Reversible cerebral vasoconstriction syndromes (RCVS) …

Stroke & Vascular Disorders

Updated 10.26.2023
Released 12.16.2003
Expires For CME 10.26.2026

Reversible cerebral vasoconstriction syndromes

Authors: Aneesh B Singhal MD, Eva A Rocha MD PhD

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Editor: Steven R Levine MD

Reversible cerebral vasoconstriction syndromes

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Introduction

Overview

Reversible cerebral vasoconstriction syndrome is 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. 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. Some cases are misdiagnosed as primary angiitis of the CNS because of overlapping clinical-angiographic features. 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.
	• 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. Yet, approximately 95% of patients have benign 3-month outcomes with little or no residual neurologic deficits
	• The RCVS2 score accurately distinguishes reversible cerebral vasoconstriction syndromes from other intracranial arteriopathies.
	• 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.
	• 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 (02; 09; 110). 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) Headache disorders	Migraine, primary thunderclap headache, benign exertional headache, benign sexual headache, primary cough headache, bath-related headache (119)
(C) Physiologic	High altitude, winter climate, cold water exposure, typhoons, severe grief
(D) Exposure to drugs and blood products	Sympathomimetic medications: phenylpropanolamine, pseudoephedrine, phenylephrine, epinephrine, ergotamine tartrate, isometheptene, midodrine, methylergonovine, bromocriptine, methergine, lisuride Antidepressants: selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors (SNRIs) Migraine medications: sumatriptan and other triptans, erenumab (117) Anti-inflammatory: indomethacin, etoricoxib Illicit drugs: cocaine, ecstasy, amphetamine derivatives, marijuana, lysergic acid diethylamide Immunosuppressants/immunomodulators: tacrolimus (FK-506), cyclophosphamide, interferon, fingolimod, etanercept, tocilizumab, ustekinumab, adalidumab Hormonal agents: oral contraceptive pills, ovarian stimulation, isoflavones, levonorgestrel (145) Other: Hydroxycut, bromocriptine, erythropoietin, intravenous immune globulin (IVIg), nicotine patches, red blood cell transfusions, methotrexate (153), intrathecal cytarabine (91), licorice, Ma Huang (ephedra), khat leaves, atovaquone, caffeine withdrawal, eucalyptus, isoflavone, ethylene oxide exposure, tetrodotoxin, oleoresin capsicum (pepper spray), ferric carboxymaltose (100)
(E) Procedures	carotid endarterectomy or carotid stenting, neurosurgical procedures, tonsillectomy, neck surgery, repetitive transcranial magnetic stimulation, dural puncture
(F) Miscellaneous	Hypercalcemia, porphyria, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, pheochromocytoma, bronchial carcinoid tumor, unruptured saccular cerebral aneurysm, head trauma, spinal subdural hematoma, carotid glomus tumor, Takotsubo cardiomyopathy, transient global amnesia, Covid-19 infection (111), Covid-19 vaccination (87), Leigh syndrome, elevated anti-phospholipid antibodies (142), thyrotoxicosis, cerebral venous sinus thrombosis, Chikungunya infection (141), Leigh syndrome (106)
(G) Idiopathic	No identifiable precipitating factor.

Given the diversity of the associated conditions, patients with these syndromes have been described in the literature using variable nosology. For example, “migrainous vasospasm” (121) or “migraine angiitis” (62) for patients with prior migraine; “postpartum angiopathy” (110; 05; 109) when associated with pregnancy or puerperium; and “drug-induced vasculitis” (70) 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” (14).

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 publications have characterized reversible cerebral vasoconstriction syndromes over the last few years (134; 124; 130; 10; 34; 22; 35; 127; 33; 159; 128; 30; 16). 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 (83).

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 (138; 04; 150). Before the 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 (11). 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 (12). 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 (52).

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 (136; 32). 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 (13; 147).

Aiming to differentiate reversible cerebral vasoconstriction syndromes from other intracranial arteriopathies, the RCVS2 diagnostic score (Table 2) and clinical approach has been developed (114). 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. An external cohort validated the RCVS2 score with a specificity of 94% and sensitivity of 64% (78).

