meats, egg and egg dishes, added fats, high-fat dairy foods, sugar-sweetened beverages, and bread.10,11 The Southern diet has been associated with an increased risk of incident stroke, coronary heart disease, end-stage renal disease, chronic kidney disease, sepsis, fatal cancer, and cognitive decline.12-16 The Southern diet as well as a high dietary ratio of sodium to potassium have been shown to be mediating factors for the difference in stroke risk between Black and White individuals. Less adherence to the Dietary Approaches to Stop Hypertension (DASH) diet (vegetables, fruits, and lowfat dairy products) was a significant mediating factor among Black and White women.11 In 2018, Howard et al found that Black women have a higher mean BMI and larger waist circumference than White women, and both waist circumference and BMI are significantly associated with incident hypertension.10 Among Black women, BMI was the second-largest mediating factor for hypertension and larger waist circumference was the third-largest mediating factor.The prevalence of obesity in Black women has doubled over the last 2 decades.17 The higher incidence of hypertension among Black women has been linked to social factors such as low income (≤ $35,000) and education level (high school degree or less).10 A lower socioeconomic status may be associated with living
in a high-stress or segregated environment with higher crime rates and more marital divisions, which has been linked to increased blood pressure among Black individuals.8,18 Still et al found that Black women often take on the role of caregiver for older family members and children, as well as take care of the home, which increases their susceptibility to psychological stressors.18 A number of studies have focused on the societal factor of minority stress and its association with health outcomes. Racial discrimination and stressors related to minority status have been associated with hypertension and increased cardiometabolic health risks in Black women.19-22 Prevention: Health and Lifestyle Modifications
Cardiovascular health promotion strategies are key to preventing hypertension in Black women. The primary approach of any antihypertensive treatment plan is education about lifestyle modifications. These modifications include managing weight, exercising, limiting alcohol intake, and adopting a DASH diet that restricts sodium intake, enhances potassium intake, and increases intake of fruits, vegetables, and low-fat dairy products.23 However, adherence to lifestyle modification and antihypertensive treatment is problematic within this population, according to a number of published studies.24-26 Black women who were prescribed a low-salt diet were less successful than Black men in adhering to the diet, and it has been suggested that factors such as poor social support and lack of education influence the lack of adherence.26,27 Healthcare providers need to educate themselves about cultural aspects of the Black community to help enact preventive health strategies. Social factors can act as barriers to health promotion and medication adherence. Enhanced patient education about cardiovascular health and continual patient support to promote adherence to treatment are healthcare strategies needed within the Black community, as nonadherence to medication is a major problem in the Black community.28 Lack of health insurance, low income, and an inability to pay for medications prevent some patients from consistently adhering to their treatment regimens.29 Lack of access to healthy food, fruits, and vegetables in Black communities diminishes a patient’s ability to adhere to the DASH diet.30 It is important for healthcare providers to be aware of the phenomenon of minority stress and how it negatively affects cardiovascular health in Black individuals.20,22 Clinicians should be cautious not to perpetuate the factors that cause minority
18 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 • www.ClinicalAdvisor.com
Continues on page 24
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INDICATION AND USAGE TWIRLA is indicated as a method of contraception for use in women of reproductive potential with a BMI <30 kg/m2 for whom a combined hormonal contraceptive is appropriate. Limitations of Use: Consider the reduced effectiveness of TWIRLA in women with a BMI ≥25 to <30 kg/m2 before prescribing TWIRLA. TWIRLA is contraindicated in women with a BMI ≥30 kg/m2.
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IMPORTANT SAFETY INFORMATION WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS and CONTRAINDICATED IN WOMEN WITH A BMI ≥30 kg/m2 Cigarette Smoking and Serious Cardiovascular Events Cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive (CHC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, CHCs, including TWIRLA, are contraindicated in women who are over 35 years of age and smoke. Contraindicated in Women with a BMI ≥30 kg/m2 TWIRLA is contraindicated in women with a BMI ≥30 kg/m2. Compared to women with a lower BMI, women with a BMI ≥30 kg/m2 had reduced effectiveness and may have a higher risk for venous thromboembolic events (VTEs). Please see additional Important Safety Information on next page and Brief Summary of full Prescribing Information.
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A DIVERSE STUDY POPULATION
IMPORTANT SAFETY INFORMATION (con’t)
CONTRAINDICATIONS TWIRLA is contraindicated and should not be used in women with a high risk of arterial or venous thrombotic disease, including women with a BMI ≥30 kg/m2; headaches with focal neurological symptoms, migraine with aura, women over 35 years of age with any migraine headache; liver tumors, acute viral hepatitis, or severe (decompensated) cirrhosis, or liver disease; undiagnosed abnormal uterine bleeding; pregnancy; current or history of breast cancer or other estrogen- or progestin-sensitive cancer; hypersensitivity to any components of TWIRLA; and use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir. WARNINGS AND PRECAUTIONS • Thromboembolic Disorders and Other Vascular Conditions – Women are at increased risk for a VTE when using TWIRLA. ° Stop TWIRLA if an arterial or VTE occurs. ° Stop TWIRLA if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. ° Discontinue TWIRLA during prolonged immobilization and, if feasible, stop TWIRLA at least 4 weeks before and through 2 weeks after major surgery. ° Start TWIRLA no earlier than 4 weeks after delivery in women who are not breast-feeding. ° Before starting TWIRLA, evaluate any past medical history or family history of thromboembolism or thromboembolic disorders and consider whether history suggests inherited or acquired hypercoagulopathy.
Arterial Events – CHCs increase the risk of cardiovascular events and cerebrovascular events, such as myocardial infarction and stroke, particularly among older women (>35 years of age), smokers, and women with hypertension, dyslipidemia, diabetes, or obesity. • Liver Disease – Discontinue TWIRLA if jaundice develops. • Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment – Discontinue TWIRLA prior to starting therapy with the hepatitis C combination drug regimen ombitasvir/paritaprevir/ ritonavir, with or without dasabuvir. TWIRLA can be restarted approximately 2 weeks following completion of treatment with that combination drug regimen. • Hypertension – Monitor blood pressure at routine visits and stop TWIRLA if blood pressure rises significantly. An increase in blood pressure has been reported in women using CHCs, and this increase is more likely in older women with extended duration of use. • Gallbladder Disease – Studies suggest CHCs increase the risk of developing gallbladder disease and may also worsen existing gallbladder disease. • Adverse Carbohydrate and Lipid Metabolic Effects – ° TWIRLA may decrease glucose tolerance. Carefully monitor prediabetic and diabetic women who are using TWIRLA. ° Consider alternative contraception for women with uncontrolled dyslipidemia. TWIRLA may cause adverse lipid changes. Women with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using TWIRLA, which may increase the risk of pancreatitis.
Please see additional Important Safety Information on next page and Brief Summary of full Prescribing Information.
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A TRIAL THAT WAS INTENTIONALLY
Representative and inclusive The Twirla pivotal study – the SECURE Trial – was intentionally designed to include broad enrollment criteria and a patient population of women likely to use hormonal contraceptives.3 The SECURE Trial design and implementation reflected the recent FDA draft guidance for hormonal contraceptive studies and was the first CHC study to include all of the criteria listed below.4
SECURE Trial and FDA Draft Guidance
The SECURE Trial 3
No enrollment restrictions on weight or BMI Included women >35 years old to assess safety Anticipated regular sexual activity (at least once per month) Completed eDiary and captured backup contraception and sexual activity
To learn more about the SECURE Trial, visit
Regular pregnancy testing at clinic and home
Consider the reduced effectiveness of Twirla in women with a BMI ≥25 to <30 kg/m2 before prescribing. Twirla is contraindicated in women with a BMI ≥30 kg/m2.
SECURE=Study to Evaluate Contraceptive Use, Reliability, and Effectiveness.
IMPORTANT SAFETY INFORMATION (con’t) WARNINGS AND PRECAUTIONS (con’t) • Headache – If a woman using TWIRLA develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue TWIRLA as indicated. Consider discontinuation of TWIRLA if there is any increased frequency or severity of migraines during CHC use (which may be prodromal of a cerebrovascular event). • Bleeding Irregularities and Amenorrhea – Women using TWIRLA may experience unscheduled bleeding, especially during the first 3 months of use, or experience absence of scheduled bleeding. If bleeding persists or occurs after previously regular cycles on TWIRLA, or if scheduled bleeding does not occur, evaluate for causes such as pregnancy or, in the case of unscheduled bleeding, malignancy. • Other Warnings and Precautions – Other warnings and precautions include depression, cervical cancer, increased serum concentrations of binding globulins, hereditary angioedema, and chloasma. ADVERSE REACTIONS The following serious adverse reactions occurred in <1% of women who received TWIRLA: cholelithiasis, cholecystitis, major depression, suicidal ideation, appendicitis, ectopic pregnancy, pneumonia, and
gastroenteritis. A total of 4 VTEs in TWIRLA-treated patients were identified in the phase 3 clinical trial. The most common adverse reactions (≥2%) in clinical trials for TWIRLA are application site disorders, nausea, headache, dysmenorrhea, and increased weight. Patients should be counseled that TWIRLA does not protect against HIV infection (AIDS) and other sexually transmitted infections (STIs). DRUG INTERACTIONS Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of TWIRLA or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with TWIRLA. This is not a comprehensive list of safety information related to TWIRLA. Please see full Prescribing Information, including BOXED WARNING. To report SUSPECTED ADVERSE REACTIONS, call 1-855-888-2467 or report via the FDA MedWatch Program at www.fda.gov/medwatch or 1-800-FDA-1088.
References: 1. Xulane [prescribing information]. Morgantown, WV: Mylan Pharmaceuticals; 2020. 2. Humes KR, Jones NA, Ramirez RR. Overview of Race and Hispanic Origin: 2010. Washington, DC: US Census Bureau; 2011. 3. Data on file, Clinical Study Report 023; Agile Therapeutics. 4. US Food and Drug Administration. Guidance for Industry: Establishing Effectiveness and Safety of Hormonal Drug Products Intended to Prevent Pregnancy. Silver Spring, MD: US Food and Drug Administration, US Department of Health and Human Services; 2019.
