Reversible Cerebral Vasoconstriction Syndrome Patients Research Articles

Dynamic changes in glymphatic function in reversible cerebral vasoconstriction syndrome.

The pathophysiology of the reversible cerebral vasoconstriction syndrome (RCVS) remains enigmatic and the role of glymphatics in RCVS pathophysiology has not been evaluated. We aimed to investigate RCVS glymphatic dynamics and its clinical correlates. We prospectively evaluated the glymphatic function in RCVS patients, with RCVS subjects and healthy controls (HCs) recruited between August 2020 and November 2023, by calculating diffusion-tensor imaging along the perivascular space (DTI-ALPS) index under a 3-T MRI. Clinical and vascular (transcranial color-coded duplex sonography) investigations were conducted in RCVS subjects. RCVS participants were separated into acute (≤ 30days) and remission (≥ 90days) groups by disease onset to MRI interval. The time-trend, acute stage and longitudinal analyses of the DTI-ALPS index were conducted. Correlations between DTI-ALPS index and vascular and clinical parameters were performed. Bonferroni correction was applied to vascular investigations (q = 0.05/11). A total of 138 RCVS patients (mean age, 46.8years ± 11.8; 128 women) and 42 HCs (mean age, 46.0years ± 4.5; 35 women) were evaluated. Acute RCVS demonstrated lower DTI-ALPS index than HCs (p < 0.001) and remission RCVS (p < 0.001). A continuously increasing DTI-ALPS trend after disease onset was demonstrated. The DTI-ALPS was lower when the internal carotid arteries resistance index and six-item Headache Impact test scores were higher. In contrast, during 50-100days after disease onset, the DTI-ALPS index was higher when the middle cerebral artery flow velocity was higher. Glymphatic function in patients with RCVS exhibited a unique dynamic evolution that was temporally coupled to different vascular indices and headache-related disabilities along the disease course. These findings may provide novel insights into the complex interactions between glymphatic transport, vasomotor control and pain modulation.

Disrupted Brain Functional Status in Patients with Reversible Cerebral Vasoconstriction Syndrome.

The aim of this study was to investigate the functional networks in subjects with reversible cerebral vasoconstriction syndrome (RCVS) using resting-state functional magnetic resonance imaging (rs-fMRI). We prospectively recruited patients with RCVS and healthy controls (HCs) between February 2017 and April 2021. The rs-fMRI data were analyzed using graph theory methods. We compared node-based global and regional topological metrics (Bundle 1) and network-based intranetwork and internetwork connectivity (Bundle 2) between RCVS patients and HCs. We also explored the associations of clinical and vascular (ie, the Lindegaard index, LI) parameters with significant rs-fMRI metrics. A total of 104 RCVS patients and 93 HCs were included in the final analysis. We identified significantly decreased local efficiency of the left dorsal anterior insula (dAI; p = 0.0005) in RCVS patients within 30 days after disease onset as compared to HCs, which improved 1 month later. RCVS patients also had increased global efficiency (p = 0.009) and decreased average degree centrality (p = 0.045), clustering coefficient (p = 0.033), and assortativity values (p = 0.003) in node-based analysis. In addition, patients with RCVS had increased internetwork connectivity of the default mode network (DMN) with the salience (p = 0.027) and dorsal attention (p = 0.016) networks. Significant correlations between LI and regional local efficiency in left dAI (rs = -0.418, p = 0.042) was demonstrated. The significantly lower local efficiency of the left dAI, suggestive of impaired central autonomic modulation, was negatively correlated with vasoconstriction severity, which is highly plausible for the pathogenesis of RCVS. ANN NEUROL 2023;94:772-784.

Reversible cerebral Vasoconstriction syndrome intERnational CollaborativE (REVERCE) network: Study protocol and rationale of a multicentre research collaboration.

