Aneesh B. Singhal

Narrative review: reversible cerebral vasoconstriction syndromes.

Key Summary Points Reversible cerebral vasoconstriction syndromes (RCVS) are characterized by multifocal areas of constriction involving the cerebral arteries that resolve within days to weeks. Patients with RCVS often present with acute onset of severe headache (thunderclap headache) with or without neurologic symptoms and signs. RCVS can occur without identifiable cause, during pregnancy or the puerperium period, as an idiosyncratic response to certain medications or illicit drugs, and in the setting of catecholamine-secreting tumors. Diagnosis is made by characteristic symptoms and signs in the setting of normal results on cerebrospinal fluid analysis, exclusion of other causes of sudden severe headache, segmental cerebral arterial vasoconstriction demonstrated by direct or indirect angiography, and reversibility of the vasoconstriction within 12 weeks. RCVS must be differentiated from primary angiitis of the central nervous system, a condition with similar angiographic abnormalities but a substantially different diagnostic and therapeutic approach. Treatment is empirical and includes observation, calcium-channel blockers (nimodipine or verapamil), and possibly high-dose corticosteroids. Prognosis is uncertain, but most patients do well. Permanent neurologic deficits and deaths have been reported. Reversible cerebral vasoconstriction syndromes (RCVS) comprise a group of disorders characterized by prolonged but reversible vasoconstriction of the cerebral arteries, usually associated with acute-onset, severe, recurrent headaches, with or without additional neurologic signs and symptoms. These syndromes are diverse (Table 1) (1) and have been given various eponymic or syndromic labels, including the Call syndrome (or the CallFleming syndrome) (2, 3), benign angiopathy of the central nervous system (4), postpartum angiopathy (5), thunderclap headache with reversible vasospasm (68), migrainous vasospasm or migraine angiitis (912), and drug-induced cerebral arteritis or angiopathy (1315). In general, these disorders have been poorly characterized and continue to be frequently confused with cerebral vasculitis because the latter condition has overlapping angiographic features, and to a certain degree, clinical features. Table 1. Conditions Associated with Reversible Cerebral Vasoconstriction Syndromes* An understanding of RCVS has been limited by the lack of a clear underlying pathologic basis and consensus definition. Furthermore, patients with RCVS have historically presented to different specialists, including stroke neurologists, headache specialists, obstetricians, and rheumatologists, and all in turn impart their own biases on nomenclature, theories of pathogenesis, and clinical approach. Some authors (1, 1618) only recently started defining the unifying features of these conditions and proposing that they be collectively called RCVS. It is likely that primary care providers, internists, emergency department physicians, neurologists, neurosurgeons, intensivists, rheumatologists, obstetricians, and other clinicians will detect RCVS in more patients because of the wider availability of newer, relatively noninvasive technologies to assess cerebral vasculature and blood flow velocity (computed tomography angiography [CTA], magnetic resonance angiography [MRA], and transcranial Doppler ultrasonography). In addition, use of vasoactive drugs, especially diet pills; exercise stimulants; certain antidepressants; nasal decongestants; and drugs of abuse, such as amphetamines, cocaine, and ecstasy, is increasing. This narrative review, by specialists in the field of rheumatology, headache, and stroke, will outline the cause and pathophysiology, symptoms and signs, diagnosis, treatment, and prognosis of RCVS and areas of uncertainty. The funding source had no role in the design, analysis, or reporting of this study or in the decision to submit the manuscript for publication. Cause and Pathophysiology Reversible cerebral vasoconstriction syndromes have been reported to occur in various clinical settings (Table 1), and although the pathophysiology is not clearly understood, a disturbance in the control of cerebral vascular tone seems to be a critical element. This alteration in vascular tone may be spontaneous or evoked by various exogenous or endogenous factors. Sympathomimetic and serotonergic drugs and tumors (3, 1315, 1922), endocrine factors, direct or neurosurgical trauma (18, 2328), and uncontrolled hypertension (29, 30) have all been implicated. The molecular pathophysiology of RCVS is unknown. It is conceivable that the numerous immunologic and biochemical factors known to be involved in subarachnoid hemorrhagerelated vasospasm (catecholamines, endothelin-1, serotonin, nitric oxide, and prostaglandins) (31, 32) play a similar role in the pathophysiology of vasoconstriction in RCVS. Ultimately, because vascular tone and caliber is dependent on vascular receptor activity