Acquired Dysautonomia

Educational Objectives

The goal of this program is to improve the management of acquired dysautonomia in pediatric patients. After hearing and assimilating this program, the clinician will be better able to:

1. Recommend lifestyle modifications for patients with postural orthostatic tachycardia syndrome.
2. Assess the efficacy of new treatments for migraine.

Summary

Acquired dysautonomia: common; migraine, orthostatic intolerance, postural orthostatic tachycardia syndrome (POTS), postconcussive symptoms, and post-COVID syndrome all involve dysautonomia; despite the fact that dysautonomia is twice as prevalent as asthma, diabetes, and osteoarthritis combined, it receives relatively little attention; risk factors — include female sex, adolescent age, obesity, a family history of conditions (eg, migraine, syncope), joint hypermobility, type A personality, and socioeconomic status; environmental triggers, eg, trauma, infection, vaccination, anesthesia, hormonal changes, may contribute to the development of dysautonomia; symptoms include headache, lightheadedness, body and joint pain, bloating, nausea, constipation, temperature intolerance, and anxiety; these symptoms manifest as various clinical syndromes, including migraine, new daily persistent headache, POTS, amplified musculoskeletal pain syndrome (AMPS), myalgic encephalopathy (fibromyalgia), complex regional pain syndrome, post-COVID syndrome, postconcussive syndrome, and Raynaud syndrome

Manifestations of dysautonomia: migraine−affects ≈25% of the population, with ≈1% experiencing headaches 15 days/mo and ≈3% having daily headaches; boys have a disproportionately high rate of migraine before puberty (may have migraine precursors, eg, cyclic vomiting); orthostatic intolerance — patients experience, eg, dizziness, lightheadedness, upon standing because of a drop in blood pressure (BP); POTS — development of tachycardia upon standing, without a significant drop in BP; affects 1 to 3 million Americans; postconcussive syndromes — symptoms last >4 mo after a concussion, potentially overlapping with other dysautonomia-related conditions; post-COVID syndrome (long COVID) — symptoms last >12 wk after infection and include fatigue, “brain fog,” numbness, headache, depression, insomnia, and changes in heart rate, taste, and smell

Pathophysiology: the autonomic nervous system (ANS) is responsible for automatic bodily functions, eg, heart rate, BP, digestion, temperature, pain perception; linked to the amygdala (emotional memory cortex) and evolved to provide protection from danger; although modern humans seldom face the dangers for which the response evolved, it is now induced by less threatening situations; manifestations include, eg, rapid heartbeat, abdominal pain, sweating; dysautonomia occurs when the ANS becomes imbalanced, causing excessive parasympathetic activity and a lack of glucose supply to the brain, leading to, eg, lightheadedness, brain fog, memory issues, headaches, nausea, temperature instability, reticular rash; patients develop hypervigilance for symptoms and constantly scan their bodies for symptoms; psychological support plays a crucial role in treatment

Migraine: >38 migraine-related genes have been identified; environmental triggers include changes in barometric pressure, metabolic factors (eg, skipping meals, menstruation), and medication use or withdrawal; the migraine prodrome occurs ≈36 hr before a migraine and involves yawning, hunger, irritability, and a cold sensation (ie, hypothalamic functions); the brainstem becomes activated and calcitonin gene-related peptide (CGRP) is released, which triggers spreading cortical depolarization (ie, a wave of neuronal activity that moves from posterior to anterior), leading to blood vessel dilation, trigeminal nerve stretching, and head pain; migraine auras follow this pattern, starting occipitally with visual auras and progressing to sensory, speech, and motor auras

Postural orthostatic tachycardia syndrome: vasodilation causes relative hypovolemia; blood primarily pools in the lower extremities and the brain receives insufficient energy; autonomic denervation is present to some degree, as evidenced by small-fiber neuropathy on skin biopsy; deconditioning, which occurs when chronic symptoms cause individuals to rest frequently, exacerbates the vasodilation and increases cortisol levels; deconditioning makes exercise difficult, creating a “vicious cycle”

Lifestyle and behavioral recommendations: maintaining proper hydration is essential; patients may be counseled to consume an amount of water in ounces equal to their weight in pounds, up to a maximum of 100 oz; caffeine mimics the sympathetic nervous system and artificial sweeteners mimic the parasympathetic system (patients are advised to avoid these substances to avoid worsening symptoms); high-intensity interval training and specific aerobic exercise protocols can help recalibrate the ANS; although it can be challenging, regular exercise is vital for improvement; adequate sleep based on age (typically, 8-12 hr) is crucial; maintaining consistent sleep-wake times and avoiding daytime naps are recommended for regulating circadian rhythms; consuming some glucose immediately on waking and a high-protein snack at bedtime may help maintain glycemia; patients should remain engaged in daily activities (ie, school) and avoid symptom-focused discussions or diaries