TWIRLA is a registered trademark of Agile Therapeutics, Inc. © 2020 All Rights Reserved. PM-US-TW-0046 08/20
1/8/21 4:23 PM
TWIRLA® (levonorgestrel and ethinyl estradiol) transdermal system BRIEF SUMMARY (For full Prescribing Information, see package insert) Women should be informed that this product does not protect against HIV infection (the virus that causes AIDS) or other sexually transmitted diseases. WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS and CONTRAINDICATED IN WOMEN WITH A BMI ≥30 kg/m2 See full prescribing information for complete boxed warning • TWIRLA is contraindicated in women over 35 years old who smoke. Cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive (CHC) use. • TWIRLA is contraindicated in women with a BMI ≥30 kg/m2. Compared to women with a lower BMI, women with a BMI ≥30 kg/m2 had reduced effectiveness and may have a higher risk for venous thromboembolic events. INDICATION AND USAGE
TWIRLA is a combination of levonorgestrel, a progestin, and ethinyl estradiol, an estrogen, indicated as a method of contraception for use in women of reproductive potential with a BMI <30 kg/m2 for whom a combined hormonal contraceptive is appropriate.
Limitations of Use
Consider TWIRLA’s reduced effectiveness in women with a BMI ≥25 to <30 kg/m2 before prescribing.
CONTRAINDICATIONS TWIRLA should not be used in women with any of the following conditions: • At high risk for arterial or venous thromboembolic events. • Headaches with focal neurological symptoms, migraine headaches with aura • Women over 35 years of age with any migraine headache [see Warnings and Precautions] • BMI ≥30 kg/m2 • Liver tumors (benign or malignant), acute viral hepatitis, or severe (decompensated) cirrhosis, or liver disease • Undiagnosed abnormal uterine bleeding • Pregnancy, given there is no reason to use CHCs during pregnancy • Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past • Hypersensitivity to any components of TWIRLA. Observed reactions include itching and irritation at the TDS application site • Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for alanine aminotransferase (ALT) elevations
WARNINGS AND PRECAUTIONS Thromboembolic Disorders and Other Vascular Conditions
Stop TWIRLA if an arterial or venous thromboembolic event occurs. Stop TWIRLA if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. Discontinue TWIRLA during prolonged immobilization and resume treatment based on clinical judgement. If feasible, stop TWIRLA at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start TWIRLA no earlier than four weeks after delivery in women who are not breast-feeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week. Before starting TWIRLA, evaluate any past medical history or family history of thromboembolism or thromboembolic disorders. Consider whether the history suggests an inherited or acquired hypercoagulopathy.
Elevated Liver Enzymes Discontinue TWIRLA if jaundice develops. Acute liver test abnormalities may necessitate the discontinuation of CHC use until the liver tests return to normal and CHC causation has been excluded. Liver Tumors CHCs increase the risk of hepatic adenomas. Rupture of hepatic adenomas may cause death from abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) CHC users.
Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment
In clinical trials with Hepatitis C combination drug regimens containing ombitasvir/paritaprevir/ ritonavir, with or without dasabuvir, ALT elevations >5 times the upper limit of normal (ULN), including some cases >20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as CHCs. Discontinue TWIRLA prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. TWIRLA can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.
For all women, including those with well-controlled hypertension, monitor blood pressure at routine visits and stop TWIRLA if blood pressure rises significantly. An increase in blood pressure has been reported in women using CHCs, and this increase is more likely in older women with extended duration of use.
The risk for cardiovascular disease and prevalence of risk factors for cardiovascular disease increase with age. Consider the presence of underlying risk factors that may increase the risk of cardiovascular disease or VTE, particularly before initiating a CHC for women over 35 years, such as; hypertension, diabetes, dyslipidemia, obesity.
Studies suggest an increased risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease. A past history of CHC-related cholestasis predicts an increased risk with subsequent CHC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis.
Adverse Carbohydrate and Lipid Metabolic Effects
Hyperglycemia TWIRLA may decrease glucose tolerance. Carefully monitor prediabetic and diabetic women who are using TWIRLA. Dyslipidemia Consider alternative contraception for women with uncontrolled dyslipidemia. TWIRLA may cause adverse lipid changes. Women with hypertriglyceridemia, or a family history thereof, may have an increase in serum triglyceride concentrations when using TWIRLA, which may increase the risk of pancreatitis.
If a woman using TWIRLA develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue TWIRLA if indicated. Consider discontinuation of TWIRLA if there is any increased frequency or severity of migraines during use (which may be prodromal of a cerebrovascular event).
Bleeding Irregularities and Amenorrhea
Unscheduled and Scheduled Bleeding and Spotting Women using TWIRLA may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first three months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If bleeding persists or occurs after previously regular cycles on TWIRLA, evaluate for causes such as pregnancy or malignancy. Amenorrhea and Oligomenorrhea Women who use TWIRLA may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant. If scheduled bleeding does not occur, consider the possibility of pregnancy. If the woman has not adhered to the prescribed dosing schedule, consider the possibility of pregnancy at the time of the first missed period and perform appropriate diagnostic measures. If the woman has adhered to the prescribed dosing schedule and misses two consecutive periods, rule out pregnancy. After discontinuation of TWIRLA, amenorrhea or oligomenorrhea may occur, especially if these conditions were pre-existent.
Carefully observe women with a history of depression and discontinue TWIRLA if depression recurs to a serious degree. Data on the association of CHCs with onset of depression or exacerbation of existing depression are limited.
Some studies suggest that CHCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. There is controversy about the extent to which these findings are due to differences in sexual behavior and other factors.
Effect on Binding Globulins
The estrogen component of TWIRLA may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin.
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.
Chloasma may occur with TWIRLA use, especially in women with a history of chloasma gravidarum. Advise women with a history of chloasma to avoid exposure to the sun or ultraviolet radiation while using TWIRLA.
ADVERSE REACTIONS CLINICAL TRIAL EXPERIENCE
The safety of TWIRLA was evaluated in a 12-month, multicenter, open-label, single-arm clinical trial conducted in the United States. Women applied TWIRLA (120 mcg LNG/30 mcg EE) for 13 28-day treatment cycles. One treatment cycle is defined as three consecutive weeks that one TWIRLA TDS is applied for seven-day wear followed by one week that TWIRLA is not applied. The most common adverse reactions that occurred in ≥2% of the 2,031 women that used TWIRLA were: application site disorder (6.2%), nausea (4.1%), headache (3.6%), dysmenorrhea (2.3%) and weight increased (2.0%). Venous Thromboembolic Events (VTEs) A total of four VTEs (including pulmonary embolism and deep vein thrombosis) in TWIRLA-treated patients were identified in the clinical trial. Of these, all were in women with a BMI ≥30 kg/m2. Other Serious Adverse Reactions The following serious adverse reactions occurred in <1% of women who received TWIRLA: cholelithiasis, cholecystitis, major depression, suicidal ideation, appendicitis, ectopic pregnancy, pneumonia, and gastroenteritis.
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DRUG INTERACTIONS Effects of Other Drugs on Combined Hormonal Contraceptives
CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase systemic exposure of the estrogen and/or progestin component of CHCs. Concomitant use of CHCs with metabolic enzyme inducers may decrease the plasma concentrations of the estrogen and/or progestin component of CHCs, potentially diminishing effectiveness. Counsel women to use a backup or alternative method of contraception when enzyme inducers are used with TWIRLA. Significant increases and/or decreases in systemic exposure of the estrogen and or progestin have been noted when CHCs are co-administered with some HIV protease inhibitors, HCV protease inhibitors, and some non-nucleoside reverse transcriptase inhibitors.
Effects of Combined Hormonal Contraceptives on Other Drugs
Concomitant use of CHCs with lamotrigine, acetaminophen, morphine, salicylic acid, and temazepam may decrease systemic exposure of these drugs. Concomitant use of CHCs with thyroid hormone replacement therapy or corticosteroid replacement therapy may increase systemic exposure of thyroid-binding and cortisol-binding globulin. Concomitant of other drugs (e.g., cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole), may increase systemic exposure of these drugs.
USE IN SPECIFIC POPULATIONS Pregnancy
Discontinue TWIRLA if pregnancy occurs. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects following exposure to CHCs before conception or during early pregnancy.
Contraceptive hormones and/or metabolites are present in human milk. CHCs can reduce milk production in breastfeeding women. This reduction can occur at any time but is less likely to occur once breastfeeding is well established. Advise the nursing woman to use another method of contraception until she discontinues breastfeeding. No studies have been conducted on the use of TWIRLA in breastfeeding women.
There have been no reports of serious adverse outcomes from overdose of CHCs, including ingestion by children. Overdose may cause uterine bleeding in women and nausea. In case of suspected overdose, the TWIRLA TDS should be removed and symptomatic treatment given.
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information and Instructions for Use). • Advise the woman that cigarette smoking increases the risk of serious cardiovascular events from CHC use. Women who are over 35 years old and smoke should not use TWIRLA. • Advise the woman that an increased risk of VTE compared to non-users of CHCs is greatest after initially starting a CHC or restarting (following a 4-week or greater interruption in intake) the same or a different CHC. • TWIRLA is not to be used during pregnancy. Instruct the woman to stop TWIRLA if pregnancy is confirmed during treatment. • Advise the woman that TWIRLA does not protect against HIV infection and other sexually transmitted infections. • Apply one TDS weekly for 3 weeks followed by one TDS free week. Instruct women what to do in the event TDS change is missed. • Postpartum women who have not yet had a period when they start TWIRLA need to use an additional method of contraception until they have used the TDS for one week. • A back-up or alternative method of contraception is needed when enzyme inducers are used with TWIRLA. • TWIRLA may reduce breast milk production. This is less likely to occur if breast-feeding is well established. When possible, nursing women should use other methods of contraception until they have discontinued breast-feeding. • Amenorrhea may occur. Advise the woman to contact a health care provider in the event of amenorrhea in two or more consecutive cycles or in case of symptoms of pregnancy such as morning sickness or unusual breast tenderness. • Resumption of fertility after discontinuing TWIRLA is expected. • Advise women to avoid frequent or prolonged water exposure and to avoid use of large amounts of body lotions or oils. Advise women to check the TDS for partial or complete TDS detachment daily and after frequent or prolonged water exposure.