Reversible cerebral vasoconstriction syndrome (RCVS) is a rare, but increasingly recognised cerebrovascular condition with an estimated annual age-standardised incidence of approximately three cases per million. Knowledge about risk factors and triggering conditions and information about prognosis and optimal treatment in these patients are limited. The REversible cerebral Vasoconstriction syndrome intERnational CollaborativE (REVERCE) project aims to elucidate the epidemiological and clinical characteristics of RCVS by collecting individual patient data from four countries (France, Italy, Taiwan and South Korea) in the setting of a multicentric study. All patients with a diagnosis of definite RCVS will be included. Data on the distribution of risk factors and triggering conditions, imaging data, neurological complications, functional outcome, risk of recurrent vascular events and death and finally the use of specific treatments will be collected. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and geographical region of residence. Ethical approval for the REVERCE study will be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of clinical and epidemiological characteristics of RCVS patients.

Vasoconstriction and long-term headache in reversible cerebral vasoconstriction syndrome.

Angiographic vasoconstriction in reversible cerebral vasoconstriction syndrome (RCVS) is often undetectable at symptom onset and the diagnosis relies on clinical presentation. Although thunderclap headache is a hallmark feature of RCVS, the incidence and predictors of long-term headaches (LTH) are incompletely understood. Our study aims were twofold: to examine the sensitivity and specificity of a recently developed score (RCVS2) for vasoconstriction detection in a real-world clinical context and describe the incidence and predictors of LTH beyond the acute phase of RCVS. Retrospective analysis of consecutive patients with clinical diagnosis of RCVS in a tertiary hospital between 2017 and 2021. We examined associations between demographic factors, comorbidities, medications, imaging characteristics, and LTH (defined as at least one episode present at greater than 6-months follow-up necessitating medication). We separately examined the association between RCVS2 score and angiographic vasoconstriction and computed its sensitivity, specificity, and negative and positive predictive value based on established cutoffs (certain ≥ 5, negative ≤ 2). We included 55 patients, 50.5 (± 13.7) years; 41 (75%) female. 25 (49%) patients had LTH; only prior history of headache was significantly associated with LTH [OR 4.3, 95% CI (1.1-16.2), p = 0.03]. We found a significant association between RCVS2 score and angiographic vasoconstriction [OR 1.49, 95% CI (1.18-1.88), p = 0.001]; sensitivity, specificity, and positive and negative predictive value were 64%, 94%, 95% and 58% respectively. Approximately 50% of RCVS patients experienced LTH; only prior headache history was associated with its incidence. The RCVS2 score had a significant association with high specificity and positive predictive value for angiographic vasoconstriction in our cohort, validating its utility in improving the accuracy of diagnosis in the clinical setting.

Abstract WP157: Outcomes Of Reversible Cerebral Vasoconstriction Syndrome: Analysis Of The National Inpatient Sample Databases, 2016-2018

Introduction: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe headaches accompanied by reversible segmental vasoconstriction of cerebral arteries. Ischemic and hemorrhagic stroke are considered major complications of RCVS. We aimed to assess outcomes of RCVS patients with and without stroke, and to compare presentation with ischemic or hemorrhagic stroke. Methods: Data was extracted from the National Inpatient Sample (NIS) spanning 2016 to 2018. All adult patients diagnosed with RCVS were identified using ICD-10 codes after excluding patients with a concurrent diagnosis of primary angiitis. Measured outcomes included adverse events during hospitalization and discharge disposition. Standard bivariate statistical tests were applied to compare groups. Results: Of 3170 patients (mean age 48.0±15.7 years; 73.3% female) who were admitted with the diagnosis of RCVS, 1565 patients (49.4%) had no stroke and 1605 patients (50.6%) presented with stroke. In patients who presented with stroke, 375 patients (26.1%) had only ischemic stroke and 1060 (73.9%) presented with only hemorrhagic stroke. Rates of routine discharge were higher in patients with no stroke (75.4% vs 57.9%, p&lt;0.001) versus those presenting with stroke (Table). In patients who presented with stroke, rates of percutaneous gastrostomy (PEG) placement were higher in ischemic stroke group compared to patients with hemorrhagic stroke (5.3% vs 2.4%, p=0.004), whereas rates of ventilation/intubation were higher in patients with hemorrhagic stroke (10.8% vs 4.0%, p=0.001). Routine discharge was more frequent in RCVS patients presenting with hemorrhagic rather than ischemic stroke (66.0% vs 48.0%, p&lt;0.001). Conclusions: More than half of patients admitted with a diagnosis of RCVS presented with stroke. RCVS patients presenting with ischemic stroke have higher rates of PEG placement and lower rates of routine discharge than those presenting with hemorrhagic stroke.