New medications

Ditans: lasmiditan (Reyvow) binds to a different subreceptor than tryptans; does not cause the vasoconstriction that causes patients to feel unwell; likely safe, even for patients with sickle cell disease; however, it induces sleep for 4 hr, which can be challenging

CGRP-receptor antagonists: monoclonal antibodies erenumab (Aimovig), fremanuzumab (Ajovy), and galcanezumab (Emgality) are given monthly for migraine prevention, and eptinezumab (Vyepti) is an infusion that lasts for 3 mo; adverse effects (eg, constipation, dislike of injections) occur in <5% of users; whereas earlier studies defined efficacy as a 50% reduction in headache frequency, studies of these newer medications use median number of headaches per month as the primary outcome; as a result, efficacy of the new medications may be inflated; oral CGRP antagonists (gepants) — include rimegepant (Nurtec) and ubrogepant (Ubrelvy); show more promise in terms of efficacy and are generally well tolerated; not yet approved for children

Remote electrical neuromodulation (Nerivio): approved by the US Food and Drug Administration for headache treatment and prevention; worn on the arm and connects to a smartphone; users select an intensity level just below their pain threshold; the stimulation of nociceptors in the arm exhausts the sensory cortex and reduces sensory perception for ≈24 hr; ≈60% of adolescents respond positively; of these, 90% are free of pain for 24 hr; the main risk is discomfort; not usually covered by insurance but offers a cost-effective alternative to emergency department visits and multiple medications

Indomethacin: some headache disorders (eg, trigeminal autonomic cephalgias [TACs], which include cluster headaches) respond to indomethacin, a nonsteroidal anti-inflammatory drug; patients with post-COVID TAC-like symptoms (eg, unilateral swollen eyelid) have shown complete response to indomethacin; similar results were reported in a South American trial; indomethacin stimulates the ANS

Research paradigm: clinical trials increasingly follow a patient-centric model; basket trials use targeted therapies for multiple diseases that have shared molecular alterations; umbrella trials study one disease with different molecular variations, with testing of several medications; platform trials test multiple interventions for a single disease and track outcomes over time; master observation trials gather extensive patient data, including genomics, and use artificial intelligence (AI) to identify effective treatments based on individual characteristics; these innovative trial approaches aim to transform drug development, which currently takes ≥15 yr and billions of dollars; AI-driven research can potentially shorten this timeframe to <5 yr; AI uses diverse data sources (eg, electronic health records, wearables) to better gauge treatment effectiveness and allow personalization of therapies

Readings

Fu Q, Levine BD. Exercise and non-pharmacological treatment of POTS. Auton Neurosci. 2018;215:20-27. doi:10.1016/j.autneu.2018.07.001; Goadsby PJ, Wietecha LA, Dennehy EB, et al. Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine. Brain. 2019;142(7):1894-1904. doi:10.1093/brain/awz134; Goadsby PJ. Pathophysiology of migraine. Ann Indian Acad Neurol. 2012;15(Suppl 1):S15-S22. doi:10.4103/0972-2327.99993; Hovaguimian A. Dysautonomia: diagnosis and management. Neurol Clin. 2023;41(1):193-213. doi:10.1016/j.ncl.2022.08.002; Krymchantowski AV, Silva-Néto RP, Jevoux C, et al. Indomethacin for refractory COVID or post-COVID headache: a retrospective study. Acta Neurol Belg. 2022;122(2):465-469. doi:10.1007/s13760-021-01790-3; Nierenburg H, Stark-Inbar A. Nerivio^® remote electrical neuromodulation for acute treatment of chronic migraine. Pain Manag. 2022;12(3):267-281. doi:10.2217/pmt-2021-0038; Olshansky B, Cannom D, Fedorowski A, et al. Postural Orthostatic Tachycardia Syndrome (POTS): A critical assessment. Prog Cardiovasc Dis. 2020;63(3):263-270. doi:10.1016/j.pcad.2020.03.010; Orr SL, Kabbouche MA, O'Brien HL, et al. Paediatric migraine: evidence-based management and future directions. Nat Rev Neurol. 2018;14(9):515-527. doi:10.1038/s41582-018-0042-7; Safavi-Naeini P, Razavi M. Postural orthostatic tachycardia syndrome. Tex Heart Inst J. 2020;47(1):57-59. Published 2020 Feb 1. doi:10.14503/THIJ-19-7060; Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16(6):425-434. doi:10.1016/S1474-4422(17)30083-2; Vandervorst F, Van Deun L, Van Dycke A, et al. CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs. J Headache Pain. 2021;22(1):128. Published 2021 Oct 25. doi:10.1186/s10194-021-01335-2.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. DiSabella's lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. DiSabella was recorded at Hot Topics in Pediatrics 2023, held July 20-22, 2023, in Lake Buena Vista, FL, and presented by the Nemours Children's Health. For information about upcoming CME activities from this presenter, please visit https://www.nemours.org/education/cme.html. Audio Digest thanks Dr. DiSabella and Nemours Children's Health for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

NE142402

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.