Manufactured by: Corium International, Inc. 4558 50th Street, SE Grand Rapids, MI 49512 Manufactured for: Agile Therapeutics, Inc. 101 Poor Farm Rd. Princeton, NJ 08540
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Healthcare providers need to educate themselves about cultural aspects of the Black community to help enact preventive health strategies. stress. Unconscious and implicit bias among clinicians contributes to the discrimination experienced by persons of color and incites distrust in the healthcare system. Self-examination and dialogue are needed among healthcare providers to improve cultural sensitivity and recognition of factors in the healthcare system that may be perpetuating minority stress.31-33 It is imperative for healthcare providers to make efforts to reach Black patients in their communities to teach and support lifestyle modifications.28 In 2019, Brewer et al used a community-based approach to cardiovascular health promotion for Black patients.34 In the study, community churches participated in the design and development of a culturally relevant cardiovascular health and wellness digital application. The team created an educational mobile app that used evidence-based, simple health information and social networking to reach Black people in the community. They engaged the community in all phases of the process, which allowed them to better understand the population’s mobile technology preferences and experiences.This model resulted in a culturally tailored cardiovascular health and wellness app prototype (FAITH! App) developed with input from the community.34 In 2019, Dutta et al developed a culture-centered patient education campaign about cardiovascular disease prevention designed by community members in 2 counties in Indiana.35 The campaign was carried out through radio and television advertisements, face-to-face peer leaders, and local
networks such as Black churches, health fairs, and barbershops. Community-wide presentations were held during health fairs, postcard mailings were sent, and peer leaders handed out patient education materials. Their campaign successfully reached more than 300,000 residents.35 Among rural Black communities, Abbott et al developed a cardiovascular health promotion campaign titled “With Every Heartbeat Is Life,” designed to reach Black congregants of 12 rural churches in northern Florida.36 Nurses delivered weekly cardiovascular health education seminars to groups in community church settings over 6 weeks.The 90-minute intervention sessions included a lecture, discussion, and multimedia visual aids, such as pictures, videos, and handouts.There also were interactive activities such as role playing, problem solving scenarios, and interpreting nutrition information on food labels. The campaign had a positive influence on the intentions, attitudes, norms, and self-efficacy of rural Black patients to increase produce consumption and reduce saturated fat intake.The intervention also enhanced participants’ attitudes and self-efficacy about exercise.36 Such innovative health promotion strategies are needed to enhance lifestyle modifications and patient education about cardiovascular risk factors within the Black community. Nurseled community health education programs, peer-led health campaigns within the community, and development of programs using digital technology are examples of effective strategies. Medication for Black Patients
POLL POSITION Which of the following does not contribute to risk for hypertension among Black women? 9.41% ■ Genetic factors
■ Institutional racism 40.00%
■ Poor sleep quality ■ Lack of access to fresh food
For more polls, visit ClinicalAdvisor.com/Polls.
When patients cannot obtain blood pressure control with lifestyle modifications alone, antihypertensive agents should be prescribed. Generally, a single agent is prescribed initially, but combination antihypertensive drug treatment is commonly needed. Using drugs from different classes in combination has a significantly greater effect in lowering blood pressure than doubling the dose of a single drug.23 In a review of best medications for Black patients, Egan et al recommended a dihydropyridine calcium channel blocker or a thiazide-like diuretic (such as chlorthalidone) as initial drug treatment.37 If monotherapy is insufficient, a dihydropyridine calcium channel blocker combined with either an angiotensinconverting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) is recommended.37 For Black patients,ACE inhibitors or ARBs are not recommended as monotherapy but should be combined with calcium channel blockers or thiazide diuretics to obtain optimal control of hypertension.38 However, a high number of Black women
24 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 • www.ClinicalAdvisor.com
Black patients are at greater risk for treatmentresistant hypertension than White patients; thus, addition of another agent often may be required. have been prone to the side effect of cough when treated with an ACE inhibitor.Therefore, agents other than ACE inhibitors may be preferable for Black women.39 Black patients are at greater risk for treatment-resistant hypertension than White patients; thus, addition of another agent often may be required. In such patients, a potassium-sparing diuretic (in particular, a mineralocorticoid receptor antagonist such as spironolactone or eplerenone) is recommended.37 However, patients who have moderate to advanced chronic kidney disease or a baseline serum potassium level greater than 4.6 mEq/L have an increased risk of hyperkalemia with these agents. Serum potassium levels should be monitored in all patients treated with potassium-sparing diuretics or mineralocorticoid receptor antagonists.37
4. US Department of Health and Human Services Office of Minority Health. Heart disease and African Americans. Accessed December 10, 2020. OMH website. https://www.minorityhealth.hhs.gov/omh/browse.aspx?lvl=4&lvlid=19 5. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-2572. 6. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics — 2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2-e220. 7. Jamerson KA. The disproportionate impact of hypertensive cardiovascular disease in African Americans: getting to the heart of the issue. J Clin Hypertens. 2004;6(4 Suppl 1):4-10. 8. Musemwa N, Gadegbeku CA. Hypertension in African Americans. Curr Cardiol Rep. 2017;19(12):129. 9. Zilbermint M, Hannah-Shmouni F, Stratakis CA. Genetics of hypertension
in African Americans and others of African descent. Int J Mol Sci.
Black women are disproportionately affected by hypertension. The high rate of hypertension in Black women stems from biological, genetic, and social factors that are more common within the Black population. Cardiovascular health promotion strategies that include education and social support are key for prevention of hypertension in Black women. Healthcare providers need to reach out to the community to support Black patients. Healthcare providers should understand the unique risk factor of minority stress and deliver culturally competent care. Innovative health promotion strategies are needed to enhance lifestyle modification, patient education, and adherence to antihypertensive drug therapy within this population. ■
2019;20(5):1081. 10. Howard G, Cushman M, Moy CS, et al. Association of clinical and social factors with excess hypertension risk in Black compared with White US adults. JAMA. 2018;320(13):1338-1348. 11. Judd SE, Gutiérrez OM, Newby PK, et al. Dietary patterns are associated with incident stroke and contribute to excess risk of stroke in Black Americans. Stroke. 2013;44(12):3305-3311. 12. Shikany JM, Safford MM, Newby PK, et al. Southern dietary pattern is associated with hazard of acute coronary heart disease in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Circulation. 2015;132(9):804-814. 13. Gutiérrez OM, Muntner P, Rizk DV, et al. Dietary patterns and risk of death and progression to ESRD in individuals with CKD: a cohort study. Am J Kidney Dis. 2014;64(2):204-213.
Theresa Capriotti, DO, MSN, CRNP, RN, is clinical professor at Villanova University M. Louise Fitzpatrick College of Nursing in Villanova, Pennsylvania. Alaina Roman, BSN, and Molliana Schwarz, BSN, are honor students at Villanova University M. Louise Fitzpatrick College of Nursing in Villanova, Pennsylvania.
14. Gutiérrez OM, Judd SE, Voeks JH, et al. Diet patterns and risk of sepsis in community-dwelling adults: a cohort study. BMC Infect Dis, 2015;15:231. 15. Akinyemiju T, Moore JX, Pisu M, et al. A prospective study of dietary patterns and cancer mortality among Blacks and Whites in the REGARDS cohort. Int J Cancer. 2016;139(10):2221-2231. 16. Pearson KE, Wadley VG, McClure LA, Shikany JM, Unverzagt FW, Judd SE.
Dietary patterns are associated with cognitive function in the Reasons for
1. Mozaffarian D, Benjamin EJ, Go AS, et al. Executive summary: heart disease
Geographic and Racial Differences in Stroke (REGARDS) cohort.
and stroke statistics — 2016 update: a report from the American Heart
J Nutr Sci. 2016;5:e38.
Association, Circulation. 2016;133(4):447-454.
17. Centers for Disease Control and Prevention. National Center for Health
2. Carnethon MR, Pu J, Howard G, et al. Cardiovascular health in African
Statistics. Prevalence of obesity and severe obesity among adults: United
Americans: a scientific statement from the American Heart Association.
States, 2017–2018. CDC website. Accessed December 10, 2020. https://
3. Gudmundsdottir H, Høieggen A, Stenehjem A, Waldum B, Os I.
18. Still CH, Tahir S, Yarandi HN, Hassan M, Gary FA. Association of
Hypertension in women: latest findings and clinical implications. Ther Adv
psychosocial symptoms, blood pressure, and menopausal status in African-
Chronic Dis. 2012;3(3):137-146.
American women. West J Nurs Res. 2020;42(10):784-794.
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 25
19.Taylor JY, Sun YV, Barcelona de Mendoza V, et al.The combined effects of
implications. J Am Coll Cardiol. 2017;69(4):437-451.
genetic risk and perceived discrimination on blood pressure among African
29. Duru OK, Vargas RB, Kermah D, Pan D, Norris KC. Health insurance
Americans in the Jackson Heart Study. Medicine (Baltimore). 2017;96(43):e8369.
status and hypertension monitoring and control in the United States. Am J
20. Shin CN, Soltero E, Mama SK, Sunseri C, Lee RE. Association of discrimina-
tion and stress with cardiometabolic risk factors in ethnic minority women.
30. Dubowitz T, Zenk SN, Ghosh-Dastidar B, et al. Healthy food access for
Clin Nurs Res. 2017;26(6):694-712.
urban food desert residents: examination of the food environment, food
21. Lockwood KG, Marsland AL, Matthews KA, Gianaros PJ. Perceived discrim-
purchasing practices, diet and BMI. Public Health Nutr, 2015;18(12):2220-2230.
ination and cardiovascular health disparities: a multisystem review and health
31. James SA. The strangest of all encounters: racial and ethnic discrimination
neuroscience perspective. Ann NY Acad Sci. 2018;1428(1):170-207.
in US health care. Cad Saude Publica, 2017;33(Suppl 1):e00104416.
22. Michaels EK, Reeves AN, Thomas MD, et al. Everyday racial discrimination
32. Smedley BD. The lived experience of race and its health consequences.
and hypertension among midlife African American women: disentangling the
Am J Public Health. 2012;102(5):933-935.
role of active coping dispositions versus active coping behaviors. Int J Environ
33. Hall WJ, Chapman MV, Lee KM, et al. Implicit racial/ethnic bias among
Res Public Health. 2019;16(23):4759.
healthcare professionals and its influence on healthcare outcomes: a system-
23. Maraboto C, Ferdinand KC. Update on hypertension in African-Americans.
atic review. Am J Public Health. 2015;105(12):e60-e76.