Hyperintense posterior cerebral artery sign in patients with reversible cerebral vasoconstriction syndrome.

Background: This study investigated hyperintense vessel signs (HVS) on fluid-attenuated inversion recovery imaging in the P1–2 portions of posterior cerebral arteries (PCAs) as a “hyperintense PCA sign” and HVS of cortical arteries. We retrospectively examined whether these signs would be useful in diagnosing reversible cerebral vasoconstriction syndrome (RCVS) in the acute phase.Methods: Eighty patients with RCVS who underwent initial magnetic resonance imaging (MRI) within 7 days of onset were included in this study. HVS and related clinical factors were examined.Results: On initial MRI of RCVS patients, hyperintense PCA sign and HVS of cortical arteries were seen in 21 cases (26%) and 38 cases (48%), respectively. In patients showing hyperintense PCA sign, vasoconstriction of the A2–3 portion was a significant clinical factor. Conversely, vasoconstriction of the M1 and P1 portions and the presence of white matter hyperintensity on initial and chronic-stage MRI were significantly associated with the presence of HVS in cortical arteries.Conclusion: Because rich collateral flow exists around PCAs, the frequency of hyperintense PCA sign is not high. However, hyperintense PCA sign findings in patients with suspected RCVS offer credible evidence of extreme flow decreases due to vasoconstriction in peripheral PCAs and other arteries associated with the collateral circulation of PCAs. Conversely, HVS in cortical arteries tend to reflect slow antegrade circulation due to vasoconstriction of peripheral vessel and major trunks. Both signs appear useful for auxiliary diagnosis of acute-phase RCVS.

Predictors and outcomes of ischemic stroke in reversible cerebral vasoconstriction syndrome.

The clinical factors predisposing to ischemic stroke in reversible cerebral vasoconstriction syndrome (RCVS) are unclear. In this observational cross-sectional study, we aimed to evaluate the risk factors and clinical outcomes associated with the development of ischemic stroke in patients with RCVS. We utilized the Nationwide Readmissions Database 2016-2017 to identify all hospitalizations with RCVS, with or without acute ischemic stroke. Independent predictors of and clinical outcomes associated with ischemic stroke were analyzed using logistic regression. Among 1065 hospitalizations for RCVS (mean ± SD age 49.0 ± 16.7years, female 69.7%), 267 (25.1%) had ischemic stroke. Patients with ischemic stroke were more likely to have hypertension (OR 2.33, 95% CI 1.51-3.60), diabetes (OR 1.81, 95% CI 1.11-2.98), and tobacco use (OR 1.64, 95% CI 1.16-2.33) and were less likely to have a history of migraine (OR 0.56, 95% CI 0.35-0.90). Ischemic stroke was associated with higher odds of cerebral edema (OR 3.15, 95% CI 1.31-7.57) and respiratory failure (OR 2.39, 95% CI 1.28-4.44). Patients with ischemic stroke also had longer hospital stay by a mean duration of 6.7days, P < 0.001, higher hospital charges by a mean of $72,961, P < 0.001, and a higher likelihood of not being discharged to home (OR 3.57, 95% CI 2.39-5.33). They had higher in-hospital mortality rate; however, the difference was not statistically significant. Ischemic stroke affects nearly 25% of patients with RCVS and is associated with adverse clinical outcomes. RCVS patients with cerebrovascular risk factors might have a higher predisposition for developing ischemic lesions during the disease process.

Abstract P460: Comparison of Hemorrhagic Posterior Reversible Encephalopathy Syndrome and Hemorrhagic Reversible Cerebral Vasoconstriction Syndrome

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.

Narrative Review: Headaches After Reversible Cerebral Vasoconstriction Syndrome.