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

Another scoring system was created for diagnosis of reversible cerebral vasoconstriction syndromes in patients with thunderclap headache (TCH) (29). The RCVS-TCH score takes into account the pattern of thunderclap headache (recurrent or single), sex, triggering factors, and blood pressure surge. High scores have high sensitivity and specificity for the diagnosis of reversible cerebral vasoconstriction syndrome. However, because aneurysmal subarachnoid hemorrhage patients were excluded from the analysis, and because patients with primary thunderclap headache (which falls within the spectrum of reversible cerebral vasoconstriction syndrome) were not considered as having reversible cerebral vasoconstriction syndrome, the clinical utility of this scoring system remains undetermined.

Clinical manifestations

Presentation and course

Reversible cerebral vasoconstriction syndromes predominantly affect individuals between 20 and 60 years of age (134; 52; 10; 34; 127), although children can be affected (71; 85). The mean age is 42 years across multiple studies, and the female:male ratio ranges from 1.8:1 (34) to 4:1 (127). The syndrome appears to be spontaneous in approximately one third of patients, and a secondary precipitating factor can be identified in the remaining two thirds. Most reported patients have a history of migraine, pregnancy, or exposure to vasoactive drugs such as cocaine, the ergot derivatives, or diet pills. The onset is usually catastrophic, with sudden-onset, severe (“thunderclap”) headaches (48), nausea, photophobia, and encephalopathy. A retrospective analysis of 139 cases showed that 85% present with thunderclap headache (127), and in a prospective study of 67 cases, thunderclap headache was the only symptom in 76% of patients (34). In these reports, multiple thunderclap headaches occurred in 82% to 94% of patients, and the average number of recurrent headaches was 4.5 (range, two to 18). However, it should be noted that reversible cerebral vasoconstriction can occur with milder, non-thunderclap headaches (155). Thunderclap headaches are exacerbated with Valsalva maneuver and can recur for weeks but usually with decreasing frequency and intensity. Some patients develop focal neurologic deficits and generalized seizures (14; 134; 123; 127; 52; 124; 10; 34; 127). Throbbing headaches, visual blurring, scotomas, and blindness are the most common symptoms. Blood pressure can be normal or elevated. Hypertension, if present, may be primary or secondary to underlying pain, eclampsia, or exposure to drugs such as cocaine. Cortical blindness, or elements of the Balint syndrome (127; 152), are frequent. Hemiplegia and hyperreflexia are common; dysarthria, aphasia, numbness, and ataxia have also been reported. Seizures tend not to recur after the first three to four days. Symptoms usually resolve spontaneously over a period of two to six weeks, and the outcome is usually benign. However, in up to 10% of cases, clinical and angiographic progression can occur in the first few days and result in severe strokes, brain edema, and even death (09; 123; 154; 133; 127; 45; 65; 69). Ischemic strokes, when present, are usually associated with worse clinical outcomes and cerebrovascular risk factors (47).

Prognosis and complications

The prognosis is usually excellent, with most patients recovering completely or near-completely within days to weeks. Approximately 10% to 15% of patients with reversible cerebral vasoconstriction syndromes may not report a thunderclap headache; the absence of thunderclap headache may predict a worse prognosis (81). Recurrence with complications such as ischemic stroke or subarachnoid hemorrhage is virtually unknown, having been reported only once (148). However, a minority can develop recurrent thunderclap headache with or without cerebral vasoconstriction especially if the initial attack was triggered by sexual orgasm, exercise, or in patients with migraine (24; 06). The thunderclap headaches noted at onset can recur for weeks, but with diminishing frequency and intensity. Among patients with complications like ischemic stroke or lobar hemorrhage, long-lasting focal deficits are not uncommon. Fulminant vasoconstriction resulting in progressive symptoms or death occurs in a minority of cases (09; 123; 133; 127; 79; 149). Postpartum angiopathy may carry a worse prognosis (43; 45).

Some patients go on to develop long-term chronic headaches that are different from the initial thunderclap headaches (78), neurocognitive deficits (137), and psychiatric sequelae such as anxiety or depression (66). A study on 99mTc-ethyl cysteinate dimer single-photon emission computed tomography showed persistent brain damage in reversible cerebral vasoconstriction syndrome, even after complete reversal of vasoconstriction (80). About 14% of patients with reversible cerebral vasoconstriction syndromes may be readmitted within 90 days, mostly due to ongoing or recurrent symptoms or neurologic sequelae (46). There seems to be a relationship between age and types of complications in reversible cerebral vasoconstriction syndrome patients, with young age being associated with cervical artery dissections, and increasing age with hemorrhagic complications (82).