Prog Cardiovasc Dis. 2020;63(1):33-39.
34. Brewer LC, Hayes SN, Caron AR, et al. Promoting cardiovascular health and
24. Solomon A, Schoenthaler A, Seixas A, Ogedegbe G, Jean-Louis G, Lai D.
wellness among African-Americans: community participatory approach to design
Medication routines and adherence among hypertensive African Americans.
an innovative mobile-health intervention. PloS One. 2019;14(8):e0218724.
J Clin Hypertens (Greenwich). 2015;17(9):668-672.
35. Dutta MJ, Collins W, Sastry S, et al. A culture-centered community-
25. Young JH, Ng D, Ibe C, et al. Access to care, treatment ambivalence,
grounded approach to disseminating health information among African
medication nonadherence, and long-term mortality among severely hyper-
Americans. Health Commun, 2019;34(10):1075-1084.
tensive African Americans: a prospective cohort study. J Clin Hypertens
36. Abbott L, Williams C, Slate E, Gropper S. Promoting heart health among
rural African Americans. J Cardiovasc Nurs. 2018;33(1):E8-E14.
26. Bolin LP, Horne CE, Crane PB, Powell JR. Low-salt diet adherence in
37. Musemwa N, Gadegbeku CA. Hypertension in African Americans.
African Americans with hypertension. J Clin Nurs. 2018;27(19-20):3750-3757.
Curr Cardiol Rep. 2017;19(12):129.
27. Jones LM, Rosemberg MS, Wright KD. Opportunities for the advanced
38. Helmer A, Slater N, Smithgall S. A review of ACE inhibitors and ARBs in African
practice nurse to enhance hypertension knowledge and self-management
American patients with hypertension. Ann Pharmacother. 2018;52 (11):1143-1151.
among African American women. Clin Nurse Spec. 2017;31(6):311-318.
39. Di Giosia P, Giorgini P, Stamerra CA, Petrarca M, Ferri C Sahebkar A.
28. Ferdinand KC, Sentore FF, Clayton-Jeter H, et al. Improving
Gender differences in epidemiology, pathophysiology, and treatment of
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hypertension. Curr Atheroscler Rep. 2018;20(3):13.
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FEATURE: MARK KRALJEVICH, RN, MPA, MSN, FNPC
Clinical Challenge: Feeding Issues and Fussiness in a 3-Month-Old Infant Infant botulism has become the most common form of human botulism in the United States, with roughly 100 to 140 cases reported per year.
© JAMES CAVALLINI / SCIENCE SOURCE
Botulism A and B are the most common types reported in infants.
3-month-old girl (EF) presents to the office of her primary care provider (PCP) with her parents, who report that the infant has been exhibiting fussiness and decreased appetite over the course of 48 hours. Over the last 24 hours, the mother has attempted feeding with both bottle and breast, but EF makes gurgling noises and stops feeding. EF has not had a wet diaper over the last 8 hours and her mother reports that the infant has been constipated for a “few days,” with her last bowel movement 4 days earlier. EF was born via cesarean delivery at full term. Her Apgar score was 9/9, and the post delivery course was unremarkable.All newborn screening tests were negative. Well-child visits at 3 days, 2 weeks, 1 month, and 2 months demonstrated a healthy, well-developed normal newborn at the 70th percentile for length and 30th percentile for weight. Before these recent complaints, there were no feeding issues. EF is taking no medications and has no known allergies. Her parents’ health history is noncontributory. On physical examination, EF is interacting appropriately with her parents (Table). All of her immunizations are up to date. On observation of attempted bottle-feeding, EF appears uncomfortable and makes gurgling noises and ceases feeding.There is no vomiting or spitting up after the feeding attempt. However, the lack of oral intake and dry diapers are concerning.The clinician has serious concerns about potential structural or
28 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 • www.ClinicalAdvisor.com
neurologic issues, which prompts the provider to refer EF to the regional medical center for further evaluation and workup by pediatric services. Emergency Department Visit
EF presents to the emergency department (ED) shortly after leaving the office of her PCP. She initially is seen by the ED pediatric resident. Her blood sugar level is noted to be 49 mg/dL. The infant tolerates a small amount of a mixture of oral electrolyte replacement and apple juice, which brings the glucose level up to 69 mg/dL. An intravenous (IV) line is placed, blood samples are taken for routine laboratory work, and a urine sample is sent for culture and toxicology screening. All results are reported as normal. Results of a lumbar spinal puncture also are normal. A computed tomography scan of the head without contrast is normal as well.A pediatric abdomen series demonstrates nonspecific bowel gas patterns with dilated loops of bowel.Air also is noted in the rectum.A neurologic examination is notable for mild head lag, hypotonia with poor sucking, and minimal gag. At this time, EF’s parents are advised that their child has a tentative diagnosis of botulism.The case is reviewed by pediatric intensive care unit attending clinicians and, based on EF’s stable condition, the hospital staff decide to admit her to the regular pediatric floor. Discussion
Botulism was first identified in the literature in the 1820s by German physician Justin Kerner. He correctly linked the disease to Clostridium botulinum toxins released from incorrectly prepared sausage and called it botulism after the Latin term for sausage, botulus.1 There are 8 known serotypes of botulism (A-H); types A and B are responsible for most cases of infant botulism. Most cases of botulism in North America are related to exposure to spores in dust or dirt, which can be kicked up or brought into the home on footwear or clothing. Honey is responsible for only 5% of cases of infant botulism in North America. Spores of C botulinum have been isolated from both pasteurized and nonpasteurized samples of honey; hence, it is recommended that honey be avoided until 12 months of age.2 Since 1980, infant botulism has been the most common form of human botulism in the US, with roughly 100 to 140 cases reported per year; approximately 90% of those cases occur in infants 6 months of age or younger with an age range of 1.5 days to 1 year.3 Most of these cases require hospitalization ranging from regular floor admissions to intensive care support. Botulism has been found worldwide.3 Once ingested, the botulism spores germinate and colonize in the gastrointestinal tract and release botulinum neurotoxins,
which cause paralysis of the ileocecal valve and terminal ileum and, eventually, the entire bowel.3,4 The toxin is then released from the intestine and enters the systemic circulation, where it binds with presynaptic cholinergic receptors at motor nerve terminals.The toxin eventually disrupts exocytosis and inhibits the release of acetylcholine.4 Typical presentation of an infant with botulism starts with constipation, followed by poor feeding, and lethargy. Subsequently, deterioration progresses to symmetrical paralysis with the development of bulbar palsies demonstrated by an expressionless face, ptosis, head lag, and eye muscle paralysis.2,3 Gag, suck, and swallow reflexes also become impaired, with generalized weakness and decreases in deep tendon reflexes as the paralysis progresses.5 The onset of symptoms can vary from insidious — symptoms of constipation, weakness, lethargy, and poor feeding develop slowly over the course of a week — to abrupt — within 6 hours an infant goes from healthy to floppy; the latter often is misdiagnosed as meningitis.5 More than 70% of patients will require mechanical ventilation.4 Of note, the toxin does not cross the blood-brain barrier, so cognitive function is unaffected in these infants.2 TABLE. Results of Physical Examination HEENT
Oral mucosa moist
RRR, S1, and S2 noted without murmur, rub, or gallop. Peripheral pulses are 2+ to the upper and lower extremities with immediate capillary refill.
Respirations are easy and nonlabored without use of accessory muscles. Lung sounds are clear and equal unilaterally, with no adventitious breath sounds.
Soft, nontender without organomegaly or masses. Bowel sounds are diminished in all quadrants.
All extremities are moving equally, with no edema, cyanosis, or clubbing.
No rashes, lesions, or ulcers.
Awake, alert, smiling, and moving all extremities; mild head lag and weak suck and swallow.
HEENT, head, eyes, ears, nose, throat; RRR, regular rate and rhythm
www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 29
A CASE OF BOTULISM IN 3-MONTH-OLD INFANT
The formal diagnosis of infant botulism is made through stool tests for the presence of toxins of Clostridium botulinum. Diagnosis
Because botulism is rare, several conditions must be considered in the differential diagnosis when infants with neurologic symptoms present to the PCP or hospital. Although sepsis remains the most common initial diagnosis of these patients,5 Khouri et al categorized the clinical differential into the following in descending order of occurrence3: • Spinal muscular atrophy (SMA) type 1 • Guillain-Barré syndrome, acute transverse myelitis, hypothyroidism, Chiari malformation, and cervical epidural hemorrhage • Metabolic disorders: mitochondrial disorders, carnitine deficiency, congenital disorders of glycosylation, and urea cycle defects • Infectious diseases: meningitis, polio-like enterovirus, parainfluenza with macrocephaly, and human metapneumovirus pneumonia • Undetermined causes of botulism: dystonia, global developmental delay, and polyradiculopathy The formal diagnosis of infant botulism is made through stool tests for the presence of toxins of C botulinum. Stool samples should be obtained as soon as possible, and treatment should be initiated as soon as infant botulism is suspected. Treatment should not be delayed for test results because the process can take several days to complete.6 If there is no spontaneous bowel movement, then gentle digital collection from the rectal vault can be performed. If an enema is necessary, use only nonbacteriostatic water. Glycerin suppositories should not be used because they will affect the quality of the specimen. The specimen should be placed in a sterile urine container without preservatives or fixatives and refrigerated. The local Department of Public Health should be contacted for directions on where the specimen should be sent for testing.6 Treatment Options
Early treatment has been shown to dramatically decrease length of hospital stay by up to 3 weeks, length of mechanical ventilation by 2.6 weeks, and mean duration of IV feeding by 6.4 weeks.7 The current US Food and Drug Administration-approved treatment for infant botulism is an IV human-derived botulism immune globulin (BabyBIG®). The orphan drug consists of human-derived antibotulism toxin antibodies for treatment of both types A and B infant botulism in patients younger than 1 year of age. BabyBIG is available only from the California
Department of Public Health Infant Botulism Treatment and Prevention Program (IBTPP). It can be obtained by contacting the IBTPP on-call physician at 510-231-7600; the current fee for a treatment is $57,300. This is a flat fee, regardless of the number of vials shipped to treat the patient.8 Supplied in 100-mg vials, BabyBIG should be reconstituted with 2 mL of sterile water and administered intravenously (50 mg/kg). According to IBTPP, administration of the infusion should be initiated within 2 hours and completed within 4 hours of constitution. The patient should be monitored continually throughout administration for adverse reactions. The most common reaction is a generalized skin rash, which occurs in approximately 5% of patients. Less commonly noted reactions are fever, chills, muscle cramps, and nausea and vomiting. These reactions occur in less than 5% of patients, according to IBTPP.8 Result of Case
EF was evaluated by neurology shortly after admission to the pediatric floor and was noted to have marked hypotonia, poor suck, and a weak cry; her gag reflex was found to be intact. A nasogastric tube was placed and tube feeding initiated. The admitting pediatrician, neurologist, and infectious disease clinicians all concurred with the likely diagnosis of infant botulism. EF’s stool was collected with the assistance of an enema and forwarded to the Centers for Disease Control and Prevention for testing. Arrangements for obtaining BabyBIG were initiated. The patient received her infusion of BabyBIG on hospital day 2. Over the course of the ensuing hospital days, gradual improvement in head lag and hypotonia were noted. EF was evaluated by speech therapy, physical therapy, and occupational therapy on hospital day 5, and the decision was made to restart oral feedings. EF did well and was tolerating oral intake with only occasional episodes of mild cough or choking noted. By hospital day 9, EF was noted to have only a rare episode of “cough” with feeding, and both speech therapy and EF’s parents felt she was almost back to her normal feeding status. Neurologic examination on day 9 was unremarkable, with no noted head lag or hypotonia and a good suck and gag reflex. The decision was made to discharge EF, with a plan to follow up with her PCP in a week and with the infectious disease specialist in a month. Continued care by speech therapy, occupational therapy, and physical therapy also was recommended.