Reversible cerebral vasoconstriction syndrome (RCVS) is a disorder with distinct features: recurrent thunderclap headaches with reversible vasoconstriction of intracranial arteries. Substantial studies regarding outcomes after RCVS were conducted, showing favorable functional outcomes in most patients despite the potentially life-threatening complications of RCVS, including ischemic stroke, intracranial hemorrhage, or convexity subarachnoid hemorrhage. However, patients may report headaches after the resolution of RCVS while relative studies were scarce. Two prospective studies from different cohorts consistently revealed that RCVS recurred in at least 5% of patients. Patients with prior migraine history and patients whose thunderclap headaches are elicited by sexual activity or exertion are at higher risk for RCVS recurrence. On the other hand, several retrospective studies and case reports reported that chronic headaches are common in RCVS patients after the resolution of acute bouts. The chronic headaches after RCVS are sometimes disabling in certain patients. Headaches after RCVS are not uncommon but usually overseen. Medical attention and examinations are warranted in patient with RCVS who reported recurrence of thunderclap headaches or chronic headaches after RCVS.

Noninvasive Characterization of Human Glymphatics and Meningeal Lymphatics in an in vivo Model of Blood–Brain Barrier Leakage

To evaluate human glymphatics and meningeal lymphatics noninvasively. This prospective study implemented 3-dimensional (3D) isotropic contrast-enhanced T2 fluid-attenuated inversion recovery (CE-T2-FLAIR) imaging with a 3T magnetic resonance machine to study cerebral glymphatics and meningeal lymphatics in patients with reversible cerebral vasoconstriction syndrome (RCVS) with (n = 92) or without (n = 90) blood-brain barrier (BBB) disruption and a diseased control group with cluster headache (n = 35). The contrast agent gadobutrol (0.2mmol/kg [0.2ml/kg]) was administered intravenously in all study subjects. In total, 217 patients (182 RCVS, 35 cluster headache) were analyzed and separated into 2 groups based on the presence or absence of visible gadolinium (Gd) leakage. Para-arterial tracer enrichment was clearly depicted in those with overt BBB disruption, while paravenous and parasinus meningeal contrast enrichment was evident in both groups. Paravenous and parasinus contrast enrichment remained in RCVS patients in the remission stage and in cluster headache patients, suggesting that these meningeal lymphatic channels were universal anatomical structures rather than being phase- or condition-specific. Additionally, we demonstrated nodular leptomeningeal enhancement in 32.3% of participants, which might represent potential lymphatic reservoirs. Four selected RCVS patients who received consecutive contrasted 3D isotropic FLAIR imaging after gadobutrol administration showed that the Gd persisted for at least 54 minutes and was completely cleared within 18 hours. This large-scale in vivo study successfully demonstrated the putative human para-arterial glymphatic transports and meningeal lymphatics by clear depiction of para-arterial, parasinus, and paravenous meningeal contrast enrichment using high-resolution 3D isotropic CE-T2-FLAIR imaging noninvasively; this technique may serve as a basis for further studies to delineate clinical relevance of glymphatic clearance. ANN NEUROL 2021;89:111-124.

Hemorrhagic reversible cerebral vasoconstriction syndrome: A retrospective observational study.

