Reversible cerebral vasoconstriction syndrome: not just a “reversible” condition. Retrospective observational study and literature review

Microvascular brain injury is well recognized in neuropsychiatric systemic lupus erythematosus (SLE), but cerebral large artery involvement is being debated. Three females with SLE, aged 9 to 14years, had immunosuppressive treatment intensification because of lupus nephritis. Within the following days or weeks, they presented with intense cephalalgia - isolated or associated with neurological symptoms - and no or mild hypertension. Magnetic resonance angiography showed multiple stenoses within the circle of Willis. One patient had subsequent small subcortical cerebral infarction. Two patients were treated for neuropsychiatric SLE; one patient was treated for reversible cerebral vasoconstriction syndrome (RCVS). Angiography normalized within a few weeks in all three patients. Retrospectively, clinical and radiological features suggest that RCVS was the most likely diagnosis in all patients. Multidisciplinary analysis of clinical and angiographic features is recommended, as RCVS is rare in children and its recognition may help to adjust treatment. WHAT THIS PAPER ADDS: Reversible vasoconstriction syndrome was observed in paediatric systemic lupus erythematosus. Thorough imaging analysis was necessary to address this diagnosis in paediatric patients.

Introduction: Reversible cerebral vasoconstriction syndrome (RCVS) is a syndrome of recurrent thunderclap headaches with transient cerebral vasoconstriction which can cause stroke. There are few population-based data on the incidence of RCVS as well as associated risk factors and complications. Methods: We performed a retrospective cohort study using administrative claims data from all nonfederal emergency department (ED) visits and hospitalizations in 11 U.S. states during 2016. Using ICD-10 diagnosis code I67.841, we identified adult patients hospitalized with RCVS and evaluated associated diagnoses during prior, concurrent, and subsequent ED visits and hospitalizations. We used U.S. census data to estimate the age- and sex-standardized incidence of RCVS in the U.S. adult population. In a validation study, we reviewed the records of patients with a discharge diagnosis of RCVS and a random sample of patients with other cerebrovascular diagnoses at our medical center to estimate the sensitivity and specificity of the RCVS diagnosis code, and calculated the RCVS 2 score of patients with RCVS. Results: In our validation study, the sensitivity of the RCVS ICD-10 code was 100% (95% CI, 66-100%) and the specificity 90% (95% CI, 74-98%); the median RCVS 2 score among patients diagnosed with RCVS was 6, supporting that the diagnosis code generally identified true cases of RCVS. In our statewide analysis, we identified 222 patients diagnosed with RCVS in 2016, equating to a U.S. incidence of 2.7 (95% CI, 2.4-3.1) per million adults per year. The mean age was 46.8 (±14.3) years, 63.5% of patients were white, and 77.5% were female. There were 17 ED visits (22% of all ED visits) for headache in the 3 months before RCVS diagnosis. During the RCVS hospitalization, the most common complications were subarachnoid hemorrhage (33.5%), followed by ischemic stroke (14.9%), intracerebral hemorrhage (9.3%), and seizures (9.3%). Most patients were discharged home after admission for RCVS (76.6%). Conclusions: Hospitalization with a recognized case of RCVS occurs in about 3 per million adults in the U.S. per year. Although majority of patients hospitalized with RCVS were discharged home, a substantial proportion had serious cerebrovascular complications.

