Reversible cerebral vasoconstriction syndromes

Aneesh B Singhal MD (

Dr. Singhal of Harvard Medical School received consulting fees from Deck Therapeutics and Omniox, and his wife is an employee and owns stock in Biogen.

)
Eva A Rocha MD (

Dr. Rocha of Universidade Federal de São Paulo has no relevant financial relationships to disclose.

)
Steven R Levine MD, editor. (

Dr. Levine of the SUNY Health Science Center at Brooklyn has no relevant financial relationships to disclose.

)
Originally released December 16, 2003; last updated April 5, 2020; expires April 5, 2023

This article includes discussion of reversible cerebral vasoconstriction syndromes, benign angiopathy of the central nervous system, benign cerebral vasculitis, Call syndrome, Call-Fleming syndrome, cerebral pseudovasculitis, cerebral Raynaud phenomenon, migraine angiitis, migrainous vasospasm, postpartum angiopathy, reversible cerebral vasoconstriction syndrome, reversible angiitis, and reversible cerebral angiopathy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Reversible cerebral vasoconstriction syndromes are characterized by recurrent, severe “thunderclap” headaches and multifocal cerebral arterial narrowing and dilatation, often complicated by ischemic or hemorrhagic strokes or reversible brain edema. Reversible cerebral vasoconstriction syndromes affect young individuals, mostly women, and have been associated with diverse conditions such as pregnancy, migraine, vasoconstrictive drug use, pheochromocytoma, and neurosurgical procedures. Until recently, reversible cerebral vasoconstriction syndromes were considered rare and were frequently misdiagnosed as primary angiitis of the CNS because of overlapping clinical-angiographic features. With the publication of comprehensive review articles and large case series and the advent of relatively noninvasive diagnostic tests such as CT-angiography and MR-angiography, reversible cerebral vasoconstriction syndromes are being recognized and diagnosed more frequently. In this article, the author provides a comprehensive overview of reversible cerebral vasoconstriction syndromes.

Key points

 

• Reversible cerebral vasoconstriction syndromes are an instantly recognizable entity. They have distinct clinical, laboratory, imaging, and angiographic features that allow easy diagnosis and distinction from mimics such as cerebral vasculitis and ruptured brain aneurysms. The recently developed RCVS2 score accurately distinguishes reversible cerebral vasoconstriction syndromes from other intracranial arteriopathies.

 

• Most patients present with recurrent thunderclap headaches. Ischemic stroke, brain hemorrhage, and cerebral edema can develop in approximately 35% to 40% of patients within the first one to three weeks, but approximately 95% of patients have benign 3-month outcomes with little or no residual neurologic deficits.

 

• Because the natural history of reversible cerebral vasoconstriction syndrome is spontaneous resolution within a few weeks, simple observation with liberal pain control and avoidance of physical exertion is usually adequate. Calcium-channel blockers may reduce the intensity of headaches. Glucocorticoids should be avoided. Intraarterial vasodilator therapy should be reserved for the rare patient with unrelenting clinical progression.

Historical note and terminology

Angiographic narrowing of intracerebral arteries usually results from pathological conditions such as atherosclerosis, inflammatory vasculitis, infectious arteritis, and fibromuscular dysplasia. Reversible cerebral arterial vasoconstriction has been considered a rare phenomenon, except when associated with aneurysmal subarachnoid hemorrhage (“vasospasm”). However, over the last six decades, numerous case reports have documented reversible multifocal cerebral vasoconstriction on serial angiography in patients without aneurysmal subarachnoid hemorrhage and without evidence for infection or inflammation. Descriptions of this phenomenon date back to the 1960s (Armstrong and Hayes 1961; Buckle 1964; Rascol 1979). Reversible cerebral vasoconstriction has been associated with diverse conditions including the postpartum state, use of vasoconstrictive drugs, migraine, thunderclap headache, other primary headaches, cerebral trauma, and hypertensive encephalopathy, among others (Table 1).

Table 1. Precipitating Factors Associated with Cerebral Vasoconstriction Syndromes

(A) Pregnancy and puerperium

Early puerperium, late pregnancy, eclampsia, pre-eclampsia, delayed post-partum eclampsia

(B) Exposure to drugs
and blood products

Sympathomimetic medications: phenylpropanolamine, pseudoephedrine, phenylephrine, epinephrine, ergotamine tartrate, isometheptene, midodrine, methylergonovine, bromocriptine, hydroxycut, lisuride
Antidepressants: selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors (SNRIs)
Migraine medications: sumatriptan and other triptans
Anti-inflammatory: indomethacin, etoricoxib
Illicit drugs: cocaine, ecstasy, amphetamine derivatives, marijuana, lysergic acid diethylamide
Immunosuppressants/immunomodulators: tacrolimus (FK-506), cyclophosphamide, interferon, fingolimod, etanercept, tocilizumab
Hormonal agents: oral contraceptive pills, ovarian stimulation, isoflavones
Other: methylergonovine, hydroxycut, lisuride, bromocriptine, erythropoietin, intravenous immune globulin (IVIg), nicotine patches, red blood cell transfusions, licorice, Ma Huang (ephedra), atovaquone, caffeine withdrawal, eucalyptus

(C) Miscellaneous

Hypercalcemia, porphyria, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, pheochromocytoma, bronchial carcinoid tumor, unruptured saccular cerebral aneurysm, head trauma, spinal subdural hematoma, post-carotid endarterectomy or carotid stenting, neurosurgical procedures, carotid glomus tumor, tonsillectomy, neck surgery, high altitude, winter climate, repetitive transcranial magnetic stimulation

(D) Idiopathic

No identifiable precipitating factor.