Clinical vignette

Angiography and brain MRI studies reveal classic patterns of reversible cerebral arterial segmental vasoconstriction.

Reversible cerebral arterial segmental vasoconstriction

Classic angiographic pattern of reversible cerebral arterial segmental vasoconstriction. Note the “sausage on a string” appearance of the medium-sized intracerebral arteries. (Contributed by Dr. Aneesh Singhal.)
Reversible cerebral vasoconstriction syndrome (MRI)

Typical brain imaging findings in reversible cerebral vasoconstriction syndrome. (A) Diffusion-weighted MRI shows bilateral symmetric infarctions in the watershed distribution of the middle and posterior cerebral arteries. (B) FLA...

Biological basis

Etiology and pathogenesis

The etiology of the abrupt-onset and prolonged but reversible vasoconstriction is not known. The wide range of associated conditions (Table 1) suggests that there may be multiple molecular pathways involved with an underlying common link that has yet to be identified. “Migrainous vasospasm,” chemical factors (eg, norepinephrine, serotonin, and calcium), hormonal factors (41; 140; 151), and mechanical factors have been implicated because of the association of reversible cerebral vasoconstriction syndromes with migraine, vasoactive substances, hypercalcemia, pregnancy, and head trauma, respectively. A role for common vasoconstrictive drugs such as sumatriptan and the serotonergic antidepressants has been proposed (109; 92; 123; 104). The association with these medications and over-the-counter serotonin-enhancing agents such as licorice (18) and diet pills, as well as the serotonin syndrome (65) supports the role of serotonin. Single case reports have described reversible cerebral vasoconstriction syndromes after the injection of epinephrine for anaphylaxis (107), and fingolimod for multiple sclerosis (75). An association with transient global amnesia, another condition linked to ‘vasospasm,’ has been reported (61; 07). Physiological triggers such as grief (108), high altitude with respiratory alkalosis, and airplane descent are also implicated (102; 146; 56). Cases of reversible cerebral vasoconstriction following Covid-19 infection and vaccination have also been reported (87; 111).

Some authors have speculated that the vasoconstriction is related to transient vasculitis; however, there is no evidence to support a role for inflammation. CSF examination and extensive serological tests are normal and pathological studies of the brain and temporal arteries show no abnormality (138; 121; 52; 123; 123; 154; 133). However, in rare cases prolonged and severe vasoconstriction may result in secondary inflammatory changes (13). One group has linked reversible cerebral vasoconstriction syndromes to polymorphisms in the brain-derived neurotrophic factor gene and oxidative stress (26; 21), but further studies are required to validate these findings.

The pathophysiology of reversible cerebral vasoconstriction syndrome is probably multifactorial. Possible mechanisms of disease include dysregulation of vascular tone, sympathetic overactivity, endothelial dysfunction, oxidative stress, blood-brain barrier disruption, and altered trigeminovascular nociception. Patients may have predisposing genetic abnormalities and hormonal changes (27). A functional MRI study showed decreased efficiency of the left dorsal anterior insula, suggesting impaired central autonomic modulation in reversible cerebral vasoconstriction syndrome patients within 30 days after disease onset as compared to healthy controls, with improvement one month later (158). Angiographic vasoconstriction and vasodilatation (“sausaging”) of large- and medium-sized cerebral arteries is the pathognomonic feature and suggests an abnormality in the control of cerebrovascular tone. It remains unclear whether the angiographic abnormalities trigger the headaches or result from severe headache, but there certainly is a close relationship between thunderclap headache and reversible cerebral vasoconstriction syndrome (01).

Reversible cerebral arterial segmental vasoconstriction

Classic angiographic pattern of reversible cerebral arterial segmental vasoconstriction. Note the “sausage on a string” appearance of the medium-sized intracerebral arteries. (Contributed by Dr. Aneesh Singhal.)

In general, angiographic changes outlast the headaches by several weeks. Ischemic strokes are common and are usually located in borderzone arterial territories, suggesting severe proximal vasoconstriction with “low-flow” ischemia or distal thromboembolism as the mechanism.