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches associated with segmental vasoconstriction of cerebral arteries, which may result in intracranial hemorrhage (ICH). There is a lack of contemporary data available regarding the ICH burden in RCVS cohort. Our aim of the study is to assess the ICH burden, associated risk factors, and discharge outcome of ICH in patients with RCVS. All patients diagnosed with RCVS in the 2016 Nationwide Readmission Database were identified using ICD-10 code after excluding patients with the concurrent diagnosis of primary angiitis. ICH was defined as both intraparenchymal (IPH), subarachnoid hemorrhage (SAH), and subdural hematoma (SDH). Categorical and continuous variables were assessed by the Rao-Scott Chi-square test and the Wilcoxon signed-rank sum test respectively. We used a multivariable survey-weighted logistic model to determine the association between ICH and RCVS patient-level characteristics. A total of 799 patients were identified with RCVS. Total hospitalization of ICH was 43.4% [(95% CI 36.4-50.4%); (n = 346)] including SAH 35.9% [(95% CI 29.7-42.1%); (n = 287)], IPH 13.1% [(95% CI 9.5-16.7%); (n = 105)] and SDH 3.6% [(95% CI 1.5-5.6%); (n = 28)]. Patients with hemorrhagic RCVS (H-RCVS) had a mean age (years ± SE) of 47.4 ± 1.1 vs. 45.5 ± 1.2years in R-RCVS (p = 0.247); and were predominantly female (84.0% vs. 68.8%; p = 0.001); with longer inpatient stays (10.9 vs. 6.8days; p = 0.016); and a higher inpatient cost ($44,300 vs. $21,350; p < 0.001). On multivariable analyses, higher odds of ICH were female sex 2.57 (95% CI 1.45-4.55; p = 0.001), middle age-group (45-64years) 1.87 (CI: 1.11-3.15; p = 0.018) and older age group (> 64years) 3.72 (CI: 1.15-12.03; p = 0.029). About 67.0% of all H-RCVS patients were discharged home, with no observed inpatient mortality. Intracerebral hemorrhage is the most common vascular complication in hospitalized RCVS patients, resulting in longer hospitalizations with more invasive procedures and higher healthcare expenditure. However, overall outcomes are excellent regardless of types of ICH, with no inpatient mortality observed in patients with hemorrhagic RCVS. Female sex and middle to older age-group are associated with higher odds of ICH.

Abstract WP401: Burden of Intracranial Hemorrhage in Patients With Reversible Cerebral Vasoconstriction Syndrome

Introduction: Reversible Cerebral Vasoconstriction Syndrome (RCVS) is described as reversible constriction of cerebral arteries, presenting with severe headaches and associated with hemorrhagic or ischemic strokes. There is a dearth of the literature on demographics and risk factors associated with intracranial hemorrhage (ICH) in patients with RCVS in the US. Methods: All patients with a primary or secondary diagnosis of RCVS in 2016 Nationwide Readmission Database (NRD) using ICD-10 code I67.841 after excluding cerebral angiitis (N=57). Unique patients were included using a unique patient identifier. Weighted discharges were used to generate national estimates. ICH was defined as both intraparenchymal and subarachnoid hemorrhage. A multivariable logistic model was used to identify ICH predictors. Results: Among total 1,152 RCVS patients, 25.7% (296) patients developed ICH. Patients with ICH mean age was (years) (Mean±SE) 47.8 ±1.2 vs. 47.0±1.1 (P=0.62), female 85.4% vs. 78.0% (P=0.06), longer inpatient LOS 12.1±0.9 vs. 6.4±0.5 days (P&lt;0.0001) and higher inpatient cost 42,638±4,451 vs. 18,199±1,117 (P=0.018). After multivariable analysis, two independent predictors of ICH were identified: increasing age (OR 1.02, 95% CI: 1.01-1.04, P=0.042) and female gender (OR 2.37, 95%CI: 1.25-4.50, P=0.009). Patients with ICH were at a greater risk of cerebral edema (OR 13.25, 95% CI: 5.10-34.43, P&lt;0.0001) (Figure). Among disposition, 63.2% of patients with ICH were discharged home requiring no assistance and no mortality was observed. Conclusion: This nationally representative sample suggests that increasing age and female gender were independent predictors of ICH. There is no difference in comorbidities including migraine contrary to prior literature, modifiable lifestyle risk factors and pregnancy in this cohort. Excellent outcome was observed as the majority of patients were discharged home. Higher LOS and cost were reported in ICH cohort.

