Abstract
Purpose of Review
Dysautonomia refers to the dysfunction of the autonomic nervous system and encompasses a wide variety of autonomic symptoms and disorders. The most common autonomic disorders are postural orthostatic tachycardia syndrome (POTS), neurocardiogenic syncope (NCS), and orthostatic hypotension (OH), which may be encountered in clinical practice as part of a triad of dysautonomia, hypermobility spectrum disorders (HSD), and mast cell activation syndrome (MCAS). Migraine is one of the most common comorbidities of POTS, HSD, and MCAS; conversely, these conditions are also prevalent in patients with migraine, especially in those with multiple systemic symptoms, such as chronic dizziness, lightheadedness, orthostatic intolerance, joint pain, and allergic symptoms. Diagnostic criteria, pathophysiologic mechanisms, and therapeutic considerations in patients with migraine and comorbid dysautonomia, HSD, and MCAS are reviewed.
Recent Findings
Numerous studies indicate a significant overlap and shared pathophysiology in migraine, dysautonomia, HSD, and MCAS. In clinical setting, dysautonomia, HSD, and MCAS may present a diagnostic and therapeutic challenge in patients with migraine and require a high index of suspicion on the part of the neurologist.
Summary
Diagnosis and treatment of these complex disorders in patients with migraine is essential to comprehensive patient-centric care, reduced symptom burden, and improved functional impairment secondary to both migraine and comorbidities.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance
Sheldon RS, Grubb BP II, Olshansky B, et al. Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 2015;2015(12):e41-63.
Freeman R, Weiling W, Axelrod F, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res. 2011;21:69–72.
Robertson D. The Epidemic of Orthostatic Tachycardia and Orthostatic Intolerance. Am J Med Sci. 1999;317:75–7.
Kizilbash SJ, Ahrens SP, Bruce BK, et al. Adolescent fatigue, POTS, and recovery: a guide for clinicians. Curr Probl Pediatr Adolesc Health Care. 2014;44:108–33.
Low PA, Sandroni P, Joyner M, et al. Postural tachycardia syndrome (POTS). J Cardiovasc Electrophysiol. 2009;20:352–8.
Blitshteyn S. Autoimmune markers and autoimmune disorders in patients with postural tachycardia syndrome (POTS). Lupus. 2015;24:1364–9.
Kharraziha I, Axelsson J, Ricci F, et al. Serum activity against g protein-coupled receptors and severity of orthostatic symptoms in postural orthostatic tachycardia syndrome. J Am Heart Assoc. 2020;9:e015989.
Gunning WT 3rd, Kvale H, Kramer PM, et al. Postural orthostatic tachycardia syndrome is associated with elevated g-protein coupled receptor autoantibodies. J Am Heart Assoc. 2019;8:e013602.
Watari M, Nakane S, Mukaino A, et al. Autoimmune postural orthostatic tachycardia syndrome. Ann Clin Transl Neurol. 2018;5:486–92.
Yu X, Li H, Murphy TA, Nuss Z, et al. Angiotensin II type 1 receptor autoantibodies in postural tachycardia syndrome. J Am Heart Assoc. 2018;7:e008351.
Thieben MJ, Sandroni P, Sletten DM, et al. Postural orthostatic tachycardia syndrome: the Mayo Clinic experience. Mayo Clin Proc. 2007;82:308–13.
Li H, Yu X, Liles C, et al. Autoimmune basis for postural tachycardia syndrome. J Am Heart Assoc. 2014;3:e000755.
Peroutka SJ. Migraine: a chronic sympathetic nervous system disorder. Headache. 2004;44:53–64.
Shechter A, Stewart WF, Silberstein SD, Lipton RB. Migraine and autonomic nervous system function: a population-based, case-control study. Neurology. 2002;58:422–7.
Gass JJ, Glaros AG. Autonomic dysregulation in headache patients. Appl Psychophysiol Biofeedback. 2013;38:257–63.
Vuković V, Plavec D, Galinović I, et al. Prevalence of vertigo, dizziness, and migrainous vertigo in patients with migraine. Headache. 2007;47:1427–35.