Reversible cerebral vasoconstriction syndrome (MRI)

Typical brain imaging findings in reversible cerebral vasoconstriction syndrome. (A) Diffusion-weighted MRI shows bilateral symmetric infarctions in the watershed distribution of the middle and posterior cerebral arteries. (B) FLA...

Brain hemorrhages occur in one third of cases (143; 101; 103; 115; 15; 126; 118; 156; 35; 127). Hemorrhages are often multiple, located in lobar regions, and coexist with ischemic strokes, suggesting a role for post-ischemic reperfusion injury (35). Small, non-aneurysmal subarachnoid hemorrhages along the cortical surface are observed in up to one third of patients with reversible cerebral vasoconstriction syndrome, presumably resulting from rupture of pial vessels in the face of impaired autoregulation (125; 126; 130; 95; 34; 36; 96; 112).

Reversible cerebral vasoconstriction syndrome (MRI)

In this brain MRI (fluid attenuated inversion recovery or FLAIR image) from a patient with RCVS, there is a small cortical surface subarachnoid hemorrhage overlying the left hemisphere (black arrow) and multiple dot- and linear-hy...

Studies of patients with cortical subarachnoid hemorrhage have shown that reversible cerebral vasoconstriction syndrome is a frequent cause, particularly in young individuals (112; 77). Rarely, such hemorrhages can result in superficial siderosis (86). Several patients with reversible cerebral angiographic changes develop reversible brain edema in a pattern identical to the posterior reversible encephalopathy syndrome (PRES), suggesting a shared pathophysiology between these syndromes (125; 10; 40; 133).

Reversible cerebral vasoconstriction syndrome (MRI)

Differential diagnosis

Confusing conditions

Patients with reversible cerebral vasoconstriction syndrome pose major diagnostic and therapeutic challenges because a similar clinical and angiographic picture can result from a wide range of conditions that have ill-defined treatment options and considerably worse prognosis. Sudden and severe headaches, invariably present at onset in patients with reversible cerebral vasoconstriction syndrome, appropriately raise concern for aneurysmal subarachnoid or intracranial hemorrhage, pituitary apoplexy, venous sinus thrombosis, meningitis, or spontaneous intracranial hypotension (49). However, recurrent thunderclap headaches are rarely seen in conditions other than reversible cerebral vasoconstriction syndrome. Because patients with reversible cerebral vasoconstriction syndrome usually present with thunderclap headaches (also the most common presenting symptom of a ruptured brain aneurysm), and approximately one third develop convexal subarachnoid hemorrhage, it can be challenging to distinguish reversible cerebral vasoconstriction syndrome from other causes of subarachnoid hemorrhage (eg, aneurysmal, perimesencephalic, and nonperimesencephalic “cryptogenic” subarachnoid hemorrhage). One large retrospective study identified the following predictors of reversible cerebral vasoconstriction syndrome in patients with subarachnoid hemorrhage: younger age, history of chronic headaches, depression, chronic obstructive pulmonary disease, lower Hunt-Hess grade, lower Fisher subarachnoid hemorrhage group, higher number of affected arteries, and the presence of bilateral arterial narrowing (98).

Similar angiographic abnormalities can result from intracranial atherosclerosis, infectious arteritis, inflammatory vasculitis, and fibromuscular dysplasia. Although the latter conditions are usually chronic and progressive, reversible cerebral vasoconstriction syndrome is a disorder that begins abruptly. A carefully documented headache history combined with a review of the type and distribution of lesions on brain imaging, and cerebral angiographic features, is invaluable in distinguishing between reversible cerebral vasoconstriction syndrome and these other conditions, particularly from primary angiitis of the central nervous system (136; 32).

Reversible cerebral vasoconstriction syndrome (MRI)

The RCVS2 score can be an easily applicable tool with high accuracy for distinguishing reversible cerebral vasoconstriction syndrome from other arteriopathies (114; 78). In challenging cases, high-resolution contrast MRI may help because preliminary reports suggest a lack of concentric enhancement of the cerebral arteries in reversible cerebral vasoconstriction syndrome, but not inflammatory cerebral vasculitis or intracranial atherosclerosis (19).