Introduction: Nontraumatic convexity subarachnoid hemorrhage (cSAH) is a non-aneurysmal variant associated with various etiologies. Methods: We performed retrospective review of consecutive cSAH admitted to a large comprehensive stroke center, from 8/1/06-1/1/16. We abstracted data on demographics, neuroimaging, and clinical presentation; trauma was excluded. Cases were categorized: cryptogenic (negative work-up), susceptibility-weighted imaging-confirmed amyloid angiopathy (AA), posterior reversible encephalopathy syndrome (PRES), imaging-confirmed reversible cerebral vasoconstriction syndrome (RCVS), cerebral venous thrombosis (CVT), large artery occlusion (LA), or other known cause (sepsis, endocarditis, cerebral infarcts, or malignancy). Results: We identified 84 cases of cSAH occurring in 83 patients. Etiology subgroups were: 25% cryptogenic (N=21), 16% AA (N=13), 13% PRES (N=11), 13% RCVS (N=11), 11% CVT (N=9), 8% LA (N=7), and 14% other (N=12). Among cryptogenic patients, 8 had suspected clinical RCVS and 1 had suspected AA. There were significant differences in age, gender, and clinical presentation among etiology subgroups. AA patients were the oldest (mean 75.6 years), while RCVS patients were the youngest (45.6 years, p<0.0001). The majority of AA cohort was male (61%), whereas PRES and RCVS cohorts were exclusively female (100%, p=0.0002). Transient neurologic symptoms were common in AA (69%) but rare in RCVS (0%, p=0.01); headache was common in RCVS (80%) but unusual in AA (15%, p=0.001). Among 11 patients with confirmed RCVS, initial vascular imaging was negative in 6 (55%); repeat vascular imaging was necessary to diagnosis vasoconstriction (mean delay 5 days, range 3 -16 days). Conclusions: To our knowledge, this is the largest case series of cSAH patients. Convexity SAH has a broad range of etiologies, with the most common being cryptogenic, RCVS, PRES, and AA. In our cohort, cSAH due to AA most typically presented as older males with transient neurological symptoms; cSAH due to RCVS presented as younger females with headache. Over half of patients with cSAH due to RCVS required repeat vascular imaging to confirm vasoconstriction. Further research is warranted to clinically characterize this complex variant of SAH.

Introduction: Reversible cerebral vasoconstriction syndrome (RCVS) may co-occur with brain MRI T2/FLAIR sequence changes, and posterior reversible encephalopathy syndrome (PRES) may be associated with cerebral vasoconstriction. Both entities with overlapping features may be considered as a single group. We compared the isolated RCVS group to the overlapping group to investigate clinical and radiological features, with a focus on vessel involvement. Methods: We performed a retrospective study of adult patients admitted to a tertiary medical center from February 2008 until February 2018 and who were diagnosed with PRES or RCVS. Overlap cases consisting of PRES with vasoconstriction and RCVS with reversible MRI T2/FLAIR changes were compared to isolated RCVS cases. Clinical and radiological features of both groups were compared with each other. Involved vessel segments were classified as internal carotid artery, M1 and M2 middle cerebral artery, A1 and A2 anterior cerebral artery, P1 and P2 posterior cerebral artery, vertebral artery, and basilar artery. Severity was also graded (1-49% or >49%). Appropriate statistical tests were used to compare the variables and significant findings reported. Results: There were 86 cases with isolated RCVS and 44 cases of overlap. Seizures (19, 43%) and encephalopathy (13, 30%) were common in the overlap group, whereas headache was common in the isolated RCVS group (79, 92%). Immunosuppressant use was more often present in the overlap group (9, 20%), but there were no differences in antidepressant, cocaine, or marijuana use. Intracerebral hemorrhage was more common in the overlap group (12/44, p=0.003), but there were similar numbers of ischemic strokes and subarachnoid hemorrhages. There were no differences in the number or location of segments involved or stenosis severity between the groups. Home discharge was more frequent among pure RCVS (73, 85%) than among overlap patients (27, 61%, p=0.004). Conclusion: Clinical presentations and short-term prognosis differed among isolated RCVS and group with PRES-RCVS overlap characteristics. There was no difference in vascular involvement between the groups.

