External validation of the SI2NCAL2C score for outcomes following cerebral venous thrombosis.

OBJECTIVES: Prognostication for cerebral venous thrombosis (CVT) remains difficult. We sought to validate the SI2NCAL2C score in an international cohort. MATERIALS AND METHODS: The SI2NCAL2C score was originally developed to predict poor outcome (modified Rankin Scale (mRS) 3-6) at 6 months, and mortality at 30 days and 1 year using data from the International CVT Consortium. The SI2NCAL2C score uses 9 variables: the absence of any female-sex-specific risk factors, intracerebral hemorrhage, central nervous system infection, focal neurological deficits, coma, age, lower level of hemoglobin, higher level of glucose, and cancer. The ACTION-CVT study was an international retrospective study that enrolled consecutive patients across 27 centers. The poor outcome score was validated using 90-day mRS due to lack of follow-up at the 6-month time-point in the ACTION-CVT cohort. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) and calibration plots. Missing data were imputed using the additive regression and predictive mean matching methods. Bootstrapping was performed with 1000 iterations. RESULTS: Mortality data were available for 950 patients and poor outcome data were available for 587 of 1,025 patients enrolled in ACTION-CVT. Compared to the International CVT Consortium, the ACTION-CVT cohort was older, less often female, and with milder clinical presentation. Mortality was 2.5% by 30 days and 6.0% by one year. At 90-days, 16.7% had a poor outcome. The SI2NCAL2C score had an AUC of 0.74 [95% CI 0.69-0.79] for 90-day poor outcome, 0.72 [0.60-0.82] for mortality by 30 days, and 0.82 [0.76-0.88] for mortality by one year. CONCLUSIONS: The SI2NCAL2C score had acceptable to good performance in an international external validation cohort. The SI2NCAL2C score warrants additional validation studies in diverse populations and clinical implementation studies.

Estimating Perfusion Deficits in Acute Stroke Patients Without Perfusion Imaging.

BACKGROUND: Perfusion weighted imaging (PWI) is critical for determining whether stroke patients presenting in an extended time window are candidates for mechanical thrombectomy. However, PWI is not always available. Fluid-attenuated inversion recovery hyperintense vessels (FHVs) are seen in patients with a PWI lesion. We investigated whether a scale measuring the extent FHV could serve as a surrogate for PWI to determine eligibility for thrombectomy. METHODS: The National Institutes of Health (NIH) FHV score was developed to quantify the burden of FHV and applied to magnetic resonance imaging scans of stroke patients with fluid-attenuated inversion recovery and perfusion imaging. The NIH-FHV was combined with the diffusion weighted image volume to estimate the diffusion-perfusion mismatch ratio. Linear regression was used to compare PWI volumes and mismatch ratios with estimates from the NIH-FHV score. Receiver operating characteristic analysis was used to test the ability of the NIH-FHV score to identify a significant mismatch. RESULTS: There were 101 patients included in the analysis, of whom 78% had a perfusion deficit detected on PWI with a mean lesion volume of 47 (±59) mL. The NIH-FHV score was strongly associated with the PWI lesion volume (P<0.001; R2=0.32; ß-coefficient, 0.57). When combined with diffusion weighted image lesion volume, receiver operating characteristic analysis testing the ability to detect a mismatch ratio ≥1.8 using the NIH-FHV score resulted in an area under the curve of 0.94. CONCLUSIONS: The NIH-FHV score provides an estimate of the PWI lesion volume and, when combined with diffusion weighted imaging, may be helpful when trying to determine whether there is a clinically relevant diffusion-perfusion mismatch in situations where perfusion imaging is not available. Further studies are needed to validate this approach.

Direct Oral Anticoagulants Versus Warfarin in the Treatment of Cerebral Venous Thrombosis (ACTION-CVT): A Multicenter International Study.