Associated or underlying disorders

Vasogenic edema occurs in about 30% of patients with reversible cerebral vasoconstriction syndrome, suggesting an overlap between reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome (PRES) (125; 34; 22; 40; 44). Both diseases share similar mechanisms, such as altered regulation of vascular tone and disruption of blood-brain barrier. There are also overlapping precipitating factors, such as immunosuppressors.

Studies have shown a close relationship between primary thunderclap headache and reversible cerebral vasoconstriction syndrome (23; 01). When neurovascular imaging is performed, a group of patients with a diagnosis of primary thunderclap headaches might present with vasoconstriction. There has been a suggestion of a link between reversible cerebral vasoconstriction syndrome and transient global amnesia because of their acute and reversible nature and reports of co-occurrence of these conditions (07; 17).

Diagnostic workup

There is no confirmatory test for reversible cerebral vasoconstriction syndrome. In patients presenting with thunderclap headache, which is the usual presenting symptom of reversible cerebral vasoconstriction syndrome, the initial focus should be to rule out other, more common conditions that have similar clinical or angiographic features (120). Urgent neuroimaging with head CT or brain MRI and CSF studies are warranted to exclude subarachnoid or parenchymal hemorrhage, arterial dissection, meningitis, intracranial hypotension, and cerebral vasculitis. Blood counts, erythrocyte sedimentation rate, serum electrolytes, and liver and renal function tests are usually normal. Rheumatoid factor, antinuclear cytoplasmic antibody tests, Lyme titer, and urine vanillylmandelic acid and 5-hydroxyindoleacetic acid levels are useful to rule out vasculitis and vasoactive tumors (pheochromocytoma and carcinoid) if clinical suspicion warrants. There is no role for brain biopsy or temporal artery biopsy other than to rule out vasculitis. However, it is important to emphasize that most patients with bona fide vasculitis have insidious-onset symptoms, a progressive clinical course, and inflammatory CSF findings, unlike that seen with reversible cerebral vasoconstriction syndrome. Serum and urine toxicology screens and a careful medication history are important to uncover exposure to vasoactive drugs like cocaine, “ecstasy,” ephedra, ma huang, and antimigraine agents.

In reversible cerebral vasoconstriction syndrome, brain imaging (CT or MRI) can be normal or can show multifocal strokes that are usually located in posterior “borderzone” regions, often sparing the cortical ribbon (123; 55; 125).

Reversible cerebral vasoconstriction syndrome (MRI)

The hyperintense MCA “dot sign”, a marker of slow flow within dilated cortical surface arteries, is frequently observed on FLAIR MRI sequences (58).

Reversible cerebral vasoconstriction syndrome (MRI)

Perfusion-MRI studies can show areas of hypoperfusion in deep watershed regions as would be expected from the angiographic vasoconstriction (116).

In addition to cytotoxic edema (ischemic stroke), diffusion-weighted MRI can show coexisting vasogenic edema, suggesting an overlap between reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome (PRES) (125; 34; 22; 40; 44). Brain hemorrhages, including lobar, subarachnoid, and subdural hemorrhages, occur in more than one third of patients—particularly in women and patients with prior migraine and medication exposure (126; 35; 127). Lobar hemorrhages can be single or multiple (101; 103; 115; 126; 118; 156). Subarachnoid hemorrhages are typically restricted to one to two sulcal spaces overlying the hemispheric convexities (122; 36; 126; 96).

Reversible cerebral vasoconstriction syndrome (MRI)

The cortical surface hemorrhages presumably result from rupture of pial vessels, and their presence makes it difficult to rule out subarachnoid hemorrhage-related vasospasm. However, multifocal, diffuse vasoconstriction at the time of symptom onset, without significant amounts of subarachnoid blood surrounding the constricted arteries, is highly atypical for subarachnoid hemorrhage-related vasospasm (39). A study with quantitative arterial spin label MRI has shown an initial decrease in cerebral blood flow with subsequent increase, especially in the second week (67).

Transcranial Doppler studies can show diffusely elevated blood flow velocities, which typically normalize over a period of days to weeks (05; 50; 60; 76; 123; 160; 105). Nearly all patients will have transcranial Doppler abnormalities peaking at 13 to 14 days after symptom onset (53). It can be difficult to distinguish between vasospasm and hyperemia based on Doppler studies alone. Chen and colleagues prospectively studied 32 women with reversible cerebral vasoconstriction syndrome using transcranial color-coded ultrasound (TCCS) (22). On serial TCCS, the maximum abnormality was detected approximately three weeks after onset; the abnormalities lasted approximately three months and outlasted the headaches. Although 81% of the patients had elevated mean flow velocities, these were generally mild, and only 13% showed abnormalities exceeding the subarachnoid hemorrhage criteria for “mild” vasospasm (VMCA greater than 120 cm/sec and Lindegaard Index higher than 3).