and sensitivity, a spontaneous or evoked central vascular discharge may underlie the alteration and reversible nature of RCVS and contribute to the severe and acute headache seen with these disorders. The anatomical basis for this may be that cerebral blood vessels are also densely innervated with sensory afferents from the first division of the trigeminal nerve and dorsal root of C2. Symptoms and Signs The typical patient with RCVS is a woman between the ages of 20 and 50 years presenting with a hyperacute severe headache, often called a thunderclap headache. Historically, this refers to a severe headache that reaches its peak intensity within seconds, like a clap of thunder (6, 33). Thunderclap headache is most characteristic of subarachnoid hemorrhage, but it has also been described as a spontaneous and idiopathic condition and a manifestation of other intracranial or extracranial disorders, such as arterial dissection and cerebral venous sinus thrombosis (33, 34). Primary thunderclap headache is by definition not associated with cerebral vasoconstriction (34). Patients with RCVS commonly have recurrent thunderclap headache associated with cerebral vasoconstriction. As with primary thunderclap headache, the RCVS headache may be occipital or diffuse; severe and throbbing; and associated with nausea, emesis, and photosensitivity. It can recur spontaneously while the patient is at rest or can be precipitated by exertion or the Valsalva maneuver. Severe neurologic symptoms and signs, including transient or permanent visual defects, hemiplegia, dysarthria, aphasia, numbness, or ataxia, can occur secondary to ischemia in brain regions that are perfused by a severely constricted artery. Transient hypertension, which at times can be marked, is not uncommon. Generalized seizures may occur during the acute period, but epilepsy does not ensue. Major ischemic or hemorrhagic stroke, progressive brain edema, and even stroke-related death from progressive or severe, sustained cerebral vasoconstriction have been described (3541). Figure 1. Neuroimaging findings in a 46-year-old man with reversible cerebral vasoconstriction syndrome. The patient, who had a history of migraine without aura, hypertension, hyperlipidemia, and cannabis abuse, developed a severe postcoital thunderclap headache. Severe headaches recurred, and on day 3, he developed cortical blindness and mild left hemiparesis. Computed tomography angiography obtained at admission showed multifocal segmental stenosis (beading) of the bilateral middle cerebral arteries (A) and the basilar, posterior cerebral, and superior cerebellar arteries (B). These abnormalities were also present on brain magnetic resonance angiography (C). Diffusion-weighted magnetic resonance imaging (D) and apparent diffusion coefficient maps (E) showed symmetrical lesions in the bilateral occipital lobes consistent with ischemic stroke. In addition, brain magnetic resonance imaging showed small infarctions in the bilateral cerebellar hemispheres and in the right frontal lobe (not shown). Serologic tests and the results of 2 cerebrospinal fluid examinations showed no evidence for vasculitis or subarachnoid hemorrhage. The patient was treated with analgesics and verapamil. His deficits resolved completely over a period of 3 weeks, and follow-up magnetic angiography (F) showed resolution of the cerebral arterial vasoconstriction. Diagnosis Although there are no validated criteria for the diagnosis of RCVS, it is not difficult to recognize or diagnose. For the diagnosis of RCVS, the patient ideally should have all of the features that are outlined in Table 2. Although these criteria have not been prospectively validated, we believe that they have considerable sensitivity and specificity in the appropriate clinical setting and are a summary of published and personal experience to date. Table 2. Summary of Critical Elements for the Diagnosis of Reversible Cerebral Vasoconstriction Syndromes* Clinically, RCVS should be considered in patients who present with a hyperacute severe headache, with or without neurologic symptoms or signs, and without evidence of aneurysmal subarachnoid hemorrhage. Reversible cerebral vasoconstriction syndrome should also be considered in patients with cryptogenic stroke, particularly in those with severe-onset headache or thunderclap headache and symmetrical brain infarctions or edema. The initial evaluation should uniformly include unenhanced brain computed tomography (CT) to exclude subarachnoid or parenchymal brain hemorrhage. If the results of the CT scan are negative for hemorrhage, lumbar puncture should be performed to exclude CT-negative subarachnoid hemorrhage and inflammatory conditions, such as infection and cerebral vasculitis. If the results of the cerebrospinal fluid examination are benign, additional brain and neurovascular imaging to assess for other causes of severe headache, including cerebral venous sinus thrombosis, arterial dissection, unruptured saccular aneurysms, and RCVS, should be p