BACKGROUND: A small randomized controlled trial suggested that dabigatran may be as effective as warfarin in the treatment of cerebral venous thrombosis (CVT). We aimed to compare direct oral anticoagulants (DOACs) to warfarin in a real-world CVT cohort. METHODS: This multicenter international retrospective study (United States, Europe, New Zealand) included consecutive patients with CVT treated with oral anticoagulation from January 2015 to December 2020. We abstracted demographics and CVT risk factors, hypercoagulable labs, baseline imaging data, and clinical and radiological outcomes from medical records. We used adjusted inverse probability of treatment weighted Cox-regression models to compare recurrent cerebral or systemic venous thrombosis, death, and major hemorrhage in patients treated with warfarin versus DOACs. We performed adjusted inverse probability of treatment weighted logistic regression to compare recanalization rates on follow-up imaging across the 2 treatments groups. RESULTS: Among 1025 CVT patients across 27 centers, 845 patients met our inclusion criteria. Mean age was 44.8 years, 64.7% were women; 33.0% received DOAC only, 51.8% received warfarin only, and 15.1% received both treatments at different times. During a median follow-up of 345 (interquartile range, 140-720) days, there were 5.68 recurrent venous thrombosis, 3.77 major hemorrhages, and 1.84 deaths per 100 patient-years. Among 525 patients who met recanalization analysis inclusion criteria, 36.6% had complete, 48.2% had partial, and 15.2% had no recanalization. When compared with warfarin, DOAC treatment was associated with similar risk of recurrent venous thrombosis (aHR, 0.94 [95% CI, 0.51-1.73]; P=0.84), death (aHR, 0.78 [95% CI, 0.22-2.76]; P=0.70), and rate of partial/complete recanalization (aOR, 0.92 [95% CI, 0.48-1.73]; P=0.79), but a lower risk of major hemorrhage (aHR, 0.35 [95% CI, 0.15-0.82]; P=0.02). CONCLUSIONS: In patients with CVT, treatment with DOACs was associated with similar clinical and radiographic outcomes and favorable safety profile when compared with warfarin treatment. Our findings need confirmation by large prospective or randomized studies.

Failure of Anticoagulation to Prevent Stroke in Context of Lupus-Associated Anti-Phospholipid Syndrome and Mild COVID-19.

Hypercoagulability and virally-mediated vascular inflammation have become well-recognized features of the SARS-CoV-2 virus infection, COVID-19. Of growing concern is the apparent ineffectiveness of therapeutic anticoagulation in preventing thromboembolic events among some at-risk patient subtypes with COVID-19. We present a 43-year-old female with a history of seropositive-antiphospholipid syndrome and systemic lupus erythematosus who developed an acute ischemic stroke in the setting of mild COVID-19 infection despite adherence to chronic systemic anticoagulation. The clinical significance of SARS-CoV-2-mediated endothelial cell dysfunction and its potential to cause macrovascular events in spite of full anticoagulation warrants further investigation and likely represents another disease-defining pathology of COVID-19.

Giant Vertebrobasilar Fusiform Aneurysm Mass Effect Heralds Rapid in Situ Thrombosis and Ischemic Stroke in the Setting of Ulcerative Colitis.

Here we describe a case of brainstem infarction secondary to rapid thrombus formation in a giant vertebrobasilar fusiform aneurysm (GVBFA) that was preceded clinically by several months of headaches and dizziness initially attributable to mass effect. Less than a month after initial identification of the aneurysm, a large partially-occluding thrombus formed leading to infarction of the brainstem. Interestingly, this patient also had ulcerative colitis, which has been associated with acquired hypercoagulability. Balancing risk versus benefit in the management of GVBFA to prevent morbidity and mortality is very challenging; thus more information is needed to better stratify treatment options for patients, particularly those that may have an accelerating clinical course or co-morbidities that increase clotting risk.

Adapting Clinical Practice of Thrombolysis for Acute Ischemic Stroke Beyond 4.5 Hours: A Review of the Literature.

Several clinical trials have demonstrated that advanced neuroimaging can select patients for recanalization therapy in an extended time window. The favorable functional outcomes and safety profile of these studies have led to the incorporation of neuroimaging in endovascular treatment guidelines, and most recently, also extended to decision making on thrombolysis. Two randomized clinical trials have demonstrated that patients who are not amenable to endovascular thrombectomy within 4.5 hours from symptoms discovery or beyond 4.5 hours from the last-known-well time may also be safely treated with intravenous thrombolysis and have a clinical benefit above the risk of safety concerns. With the growing aging population, increased stroke incidence in the young, and the impact of evolving medical practice, healthcare and stroke systems of care need to adapt continuously to provide evidence-based care efficiently. Therefore, understanding and incorporating appropriate screening strategies is critical for the prompt recognition of potentially eligible patients for extended-window intravenous thrombolysis. Here we review the clinical trial evidence for thrombolysis for acute ischemic stroke in the extended time window and provide a review of new enrolling clinical trials that include thrombolysis intervention beyond the 4.5 hour window.