Objectives To report demographics and characteristics of reversible cerebral vasoconstriction syndrome (RCVS) in the Korean cohort. Methods We prospectively recruited patients with definite (imaging-proven) RCVS and probable (imaging-negative) RCVS who visited Samsung Medical Center between June 2012 and September 2016. Clinical manifestations, neuroimaging, treatment, and clinical outcomes were evaluated in all patients. Characteristics of RCVS without typical causes ("idiopathic RCVS") were compared with those of RCVS with identifiable causes ("secondary RCVS"). International Classification of Headache Disorders (ICHD)-3 beta criteria for 6.7.3 RCVS and 6.7.3.1 probable RCVS were tested. Results A total of 138 patients (104 definite and 34 probable RCVS) were included in this study. Patients with definite RCVS were predominantly female (85.6%) and middle-aged (mean, 50.7 [range, 23-82] years). Probable RCVS was associated with less female predominance (70.6%, p = 0.049), more typical manifestations ( p < 0.001), and none of neurological complications. One-hundred and one (97.1%) patients with definite RCVS had headache, but the typical "recurrent and/or triggered" thunderclap headache was reported in only 83 (82.2%). In most patients with definite RCVS (84.6%), RCVS was idiopathic, while only 16 (15.4%) had secondary causes. Compared to those with secondary RCVS, patients with idiopathic RCVS were older (52.8 ± 11.42 vs. 39.1 ± 9.55 years, p < 0.001). Patients with secondary RCVS had more complications than those with idiopathic RCVS (40.5% vs. 12.5%, p = 0.018). Among idiopathic RCVS patients, 33 (37.5%) reported a preceding event or a change in lifestyle, environment, health, or medication within one month before onset. Conclusion In our cohort, RCVS was benign and idiopathic in most patients, and occurred frequently in middle-aged women. Manifestations of RCVS were more diverse than previously recognized, and forms without any headache existed. Different genetic, social, and environmental factors should be taken into account to unveil the spectrum and pathophysiology of RCVS.

Introduction: Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) are diagnoses that have a clinical and radiographic overlap. One particular overlap includes the presence of hemorrhage, which we studied in each population to determine its effect on outcomes. Objective: To compare characteristics and outcomes of hemorrhagic PRES and hemorrhagic RCVS populations. Methods: We conducted a review of the electronic health record at a single tertiary center from January 2008 to December 2018. Inclusion criteria were 18 years or older with clinical and radiographic evidence of PRES or RCVS. Patient demographics, presenting symptoms, imaging findings, and outcomes were compared between PRES and RCVS groups. Poor outcome was defined as discharge to skilled nursing facility or death. Analysis was performed using Pearson’s Chi-Square test. Results: Among 281 PRES and 98 RCVS cases, intracranial hemorrhage was seen on imaging in 51 PRES cases (18%) and 34 RCVS cases (35%). Headache was present in all patients with hemorrhagic RCVS but only seen in 40% of hemorrhagic PRES. Use of antidepressants or drugs of abuse was more frequent with hemorrhagic RCVS (53%) as compared to hemorrhagic PRES (7%, p &lt;0.05). Among hemorrhagic PRES, presence of intraparenchymal hemorrhage but not subarachnoid hemorrhage was associated with vasoconstriction on arterial imaging (p&lt;0.05). Length of stay was longer for both hemorrhagic PRES and hemorrhagic RCVS (p&lt;0.001) compared those without hemorrhage. Presence of focal neurological deficits, motor and sensory, was associated with poor outcomes in hemorrhagic RCVS patients (p&lt;0.05). Discharge to a rehabilitation facility was associated with hemorrhagic PRES (p&lt;0.05), no association in those without hemorrhage. There is no evidence that discharge location is significantly different between RCVS hemorrhage and non-hemorrhage groups. Conclusion: Hemorrhage in PRES and RCVS is associated with more clinical deficits at presentation and longer hospital stays. Underlying vasoconstriction is frequent and associated with hemorrhagic PRES.