Associated with headache disorders such as migraine, primary thunderclap headache, benign exertional headache, benign sexual headache, primary cough headache

Given the diversity of the associated conditions, patients with these syndromes have been described in the literature using variable nosology. For example, “migrainous vasospasm” (Serdaru et al 1984) or “migraine angiitis” (Jackson et al 1993) for patients with prior migraine; “postpartum angiopathy” (Rascol 1979; Bogousslavsky et al 1989; Raroque et al 1993) when associated with pregnancy or puerperium; and “drug-induced vasculitis” (Kaye and Fainstat 1987) when associated with drug exposure. At the 1987 Boston Stroke Society meeting, Marie Fleming presented two patients with reversible cerebral vasoconstriction. The following year Drs. Call, Fleming, C Miller Fisher, and others described these patients and several additional personal cases in a series titled “Reversible Cerebral Segmental Vasoconstriction” (Call et al 1988).

Over the past decade, Singhal and others have recognized that despite the wide range of associated conditions and varied nosology, these patients have an easily recognizable clinical-imaging syndrome characterized by severe headaches and reversible cerebral angiographic abnormalities, often complicated by seizures and ischemic or hemorrhagic stokes. Consequently, these syndromes are now collectively referred to as “reversible cerebral vasoconstriction syndromes,” (RCVS) and multiple studies have characterized reversible cerebral vasoconstriction syndromes over the last few years (Singhal et al 2001; Singhal 2004; Singhal and Bernstein 2005; Calabrese et al 2007; Ducros et al 2007; Chen et al 2008; Ducros et al 2010; Singhal et al 2011; Ducros 2012; Yancy et al 2013; Singhal 2014; Choi et al 2018; Caria et al 2019). It is conceivable that individual entities still have some unique features. The International Headache Society has developed criteria for diagnosis, which have been validated, and the latest version of the International Classification of Diseases (ICD-10) has assigned code I67.841 for reversible cerebral vasoconstriction syndromes (Lee et al 2018).

Historically, patients with reversible cerebral vasoconstriction syndromes have been misinterpreted as having primary angiitis of the central nervous system due to overlapping clinical-imaging features such as headache, stroke, and angiographic abnormalities (Snyder and McClelland 1978; Bettoni et al 1984; van Calenbergh et al 1986). Before the recent recognition of reversible cerebral vasoconstriction syndromes, primary angiitis of the central nervous system had become recognized and accepted as a devastating and potentially fatal inflammatory condition that warranted aggressive treatment with immunosuppressive agents (Calabrese et al 1997). Segmental narrowing of intracranial arteries was believed to be the “typical” angiographic feature of primary angiitis of the central nervous system. Among patients with primary angiitis of the central nervous system, there emerged a subset of patients who had an unusually benign clinical course and prompt resolution of angiographic abnormalities without prolonged immunosuppressive therapy. Calabrese and colleagues classified these patients as “benign angiopathy of the CNS” (BACNS) and noted that they were usually diagnosed solely on the basis of angiographic abnormalities, without supporting evidence for inflammation on tests like CSF examination or brain biopsy (Calabrese et al 1993). Their group has analyzed the clinical characteristics and long-term outcomes of BACNS and concluded that it is probably a vasoconstrictive rather than a vasculitic condition (Hajj-Ali et al 2002).

Important differences between primary angiitis of the central nervous system and reversible cerebral vasoconstriction syndromes have been highlighted, namely the type and frequency of onset headaches, lesion patterns on brain imaging, and distinct cerebral angiographic features (Singhal et al 2016; de Boysson et al 2018). Recurrent thunderclap headache (TCH), and single thunderclap headache associated with normal neuroimaging, border zone infarcts, or vasogenic edema, was shown to have 100% positive predictive value for diagnosing reversible cerebral vasoconstriction syndrome. The criteria make it possible to distinguish these conditions soon after admission with nearly 100% accuracy. However, severe and prolonged vasoconstriction can induce secondary inflammation and arterial necrosis with brain hemorrhages, for example, after use of potent vasoconstrictors, making the distinction between vasculitis and vasoconstriction extremely difficult in some cases (Calado et al 2004; Topcuoglu et al 2017).

Aiming to differentiate reversible cerebral vasoconstriction syndromes from other intracranial arteriopathies, the RCVS2 diagnostic score (Table 2) and clinical approach has recently been developed (Rocha et al 2019). RCVS2 scores ≥5 are highly specific (99%) and sensitive (90%) for diagnosing reversible cerebral vasoconstriction syndromes, whereas scores ≤2 are highly specific (100%) and sensitive (85%) for excluding reversible cerebral vasoconstriction syndromes. Intermediate RCVS2 scores of 3 or 4 have a lower specificity (86%) and sensitivity (10%) for diagnosing reversible cerebral vasoconstriction syndromes. For patients with intermediate scores, using a clinical approach based on the presence of recurrent thunderclap headaches, vasoactive triggers with normal brain imaging, or the presence of convexity subarachnoid hemorrhage improved diagnostic accuracy.

Table 2. RCVS2 Score

Criteria

Value

Recurrent or single thunderclap headache
Present
Absent


5
0

Carotid artery (intracranial)
Affected
Not affected


-2
0

Vasoconstrictive Trigger
Present
Absent


3
0

Sex
Female
Male


1
0

Subarachnoid hemorrhage
Present
Absent


1
0

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