Musical hallucinations with a right frontotemporal stroke.

MUSICAL HALLUCINATIONS: have been reported in association with psychiatric diseases, brain stem strokes, deafness, degenerative diseases, intoxications, pharmacologic agents, and epilepsy. We present a patient who in the absence of these disorders developed musical hallucinations from an infarction of the right hemisphere that primarily injured his right frontal and anterior temporal lobes. This report discusses some of the possible mechanisms for this patient's presentation. Although the mechanism of his musical hallucinations remains unclear, recognition of this uncommon syndrome is important when structuring rehabilitation and management for patients with stroke who have this disorder.

Proceedings from the Neurotherapeutics Symposium on Neurological Emergencies: Shaping the Future of Neurocritical Care.

Effective treatment options for patients with life-threatening neurological disorders are limited. To address this unmet need, high-impact translational research is essential for the advancement and development of novel therapeutic approaches in neurocritical care. "The Neurotherapeutics Symposium 2019-Neurological Emergencies" conference, held in Rochester, New York, in June 2019, was designed to accelerate translation of neurocritical care research via transdisciplinary team science and diversity enhancement. Diversity excellence in the neuroscience workforce brings innovative and creative perspectives, and team science broadens the scientific approach by incorporating views from multiple stakeholders. Both are essential components needed to address complex scientific questions. Under represented minorities and women were involved in the organization of the conference and accounted for 30-40% of speakers, moderators, and attendees. Participants represented a diverse group of stakeholders committed to translational research. Topics discussed at the conference included acute ischemic and hemorrhagic strokes, neurogenic respiratory dysregulation, seizures and status epilepticus, brain telemetry, neuroprognostication, disorders of consciousness, and multimodal monitoring. In these proceedings, we summarize the topics covered at the conference and suggest the groundwork for future high-yield research in neurologic emergencies.

Iodinated Contrast Extravasation on Post-Revascularization Computed Tomography Mimics Magnetic Resonance Hyperintense Acute Reperfusion Marker: A Case Study.

Hyperintense reperfusion marker (HARM) on post-contrast magnetic resonance imaging (MRI) fluid attenuated inversion recovery (FLAIR) represents gadolinium contrast extravasation in the setting of acute ischemic stroke and is a common finding after revascularization therapies. Clinically, it is a marker of blood brain barrier (BBB) disruption, predictor of hemorrhagic transformation, and predictor of poor clinical outcome in ischemic stroke. Here, we describe a case where a patient underwent mechanical thrombectomy and was later found to have evidence of contrast extravasation on CT imaging, in the same locations found on the post-contrast FLAIR MRI, demonstrating that MRI-HARM and CT contrast extravasation may mimic similar phenomena. Thus, this case demonstrates that we may be able to extrapolate what we know about HARM detected on MRI to a CT imaging biomarker that would be more readily obtainable in most stroke patients.

Post-Stroke Blood-Brain Barrier Disruption and Poor Functional Outcome in Patients Receiving Thrombolytic Therapy.

BACKGROUND AND PURPOSE: The role played by post-stroke inflammation after an ischemic event in limiting functional recovery remains unclear. One component of post-stroke inflammation is disruption of the blood-brain barrier (BBB). This study examines the relationship between post-stroke BBB disruption and functional outcome. METHODS: Acute stroke patients treated with thrombolysis underwent magnetic resonance imaging scanning 24 h and 5 days after their initial event. BBB permeability maps were generated from perfusion weighted imaging. Average permeability was calculated in the affected hemisphere. Good functional outcome, defined as a modified Rankin score of 0 or 1, was compared with average permeability using logistic regression. RESULTS: Of the 131 patients enrolled, 76 patients had the necessary data to perform the analysis at 24 h, and 58 -patients had data for the 5-day assessment. Higher BBB permeability measured at 24 h (OR 0.57; 95% CI 0.33-0.99, p = 0.045) and at 5 days (OR 0.24; 95% CI 0.09-0.66, p = 0.005) was associated with worse functional outcome 1-3 months after the acute ischemic stroke. For every percentage increase in BBB disruption at 5 days, there was a 76% decrease in the chance of achieving a good functional outcome after stroke. Multivariate analysis found this to be independent of age, stroke volume, or clinical stroke severity. CONCLUSIONS: Post-stroke BBB disruption appears to be predictive of functional outcome irrespective of stroke size.