An evidence‐based causative classification system for acute ischemic stroke

Regular, evidence‐based assignment of patients to etiologic stroke categories is essential to enable valid comparison among studies. We designed an algorithm (SSS‐TOAST) that incorporated recent advances in stroke imaging and epidemiology to identify the most probable TOAST category in the presence of evidence for multiple mechanisms. Based on the weight of evidence, each TOAST subtype was subdivided into 3 subcategories as “evident”, “probable”, or “possible”. Classification into the subcategories was determined via predefined specific clinical and imaging criteria. These criteria included published risks of ischemic stroke from various mechanisms and published reports of the strength of associations between clinical and imaging features and particular stroke mechanisms. Two neurologists independently assessed 50 consecutively admitted patients with acute ischemic stroke through reviews of abstracted data from medical records. The number of patients classified as “undetermined‐unclassified” per the original TOAST system decreased from 38–40% to 4% using the SSS‐TOAST system. The kappa value for interexaminer reliability was 0.78 and 0.90 for the original TOAST and SSS‐TOAST respectively. The SSS‐TOAST system successfully classifies patients with acute ischemic stroke into determined etiologic categories without sacrificing reliabilty. The SSS‐TOAST is a dynamic algorithm that can accommodate modifications as new epidemiological data accumulate and diagnostic techniques advance. Ann Neurol 2005;58:688–697

Reversible Cerebral Vasoconstriction Syndromes: Analysis of 139 Cases

OBJECTIVES To compare the clinical, laboratory, and imaging features of patients with reversible cerebral vasoconstriction syndromes evaluated at 2 academic centers, compare subgroups, and investigate treatment effects. DESIGN Retrospective analysis. SETTING Massachusetts General Hospital (n = 84) or Cleveland Clinic (n = 55). PATIENTS One hundred thirty-nine patients with reversible cerebral vasoconstriction syndromes. MAIN OUTCOME MEASURES Clinical, laboratory, and imaging features; treatment; and outcomes. RESULTS The mean age was 42.5 years, and 81% were women. Onset with thunderclap headache was documented in 85% and 43% developed neurological deficits. Prior migraine was documented in 40%, vasoconstrictive drug exposure in 42%, and recent pregnancy in 9%. Admission computed tomography or magnetic resonance imaging was normal in 55%; however, 81% ultimately developed brain lesions including infarcts (39%), convexity subarachnoid hemorrhage (34%), lobar hemorrhage (20%), and brain edema (38%). Cerebral angiographic abnormalities typically normalized within 2 months. Nearly 90% had good clinical outcome; 9% developed severe deficits; and 2% died. In the combined cohort, calcium channel blocker therapy and symptomatic therapy alone showed no significant effect on outcome; however, glucocorticoid therapy showed a trend for poor outcome (P = .08). Subgroup comparisons based on prior headache status and identified triggers (vasoconstrictive drugs, pregnancy, other) showed no major differences. CONCLUSION Patients with reversible cerebral vasoconstriction syndromes have a unique set of clinical imaging features, with no significant differences between subgroups. Prospective studies are warranted to determine the effects of empirical treatment with calcium channel blockers and glucocorticoids.

