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By Alexander E. Merkler, MD
Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Merkler reports no financial relationships relevant to this field of study.
SYNOPSIS: In this single-center, prospective trial, patients with reversible cerebral vasoconstriction were found to have evidence of blood-brain barrier breakdown on MRI.
SOURCE: Lee MJ, Cha J, Choi HA, et al. Blood-brain barrier breakdown in reversible cerebral vasoconstriction syndrome: Implications for pathophysiology and diagnosis. Ann Neurol 2017;81:454-466.
Reversible cerebral vasoconstriction (RCVS) is a clinical and radiographical syndrome characterized by recurrent thunderclap headache and evidence of reversible luminal narrowing of the cerebral vasculature. RCVS is recognized as the most common cause of thunderclap headache and is commonly triggered by everyday medications such as selective serotonin reuptake inhibitors, nasal decongestants, or the puerperium state.1 Although the vasoconstriction is reversible, complications are common and include ischemic stroke, intracranial hemorrhage, seizures, or death. The underlying pathophysiology of RCVS is poorly understood, but is thought to comprise of dysautoregulation, sympathetic over-activity, and blood-brain barrier (BBB) breakdown. Furthermore, the diagnosis of RCVS often is challenging, as vessel imaging may be normal given the dynamic nature of the disease. In this prospective, single-center study, contrast-enhanced fluid-attenuated inversion recovery (CE-FLAIR) MRI was used to evaluate for BBB breakdown in patients with RCVS and to investigate its role as a novel diagnostic tool. The study enrolled all patients who presented to Samsung Medical Center between 2015-2016 with thunderclap headache. Patients with aneurysmal subarachnoid hemorrhage or contraindication to MRI with gadolinium were excluded. All patients underwent brain MRI with CE-FLAIR within seven (most within two) days of thunderclap headache. Patients were classified as having definitive or probable RCVS according to the International Classification of Headache Disorders-3 beta, in which definite cases had imaging evidence of vasoconstriction and probable cases had supporting clinical features of RCVS without imaging evidence of vasoconstriction.2
Of 72 patients with thunderclap headache, 41 had RCVS (29 definite and 12 probable), seven patients had a secondary cause of thunderclap headache (i.e., ruptured cavernous malformation), and 24 had thunderclap headache of undetermined cause. BBB breakdown was present in 20 (69.0%) patients with definite RCVS, three (25.0%) patients with probable RCVS, three (12.5%) patients with thunderclap headache of undetermined cause, and no patients with a secondary cause of thunderclap headache. CSF was normal in all patients who had evidence of BBB breakdown. Patients with BBB were more likely to have evidence of vasoconstriction (P < 0.010) and were more likely to have multiple vessel involvement (P < 0.012). However, visible vasoconstriction was not always associated with BBB breakdown within the corresponding territory. BBB breakdown frequently was multifocal and most commonly found along the falx or superficially. If BBB breakdown was incorporated into the diagnosis of RCVS, 15/36 (41.7%) patients without a secondary cause of thunderclap headache and normal neuroimaging could have been classified as having RCVS.
Neurological complications, including seizures, posterior reversible encephalopathy syndrome, ischemic stroke, or subarachnoid hemorrhage, were uncommon and occurred in only six patients with RCVS (none in patients with secondary thunderclap headache or thunderclap headache of undetermined cause). All patients with neurological complications had evidence of BBB breakdown, and BBB breakdown was independently associated with the occurrence of a neurological complication (odds ratio, 1.48; 95% confidence interval, 1.04-2.12).
This is the first study to demonstrate that radiographic evidence of BBB breakdown occurs in patients with RCVS. As RCVS often poses a diagnostic challenge, particularly early in its course when angiography may be normal, CE-FLAIR MRI may prove to be a non-invasive tool that may aid in the diagnosis of RCVS.
The study is limited by the fact that it was a single-center study performed exclusively in Asian patients who are prone to intracranial atherosclerosis and potentially greater BBB breakdown. In addition, neurological complications were infrequent and, therefore, the effect of BBB breakdown as a predictor for neurological complications is uncertain.
Overall, this study provides preliminary radiographic evidence of BBB breakdown in patients with RCVS. It remains unclear whether BBB breakdown leads to vasoconstriction or, on the contrary, vasoconstriction leads to BBB breakdown. In either case, if replicated, CE-FLAIR MRI may prove to be a useful adjunct test for the diagnosis of RCVS.
Financial Disclosure: Neurology Alert’s editor in chief, Matthew Fink, MD, reports he is a consultant for Procter & Gamble. Peer reviewer M. Flint Beal, MD; executive editor Leslie Coplin; editor Jonathan Springston; and AHC Media Editorial Group Manager Terrey L. Hatcher report no financial relationships relevant to this field of study.