White Matter Hyperintensity-Associated Blood-Brain Barrier Disruption and Vascular Risk Factors.

BACKGROUND: White matter hyperintensities (WMH), the hallmark of vascular cognitive impairment, are associated with vascular risk factors (VRF). WMH can also be associated with blood-brain barrier (BBB) disruption. The purpose of this study was to look for associations between VRF and BBB disruption in stroke patients with WMH. METHODS: Magnetic resonance images of stroke patients were reviewed for the presence of WMH. Blood-brain permeability images were retrospectively generated. The degree of BBB permeability was compared with the presence of VRF using logistic regression. Patterns and extent of WMH were classified using Fazekas scores. RESULTS: Sixty-five patients were included in this study. None of the VRF tested were associated with an increase in BBB disruption. Hypertension was significantly associated with less BBB disruption (P = .04). Nonhypertensive patients in our study had a different pattern of WMH than hypertensive patients, with less involvement of the periventricular white matter. CONCLUSIONS: We found that in stroke patients with WMH, those with hypertension had less BBB disruption and greater involvement of the periventricular white matter when compared with patients who did not have a history of hypertension. Further investigation is needed to determine if the development of WMH in stroke patients with a history of hypertension has a different pathophysiology from patients who develop WMH in the absence of hypertension.

Early Change in Stroke Size Performs Best in Predicting Response to Therapy.

BACKGROUND: Reliable imaging biomarkers of response to therapy in acute stroke are needed. The final infarct volume and percent of early reperfusion have been used for this purpose. Early fluctuation in stroke size is a recognized phenomenon, but its utility as a biomarker for response to therapy has not been established. This study examined the clinical relevance of early change in stroke volume and compared it with the final infarct volume and percent of early reperfusion in identifying early neurologic improvement (ENI). METHODS: Acute stroke patients, enrolled between 2013 and 2014 with serial magnetic resonance imaging (MRI) scans (pretreatment baseline, 2 h post, and 24 h post), who received thrombolysis were included in the analysis. Early change in stroke volume, infarct volume at 24 h on diffusion, and percent of early reperfusion were calculated from the baseline and 2 h MRI scans were compared. ENI was defined as ≥4 point decrease in National Institutes of Health Stroke Scales within 24 h. Logistic regression models and receiver operator characteristics analysis were used to compare the efficacy of 3 imaging biomarkers. RESULTS: Serial MRIs of 58 acute stroke patients were analyzed. Early change in stroke volume was significantly associated with ENI by logistic regression analysis (OR 0.93, p = 0.048) and remained significant after controlling for stroke size and severity (OR 0.90, p = 0.032). Thus, for every 1 mL increase in stroke volume, there was a 10% decrease in the odds of ENI, while for every 1 mL decrease in stroke volume, there was a 10% increase in the odds of ENI. Neither infarct volume at 24 h nor percent of early reperfusion were significantly associated with ENI by logistic regression. Receiver-operator characteristic analysis identified early change in stroke volume as the only biomarker of the 3 that performed significantly different than chance (p = 0.03). CONCLUSIONS: Early fluctuations in stroke size may represent a more reliable biomarker for response to therapy than the more traditional measures of final infarct volume and percent of early reperfusion.

Identification of Reversible Disruption of the Human Blood-Brain Barrier Following Acute Ischemia.