A Computerized Algorithm for Etiologic Classification of Ischemic Stroke The Causative Classification of Stroke System

Background and Purpose— The SSS-TOAST is an evidence-based classification algorithm for acute ischemic stroke designed to determine the most likely etiology in the presence of multiple competing mechanisms. In this article, we present an automated version of the SSS-TOAST, the Causative Classification System (CCS), to facilitate its utility in multicenter settings. Methods— The CCS is a web-based system that consists of questionnaire-style classification scheme for ischemic stroke (http://ccs.martinos.org). Data entry is provided via checkboxes indicating results of clinical and diagnostic evaluations. The automated algorithm reports the stroke subtype and a description of the classification rationale. We evaluated the reliability of the system via assessment of 50 consecutive patients with ischemic stroke by 5 neurologists from 4 academic stroke centers. Results— The kappa value for inter-examiner agreement was 0.86 (95% CI, 0.81 to 0.91) for the 5-item CCS (large artery atherosclerosis, cardio-aortic embolism, small artery occlusion, other causes, and undetermined causes), 0.85 (95% CI, 0.80 to 0.89) with the undetermined group broken into cryptogenic embolism, other cryptogenic, incomplete evaluation, and unclassified groups (8-item CCS), and 0.80 (95% CI, 0.76 to 0.83) for a 16-item breakdown in which diagnoses were stratified by the level of confidence. The intra-examiner reliability was 0.90 (0.75–1.00) for 5-item, 0.87 (0.73–1.00) for 8-item, and 0.86 (0.75–0.97) for 16-item CCS subtypes. Conclusions— The web-based CCS allows rapid analysis of patient data with excellent intra- and inter-examiner reliability, suggesting a potential utility in improving the fidelity of stroke classification in multicenter trials or research databases in which accurate subtyping is critical.

A Pilot Study of Normobaric Oxygen Therapy in Acute Ischemic Stroke

Background and Purpose— Therapies that transiently prevent ischemic neuronal death can potentially extend therapeutic time windows for stroke thrombolysis. We conducted a pilot study to investigate the effects of high-flow oxygen in acute ischemic stroke. Methods— We randomized patients with acute stroke (<12 hours) and perfusion-diffusion “mismatch” on magnetic resonance imaging (MRI) to high-flow oxygen therapy via facemask for 8 hours (n=9) or room air (controls, n=7). Stroke scale scores and MRI scans were obtained at baseline, 4 hours, 24 hours, 1 week, and 3 months. Clinical deficits and MR abnormalities were compared between groups. Results— Stroke scale scores were similar at baseline, tended to improve at 4 hours (during therapy) and 1 week, and significantly improved at 24 hours in hyperoxia-treated patients. There was no significant difference at 3 months. Mean (±SD) relative diffusion MRI lesion volumes were significantly reduced in hyperoxia-treated patients at 4 hours (87.8±22% versus 149.1±41%; P=0.004) but not subsequent time points. The percentage of MRI voxels improving from baseline “ischemic” to 4-hour “non-ischemic” values tended to be higher in hyperoxia-treated patients. Cerebral blood volume and blood flow within ischemic regions improved with hyperoxia. These “during-therapy” benefits occurred without arterial recanalization. By 24 hours, MRI showed reperfusion and asymptomatic petechial hemorrhages in 50% of hyperoxia-treated patients versus 17% of controls (P=0.6). Conclusions— High-flow oxygen therapy is associated with a transient improvement of clinical deficits and MRI abnormalities in select patients with acute ischemic stroke. Further studies are warranted to investigate the safety and efficacy of hyperoxia as a stroke therapy.

