Hyperventilation during rest and exercise in orthostatic intolerance and Spiky-Leaky Syndrome

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).

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 (VO₂max). The parameters included end-tidal CO₂ (ETCO₂), end-tidal O₂ (ETO₂), peak oxygen pulse, total work performed, and peak oxygen uptake efficiency slope (OUESp).

Of 323 reviewed exercise stress tests, 44 were conducted on patients with SLS, 210 on those with OIDS, and 53 on healthy controls. VO₂max, 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. ETCO₂ 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 ETCO₂ persisted throughout exercise. In contrast, ETO₂ demonstrated a similarly strong but opposite trend.

Compared to the control group, patients with OIDS-and especially those with SLS-exhibited reduced metabolic parameters, particularly a decrease in peak oxygen pulse and ETCO₂ 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.