Background Altered cerebrovascular tone is implicated in reversible cerebral vasoconstriction syndrome (RCVS). We evaluated vasomotor reactivity using bedside transcranial Doppler in RCVS patients. Methods In this retrospective case-control study, middle cerebral artery (MCA) blood flow velocities were compared at rest and in response to breath-hold in RCVS ( n = 8), Migraineurs ( n = 10), and non-headache Controls ( n = 10). Hyperventilation response was measured in RCVS. Results In RCVS, Breath Holding Index (BHI) was severely reduced in seven of eight patients and 14/16 MCAs; seven of 16 MCAs showed exhausted (BHI < 0.1) or inverted (BHI < 0) vasomotor reactivity. Mean BHI in RCVS (0.23 ± 0.5) was significantly lower than Migraine (1.52 ± 0.57) and Controls (1.51 ± 0.32), p < 0.001. Triphasic velocity responses were seen in all groups. The maximum Vmean decline during the middle negative phase was -15.5 ± 9.2% in RCVS, -15.4 ± 7% in Migraine, and -10.3 ± 5% in Controls ( p = 0.04). In the late positive phase, average Vmean increase was 6.2 ± 14% in RCVS, which was significantly lower ( p < 0.001) than Migraine (30.5 ± 11%) and Controls (30.2 ± 6%). With hyperventilation, RCVS patients showed 23% decrease in Vmean. Conclusion Cerebral arterial tone is abnormal in RCVS, with proximal vasoconstriction and abnormally reduced capacity for vasodilation. Further studies are needed to determine the utility of BHI to diagnose RCVS before angiographic reversibility is established, and to estimate prognosis.

Preeclampsia and Cerebrovascular Disease.