The Pattern of Leptomeningeal Collaterals on CT Angiography Is a Strong Predictor of Long-Term Functional Outcome in Stroke Patients With Large Vessel Intracranial Occlusion

Background and Purpose— The role of noninvasive methods in the evaluation of collateral circulation has yet to be defined. We hypothesized that a favorable pattern of leptomeningeal collaterals, as identified by CT angiography, correlates with improved outcomes. Methods— Data from a prospective cohort study at 2 university-based hospitals where CT angiography was systematically performed in the acute phase of ischemic stroke were analyzed. Patients with complete occlusion of the intracranial internal carotid artery and/or the middle cerebral artery (M1 or M2 segments) were selected. The leptomeningeal collateral pattern was graded as a 3-category ordinal variable (less, equal, or greater than the unaffected contralateral hemisphere). Univariate and multivariate analyses were performed to define the independent predictors of good outcome at 6 months (modified Rankin Scale score ≤2). Results— One hundred ninety-six patients were selected. The mean age was 69±17 years and the median National Institute of Health Stroke Scale score was 13 (interquartile range, 6 to 17). In the univariate analysis, age, baseline National Institute of Health Stroke Scale score, prestroke modified Rankin Scale score, Alberta Stroke Programme Early CT score, admission blood glucose, history of hypertension, coronary artery disease, congestive heart failure, atrial fibrillation, site of occlusion, and collateral pattern were predictors of outcome. In the multivariate analysis, age (OR, 0.95; 95% CI, 0.93 to 0.98; P=0.001), baseline National Institute of Health Stroke Scale (OR, 0.75; 0.69 to 0.83; P<0.001), prestroke modified Rankin Scale score (OR, 0.41; 0.22 to 0.76; P=0.01), intravenous recombinant tissue plasminogen activator (OR, 4.92; 1.83 to 13.25; P=0.01), diabetes (OR, 0.31; 0.01 to 0.98; P=0.046), and leptomeningeal collaterals (OR, 1.93; 1.06 to 3.34; P=0.03) were identified as independent predictors of good outcome. Conclusion— Consistent with angiographic studies, leptomeningeal collaterals on CT angiography are also a reliable marker of good outcome in ischemic stroke.

Normobaric hyperoxia reduces MRI diffusion abnormalities and infarct size in experimental stroke

BackgroundHyperbaric oxygen therapy is considered an important stroke treatment strategy. BackgroundTo determine whether normobaric oxygen is neuroprotective, and, if so, what the therapeutic time window is. MethodsExperiment 1—Serial diffusion- and perfusion-weighted MRI (DWI and PWI) was performed after middle cerebral artery filament occlusion (MCAO) in rats randomized to FiO2 30% (normoxia) or FiO2 100% (hyperoxia). Experiment 2—48-hour lesion volumes were analyzed in rats subjected to 2-hour MCAO and randomized to normoxia or hyperoxia starting 15, 30, or 45 minutes after MCAO and ending 15 minutes after reperfusion. ResultsExperiment 1—Lesion apparent diffusion coefficient (ADC) values were persistently low in normoxic animals. In hyperoxia-treated rats, ADC values in cortical border zones showed progressive recovery from 66 ± 3% of contralateral before hyperoxia, to 104 ± 20% at ∼2 hours. Striatal ADC values showed early but ill-sustained improvement. ADC lesion volumes increased progressively in the normoxia group. In the hyperoxia group, ADC lesion volumes tended to decrease after starting hyperoxia; however, lesions later increased in size, and 2-hour lesion volumes were not significantly different from baseline. PWI showed stable right MCA hypoperfusion in all animals. Experiment 2—Hyperoxia within 30 minutes significantly reduced total and cortical lesion volumes at 48 hours after stroke. Striatal lesion volumes were significantly reduced in the hyperoxia-15 group. ConclusionIn rats subjected to transient stroke, 100% oxygen administered within 30 minutes salvages ischemic brain tissue, especially in the cerebral cortex. Reducing the time to treatment enhances the degree of neuroprotection.

