Nancy A. Melville

November 20, 2017

SCOTTSDALE, Arizona — Distinctive signs of breakdown of the blood-brain barrier (BBB) are commonly evident in patients with reversible cerebral vasoconstriction syndrome (RCVS), providing potential diagnostic clues for the serious condition even in the absence of vasoconstriction.

The findings are from a study first published in the Annals of Neurology and highlighted in a session here at the American Headache Society (AHS) 2017 Scottsdale Headache Symposium.

"The study shows that in as many as 70% of patients classified as having RCVS, contrast-enhanced flare sequencing imaging showed this remarkable breakdown of the blood-brain barrier, indicating that there is activity at the capillary level and it often is present even in the absence of initial vasoconstriction," said presenter David W. Dodick, MD, professor of neurology at the Mayo Clinic in Scottsdale. Dr Dodick, who was not involved in the study, discussed the paper during the session here.

RCVS, characterized by the acute onset of a severe, recurrent headache and reversible vasoconstriction of cerebral arteries, is increasingly recognized as the most common cause of a "thunderclap" headache and is linked to potentially serious outcomes ranging from seizure and ischemic infarcts to intracerebral hemorrhage and even death.

Early diagnosis is meanwhile challenging, with initial angiograms sometimes normal and the narrowing of distal cerebral arteries difficult to detect with certainty on resonance (MR) or computed tomography (CT) angiography.

BBB breakdown, which has been theorized to play a role in RCVS pathophysiology, can be visualized on contrast-enhanced fluid-attenuated inversion recovery (CE-FLAIR) MRI, and the modality is commonly used to evaluate BBB breakdown in various other conditions.

To look at the role of BBB breakdown in RCVS, the study authors, from the Neuroscience Center at Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, evaluated 72 patients with thunderclap headache.

Aneurysmal subarachnoid hemorrhage had been ruled out in all patients. Thirty-seven (51.4%) were recruited from the emergency department, 3 (4.2%) from inpatient consultation, and 32 (44.4%) from the outpatient clinic.

The patients were recruited a median of 7 days from onset. RCVS, based on International Classification of Headache Disorders-3 beta criteria and neuroimaging, was diagnosed in 41 (56.9%) of cases: 29 with definite RCVS and 12 with probable RCVS.

Other secondary causes of headache were identified by neuroimaging in 7 patients, and 24 (33.3%) had thunderclap headaches of undetermined cause.

CE-FLAIR MRI showed that BBB breakdown was present in as many as 20 patients (69%) diagnosed with definite RCVS, in 3 (25%) with probable RCVS, and in 3 (12.5%) with thunderclap headache of undetermined cause.

None of the patients with other secondary causes of thunderclap headache showed BBB breakdown.

The BBB breakdown was present in as many as 19 patients with RCVS who did not have concomitant posterior reversible encephalopathy syndrome (PRES) and in 4 who did have the syndrome.

Furthermore, in patients with RCVS, the extent of BBB breakdown was independently associated with neurologic complications (odds ratio, 1.48 per one territorial increase; P = .03).

The presence of BBB breakdown allowed for the new classification of RCVS in 3 patients (12.5%) who had thunderclap headache of undetermined cause.

The authors noted that the findings are important because angiographic narrowing, which is currently the only finding to initially indicate a diagnosis of RCVS, is not always conclusive as a result of significant interobserver variations and overlap with other cerebrovascular diseases.

They added that BBB breakdown was the only independent factor to be associated with any composite neurologic outcomes, in addition to the composite of subarachnoid hemorrhage and PRES.

"This is the first study to demonstrate BBB breakdown in patients with RCVS," the authors concluded.

"BBB breakdown was frequently present in patients with imaging-proven RCVS, even without concomitant PRES. It enabled the diagnosis of RCVS in patients with diagnostic uncertainty.

"Furthermore, BBB breakdown was independently associated with increased risk of neurological complications."

The authors speculated that BBB breakdown could play a role in RCVS in two ways: First, the BBB's integrity could be compromised by ischemic or hypoxic injury resulting from vasoconstriction.

Second, they suggested, "the impairment of BBB integrity may precede and determine the vulnerability to developing vasoconstriction."

Dr Dodick agreed the findings suggest important additional clues clinicians can look at in considering an RCVS diagnosis.

"Vasoconstriction can be delayed for up to 2 weeks in about 25% of these cases, so even some of the most astute physicians can miss it," he said.

"What this tells us is when you first see these patients and do your CT or MR angiography and you don't see vasoconstriction, there are other things to look at, including this cortical subarachnoid blood, elevated transcranial Doppler velocities and now blood-brain barrier breakdown on CE-FLAIR sequencing that can raise suspicion of this diagnosis."

With the potential severity of outcomes, any opportunity to improve diagnosis can be critical, he added.

"The important thing about an RCVS diagnosis is up to a third of these patients (28%) can have an intracranial hemorrhage within week 1 or 20% can have an ischemic stroke week 2," he cautioned.

"So this is not the patient you want to dismiss from your office or the emergency department, because it will come back to haunt you."

The authors have disclosed no relevant financial relationships. Dr Dodick's disclosures include consulting for Acorda, Allergan, Amgen, Alder, Promius, eNeura, Eli Lilly & Company, Insys therapeutics, Autonomic Technologies, Teva, Xenon, Tonix, Trigemina, Nocira, Colucid, Zosano, Laydenburg Thalmann, Biocentric, Biohaven, Magellan, and Charleston Laboratories. He has stock options with Nocira, Epien, Healint, Theranica, and Mobile Health and board positions with King-Devick and Epien.

American Headache Society (AHS) 2017 Scottsdale Headache Symposium.

Ann Neurol. 2017;81:454-466.  Abstract

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