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Continues on page 32
A CASE OF BOTULISM IN 3-MONTH-OLD INFANT
The current Food and Drug Administrationapproved treatment for infant botulism is an IV human-derived botulism immune globulin. EF was seen by her PCP 6 days after discharge. Her neurologic examination at this visit was normal. Episodes of mild coughing or choking during feeding were noted to have resolved almost completely. The result of EF’s stool culture, which was returned shortly after her discharge, was negative for C botulinum. Of note, Khouri et al found that up to 25% of cases tested negative but were considered to be botulism because the presentation, timing, and recovery process were consistent with that seen in infants with positive stool tests for C botulinum who received BabyBIG.3 The route of exposure to C botulinum was believed to be related to excavation and landscaping around EF’s home.
a nurse for more than 30 years working in critical care and nursing management. References 1. Waseem M. Pediatric botulism. Medscape. Accessed December 12, 2020. https://emedicine.medscape.com/article/961833-overview 2. Schwartz KL, Austin JW, Science M. Constipation and poor feeding in an infant with botulism. CMAJ. 2012;184(17):1919-1922. 3. Khouri JM, Payne JR, Arnon SS. More clinical mimics of infant botulism. J Pediatr. 2018;193:178-182. 4. Cox N, Hinkle R. Infant botulism. Am Fam Physician. 2002;65(7):1388-1392. 5. Arnon SS. Infant botulism. In: Cherry JD, Harrison GJ, Kaplan SL, Hotez PJ, Steinback WJ, eds. Feigin and Cherry’s Textbook of Pediatric Infectious Disease,
6th Ed. Elsevier-Saunders: 2009.
While rare, infant botulism should always remain on the provider’s radar screen when dealing with an infant with a history of constipation and feeding issues. A complete neurologic exam should be completed, and if any question of deficits is noted, the patient should be sent emergently for further workup and evaluation. ■
6. California Department of Public Health. Infant Botulism Treatment and Prevention Program. What is BabyBIG? Accessed December 12, 2020. http://www.infantbotulism.org/general/babybig.php 7. Arnon SS, Schechter R, Maslanka SE, Jewell NP, Hatheway CL. Human botulism immune globulin for the treatment of infant botulism. N Engl J Med. 2006;354(5):462-471. 8. California Department of Public Health. Infant Botulism Treatment and
Mark Kraljevich, RN, MPA, MSN, FNPC, is a family nurse practitioner currently working in a primary care practice. He has been
Prevention Program. How to obtain BabyBIG®. Accessed December 12, 2020. https://www.cdph.ca.gov/Programs/CID/DCDC/Pages/ObtainBabyBig.aspx
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32 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 • www.ClinicalAdvisor.com
Dermatology Clinic CASE #1
Red Lesions on Buttocks and Legs ANDREW FISCHER, MD
A 50-year-old woman presents with a crop of lesions that recently appeared on her buttocks and legs. On examination, the red macules and papules range in size from a few millimeters to a few centimeters; when pressed, the lesions do not blanch or partially blanch. The patient reports joint pain over her ankles and knees, along with malaise. When questioned, she acknowledges having had a “cold” a few weeks earlier, for which her primary care provider prescribed an antibiotic. Direct immunofluorescence of the lesions reveals immunoglobulin A (IgA) deposits around the small vessels in the papillary dermis. What is your diagnosis? Turn to page 34
Red, Swollen Finger With Fissure ANDREW FISCHER, MD
A 42-year-old woman was admitted to the hospital for complications related to type 2 diabetes. Her inpatient team noticed that her right fifth finger was swollen, red, and appeared to have a fissure. The patient stated that although the fissure was not present since birth, her finger has looked this way for “a while” and typically did not bother her. On examination, she had hyperkeratotic plaques on some of her fingers. She denied trauma to the site of injury and her family and travel history were unremarkable. What is your diagnosis? Turn to page 35 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 33
Dermatology Clinic CASE #1
Small Vessel Vasculitis
Small vessel vasculitis is an immune-mediated process involving inflammation of the postcapillary venules. In this case, the patient has IgA-mediated small vessel vasculitis (Henoch– Schönlein purpura), a type of small vessel vasculitis that can involve the gastrointestinal tract, kidneys, and joints, with prognostic implications.1 When patients present clinically with small vessel vasculitis, the clinician must consider whether or not the process might have systemic as well as cutaneous involvement. The incidence of small vessel vasculitis in adults older than 15 years of age has been reported to be 4.5 per 100,000 personyears.2 Nearly half of cases (45%) are considered to be cutaneous small vessel vasculitis (not otherwise specified), 30% are IgA vasculitis, and the remainder are other types of small vessel vasculitides (urticarial, cryoglobulinemic, antineutrophil cytoplasmic antibody-associated). Although small vessel vasculitis seems to affect all ages and genders, IgA vasculitis is more common in children, with an incidence of 20.4 per 100,000 person-years.3 Small vessel vasculitis occurs when antibody complexes lodge in the small vessels (postcapillary venules) of the papillary dermis and activate the complement system, leading to inflammation, vessel destruction, red blood cell extravasation, and clinical disease.The antibody complexes may form in response to multiple antigens; the 4 most common are infectious agents (10%-15%), medications (10%-15%), factors associated with autoimmune connective tissue disease (15%-20%), and factors associated with neoplasia (5%).4 Triggers include viral upper respiratory infections (URIs), hepatitis C virus infection, streptococcal pharyngitis, antibiotics, rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, and solid or hematologic neoplasia.4 However, the majority of cases are idiopathic (45% to 55%). In these cases, the antibody complexes form in response to an unidentified antigen.The antibody complexes may be limited to the skin but also may involve other organs, which is why a thorough review of systems is warranted. In IgA vasculitis, the antibody complexes are composed predominantly of IgA immunoglobulins.4 Patients develop symptoms approximately 7 to 10 days after antigen exposure, although there can be wide variability in timing.The key cutaneous finding of small vessel vasculitis is palpable purpura.Typically, lesions are 3 to 6 mm in size, but they may coalesce to form larger-appearing lesions. Early lesions may partially blanch but evolve to be nonblanching or truly
purpuric. Lesions may develop necrotic centers, become bullae, and ulcerate. Petechial or urticarial lesions may be present as well. Lesions tend to be located on the dependent areas of the body (typically the lower extremities) and may range in number from 10 to several hundred.1,5 In addition to these cutaneous manifestations, patients may have systemic involvement, depending on the underlying etiology. In addition to palpable purpura, adults with IgA vasculitis often have arthritis (61%), gastrointestinal symptoms including bleeding (48%), and renal insufficiency with hematuria and proteinuria (32%).5 Adults with IgA vasculitis have a higher risk of progressing to significant kidney involvement and end-stage renal disease.1,5
The incidence of small vessel vasculitis in adults older than 15 years of age has been reported to be 4.5 per 100,000 person-years. When a clinician suspects small vessel vasculitis, it is imperative that they perform a full review of systems and physical examination to search for evidence of systemic involvement and try to undercover an underlying cause. At the very least, laboratory tests including complete blood count with differential, complete metabolic panel, and urinalysis should be performed for patients with suspected small vessel vasculitis. Diagnosis should be based on the results of the history, review of systems, and physical examination. If symptoms are persistent, unexplained, and there is evidence of systemic involvement, additional considerations (for adults) include testing for infectious agents (hepatitis B and C virus, HIV, antistreptolysin O titers); levels of antinuclear antibody, rheumatoid factor, serum complement, and cryoglobulins; and the presence of fecal occult blood, as well as coagulation studies, serum protein/ urine protein electrophoresis, and chest radiography (if there are pulmonary symptoms).4 Patients should be up to date on age-appropriate malignancy screening. A skin biopsy almost always is warranted in small vessel vasculitis. Preferably 2 biopsies should be taken — 1 for routine processing and 1 for direct immunofluorescence.The biopsy should be deep enough to allow the dermatopathologist to visualize the dermal vessels, with either a punch or deep shave. On routine processing, the histopathologic hallmark is leukocytoclastic vasculitis composed of perivascular neutrophilic inflammation and nuclear dust (leukocytoclasis) around the dermal vessels, disruption of the vessel walls with fibrin deposition, and extravasated red blood cells. For routine processing,
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the biopsy should be taken within 24 to 48 hours of lesion appearance to have the best chance of visualizing these diagnostic findings. The biopsy for direct immunofluorescence should be taken directly from a lesion within 24 hours of appearance and placed in Michel medium or normal saline to allow the visualization of the immune complexes, which are destroyed thereafter. IgA deposits in the vessel wall are the key diagnostic feature of IgA vasculitis.4 There are many diseases that mimic small vessel vasculitis that may be included in the differential diagnosis, including arthropod bites, a maculopapular drug eruption, and many disorders that potentially present with purpuric lesions on the lower extremities, such as pigmented purpuric dermatoses; macular purpura from sun damage, age, platelet dysfunction, or medications; and scurvy, among others.A biopsy demonstrating leukocytoclastic vasculitis is key to differentiating small vessel vasculitis from these other disorders. It becomes more difficult, however, when not all the diagnostic histopathologic findings of leukocytoclastic vasculitis are present in the biopsy specimen, particularly if the biopsy was taken from a lesion that was too new or too old.The clinician must use clinicopathologic correlation to come to an overall conclusion.4,5 Most cases of small vessel vasculitis have minimal (or no) systemic involvement and are self-limited, resolving in a matter of weeks.6 Conservative measures such as rest, leg elevation, and compression stockings may be helpful. Topical steroids can be used on skin lesions to treat associated burning or itching. If a trigger (such as a medication) can be identified, then avoidance of it may be recommended. If an underlying process (such as lupus or neoplasia) is identified, then treatment of the condition may help the vasculitis.6,7 IgA vasculitis tends to have a longer and more protracted course, often marked by recurrences over several months.6 Persistent skin lesions can be treated with dapsone or colchicine. Prednisone may be used to enhance the rate of symptom resolution if there are severe skin lesions or systemic involvement (severe renal disease in IgA vasculitis), but it is not a good long-term medication, given its side effect profile, and it does not prevent recurrent disease or renal disease in IgA vasculitis; thus, it should not be used prophylactically.6,7 Beyond these measures, other immunosuppressant drugs, including methotrexate, azathioprine, mycophenolate mofetil, or rituximab, may be used for lesion control. The patient in this case was presumed to have vasculitis secondary to a URI (or potentially antibiotic treatment). She was treated with topical corticosteroids, which improved her lesions over the ensuing weeks. A urinalysis revealed microscopic hematuria. She was referred to the renal team, who monitored her kidney involvement, which also improved without additional intervention.