The characteristic angiographic abnormalities are best visualized on transfemoral cerebral angiography; however, newer, less invasive tests like CT and MR angiography are often the first to show abnormalities and are particularly useful as serial tests to document reversal of the vasoconstriction (116; 25). The classic angiographic pattern is that of multifocal narrowing and dilatation of the intracerebral arteries, and this pattern differs from the notched, ectatic appearance of arteries in PACNS (136). Rarely, patients can develop predominantly arterial dilatation (74). Involvement of the more proximal arterial segments may be a risk factor for complications such as ischemic stroke or posterior reversible encephalopathy syndrome (25). The angiographic abnormalities typically start shortly after the dural penetration of the cerebral arteries; extracranial arteries or the systemic arteries are rarely involved (90). Recurrent reversible vasoconstrictions of the extracranial cerebral arteries have been described usually in patients with migraine; however, it is unclear whether such cases should be included under the spectrum of reversible cerebral vasoconstriction syndrome or constitute a distinct entity (64; 157). Studies have found a strong association between reversible cerebral vasoconstriction syndrome and extracranial carotid and vertebral artery dissections (03; 89; 94). Follow-up neurovascular imaging may be performed to document reversal of the angiographic abnormalities and confirm the diagnosis of reversible cerebral vasoconstriction syndrome. Transfemoral angiography, CT or MR angiography, and serial transcranial Doppler ultrasound tests have been used for this purpose.

An increase in certain urine metabolites has been shown in the acute phase of reversible cerebral vasoconstriction syndrome, mostly associated with endothelial dysfunction and sympathetic overactivity (57). However, it is not certain if these metabolites may play a role in the pathogenesis of RCVS or aid in the diagnosis. Patients with reversible cerebral vasoconstriction syndrome also seem to have micro-RNA signatures that were linked to headache blood brain barrier integrity and vasomotor function (20).

Management

There is no established treatment protocol. Clinical and angiographic resolution typically occurs within weeks, regardless of pharmaceutical treatment.

Calcium channel blockers like nimodipine, verapamil, and intravenous magnesium are often administered in an effort to halt or reverse cerebral vasoconstriction (105; 128; 28; 93). Data from most prospective and retrospective case series have not shown efficacy in resolving vasoconstriction (34; 22; 127), however, they may reduce the intensity of headaches. Some may prefer verapamil over nimodipine to avoid the four hourly dosing and for headache prevention effects. A systematic review with 56 reversible cerebral vasoconstriction syndrome patients using verapamil showed headache improvement in 96% of patients following oral medication. Most patients used 120 mg controlled release once daily (31). A randomized controlled trial is warranted to evaluate the efficacy of these medications. The severe head pain usually requires liberal analgesics, even opioids, for relief. It is logical to avoid further exposure to vasoconstrictive agents or identified precipitants (Table 1) in any patient with reversible cerebral vasoconstriction syndromes. Subsequent re-exposure to vasoconstrictive medications such as nasal decongestants, antimigraine agents, and antidepressants (eg, to treat chronic sequelae such as daily headaches and depression) carries a risk of inducing another episode of reversible cerebral vasoconstriction syndrome. However, in this author’s opinion the risk is probably very low, so these medications should not be withheld if clinically warranted.

Antimigraine drugs like sumatriptan and ergotamine are contraindicated in patients who develop stroke. Because recurrent headaches are exacerbated by Valsalva maneuver, patients should avoid heavy physical exertion and use stool softeners for a period of four to six weeks.

Blood pressure should be carefully monitored and controlled to normal levels. Theoretically, hypoperfusion carries the risk of cerebral hypoperfusion and ischemic strokes, and severe hypertension can result in brain hemorrhage or even worsening of the cerebral vasoconstriction. Acute stroke treatments like intravenous tissue plasminogen activator, antiplatelet agents, and anticoagulants are best avoided because the mechanism of ischemic stroke is vasoconstriction and not thrombo-embolism. Moreover, these agents can theoretically induce or worsen brain hemorrhage, which often occurs many hours or days after presentation. Generalized seizures can occur at onset but tend not to recur, so long-term anticonvulsants are probably unnecessary.