Body of the Abstract: (1) To report a rare case of Reversible Cerebral Vasoconstriction Syndrome (RCVS) and associated intraparenchymal and subarachnoid hemorrhage following induction of spinal anesthesia in an uncomplicated, elective C-section (2) To discuss its potentially life threatening or well-being altering effects (3) To review the pathophysiology, diagnosis and potential treatments of the syndrome. Introduction: Reversible cerebral vasoconstriction syndrome (RCVS) is a rare condition defined clinically by symptoms of a severe recurrent headache described as a thunderclap headache, cerebral vasoconstriction of at least two different arteries on imaging, and resolution of vasoconstriction within three months. Complications include non-aneurysmal subarachnoid hemorrhage, seizure, stroke, and intracerebral hemorrhage. More than half of cases of RCVS occur postpartum or after use of vasoactive substances such as adrenergic or serotonergic drugs. Triggers include illicit drugs, eclampsia, or strenuous physical or sexual activity. As RCVS most commonly occurs during the postpartum period, it is extremely rare to encounter RCVS during the antepartum or peripartum periods. There has been only one other reported case of RCVS while undergoing spinal anesthesia for a C-section. Presented is a patient diagnosed with RCVS after spinal anesthesia during an elective C-section subsequently complicated by seizure, intracerebral and subarachnoid hemorrhage. Case Presentation: A 32-yearold G2 now P2002 patient presented at 39 6/7 weeks gestational age for elective primary C-section for a history of delivery complications with the first pregnancy. Medical history was unremarkable. First pregnancy labor epidural analgesia was uncomplicated. Spinal anesthesia induction was uneventful. Shortly thereafter, dizziness was reported and hypotension and bradycardia (P 42, BP 76/41) developed. Treatment included IV Ephedrine and Glycopyrrolate. Frontal headache developed. The patient then developed a tonic-clonic seizure with gaze deviation and upper limb rigidity lasting 45 seconds. An oral airway was placed for respiratory assistance with 100% oxygen. The patient became alert five minutes later. Vital signs: BP 168/98 P 122.C-section was performed. After incision, the patient had a second tonic-clonic seizure lasting 30 seconds. Midazolam was given. A healthy baby was delivered with Apgars of 7 and 9. The C-section was otherwise uncomplicated. Postoperatively, the patient was alert with stable vital signs. The neurologic exam was intact. The CT showed a 1.9 x 3.8 x 1.2 cm intraparenchymal hemorrhage-right frontal lobe with a subarachnoid hemorrhage in both the right frontal lobe and right sylvian fissure. Exam was normal. Headache continued. Tertiary care facility transfer was arranged. Tertiary care evaluation with 24-hour EEG monitoring, CT angiography (CTA) and CT venogram showed no evidence of venous sinus or cortical vein thrombosis. Magnetic resonance imaging (MRI) and transcranial doppler showed vasospasm diagnostic of RCVS. Subsequent CTA showed vasospasm of three branches of the carotid artery. Hospital discharge occurred on day 6. Six-month neurological follow-up showed resolution of hemorrhage and minimal residual symptoms. Discussion: Literature review discovered only one other case of RCVS with induction of regional anesthesia. To our knowledge the associated seizure activity coupled with intraparenchymal/subarachnoid hemorrhages has not been previously reported. RCVS, an extremely rare phenomenon is estimated to occur in 0.26% of headache patients; is more frequent in middle aged women and may have variable triggering factors. It may be associated with antidepressants, illicit drugs or sympathomimetic meds. Pregnancy and vasoconstrictive meds are risk factors with an occurrence rate of 5%. The pathophysiology is unknown but felt to be due to impaired cerebral vessel autoregulation. It is hypothesized that other factors and substances including endothelial dysfunction, pro and antiangiogenic factors, serotonin, cytokines and vascular endothelial growth factor may play some role. While MRI and doppler imaging may be of assistance, CTA is most useful for diagnosis. Since static imaging alone does not confirm the diagnosis, most cases likely go undiagnosed. Rarely, complications of RCVS include stroke, seizure, cerebral hemorrhage and Posterior Reversible Encephalopathy Syndrome. There is no prophylactic or therapeutic treatment proven effective for RCVS. Recommendations include symptomatic treatment of the headache, blood pressure, and delivery if eclampsia is suspected. Calcium channel blockers are often used for vasodilatory effects, although they have not been proven to improve symptoms or outcome in RCVS. Conclusion: RCVS is a very rarely occurring vascular disorder occasionally seen postpartum. This is the first reported case of associated seizure activity and resultant intraparenchymal and subarachnoid hemorrhage occurring after induction of spinal anesthesia for an uncomplicated C-section. It demonstrates the need for awareness of this disorder as well as knowledgeable hemodynamic anesthesia management specific to its unique features. The RCVS diagnostic and management challenges dictate that case collection and research be continued.

Background and ObjectivesBlood-brain barrier (BBB) disruption was found to be critical in the pathogenesis of reversible cerebral vasoconstriction syndrome (RCVS). We hypothesized that increased central arterial stiffness, resulting in the excessive transmission of central pulsatile flow to the dysregulated cerebral microcirculation, may contribute to the disruption of BBB.MethodsThis is a cross-sectional study. Participants with RCVS in the acute phase were recruited from both outpatient and inpatient settings between January 2018 and September 2020. The diagnosis was established based on clinical presentations and neuroradiologic evidence. Age-matched and sex-matched healthy controls (HCs) were recruited from nearby communities. Patients with RCVS were recruited and underwent 3-dimensional isotropic contrast-enhanced T2 fluid-attenuated inversion recovery imaging to visualize BBB disruption. The central arterial stiffness was assessed with hemodynamic parameters such as carotid-femoral pulse wave velocity (cfPWV), carotid augmentation index (cAI), and central blood pressure (ceBP). Arterial stiffness was compared between patients with RCVS and HCs, and between patients with RCVS with and without BBB disruption.ResultsSixty-five patients with RCVS (mean age 44.3 ± 9.6 years; 42 women) and 65 HCs (mean age 45.4 ± 8.9 years; 42 women) completed the study. Among the patients with RCVS, 33 exhibited imaging-proven BBB disruption. Those with BBB disruption were older (48.3 ± 9.2 vs 40.2 ± 8.3 years, p < 0.001) and had a higher proportion of women (81.8% vs 46.9%, p = 0.003). Arterial stiffness was increased in patients with RCVS, as indicated by a higher cfPWV compared with controls (10.8 ± 2.5 m/s vs 9.2 ± 2.3 m/s, p < 0.001). Among patients with RCVS, those with BBB disruption had greater central arterial stiffness, reflected by higher cfPWV and cAI (11.4 ± 2.7 m/s vs 10.1 ± 2.1 m/s, p = 0.036; 15 ± 18% vs 2 ± 19%, p = 0.007). There were no significant differences in ceBP between patients with RCVS (regardless of BBB disruption) and HCs.DiscussionOur study confirmed increased central arterial stiffness in patients with RCVS, especially among those with BBB disruption. These findings suggest a potential contribution of central arterial stiffness and excessive pulsatile flow to cerebral microvascular dysfunction in the pathogenesis of RCVS.

