Reversible Cerebral Vasoconstriction Syndromes Are Frequently Confused With CNS Vasculitis

STOWE, VT—Reversible cerebral vasoconstriction syndromes (RCVS), a diverse group of conditions characterized by reversible vasoconstriction and sudden thunderclap headache with or without associated neurologic deficits, have been poorly differentiated in the literature and are frequently confused with CNS vasculitis. At the 18th Annual Headache Symposium, David W. Dodick, MD, addressed areas of uncertainty regarding this group of conditions by discussing distinguishing clinical features, as well as treatment options.

DISTINGUISHING RCVS FROM CNS VASCULITIS

In 2007, Dr. Dodick and colleagues published a literature review in the Annals of Internal Medicine, in which they concluded that a variety of conditions may represent one syndrome—RCVS. Conditions with evidence of reversible cerebral vasoconstriction include Call-Fleming syndrome, benign angiopathy of the CNS, postpartum angiopathy, thunderclap headache with reversible vasospasm, migrainous vasospasm or migrainous angiitis, and drug-induced cerebral arteritis or angiopathy.

“If you go through the literature and you look at all of these syndromes that are described, they’re basically describing these young people with thunderclap headache with a normal CT and CSF, who have vasoconstriction on their angiogram that reverses within four to eight weeks,” said Dr. Dodick, Professor of Neurology at the Mayo Clinic College of Medicine in Scottsdale, Arizona. “Usually, there is a self-limiting benign outcome.”

The term “thunderclap headache” was originally coined in 1986 to describe an explosive headache associated with an unruptured cerebral aneurysm, with intensity that usually peaks within 30 seconds—as sudden and unexpected as a “clap of thunder.” Today, the term is used in relation to not only unruptured cerebral aneurysm but also isolated symptoms associated with primary and secondary headaches. Particularly, it can include subarachnoid hemorrhage, sentinel headache, cerebral venous sinus thrombosis, cervical artery dissection, pituitary apoplexy, acute hypertensive crisis, spontaneous intracranial hypotension, third ventricle colloid cyst, primary thunderclap headache, and primary sexual and exertional headache.

“You would never try to differentiate between [RCVS] and true CNS vasculitis based on the angiogram. It’s just too difficult,” said Dr. Dodick. However, several clinical features distinguish RCVS from CNS vasculitis. Patients with RCVS usually have severe acute headache, with or without neurologic signs and symptoms, that recurs over several days to weeks. “You rarely see thunderclap headache in patients with primary angiitis,” noted Dr. Dodick. In patients with CNS vasculitis, “the headache is indolent, it’s progressive, it’s persistent.” CSF examination results are usually normal or near normal in patients with RCVS but abnormal in more than 95% of patients with CNS vasculitis. CT and MRI scans, particularly MRI, are normal in patients with RCVS, although posterior reversible encephalopathy syndrome or “watershed” stroke may be observed; however, in primary angiitis, the MRI scan is abnormal in more than 90% of patients.

“I’ve never seen a case of true documented histologic CNS vasculitis with a normal parenchymal MRI,” said Dr. Dodick. Also, in patients with RCVS, the angiogram demonstrates multifocal segmental vasoconstriction. “Importantly, because of the term ‘reversible,’ their angiogram must come back to normal within 12 weeks,” he added.

IS RCVS OVERLOOKED AND UNDERDIAGNOSED

RCVS may be underdiagnosed, according to Dr. Dodick. “Noninvasive angiography is often not done in patients who have thunderclap headache with a negative CT and CSF,” he said. “In emergency departments all over the country, when these patients come into the hospital, they get a CT scan and a CSF, because what the physician is worried about is a subarachnoid hemorrhage. They invariably do not undergo noninvasive angiography if the CT and CSF examinations are normal.”

Dr. Dodick presented the case of a 38-year-old woman with recurrent primary sexual headache who was diagnosed presumptively with CNS vasculitis. With almost every sexual activity, she had a thunderclap headache, for which she was taking six triptans per day. An angiogram revealed multiple areas of vasoconstriction in the anterior and posterior circulation. This patient went on to experience bilateral posterior watershed infarctions after a recurrent thunderclap headache.

In another case, a 28-year-old man biked 100 miles to the top of a mountain and experienced a thunderclap headache, which recurred every time he exercised thereafter. He received a presumptive diagnosis of primary exertional headache, but a subsequent angiogram showed multiple areas of vasoconstriction. After treatment with a calcium channel blocker, his angiogram was normalized and he became asymptomatic.

“Primary sexual headache can sometimes be associated with cerebral vasoconstriction, and primary exertional headache can as well,” said Dr. Dodick. “So it behooves us to consider this diagnosis in these patients with these presumptive primary headache diagnoses. It also behooves us to consider that the classification for these primary headache disorders needs to be altered to specifically exclude RCVS.”

It is possible that RCVS is a more frequent cause of thunderclap headache than is recognized, he said, referring to a study conducted by Chen et al. Eighty-three patients with recurrent thunderclap headache were administered CSF examinations and CT. Fifty-six of the patients had thunderclap headache of unknown etiology. When these patients underwent magnetic resonance angiography (MRA), 39% were found to have reversible cerebral vasoconstriction. Dr. Dodick noted that the mean time to the first MRA was 11 days, and some patients did not have an MRA until up to 32 days, “indicating the possibility that 39% is likely a conservative estimate since resolution of vasoconstriction may have occurred by the time the MRA was done in some patients.” This notion was reinforced by a recent study by Ducros et al in 67 patients with RCVS, in which 21% of patients who ultimately demonstrated vasoconstriction on noninvasive angiography initially had normal angiographic studies; in other words, there was a lag between the onset of symptoms and the presence of vasoconstriction on noninvasive angiography. This suggests that cerebral vasoconstriction may begin in smaller distal vessels that extend beyond the resolution of MRA before involving larger proximal cerebral blood vessels.

“I think all patients with thunderclap headache require angiography, at least noninvasive; some probably require catheter angiography, after initial CSF and brain imaging are done and are found to be normal,” Dr. Dodick continued. He speculated that RCVS is a common cause of angiographic thunderclap headache, “no matter what clinical circumstance it occurs under, whether it’s during just a routine Valsalva maneuver, whether it’s spontaneous, or whether it occurs with orgasm.”

TREATMENT OF RCVS

Treatment of RCVS is based on anecdotal evidence. Differentiating between true CNS vasculitis and RCVS is important, as treatment for the two conditions differs. “We felt there was enough in the literature to suggest that patients with [RCVS], particularly if they had transient neurologic symptoms, should be treated with nimodipine or verapamil,” said Dr. Dodick. “I’ve now since changed that recommendation, suggesting that all patients with RCVS be treated with nimodipine or verapamil until angiographic resolution occurs, even if neurologic symptoms are not present.

“The only downside to using a calcium channel blocker in this group of patients would be that if their vasospasm is so severe and you precipitously drop their blood pressure, you could compromise cerebral diffuse pressure to an area of the brain that’s already compromised,” he concluded.

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