BACKGROUND AND PURPOSE: Animal models of acute cerebral ischemia have demonstrated that diffuse blood-brain barrier (BBB) disruption can be reversible after early reperfusion. However, irreversible, focal BBB disruption in humans is associated with hemorrhagic transformation in patients receiving intravenous thrombolytic therapy. The goal of this study was to use a magnetic resonance imaging biomarker of BBB permeability to differentiate these 2 forms of BBB disruption. METHODS: Acute stroke patients imaged with magnetic resonance imaging before, 2 hours after, and 24 hours after treatment with intravenous tissue-type plasminogen activator were included. The average BBB permeability of the acute ischemic region before and 2 hours after treatment was calculated using a T2* perfusion-weighted source images. Change in average permeability was compared with percent reperfusion using linear regression. Focal regions of maximal BBB permeability from the pretreatment magnetic resonance imaging were compared with the occurrence of parenchymal hematoma (PH) formation on the 24-hour magnetic resonance imaging scan using logistic regression. RESULTS: Signals indicating reversible BBB permeability were detected in 18/36 patients. Change in average BBB permeability correlated inversely with percent reperfusion (P=0.006), indicating that early reperfusion is associated with decreased BBB permeability, whereas sustained ischemia is associated with increased BBB disruption. Focal regions of maximal BBB permeability were significantly associated with subsequent formation of PH (P=0.013). CONCLUSIONS: This study demonstrates that diffuse, mild BBB disruption in the acutely ischemic human brain is reversible with reperfusion. This study also confirms prior findings that focal severe BBB disruption confers an increased risk of hemorrhagic transformation in patients treated with intravenous tissue-type plasminogen activator.

Timing and Predictors of Recanalization After Anticoagulation in Cerebral Venous Thrombosis.

BACKGROUND AND PURPOSE: Vessel recanalization after cerebral venous thrombosis (CVT) is associated with favorable outcomes and lower mortality. Several studies examined the timing and predictors of recanalization after CVT with mixed results. We aimed to investigate predictors and timing of recanalization after CVT. METHODS: We used data from the multicenter, international AntiCoagulaTION in the Treatment of Cerebral Venous Thrombosis (ACTION-CVT) study of consecutive patients with CVT from January 2015 to December 2020. Our analysis included patients that had undergone repeat venous neuroimaging more than 30 days after initiation of anticoagulation treatment. Prespecified variables were included in univariate and multivariable analyses to identify independent predictors of failure to recanalize. RESULTS: Among the 551 patients (mean age, 44.4±16.2 years, 66.2% women) that met inclusion criteria, 486 (88.2%) had complete or partial, and 65 (11.8%) had no recanalization. The median time to first follow-up imaging study was 110 days (interquartile range, 60-187). In multivariable analysis, older age (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.03-1.07), male sex (OR, 0.44; 95% CI, 0.24-0.80), and lack of parenchymal changes on baseline imaging (OR, 0.53; 95% CI, 0.29-0.96) were associated with no recanalization. The majority of improvement in recanalization (71.1%) occurred before 3 months from initial diagnosis. A high percentage of complete recanalization (59.0%) took place within the first 3 months after CVT diagnosis. CONCLUSION: Older age, male sex, and lack of parenchymal changes were associated with no recanalization after CVT. The majority recanalization occurred early in the disease course suggesting limited further recanalization with anticoagulation beyond 3 months. Large prospective studies are needed to confirm our findings.

Delayed Diagnosis in Cerebral Venous Thrombosis: Associated Factors and Clinical Outcomes.

Background Identifying factors associated with delayed diagnosis of cerebral venous thrombosis (CVT) can inform future strategies for early detection. Methods and Results We conducted a retrospective cohort study including all participants from ACTION-CVT (Anticoagulation in the Treatment of Cerebral Venous Thrombosis) study who had dates of neurologic symptom onset and CVT diagnosis available. Delayed diagnosis was defined as CVT diagnosis occurring in the fourth (final) quartile of days from symptom onset. The primary study outcome was modified Rankin Scale score of ≤1 at 90 days; secondary outcomes included partial/complete CVT recanalization on last available imaging and modified Rankin Scale score of ≤2. Logistic regression analyses were used to identify independent variables associated with delayed diagnosis and to assess the association of delayed diagnosis and outcomes. A total of 935 patients were included in our study. Median time from symptom onset to diagnosis was 4 days (interquartile range, 1-10 days). Delayed CVT diagnosis (time to diagnosis >10 days) occurred in 212 patients (23%). Isolated headache (adjusted odds ratio [aOR], 2.36 [95% CI, 1.50-3.73]; P<0.001), older age (aOR by 1 year, 1.02 [95% CI, 1.004-1.03]; P=0.01), and papilledema (aOR, 2.00 [95% CI, 1.03-3.89]; P=0.04) were associated with diagnostic delay, whereas higher National Institutes of Health Stroke Scale score was inversely associated with diagnostic delay (aOR by 1 point, 0.95 [95% CI, 0.89-1.00]; P=0.049). Delayed diagnosis was not associated with modified Rankin Scale score of ≤1 at 90 days (aOR, 1.08 [95% CI, 0.60-1.96]; P=0.79). Conclusions In a large multicenter cohort, a quarter of included patients with CVT were diagnosed >10 days after symptom onset. Delayed CVT diagnosis was associated with the symptom of isolated headache and was not associated with adverse clinical outcomes.