112. Reversible cerebral vasoconstriction syndrome associated with pregnancy in peripartum period

Introduction: Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) might represent a pathophysiological spectrum. They are commonly diagnosed separately, based on prominent clinical features. We aimed to compare clinical and radiographic findings of PRES and RCVS. Methods: We performed a retrospective study of adult patients admitted to a tertiary medical center from February 2008 until February 2018 and were diagnosed with PRES or RCVS. Patient demographics, risk factors, clinical features, imaging, and outcomes were compared. Appropriate statistical tests were used to compare the variables and significant findings are reported. Results: There were 281 PRES and 98 RCVS cases meeting diagnostic criteria. Seizures, encephalopathy, and hypertension were more common with PRES, whereas headache was more common with RCVS (p &lt;0.001). Hypertension and transplant recipient or immunocompromised status were associated with PRES (p &lt;0.001), as did diabetes mellitus (p &lt;0.05). Marijuana use, smoking, and obesity were associated with RCVS (p &lt;0.05). ). Intraparenchymal or subarachnoid hemorrhage was found in 51 PRES cases and 34 RCVS cases. Arterial stenosis was present in 19 % of PRES cases. Brain FLAIR MRI hyperintensity that was reversible on follow-up was present in 26% of RCVS cases. Conclusion: PRES and RCVS share common clinical characteristics and might represent a pathophysiological spectrum, though distinct clinical features were noted in our retrospective analysis.

BackgroundHalf of the sufferers of reversible cerebral vasoconstriction syndrome (RCVS) exhibit imaging-proven blood-brain barrier disruption. The pathogenesis of blood-brain barrier disruption in RCVS remains unclear and mechanism-specific intervention is lacking. We speculated that cerebrovascular dysregulation might be associated with blood-brain barrier disruption in RCVS. Hence, we aimed to evaluate whether the dynamic cerebral autoregulation is altered in patients with RCVS and could be associated with blood-brain barrier disruption.MethodsA cross-sectional study was conducted from 2019 to 2021 at headache clinics of a national tertiary medical center. Dynamic cerebral autoregulation was evaluated in all participants. The capacity of the dynamic cerebral autoregulation to damp the systemic hemodynamic changes, i.e., phase shift and gain between the cerebral blood flow and blood pressure waveforms in the very-low- and low-frequency bands were calculated by transfer function analysis. The mean flow correlation index was also calculated. Patients with RCVS received 3-dimensional isotropic contrast-enhanced T2 fluid-attenuated inversion recovery imaging to visualize blood-brain barrier disruption.ResultsForty-five patients with RCVS (41.9 ± 9.8 years old, 29 females) and 45 matched healthy controls (41.4 ± 12.5 years old, 29 females) completed the study. Nineteen of the patients had blood-brain barrier disruption. Compared to healthy controls, patients with RCVS had poorer dynamic cerebral autoregulation, indicated by higher gain in very-low-frequency band (left: 1.6 ± 0.7, p = 0.001; right: 1.5 ± 0.7, p = 0.003; healthy controls: 1.1 ± 0.4) and higher mean flow correlation index (left: 0.39 ± 0.20, p = 0.040; right: 0.40 ± 0.18, p = 0.017; healthy controls: 0.31 ± 0.17). Moreover, patients with RCVS with blood-brain barrier disruption had worse dynamic cerebral autoregulation, as compared to those without blood-brain barrier disruption, by having less phase shift in very-low- and low-frequency bands, and higher mean flow correlation index.ConclusionsDysfunctional dynamic cerebral autoregulation was observed in patients with RCVS, particularly in those with blood-brain barrier disruption. These findings suggest that impaired cerebral autoregulation plays a pivotal role in RCVS pathophysiology and may be relevant to complications associated with blood-brain barrier disruption by impaired capacity of maintaining stable cerebral blood flow under fluctuating blood pressure.Graphical

