Fig. 4

Proposed model of the pathophysiology of RCVS. Development of RCVS is sequential, which may require both predisposition and precipitating factors to initiate and perpetuate a vicious cycle of pathogenic mechanisms that result in the clinical and radiological manifestations (as indicated by the gradient arrow on the left of the figure). Dysregulation of cerebral vascular tone and disruption of blood–brain barrier (BBB) (i.e., dysfunctional neurovascular unit) might play the key roles in the pathophysiology of RCVS, which could be mediated by the mechanical and biochemical consequences of heightened sympathetic drive, endothelial dysfunction and oxidative stress. This could particularly occur in vulnerable subjects with certain predisposition when they encounter secondary causes (e.g., vasoactive substances, post-partum state, etc.), triggers (e.g., exertion, defecation, sexual activity, cough or bathing), or adverse environment (e.g., cold weather). When the dysfunctional autoregulation and BBB disruption exacerbate and the endogenous protective mechanisms fail, headache, vasoconstrictions, and complications may ensue. The thunderclap headache could be attributed either to the dilatation of distal arterioles or meningeal arteries, that activate the trigeminovascular nociceptive fibers. Hemorrhagic complications (cSAH and ICH) or PRES may be attributed to the breakdown of BBB, while the ischemic stroke is related to hypoperfusion caused by vasoconstriction of major cerebral arteries. White matter hyperintensity lesions could be attributed to either increased BBB permeability or partial ischemia due to cerebral hypoperfusion. BDNF brain-derived neurotrophic factor, cSAH convexity subarachnoid hemorrhage, ET-1 endothelin-1, ICH intracerebral hemorrhage, NPY neuropeptide Y, PRES posterior reversible encephalopathy syndrome, TCH thunderclap headache, TGFBR2 transforming growth factor-beta receptor 2, WMH white matter hyperintensity lesion