Complete resolution of advanced Mycoplasma pneumoniae encephalitis mimicking brain mass lesions: report of two pediatric cases and review of literature.

Mycoplasma pneumoniae is a well-known cause of atypical pneumonia. CNS involvement is a relatively frequent extrapulmonary manifestation, most commonly manifesting as encephalitis in the pediatric population. We present two unusual cases of M. pneumoniae encephalitis that presented with symptoms and imaging findings suggesting mass occupying lesions, and worsening altered mental status. Biopsy of the lesions was necessary in both cases to aid with diagnosis. Histopathologic features excluded neoplasm, and established the diagnosis of encephalitis, but did not point toward its etiology. The only finding that indicated M. pneumoniae as the most likely pathogen was serum IgM positivity in the absence of any other identifiable infectious source, and complete neurologic recovery following specific anti-mycoplasmal treatment. The patients were successfully treated with antibiotics and steroids, with the second case also requiring intravenous immunoglobulin and anti-epileptics. The clinical presentation and histopathologic findings suggested an immune-mediated pathogenesis, but acute disseminated encephalomyelitis was excluded due to extensive gray matter involvement. Disease resolution despite status epilepticus and herniation in case 2 is a novel finding of the study. Current principles of diagnosis and management of encephalitis as the presenting manifestation of mycoplasmal infection are discussed.

Apparent Treatment-Resistant Hypertension Among Stroke Survivors: A Transcontinental Study Assessing Impact of Race and Geography.

BACKGROUND: Race and geographic differences in the prevalence and predictors of hypertension in stroke survivors have been reported, but apparent treatment-resistant hypertension (aTRH) among stroke survivors by race (African ancestry vs. non-Hispanic Caucasians) and by geography (continental Africa vs. the United States) are under studied. METHODS: This is a cross-sectional study using ethically approved stroke registries from the University of Florida and the Kwame Nkrumah University of Science and Technology, Kumasi, Ghana. Univariate and multivariate regression was used to evaluate for differences in prevalence of aTRH and associations with clinical covariates. RESULTS: Harmonized data were available for 3,365 stroke survivors of which 943 (28.0%) were indigenous Africans, 558 (16.6%) African Americans, and 1,864 (55.4%) non-Hispanic Caucasians with median ages (interquartile range) of 59 (49-68), 61 (55-72), and 70 (62-78) years, P < 0.0001. The overall frequency of aTRH was 18.5% (95% confidence interval [CI]: 17.2%-19.8%) with 42.7% (95% CI: 39.6%-46.0%) among indigenous Africans, 16.1% (95% CI: 13.2%-19.5%) among African Americans, and 6.9% (95% CI: 5.8%-8.2%) among non-Hispanic Caucasians, P < 0.0001. Five factors associated with aTRH: age, adjusted odds ratio (95% CI) of 0.99 (0.98-0.99), female sex 0.70 (0.56-0.87), cigarette smoking 1.98 (1.36-2.90), intracerebral hemorrhage 1.98 (1.57-2.48), and Black race namely indigenous Africans 4.42 (3.41-5.73) and African Americans 2.44 (1.81-3.29). CONCLUSIONS: Future studies are needed to investigate the contribution of socioeconomic disparities in the prevalence aTRH in those with African Ancestry to explore the long-term impact, and evaluate effective therapeutic interventions in this subpopulation.