References 1. Villatoro-Villar M, Crowson CS, Warrington KJ, Makol A,Ytterberg SR, Koster MJ. Clinical characteristics of biopsy-proven IgA vasculitis in children and adults: a retrospective cohort study. Mayo Clin Proc. 2019;94(9):1769-1780. 2. Arora A, Wetter DA, Gonzalez-Santiago TM, Davis MD, Lohse CM. Incidence of leukocytoclastic vasculitis, 1996 to 2010: a population-based study in Olmsted County, Minnesota. Mayo Clin Proc. 2014;89(11):1515-1524. 3. Gardner-Medwin JM, Dolezalova P, Cummins C, Southwood TR. Incidence of Henoch-Schönlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet. 2002;360(9341):1197-1202. 4. Shinkai K, Fox LP. Cutaneous vasculitis. In: Bolognia JL, Jorizzo JL, Schaffer JV, ed. Dermatology. 3rd ed. Elsevier; 2012:385-410. 5. Pillebout E, Thervet E, Hill G, Alberti C, Vanhille P, Nochy D. HenochSchönlein purpura in adults: outcome and prognostic factors. J Am Soc Nephrol. 2002;13(5):1271-1278. 6. Saulsbury FT. Henoch-Schönlein purpura in children. Report of 100 patients and review of the literature. Medicine (Baltimore). 1999;78(6):395-409. 7. Dudley J, Smith G, Llewelyn-Edwards A, Bayliss K, Pike K, Tizard J. Randomised, double-blind, placebo-controlled trial to determine whether steroids reduce the incidence and severity of nephropathy in Henoch-Schonlein purpura (HSP). Arch Dis Child. 2013;98(10):756-763.
Constricting Band (Pseudoainhum)
The patient’s presentation is consistent with the formation of a constricting band around her right fifth digit. This rare and poorly understood process may progress to autoamputation. It was first described in the medical literature in the early 1800s.1 The terminology surrounding this process is somewhat confusing — constricting band, ainhum, pseudoainhum, dactylolysis spontanea — and has led to misclassification in the literature. In today’s vernacular, ainhum refers to an idiopathic, constricting band or groove that forms on the digits of dark-skinned patients in tropical or subtropical countries that can progress to spontaneous dactylolysis and spontaneous amputation.2 West African and Brazilian tribal languages have terms similar to ainhum that mean “to saw or file” and “fissure,” respectively.2 Pseudoainhum describes an analogous process that develops as a result of an associated disease process (not idiopathic).2 It has been further subclassified by some as either a primary process presenting at birth or early in life or a secondary process presenting
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Dermatology Clinic later in life. Pseudoainhum is not associated with any particular ethnic background, and it can occur anywhere on the body. Ainhum has been reported to have an incidence of 0.015% to 2.2% in tropical and subtropical climates but is exceedingly rare in North America.3,4 Likewise, pseudoainhum is extremely rare, and no data on the incidence have been published.The etiology of these conditions is poorly understood. Whereas ainhum is an idiopathic process, the etiology of pseudoainhum is attributed to the condition(s) with which it is associated, including mechanical effects associated with hyperkeratosis (which often is present), infection, and vascular changes.2 Pseudoainhum has been reported in association with several
Ainhum tends to present on the small toe, whereas pseudoainhum can present on any digit or even on the extremities. conditions, including disorders of keratinization (Vohwinkel syndrome), psoriasis, diabetes, Raynaud phenomenon and scleroderma, syphilis, leprosy, and trauma (such as a hair wrapped around the digit).2 Typically, this condition is identified easily with recognition of the fissure. It tends to progress through stages, beginning with the formation of a circumferential groove or crease, followed by edema and deepening of the fissure, with corresponding arterial narrowing.This is followed by separation of the bones from the joint and eventually autoamputation, leaving a dangling and twisted digit. In the final stage, necrosis completes the amputation.There often is associated hyperkeratosis, and pain may or may not be present. Ainhum tends to present on the fifth digit of the toe, whereas pseudoainhum can present on any digit or even on the extremities.3,4 The diagnosis typically is made by history and clinical examination. A biopsy at the site of constriction will show hyperkeratosis and fibrosis. In pseudoainhum, a biopsy may provide a clue to the associated condition if related changes are recognized (such as psoriasis or a foreign body); thus, it may be diagnostically useful in that situation. A lucent band may be seen on radiograph, along with osteolysis in advanced cases. The clinician should distinguish this condition from others that may appear clinically similar: frostbite, distal gangrene in patients with diabetes, or congenital maldevelopment of the digits or extremities. In these cases, however, a fissure corresponding to a constricting band would not be present. Infants may present with hair or thread wrapped around a digit, leading to a very similar clinical scenario termed hair-thread tourniquet syndrome.5
In the case of pseudoainhum, the provider should perform a workup that includes family history and possibly genetic testing for associated conditions, including diabetes, connective tissue diseases, psoriasis, and certain genodermatoses. The patient also should be evaluated for a history of trauma or foreign body at the site. Treatment efficacy is limited. If an associated or underlying condition can be determined, targeted therapy may be helpful. In hyperkeratotic conditions, a topical keratolytic or oral agents such as etretinate or isotretinoin may provide some benefit, but there may be relapse upon discontinuation of the treatment.6,7 Surgery aimed at releasing the constricting band via a z-plasty or excision with skin grafting can be attempted.8 Surgery typically is indicated when the constricting band is symptomatic or causing neurovascular compromise. Amputation may be the only viable solution in advanced cases of impending autoamputation. The patient in this case was evaluated by a hand surgeon and not deemed to be in need of urgent surgery because she had good perfusion and mobility of the digit. She was started conservatively on a topical keratolytic agent, with a plan to visit the outpatient clinic. She subsequently was lost to follow-up. ■ Andrew Fischer, MD, is a board-certified dermatologist at Elite Dermatology in Houston,Texas. References 1. Peterka ES, Karon IM. Congenital pseudoainhum of the fingers. Report of a case. Arch Dermatol. 1964;90:12-14. 2. Rashid R, Cowan E, Abbasi SA, Brieva J, Alam M. Destructive deformation of the digits with auto-amputation: a review of pseudo-ainhum. J Eur Acad Dermatol Venereol. 2007;21(6):732-737. 3. Cole GJ. Ainhum: an account of 45 patients with special reference to etiology and treatment. J Bone Joint Surg Br. 1965;47:43-51. 4. Kean BH, Tucker HA, Miller WC. Ainhum; a clinical summary of 45 cases on the Isthmus of Panama. Trans R Soc Trop Med Hyg. 1945-1946;39(4):331-334. 5. Mat Saad AZ, Purcell EM, McCann JJ. Hair-thread tourniquet syndrome in an infant with bony erosion: a case report, literature review, and meta-analysis. Ann Plast Surg. 2006;57(4):447-452. 6. Chang Sing Pang A, Oranje A, Vuzevki VD, Stolz E. Successful treatment of keratoderma hereditaria mutilans with an aromatic retinoid. Arch Dermatol. 1981;117(4): 225-228. 7. Camisa C, Rossana C. Variant of keratoderma hereditaria mutilans (Vohwinkel’s syndrome). Treatment with orally administered isotretinoin. Arch Dermatol. 1984;120(10):1323-1328. 8. Simkin D, Ho JD, Simkin DJ, Tomany K. A novel association of pseudoainhum and epidermolytic ichthyosis, successfully treated with full thickness skin graft after failed z-plasty repair. Dermatol Online J. 2018;24(1):13030/qt1ph217qf.
36 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 • www.ClinicalAdvisor.com
Dermatologic Look-Alikes Hyperpigmented Plaque on Trunk DINA ZAMIL, BS; TARA L. BRAUN, MD; CHRISTOPHER RIZK, MD
A 64-year-old Black man presents with an asymptomatic rash on his back that his wife noticed about 1 year ago. He has a history of obesity, diabetes, and hypertension. He has no other skin conditions and has not had a similar rash before. He tried an antifungal cream, which did not help clear up the rash. He takes showers daily, scrubbing the lesions with soap and water, with no improvement. The rash has been progressing slowly.