Reversible cerebral vasoconstriction syndrome (RCVS) is one of the most important differential diagnosis in patients with thunderclap headache (TCH). We aimed to develop a new scoring system for RCVS in patients with TCH. We retrospectively analyzed 72 patients enrolled in the prospective study of TCH conducted in 2015–2016 (derivation set). We identified possible predictors for the diagnosis of RCVS and constructed a prediction model (RCVS–TCH score) using the multivariable logistic regression model. Diagnostic performance was validated to an independent validation set from our headache registry. The derivation set comprised 41 patients with RCVS and 31 with non-RCVS, and the validation set included 253 patients with TCH (165 with RCVS and 88 with non-RCVS). The RCVS–TCH score (range: 0–12) contained four predictors: recurrent TCHs, female sex, triggering factor for TCH (single or multi) and blood pressure surge. The C-index of RCVS–TCH score was 0.929 (95% CI = 0.874–0.984). The RCVS–TCH score ≥ 7 had a sensitivity of 80% and a specificity of 97% in discriminating RCVS from non-RCVS. In the validation set, RCVS–TCH score showed a C-index of 0.861 (95% CI = 0.815–0.908). In our study, the RCVS–TCH showed good performance, which may aid the diagnosis of RCVS among patients with TCH.

Diagnosis of reversible cerebral vasoconstriction syndrome (RCVS) is currently based on luminographic findings of vasoconstriction. In addition to vasoconstriction, the blood-brain barrier (BBB) breakdown has been postulated as a central mechanism of RCVS. Our aim was to document BBB breakdown in patients with RCVS and its role for the pathophysiology-based diagnosis of RCVS. We prospectively recruited 72 consecutive patients with thunderclap headache who did not have aneurysmal subarachnoid hemorrhage from April 2015 to July 2016 at the Samsung Medical Center. Based on the International Classification of Headache Disorders-3 beta criteria and neuroimaging, patients were classified as having RCVS (n = 41; "definite" in 29 imaging-proven patients and "probable" in 12 imaging-negative patients), other secondary causes (n = 7), and thunderclap headache of undetermined cause (n = 24). BBB breakdown was evaluated using contrast-enhanced fluid-attenuated inversion recovery magnetic resonance imaging. BBB breakdown was documented in 20 (69.0%) patients with definite RCVS, 3 (25.0%) patients with probable RCVS, and none with other secondary causes. BBB breakdown was present in RCVS patients with (n = 4) and without (n = 19) concomitant posterior reversible encephalopathy syndrome. In patients with RCVS, the extent of BBB breakdown was independently associated with neurological complications (multivariate odds ratio = 1.48 per 1 territorial increase, 95% confidence interval = 1.04-2.12, adjusted p = 0.032). Three (12.5%) patients with thunderclap headache of undetermined cause were newly classified as having RCVS by the presence of BBB breakdown. This is the first study to show BBB breakdown in patients with RCVS. This finding might broaden our understanding of the pathophysiology and clinical spectrum of RCVS. Ann Neurol 2017;81:454-466.