A large retrospective analysis showed that glucocorticoid treatment is associated with worse clinical, imaging and angiographic outcomes (135). It is, hence, even more important to focus on distinguishing reversible cerebral vasoconstriction syndrome from primary angiitis of the CNS on the basis of the initial clinical and imaging features.

An increasing number of case reports claim success with balloon angioplasty or direct intraarterial or intravenous infusion of vasospasm-relieving agents (113; 08; 37; 73; 51; 38; 84; 68; 54; 144). However, this approach often requires repeated intervention (42; 59) and carries the risk of reperfusion injury (139; 133). Because reversible cerebral vasoconstriction syndrome is easily diagnosed at the bedside and more than 90% to 95% of patients with reversible cerebral vasoconstriction syndrome have a benign and self-limited syndrome despite the presence of severe angiographic vasoconstriction and ischemic or hemorrhagic brain lesions, invasive diagnostic angiograms are best avoided, and therapeutic approaches should be reserved for patients in whom there is clear evidence for clinical progression (127). Decompressive hemicraniectomy has been utilized in patients with refractory raised intracranial pressure (97; 99).

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References

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Aneesh B Singhal MD

Dr. Singhal of Harvard Medical School has no relevant financial relationships to disclose.
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Eva A Rocha MD PhD

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

Steven R Levine MD

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

Age range of presentation: 13 to 64 years
Sex preponderance: female>male, >2:1
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Intracerebral hemorrhage: 431.0

Acute, but ill-defined, cerebrovascular disease: 436.0

Cerebral arteritis: 437.4

Stricture of artery: 447.1

Rupture of artery: 447.2

Arteritis, unspecified: 447.6

Other specified disorders of arteries and arterioles: 447.8

Other and unspecified complications of the puerperium, not elsewhere classified: 674.00
ICD-10: Intracerebral hemorrhage: I61.9

Acute, but ill-defined, cerebrovascular disease: I64

Cerebral arteritis: I67.7

Stricture of artery: I77.1

Rupture of artery: I77.2

Arteritis, unspecified: I77.6

Other specified disorders of arteries and arterioles: I77.8

Other and unspecified complications of the puerperium, not elsewhere classified: O90.8

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Reversible cerebral vasoconstriction syndromes

Associated Disorders

Bronchial carcinoids
Drug-induced vasculitis (Drug-induced cerebrovascular disease)
Drug-induced vasoconstriction (Headache associated with illicit drug use)
Eclampsia (Pregnancy and stroke)
Hemolytic uremic syndrome
- Hypercalcemia
- Hypertensive encephalopathy
- Many trigger
- Migraine (Migraine: clinical aspects)
- Pheochromocytoma
- Porphyria
- Primary headaches (Acute headache: diagnosis)
- Recurrent thunderclap headaches (Acute headache: diagnosis)
- Severe closed head injury
- Spinal subdural hematoma (Vascular disorders of the spinal cord)
- Superficial siderosis
- Thrombotic thrombocytopenic purpura: neurologic complications
- Posterior reversible encephalopathy syndrome

Differential Diagnosis

Cerebral venous thrombosis
Fibromuscular dysplasia
Infectious arteritis
Intracranial atherosclerosis
Meningitis
- Nontraumatic intracerebral hemorrhage
- Other cerebral arteriopathies
- Pituitary apoplexy
- Posterior reversible encephalopathy syndrome
- PRES
- Primary CNS angiitis
- Spontaneous intracranial hypotension
- Subarachnoid hemorrhage

Also Relevant

Cerebral arteriopathies
Cerebral vasospasm: treatment
Coma due to drug intoxication
Neuroimaging of headache
Pregnancy: CNS complications

Reversible cerebral vasoconstriction syndromes

Introduction

Overview

Key points

Historical note and terminology

Table 1. Precipitating Factors Associated with Cerebral Vasoconstriction Syndromes

Table 2. RCVS2 Score

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Authors

Editor

Patient Profile

ICD & OMIM codes

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Also in This Category

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