A 25-year-old Black man presents with a 4-month history of a nonitchy, painless rash on his chest. He is otherwise healthy and does not take any medications or supplements other than a daily multivitamin and ibuprofen as needed for headaches. He has not tried any treatments for this skin problem and has not noticed any recent changes to the rash. He has no other skin lesions on his body. He showers daily with a scented soap and does not moisturize.
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Dermatologic Look-Alikes CASE #1
Terra Firma–Forme Dermatosis
Terra firma–forme dermatosis, first reported in 1987 and commonly known as Duncan dirty dermatosis, is a hyperpigmented plaque that often looks like dirt on the skin.1,2 Terra firma–forme dermatosis can occur in patients of any age but occurs more frequently in children and adolescents.3,4 Men and women are affected equally by the disease, and it has been described as having a predilection for overweight individuals.4,5 It is not known to be related to a specific gene or display familial inheritance.3,4,6 The Latin phrase terra firma means “dry land,” which well describes the hyperpigmented skin findings of terra firma– forme dermatosis caused by dirt accumulation in the epidermis.1,2 Lesions can be verrucous, reticular, or papillomatous and usually are black or brown in color.4 The symmetrical plaques can appear anywhere on the body, although they most commonly are present on the trunk and neck. Other potentially involved areas include ankles, face, legs, back, and axillary, pubic, and umbilical regions.3,4 The rash is more likely to be found in concave skin areas and skin folds and can be localized or generalized.2,4,5
Histopathologic studies have reported lamellar hyperkeratosis, increased melanin, and compact orthokeratosis with whorls. The etiology of terra firma-forme dermatosis is unknown. One theory is that it results from slowed or delayed keratinocyte maturation, incomplete development of keratin squames, melanin retention, and dirt and sebum buildup.1-3 Predisposing risk factors are ill-defined; sun exposure and use of emollients containing urea have been cited in the literature as potential causes.2,6,7 In addition, terra firma–forme dermatosis has been associated with atopic dermatitis and xerosis.7,8 Applying oil, ointments, cleansers, and adhesives on eczematous, xerotic, or scaly skin may lead to inadequate exfoliation and dirt buildup characteristic of terra firma–forme dermatosis.7,9 This condition can occur even when affected patients have good hygiene.1,2 Diagnosis of terra firma–forme dermatosis can be made in the clinic.The plaque will disappear when rubbed with 70% isopropyl or ethyl alcohol.2,4 At times, aggressive rubbing will
be necessary to remove hyperpigmentation completely.4,9 Biopsies rarely are performed, and further diagnostic tests, such as examination under a Wood lamp or cultures, are conducted only when infection is suspected.3 Reflectance confocal microscopy recently was recommended as an additional, noninvasive diagnostic tool.3 Histopathologic studies of terra firma–forme dermatosis have reported lamellar hyperkeratosis, increased melanin, and compact orthokeratosis with whorls.1,2,4 Acanthosis, parakeratosis, and papillomatosis may be absent, and toluidine blue staining can show keratin globules in the stratum corneum.4 Basal layer spores of the fungus Malassezia furfur also have been described.2 Dermoscopy generally displays a mosaic or tile-like pattern of polygonal black or brown scales with interrupting furrows.3,7 Although simple to diagnose, terra firma–forme dermatosis can be confused with other diseases, leading to unnecessary diagnostic tests, medications, and referrals.4 The differential diagnosis includes dermatosis neglecta and dirty dermatosis, which arise from inadequate hygiene habits. Dermatosis neglecta generally occurs in patients with disabilities and is not characterized by brown cornflake-like scales, differentiating it from terra firma–forme dermatosis. Numerous similar lesions include confluent and reticulated papillomatosis, nipple hyperkeratosis, acanthosis nigricans, idiopathic deciduous skin, ichthyosis, Darier disease, extensor surface darkening from friction, postinflammatory hyperpigmentation, and dirty neck syndrome with atopic dermatitis. Such skin conditions can be differentiated from terra firma–forme dermatosis by a negative alcohol swipe test.3 Other similar conditions include epidermal nevi, granular parakeratosis, omphalith, seborrheic keratosis, epidermolytic hyperkeratosis, pseudoacanthosis nigricans, and tinea versicolor.4 It was suggested that tinea versicolor could be distinguished from terra firma–forme dermatosis by a negative Wood lamp test, but more recent documentation suggests terra firma–forme dermatosis also may show fluorescence.3,7 The standard treatment for terra firma–forme dermatosis is rubbing with 70% isopropyl or ethyl alcohol.3,4 However, other methods, including lactic acid, 2% salicylic acid, lemon juice, urea lotion, oral retinoids, and topical and oral antifungals, also have been used successfully.3 Patients may wish to moisturize areas treated with isopropyl alcohol to avoid dryness. If lesions recur, patients may continue to rub the affected area with isopropyl alcohol and can rub weekly for prophylactic therapy.4 The patient’s plaque in this case was treated partially in clinic with 70% isopropyl alcohol.The patient and his wife continued this treatment at home, which led to complete resolution of the lesions on his back.The lesions have not recurred.
38 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 • www.ClinicalAdvisor.com
Confluent and Reticulated Papillomatosis
Confluent and reticulated papillomatosis (CARP) is an epidermal dermatosis resulting from disordered keratinization.10,11 Also referred to as Gougerot-Carteaud syndrome, CARP was first reported in 1927; an American case was not reported until 1937.10-12 Although initially thought to be a form of acanthosis nigricans, CARP was later recategorized as a distinct dermatosis.10 CARP has been reported in patients ranging from 5 to 63 years of age, but the most common age of onset is during puberty.13 Studies in Japan and the United States have reported similar ages of onset (17 and 15 years of age, respectively).10,13,14 Reports in the literature conflict about the male to female ratio, with some citing a greater frequency in men10,14,15 and others reporting the opposite.13 Cases of CARP have been reported worldwide.10,11,15 Theories on the etiology of CARP have evolved over time. Initially CARP was thought to be caused by an abnormal host
response to Malassezia furfur,10,11,13 whereas current theories propose that CARP is caused by the gram-positive anaerobic bacteria Dietzia papillomatosis.10,11,13,16 Other potential noninfectious causes include ultraviolet light, overexpression of keratin-16, and amyloidosis.10,11 The histology of CARP demonstrates focal acanthosis, hyperkeratosis, and papillomatosis. CARP displays increased lamellar granules in the stratum granulosum and increased melanosomes in the stratum corneum.13 Coupled with its response to treatment with vitamin A and D derivatives, these findings suggest that CARP is a disorder of impaired keratinization.11,13 Risk factors for CARP include obesity and diabetes, which cause hyperinsulinemia leading to increased activation of insulin-like growth factor, epidermal growth factor, fibroblast growth factor, and tyrosine kinase receptors.This, ultimately, results in epidermal proliferation, mitogenesis, and inhibited apoptosis.10,11 CARP has been found to arise more frequently in women with polycystic ovarian syndrome and may be accompanied by acanthosis nigricans in such instances.17 Clinically, CARP rarely is symptomatic, although some patients experience pruritus. The disease is limited to the skin, with no systemic findings. It is found most commonly
TABLE. Terra Firme−Forme Dermatosis vs Confluent and Reticulated Papillomatosis Terra Firma–Forme Dermatosis1-9
Confluent and Reticulated Papillomatosis10-19
• Brown/black hyperkeratotic and hyperpigmented, verrucous, reticular, or papillomatous “dirty” lesions • Can be raised
• Velvety, hyperpigmented papules that reticulate peripherally and gather in plaques centrally • May see epidermal changes
• More common in adolescents and children • Predilection for overweight patients
• Common onset at puberty • Seen in both sexes and found around the world
Potential risk factors
Sun exposure, urea-containing emollient use, atopic dermatitis, xerosis
Obesity, diabetes, polycystic ovarian syndrome
• Unknown • Hypothesized to arise from delayed keratinocyte maturation and buildup of melanin, dirt, and sebum
• Keratinization disorder • Causes include bacteria (Dietzia papillomatosis), UV light exposure, K16 mutation, amyloidosis
Trunk and neck, concave skin areas, skin folds
Axilla, interscapular region, submammary creases in women, upper trunk, neck
Lamellar hyperkeratosis, compact orthokeratotic whorls, increased melanin, keratin globules in stratum corneum
• Focal acanthosis, hyperkeratosis, papillomatosis • Increased lamellar granules, melanosomes, and transition cell layer
Disappears with 70% isopropyl or ethyl alcohol rub
• Clinical (appearance and location of lesion, etc) • Negative fungal staining • Response to minocycline and no response to antifungals
70% isopropyl or ethyl alcohol
• Minocycline (first line) • Other antibiotics and topical therapies
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Dermatologic Look-Alikes on the upper trunk, axillae, and inframammary regions.10,13 It presents as velvety, hyperpigmented, verrucous papules that reticulate on the periphery and coalesce as plaques in the center.10,11,14 CARP also can form a distinct rhomboidal pattern posteriorly in the interscapular region or anteriorly on the chest.10,13 In White individuals, the macules or papules can be erythematous or scaly and also can appear dry and mottled.10,11,13,14 The velvety look of CARP can appear similar to acanthosis nigricans.13 Diagnostic criteria for CARP, established by Davis et al14 and revised by Jo et al,18 are as follows: scaly brown patches and macules that include reticulated or papillomatous lesions, negative fungal staining, lack of response to antifungal therapy, excellent response to minocycline or antibiotic therapy, and involvement of the upper trunk and neck.11 Dermoscopy may aid in diagnosis, revealing sulci and gyri folds, brown pigmentation, and white scale.10,19 The differential diagnosis of CARP includes acanthosis nigricans, which can be differentiated from CARP histologically or by the clinical absence of peripheral reticulation.The 2 diseases can also occur concomitantly in the same individual.10 Other conditions in the differential diagnosis include tinea versicolor, Galli-Galli disease, Dowling-Degos disease, dyskeratosis congenita, prurigo pigmentosa, and terra firma–forme dermatosis (Table).10,11,19 Prurigo pigmentosa may be differentiated by a skin biopsy and terra firma–forme dermatosis by a swab test with 70% isopropyl alcohol.10 Treatments for CARP include antibiotics and topical (tazarotene) and systemic retinoids.10,11 Minocycline is the first-line antibiotic therapy11; tetracycline and doxycycline also have shown effectiveness.10 The recommended dosage of minocycline is 50 mg twice daily for 6 weeks.11,13 For individuals unable to take minocycline due to pregnancy, azithromycin is first-line treatment.10,11 Clarithromycin and erythromycin also have been described as effective treatment options.10,11,13 Other topical therapies include calcipotriol, tacrolimus, and urea.10,13 When patients do not respond to minocycline, systemic isotretinoin may be considered.10 Patients generally have a good response to therapy, with greater than 50% improvement in those treated with minocycline or azithromycin. Recurrences tend to occur in patients who were not treated with antibiotic therapy.10 The patient in this case was diagnosed with CARP clinically and was prescribed 6 weeks of minocycline, which led to regression of his lesions. ■