Reversible Cerebral Vasoconstriction Syndrome: an Update of Recent Research

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches (TCH) and reversible segmental and multifocal vasoconstriction of cerebral arteries. Noninvasive neuroimaging such as computed tomography (CT), and magnetic resonance imaging (MRI) are widely used to assess cerebral vasculature, ischemic or hemorrhagic stroke, and posterior reversible encephalopathy (PRES). The significant differential diagnoses of RCVS center on the clinical presentation of headache and similar radiographic features including aneurysmal subarachnoid hemorrhage (SAH), cervical artery dissection, and central nervous system vasculitis (CNS-V). In this review we present a comprehensive overview of RCVS with the newest findings in the reported literature. Pathophysiology: Several surrogate markers including plasma endothelin-1 (E-1) have been investigated to elucidate the pathogenesis of RCVS. Clinical evaluation and diagnosis: The RCVS2 score is a simple scoring system has been proposed to distinguish RCVS from other intracranial vasculopathies. Neuroimaging: High-resolution contract-enhanced MRI (HR-MRI) vessel wall imaging is a feasible tool in differentiating vessel wall patterns of RCVS and CNS-V. Treatment: Early initiation of calcium channel blockers effectively prevents recurrent TCH and shorten the clinical courses. Clinical scoring system and newer imaging tools are helpful for the early distinction of RCVS. These approaches may serve increased sensitivity and specificity for the diagnosis and lead to appropriate management in RCVS patients.

Urine metabolomics signatures in reversible cerebral vasoconstriction syndrome.

The pathophysiology of reversible cerebral vasoconstriction syndrome is unclear. An unbiased systems-based approach might help to illustrate the metabolite profiling and underlying pathophysiology. Urine samples were collected from reversible cerebral vasoconstriction syndrome patients and matched controls recruited in Taipei Veterans General Hospital. 1H-Nuclear magnetic resonance was used to initially explore the metabolic profile, and liquid chromatography tandem mass spectrometry was then used to identify metabolic alterations in reversible cerebral vasoconstriction syndrome. Untargeted metabolite screening was randomly performed on 10 reversible cerebral vasoconstriction syndrome patients and 10 control subjects in the discovery phase. The selected untargeted metabolites were further validated on 47 reversible cerebral vasoconstriction syndrome patients during their ictal stage (with 40 of them having remission samples) and 47 controls in the replication phase. Six metabolites-hippurate, citrate, 1,3,7-trimethyluric acid, ascorbic acid, D-glucurono-6,3-lactone, and D-threo-isocitric acid-with t-test derived p-value < 0.05 and VIP score >1, were identified as potential urine signatures that can well distinguish reversible cerebral vasoconstriction syndrome subjects at ictal stage from controls. Among them, citrate, hippurate, ascorbic acid, and D-glucurono-6,3-lactone were significantly lower, and 1,3,7-trimethyluric acid and D-threo-isocitric acid were higher in reversible cerebral vasoconstriction syndrome patients. Of these, four selected metabolites, citrate, D-glucurono-6,3-lactone, ascorbic acid, and 1,3,7-trimethyluric acid, returned to normal levels in remission. These metabolites are related to pathways associated with free radical scavenging, with the hub molecules being associated with endothelial dysfunction or sympathetic overactivity. Whether these metabolites and their implicated networks play a role in the pathogenesis of reversible cerebral vasoconstriction syndrome remains to be confirmed.

Long-Term Outcomes After Reversible Cerebral Vasoconstriction Syndrome.

Background and Purpose- We aimed to further investigate the long-term outcomes after reversible cerebral vasoconstriction syndrome (RCVS). Methods- A longitudinal follow-up study was conducted in 173 RCVS patients. Results- Of the 172 patients who completed a mean follow-up of 9.2±3.3 years, 10 had a recurrent RCVS that was benign in all. Independent predictors of relapse were having a history of migraine and having exercise as a trigger for thunderclap headache during initial RCVS. After new delivery, the rate of postpartum RCVS was 9%. Conclusions- Overall, long-term outcome after RCVS is excellent.

