{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T03:40:30Z","timestamp":1780630830678,"version":"3.54.1"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T00:00:00Z","timestamp":1744848000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Orthostatic intolerance, with or without postural orthostatic tachycardia syndrome (POTS), is collectively referred to as orthostatic intolerance dysautonomia syndromes (OIDS). This condition often presents with daytime hyperventilation, which is considered to be secondary to sympathetic hyperactivity. This hyperventilation appears to be a key characteristic in a newly described subset of patients with OIDS who also exhibit craniocervical instability, mast cell activation syndrome (MCAS), hypermobility spectrum disorder (HSD), and the phenomenon of alternating intracranial hypertension with hypotension due to cerebrospinal fluid (CSF) leaks, collectively termed Spiky-Leaky Syndrome (SLS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed a retrospective review of clinical metabolic exercise data in young patients with SLS, comparing them to matched patients with OIDS and healthy controls (CTL). We assessed metabolic parameters at rest, at the anaerobic threshold (AT), and at maximal oxygen consumption (VO<jats:sub>2<\/jats:sub>max). The parameters included end-tidal CO<jats:sub>2<\/jats:sub> (ETCO<jats:sub>2<\/jats:sub>), end-tidal O<jats:sub>2<\/jats:sub> (ETO<jats:sub>2<\/jats:sub>), peak oxygen pulse, total work performed, and peak oxygen uptake efficiency slope (OUESp).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of 323 reviewed exercise stress tests, 44 were conducted on patients with SLS, 210 on those with OIDS, and 53 on healthy controls. VO<jats:sub>2<\/jats:sub>max, AT, peak oxygen pulse, total work performed, and OUESp were all significantly reduced in patients with OIDS and were further reduced in those with SLS. ETCO<jats:sub>2<\/jats:sub> levels were notably lower at rest, at the time of the anaerobic threshold, and at the time of maximal oxygen uptake in the OIDS group, and even more so in the SLS group. These lower levels of ETCO<jats:sub>2<\/jats:sub> persisted throughout exercise. In contrast, ETO<jats:sub>2<\/jats:sub> demonstrated a similarly strong but opposite trend.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Compared to the control group, patients with OIDS\u2014and especially those with SLS\u2014exhibited reduced metabolic parameters, particularly a decrease in peak oxygen pulse and ETCO<jats:sub>2<\/jats:sub> levels during both rest and exercise. These findings suggest a reduction in ventricular preload and chronic daytime hyperventilation. These exercise parameters may serve as markers for POTS physiology and sympathetic hyperactivity, both of which could play a role in the pathophysiology of SLS.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2025.1512671","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T04:10:16Z","timestamp":1744863016000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Hyperventilation during rest and exercise in orthostatic intolerance and Spiky-Leaky Syndrome"],"prefix":"10.3389","volume":"16","author":[{"given":"Amir","family":"Hashemizad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerriel","family":"Dela Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditya","family":"Narayan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Maxwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1007\/s10484-022-09536-4","article-title":"Cardiovascular autonomic regulation, Etco(2) and the heart rate response to the tilt Table test in patients with orthostatic intolerance","volume":"47","author":"Wheeler","year":"2022","journal-title":"Appl Psychophysiol Biofeedback"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1161\/HYPERTENSIONAHA.113.02824","article-title":"Reduced cerebral blood flow with orthostasis precedes hypocapnic hyperpnea, sympathetic activation, and postural tachycardia syndrome","volume":"63","author":"Del Pozzi","year":"2014","journal-title":"Hypertension"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1203\/00006450-200008000-00016","article-title":"Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion","volume":"48","author":"Stewart","year":"2000","journal-title":"Pediatr Res"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1659","DOI":"10.1152\/japplphysiol.00266.2012","article-title":"Mechanisms of sympathetic regulation in orthostatic intolerance","volume":"113","author":"Stewart","year":"2012","journal-title":"J Appl Physiol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.crphys.2021.01.002","article-title":"Postural orthostatic tachycardia syndrome: a respiratory disorder?","volume":"4","author":"Stewart","year":"2021","journal-title":"Curr Res Physiol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1016\/j.jacbts.2024.04.011","article-title":"Reduced stroke volume and brain perfusion drive postural hyperventilation in postural orthostatic tachycardia syndrome","volume":"9","author":"Baker","year":"2024","journal-title":"JACC Basic Transl Sci"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e0204419","DOI":"10.1371\/journal.pone.0204419","article-title":"Hypocapnic cerebral hypoperfusion: a biomarker of orthostatic intolerance","volume":"13","author":"Novak","year":"2018","journal-title":"PLoS One"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1161\/01.STR.29.9.1876","article-title":"Hypocapnia and cerebral hypoperfusion in orthostatic intolerance","volume":"29","author":"Novak","year":"1998","journal-title":"Stroke"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/s10286-013-0199-5","article-title":"Orthostatic intolerance without postural tachycardia: how much dysautonomia?","volume":"23","author":"Parsaik","year":"2013","journal-title":"Clin Auton Res"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.1161\/HYPERTENSIONAHA.120.16113","article-title":"Supine parasympathetic withdrawal and upright sympathetic activation Underly abnormalities of the Baroreflex in postural tachycardia syndrome: effects of Pyridostigmine and digoxin","volume":"77","author":"Stewart","year":"2021","journal-title":"Hypertension"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"e15639","DOI":"10.14814\/phy2.15639","article-title":"Influence of end-tidal co(2) on cerebral blood flow during orthostatic stress in controls and adults with myalgic encephalomyelitis\/chronic fatigue syndrome","volume":"11","author":"Van Campen","year":"2023","journal-title":"Physiol Rep"},{"key":"ref12","author":"Maxwell","year":"2022"},{"key":"ref13","article-title":"The embryology and potential mechanisms that tie together the pentad. 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