Thijs RD, Kruit MC, van Buchem MA, et al. Syncope in migraine: the population-based CAMERA study. Neurology. 2006;66:1034–7.
Blitshteyn S, Cheshire WP Jr. Syncope in migraine: the population-based CAMERA study. Neurology. 2007;68:878.
Thieben MJ, Sandroni P, Sletten DM, et al. Postural orthostatic tachycardia syndrome: the Mayo Clinic experience. Mayo Clinic Proc. 2007;82:308–13.
Ulas UH, Chelimsky TC, Chelimsky G, et al. Comorbid health conditions in women with syncope. Clin Auton Res. 2010;20:223–7.
Khurana RK, Eisenberg L. Orthostatic and non-orthostatic headache in postural tachycardia syndrome. Cephalalgia. 2011;31:409–15.
Shaw BH, Stiles LE, Bourne K et al. The face of postural tachycardia syndrome – insights from a large cross-sectional online community-based survey. JIM. 2019;286:438–448. This study describes the most common comorbidities in a large cohort of patients with POTS.
Blitshteyn S. Is postural orthostatic tachycardia syndrome (POTS) a central nervous system disorder? J Neurol. 2021;7:1–8. This review discusses the shared pathophysiology of POTS and migraine and outlines supporting evidence of both conditions being central nervous system disorders.
Goadsby PJ, Holland PR, Martins-Oliveira M, et al. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. 2017;97:553–622.
Akerman S, Holland P, Goadsby P. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci. 2011;12:570–84.
Kruit MC, Thijs RD, Ferrari MD, et al. Syncope and orthostatic intolerance increase risk of brain lesions in migraineurs and controls. Neurology. 2013;80:1958–65.
Raj SR. Postural tachycardia syndrome (POTS). Circulation. 2013;127:2336–42.
Blitshteyn S. Dietary sodium intake and migraine: is salt the answer? Headache. 2016;56:1210–1.
Pogoda JM, Gross NB, Arakaki X, et al. Severe headache or migraine history is inversely correlated with dietary sodium intake: NHANES 1999–2004. Headache. 2016;56:688–98.
Thijs RD, Brignole M, Falup-Pecurariu C, et al. Recommendations for tilt table testing and other provocative cardiovascular autonomic tests in conditions that may cause transient loss of consciousness. Clin Auton Res. 2021;31:369–84.
Goodman BP. Evaluation of postural tachycardia syndrome (POTS). Auton Neurosci. 2018;215:12–9.
Blitshteyn S, Whiteson JH, Abramoff B, et al. Multi-disciplinary collaborative consensus guidance statement on the assessment and treatment of autonomic dysfunction in patients with post-acute sequelae of SARS-CoV-2 infection (PASC). PM R. 2022;14(10):1270–91.
Schofield JR, Hassell KL. What you need to know about migraine in Hughes syndrome patients. Lupus. 2023;32:319–24.
Del Pozzi AT, Enechukwu M, Blitshteyn S. Postural orthostatic tachycardia syndrome in primary care: diagnosis, treatment and a case of African-American man presenting with POTS. BMJ Case Rep. 2019;12:e229824.
Bourne KM, Sheldon RS, Hall J, et al. Compression garment reduces orthostatic tachycardia and symptoms in patients with Postural Orthostatic Tachycardia Syndrome. J Am Coll Cardiol. 2021;77:285–96.
Ruzieh M, Baugh A, Dasa O, et al. Effects of intermittent intravenous saline infusions in patients with medication-refractory postural tachycardia syndrome. J Interv Card Electrophysiol. 2017;48:255–60.
Silberstein SD, Yuan H, Najib U, et al. Non-invasive vagus nerve stimulation for primary headache: a clinical update. Cephalalgia. 2020;40:1370–84.
Deng J, Li H, Guo Y, et al. Transcutaneous vagus nerve stimulation attenuates autoantibody-mediated cardiovagal dysfunction and inflammation in a rabbit model of postural tachycardia syndrome. J Interv Card Electrophysiol. 2022. https://doi.org/10.1007/s10840-022-01144-w
Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175:8–26.