The Spectrum of Nontraumatic Convexity Subarachnoid Hemorrhage

Background: Nontraumatic convexity subarachnoid hemorrhage (cSAH) is a nonaneurysmal variant that is associated with diverse etiologies. Methods: With IRB approval, we retrospectively reviewed consecutive nontraumatic cSAH from July 1, 2006 to July 1, 2016. Data were abstracted on demographics, medical history, neuroimaging, etiology, and clinical presentation. Results: We identified 94 cases of cSAH. The cases were classified according to the following etiologies: reversible cerebral vasoconstriction syndrome (RCVS) 17 (18%), cerebral amyloid angiopathy (CAA) 15 (16%), posterior reversible encephalopathy syndrome 16 (17%), cerebral venous thrombosis 10 (11%), large artery occlusion 7 (7%), endocarditis 6 (6%), and cryptogenic 25 (27%). Early rebleeding occurred in 9 (10%) patients. Time from initial imaging to CT rebleeding was 40 hours (range, 5-74). CAA was associated with the highest mean age at 75.8 and RCVS the lowest at 47.6 years (P< .0001). Among patients with RCVS, initial vascular imaging was negative in 6 (35%), and repeat imaging documented vasoconstriction at a mean delay of 5 days (range, 3-16). Conclusion: There were significant differences among the subgroups in cSAH, with CAA presenting as older men with transient neurological deficits, and RCVS presenting as younger women with thunderclap headache. Rebleeding was seen in 10% of cSAH patients. One-third of RCVS patients with cSAH required repeat vascular imaging to diagnose vasoconstriction.

Urine Metabolomics Signatures in Reversible Cerebral Vasoconstriction Syndrome

Background: The pathophysiology of reversible cerebral vasoconstriction syndrome (RCVS) is unclear. An unbiased systems-based approach might help to illustrate the metabolite profiling and underlying pathophysiology. Methods: Urine samples were collected from RCVS patients and matched controls recruited in Taipei Veterans General Hospital. 1H-Nuclear magnetic resonance (1H-NMR) was used to initially explore the metabolic profile, and liquid chromatography tandem mass spectrometry (LC-MS/MS) was then used to identify metabolic alterations in RCVS. Untargeted metabolite screening was randomly performed on 10 RCVS patients and 10 control subjects in the discovery phase. The selected untargeted metabolites were further validated on 47 RCVS patients during their ictal stage (with 40 of them having remission samples) and 47 controls in the replication phase. Findings: Six metabolites-hippurate, citrate, 1,3,7-trimethyluric acid, ascorbic acid, D-glucurono-6,3-lactone, and D-threo-isocitric acid-with t-test derived p-value 1, were identified as potential urine signature that can well distinguish RCVS subjects at ictal stage from controls. Among them, citrate, hippurate, ascorbic acid, and D-glucurono-6,3-lactone were significantly lower, and 1,3,7-trimethyluric acid and D-threo-isocitric acid were higher in RCVS patients. Of these, four selected metabolites, citrate, D-glucurono-6,3-lactone, ascorbic acid, and 1,3,7-trimethyluric acid, returned to normal levels in remission. These metabolites are related to pathways associated with free radical scavenging, with the hub molecules being associated with endothelial dysfunction or sympathetic overactivity. Our study demonstrated that six urine metabolites are significantly changed in RCVS patients, with the implicated networks highly relevant to the pathogenesis of RCVS. Funding: This work was supported by the grants from Ministry of Science and Technology of Taiwan MOST 105-2320-B-039-055-MY3, 105-2811-B-039-026, 106-2811-B-039-014 and 106-2320-B-039-053 (to YLL & WHH); Brain Research Center, National Yang-Ming University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan (to SJW & SPC); Taipei Veterans General Hospital [V100E6-001, V106C-117] (to SWJ & SPC); MOST 104-2314-B-010-015-MY2, MOST 104-2314-B-075-006 -MY3, and MOST 107-2314-B-010-021 -] (to SWJ & SPC); and Ministry of Health and Welfare, Taiwan [MOHW 103-TDU-B-211-113-003, MOHW 104-TDU-B-211-113-003, MOHW 105-TDU-B-211-113-003] (to SJW). Declaration of Interest: The authors have disclosed no potential conflicts of interest. Ethical Approval: The study protocol was approved by the Institutional Review Board of TVGH (IRB No. 98-05-04A). All participants provided written informed consent before entering the study. All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki.

Abstract TP554: Etiologies of Nontraumatic Convexity Subarachnoid Hemorrhage

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&lt;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.

Characteristics and demographics of reversible cerebral vasoconstriction syndrome: A large prospective series of Korean patients.

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.

Blood-brain barrier breakdown in reversible cerebral vasoconstriction syndrome: Implications for pathophysiology and diagnosis.

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.