References 1. Duncan WC,Tschen JA, Knox JM.Terra firma–forme dermatosis. Arch Dermatol. 1987;123(5):567-569. 2. Aslan NÇ, Güler Ş, Demirci K, Isiyel E. Features of terra firma–forme dermatosis. Ann Fam Med. 2018;16(1):52-54. 3. Unal E, Guarneri C, Chokoeva AA, Wollina U,Tchernev G.Terra firma–forme dermatosis. Wien Med Wochenschr. 2017;167(3-4):66-69. 4. Greywal T, Cohen PR. Terra firma–forme dermatosis: a report of 10 individuals with Duncan’s dirty dermatosis and literature review. Dermatol Pract Concept. 2015;5(3):29-33. 5. Berk DR, Mutizwa MM. Comment regarding the histopathology of terra firma– forme dermatosis. J Cutan Pathol. 2012;39(2):300-301; author reply 302-303. 6. Erkek E, Sahin S, Çetin ED, Sezer E.Terra firma–forme dermatosis. Indian J Dermatol Venereol Leprol. 2012;78(3):358-360. 7. Ozturk Durmaz E. Chalk-white fluorescence under wood light in a case of terra firma–forme dermatosis. Clin Exp Dermatol. 2021;46(1):165-166. 8. Berk DR.Terra firma–forme dermatosis: a retrospective review of 31 patients. Pediatr Dermatol. 2012;29(3):297-300. 9. Oztürk F, Kocabaş E, Ertan P, Ermertcan AT. Terra firma–forme dermatosis. Cutan Ocul Toxicol. 2010;29(4):303-305. 10. Lim JH,Tey HL, Chong WS. Confluent and reticulated papillomatosis: diagnostic and treatment challenges. Clin Cosmet Investig Dermatol. 2016;9:217-223. 11. Le C, Bedocs PM. Confluent and reticulated papillomatosis. In: StatPearls. StatPearls Publishing; 2020. Accessed November 1, 2020. https://www.ncbi.nlm. nih.gov/books/NBK459130/ 12. Wise F. Cutaneous papillomatosis: papillomatose confluente et reticulee. Arch Derm Syphilol. 1937;36(3):475. 13. Scheinfeld N. Confluent and reticulated papillomatosis : a review of the literature. Am J Clin Dermatol. 2006;7(5):305-313. 14. Davis MDP, Weenig RH, Camilleri MJ. Confluent and reticulate papillomatosis (Gougerot-Carteaud syndrome): a minocycline-responsive dermatosis without evidence for yeast in pathogenesis. A study of 39 patients and a proposal of diagnostic criteria. Br J Dermatol. 2006;154(2):287-293. 15. Huang W, Ong G, Chong W-S. Clinicopathological and diagnostic characterization of confluent and reticulate papillomatosis of Gougerot and Carteaud: a retrospective study in a South-East Asian population. Am J Clin Dermatol. 2015;16(2):131-136. 16. Jones AL, Koerner RJ, Natarajan S, Perry JD, Goodfellow M. Dietzia papillomatosis sp. nov., a novel actinomycete isolated from the skin of an immunocompetent patient with confluent and reticulated papillomatosis. Int J Syst Evol Microbiol. 2008;58(Pt 1):68-72. 17. Basu P, Cohen PR. Confluent and reticulated papillomatosis associated with polycystic ovarian syndrome. Cureus. 2019;11(1):e3956. 18. Jo S, Park HS, Cho S, Yoon HS. Updated diagnosis criteria for confluent and reticulated papillomatosis: a case report. Ann Dermatol.
Dina Zamil, BS, is a medical student at Baylor College of Medicine, Tara L. Braun, MD, is a resident in the Department of Dermatology at Baylor College of Medicine, and Christopher Rizk, MD, is a dermatologist affiliated with Baylor College of Medicine in Houston,Texas.
2014;26(3):409-410. 19. Bernardes Filho F, Quaresma MV, Rezende FC, Kac BK, Nery JA, AzulayAbulafia L. Confluent and reticulate papillomatosis of Gougerot-Carteaud and obesity: dermoscopic findings. An Bras Dermatol. 2014;89(3):507-509.
40 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 • www.ClinicalAdvisor.com
LEGAL ADVISOR CASE
© KIRILL VASIKEV / EYEEM / GETTY IMAGES
Cannabis Use Leads to Dismissal Nursing student sues for disability discrimination after being terminated for medical marijuana use. BY ANN W. LATNER, JD
Ms H was admitted to a nursing program at her local college. As part of the nursing program, Ms H was told that she must successfully complete a series of nursing courses featuring both classwork and clinical training. She also was told that students in the program were required to submit to a urine drug screening test on a yearly basis and any student who tested positive would be removed from the program. When Ms H heard about the drug testing, she became concerned. Her clinician recommended medical cannabis to mitigate her symptoms of irritable bowel syndrome (IBS) and posttraumatic stress disorder (PTSD), and she has been using it regularly. Ms H informed the director of nursing at the college about her medical condition and requested that she be permitted to continue to use medical marijuana, which has been legalized in her state. The director informed Ms H that use of medical cannabis was not permitted, saying,“You must comply with the school’s drug policy in order to stay in the program.”The director also noted that the school would be in violation of its contracts
Is a nursing school required to accommodate a student’s use of medical cannabis in a state where it is legal?
with various clinics if it allowed students to use marijuana. Ms H was informed that she would have to take a urine drug test in 90 days. Instead of submitting for a drug screen, Ms H sought counsel from an attorney and filed a discrimination complaint against the school with the state’s Human Relations Commission. The complaint alleged that Ms H has a medical disability (IBS and PTSD) but that she is able to complete the school’s nursing program as long as she is granted the reasonable accommodation of being permitted to take her legally obtained medical cannabis. The complaint claimed that the school was violating the state’s Fair Education Opportunities Act (FEOA) by denying Ms H reasonable accommodation for her disability. The school made a motion to dismiss, but the Commission denied it.The Commission reasoned Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.
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LEGAL ADVISOR that Ms H’s use of cannabis to mitigate her symptoms made the claim viable under the state’s medical marijuana act, in combination with the FEOA and the state’s Human Relations Act (HRA). The school appealed, and the case went to an appellate court. The Court’s Decision
The court held that the only issue on appeal was whether antidiscrimination provisions of the FEOA and HRA require accommodation of Ms H’s lawful use of medical marijuana under the state’s medical marijuana act. Both the FEOA and the HRA require that employers and schools make reasonable accommodations for qualified individuals with disabilities. Employers must make reasonable accommodations so that employees can carry out their job functions. In the case of schools, institutions of higher education must provide equal access to the school’s programs and activities to those with disabilities.
The court concluded that the college was under no obligation to accommodate Ms H’s use of medical cannabis. The school, while admitting that the laws require reasonable accommodations to qualified disabled students, argued that individuals who currently and illegally use controlled substances, including marijuana, are exempt from the disability definitions under both the FEOA and the state’s HRA. The school pointed out that both statutes use the Federal Controlled Substances Act (CSA) definition of controlled substances, which defines marijuana as a Schedule I controlled substance, meaning it has no medically acceptable use under federal law. The school also noted that although the state’s medical marijuana act legalized use of the drug for certain purposes, it did not amend the FEAO or HRA definition of illegal use of controlled substances — both statutes continue to rely on the federal definition. Ultimately, the court sided with the school. It held that the medical marijuana act did not require an accommodation for medical marijuana use — but rather the act prohibits discrimination based on a person’s status as a medical marijuana patient.The court held that the medical marijuana act expressly provides “that employers are not required to provide an accommodation to employees on their premises, nor are employers prohibited from disciplining employees
who are under the influence of medical marijuana on work premises.” “While an employer cannot discriminate on the basis of an employee’s status as a certified medical marijuana user, an employer is not required to make any accommodation for the use of medical marijuana on its property or the premises of any place of employment,” according to the state’s medical marijuana act. The court concluded that the college was under no obligation to accommodate Ms H’s use of medical marijuana. It pointed out that after the state passed its medical marijuana act, its General Assembly chose not to amend the state’s FEOA or HRA to remove the Federal CSA language prohibiting use of Schedule I drugs, including medical marijuana. Because the medical marijuana act did not change or remove the reference to the Federal CSA, the court found that Ms H’s medical marijuana use was still “illegal” under the state’s FEOA and HRA.The court thus held that Ms H was not entitled to an accommodation from the school for her medical marijuana use, and the case was dismissed. In a separate opinion, a judge called on the state legislature to remove the Federal CSA wording. “The conflict among these statutes has created an absurd result in requiring … citizens to choose the benefits of medical marijuana or the protections of the HRA and the FEOA,” she wrote. “This quagmire for individuals whose physicians have [recommended] medical marijuana for their use as authorized by the medical marijuana act, but who are then precluded from using the same because of the risk to their employment and education since such use is still illegal under the law, is an untenable position.” Protecting Yourself
The juxtaposition of state and federal law differing on whether marijuana is a Schedule I drug is surely coming to a head as over 33 states and the District of Columbia have medical marijuana programs. ■ Editor’s Note: On December 4, 2020, the US House of Representatives voted 228-164 to pass a bill that would decriminalize marijuana and expunge nonviolent marijuana-related convictions. The legislation, known as the Marijuana Opportunity, Reinvestment, and Expungement (MORE) Act, does not legalize marijuana at the federal level, but would remove cannabis from the Drug Enforcement Administration’s Schedule I drug classification. The Senate has yet to take up the bill. Ann W. Latner, JD, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.
42 THE CLINICAL ADVISOR • JANUARY/FEBRUARY 2021 • www.ClinicalAdvisor.com