Boris JR, Bernadzikowski T. Prevalence of joint hypermobility syndromes in pediatric postural orthostatic tachycardia syndrome. Auton Neurosci. 2021;231:102770.
Puledda F, Viganò A, Celletti C et al. A study of migraine characteristics in joint hypermobility syndrome a.k.a. Ehlers-Danlos syndrome, hypermobility type. Neurol Sci. 2015;36:1417–1424.
Zloof Y, Simchoni M, Derazne E et al. Hypermobility spectrum disorders and active migraine in Israeli adolescents: A nationwide study.Headache. 2023;63:934–941. This recent study found a significant association between HSD/hEDS and active migraine in adolescents.
Malhotra A, Pace A, Ruiz MT, et al. Headaches in hypermobility syndromes: A pain in the neck? Am J Med Genet A. 2020;182:2902–8.
Sahjwani D, Cameron M, Stelzik J. et al. Joint hypermobility and associated headache disability. CNS 2019, Abstract 101. CNS Annual Meeting, October 24–26, 2019, Charlotte, NC. 48th National Meeting of the Child Neurology Society 2019. Ann Neurol. 2019;86(Supplement 23):S1–S177. https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.25559.
Henderson FC, Austin C, Benzel E, et al. Neurological and spinal manifestations of the Ehlers-Danlos syndromes. Am J Med Genet Part C Semin Med Genet. 2017;175C:195–211.
Igharo D, Thiel JC, Rolke R, et al. Skin biopsy reveals generalized small fibre neuropathy in hypermobile Ehlers-Danlos syndromes. Eur J Neurol. 2023;30:719–28.
Cazzato D, Castori M, Lombardi R, et al. Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes. Neurology. 2016;87:155–9.
Afrin LB, Self S, Menk J, Lazarchick J. Characterization of Mast Cell Activation Syndrome. Am J Med Sci. 2017;353:207–15.
Afrin LB, Ackerley MB, Bluestein LS, et al. Diagnosis of mast cell activation syndrome: a global "consensus-2". Diagnosis (Berl) 2020;8:137–152. Diagnostic criteria for mast cell activation syndrome is discussed.
Zha K, Brook J, McLaughlin A, Blitshteyn S. Gluten-free diet in postural orthostatic tachycardia syndrome (POTS). Chronic Illn. 2023;19:409–17.
Baun M, Pedersen MH, Olesen J, et al. Dural mast cell degranulation is a putative mechanism for headache induced by PACAP-38. Cephalalgia. 2012;32:337–45.
Ramachandran R, Wang Z, Saavedra C, et al. Role of Toll-like receptor 4 signaling in mast cell-mediated migraine pain pathway. Mol Pain. 2019;15:1744806919867842.
Kilinc E, Torun IE, Baranoglu Kilinc Y. Meningeal mast cell-mediated mechanisms of cholinergic system modulation in neurogenic inflammation underlying the pathophysiology of migraine. Eur J Neurosci. 2022. https://doi.org/10.1111/ejn.15888.
Wang E, Ganti T, Vaou E, Hohler A. The relationship between mast cell activation syndrome, postural tachycardia syndrome, and Ehlers-Danlos syndrome. Allergy Asthma Proc. 2021;42:243–6.
Kohno R, Cannom DS, Olshansky B et al. Mast Cell Activation Disorder and Postural Orthostatic Tachycardia Syndrome: A Clinical Association. J Am Heart Assoc. 2021;10:e021002. The authors found clinical and laboratory evidence of mast cell activation disorder in a majority of 69 patients with POTS who present with migraine, gastrointestinal, cutaneous, and allergic symptoms.
Novak P, Giannetti MP, Weller E, et al. Mast cell disorders are associated with decreased cerebral blood flow and small fiber neuropathy. Ann Allergy Asthma Immunol. 2022;128:299–306.
Funding
No funds, grants, or other support was received.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Svetlana Blitshteyn declares no potential conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Blitshteyn, S. Dysautonomia, Hypermobility Spectrum Disorders and Mast Cell Activation Syndrome as Migraine Comorbidities. Curr Neurol Neurosci Rep 23, 769–776 (2023). https://doi.org/10.1007/s11910-023-01307-w
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11910-023-01307-w