Collateral vessels on CT angiography predict outcome in acute ischemic stroke.

Background and Purpose— Despite the abundance of emerging multimodal imaging techniques in the field of stroke, there is a paucity of data demonstrating a strong correlation between imaging findings and clinical outcome. This study explored how proximal arterial occlusions alter flow in collateral vessels and whether occlusion or extent of collaterals correlates with prehospital symptoms of fluctuation and worsening since onset or predict in-hospital worsening. Methods— Among 741 patients enrolled in a prospective cohort study involving CT angiographic imaging in acute stroke, 134 cases with proximal middle cerebral artery occlusion and 235 control subjects with no occlusions were identified. CT angiography was used to identify occlusions and grade the extent of collateral vessels in the sylvian fissure and leptomeningeal convexity. History of symptom fluctuation or progressive worsening was obtained on admission. Results— Prehospital symptoms were unrelated to occlusion or collateral status. In cases, 37.5% imaged within 1 hour were found to have diminished collaterals versus 12.1% imaged at 12 to 24 hours (P=0.047). No difference in worsening was seen between cases and control subjects with adequate collaterals, but cases with diminished sylvian and leptomeningeal collaterals experienced greater risk of worsening compared with control subjects measured either by admission to discharge National Institutes of Health Stroke Scale increase ≥1 (55.6% versus 16.6%, P=0.001) or ≥4 (44.4% versus 6.4%, P<0.001). Conclusion— Most patients with proximal middle cerebral artery occlusion rapidly recruit sufficient collaterals and follow a clinical course similar to patients with no occlusions, but a subset with diminished collaterals is at high risk for worsening.

Cerebral vasoconstriction and stroke after use of serotonergic drugs

Serotonin (5-hydroxytryptamine) is a potent vasoconstrictor amine. The authors report three patients who developed thunderclap headache, reversible cerebral arterial vasoconstriction, and ischemic strokes (i.e., the Call–Fleming syndrome). The only cause for vasoconstriction was recent exposure to serotonergic drugs in all patients, and to pseudoephedrine in one patient. These cases, and the literature, suggest that the use of serotonin-enhancing drugs can precipitate a cerebrovascular syndrome due to reversible, multifocal arterial narrowing.

Effects of Normobaric Hyperoxia in a Rat Model of Focal Cerebral Ischemia—Reperfusion

Recent studies suggest that normobaric hyperoxia can be beneficial, if administered during transient stroke. However, increased oxygenation theoretically may increase oxygen free-radical injury, particularly during reperfusion. In the present study, the authors assessed the benefit and risks of hyperoxia during focal cerebral ischemia and reperfusion. Rats were subjected to hyperoxia (Fio2 100%) or normoxia (Fio2 30%) during 2-hour filament occlusion and 1-hour reperfusion of the middle cerebral artery. At 24 hours, the hyperoxia group showed 70% (total) and 92% (cortical) reduction in infarct volumes as compared to the normoxia group. Levels of oxidative stress were evaluated using three indirect methods. First, since oxygen free radicals increase blood—brain barrier (BBB) damage, Evans blue dye extravasation was quantified to assess BBB damage. Second, the expression of heme oxygenase-1 (HO-1), a heat shock protein inducible by oxidative stress, was assessed using Western blot techniques. Third, an immunoblot technique (“OxyBlot”) was used to assess levels of protein carbonyl formation as a marker of oxidative stress—induced protein denaturation. At 24 hours, Evans blue dye extravasation per average lesion volume was similar between groups. There were no significant differences in HO-1 induction and protein carbonyl formation between groups, in the ipsilateral or contralateral hemispheres, at 6 hours and at 24 hours. These results indicate that hyperoxia treatment during focal cerebral ischemia—reperfusion is neuroprotective, and does not increase oxidative stress.