Anticoagulation Versus Antiplatelets in Spontaneous Cervical Artery Dissection: A Systematic Review and Meta-Analysis.

BACKGROUND: It is uncertain whether antiplatelets or anticoagulants are more effective in preventing early recurrent stroke in patients with cervical artery dissection. Following the publication of the observational Antithrombotic for STOP-CAD (Stroke Prevention in Cervical Artery Dissection) study, which has more than doubled available data, we performed an updated systematic review and meta-analysis comparing antiplatelets versus anticoagulation in cervical artery dissection. METHODS: The systematic review was registered in PROSPERO (CRD42023468063). We searched 5 databases using a combination of keywords that encompass different antiplatelets and anticoagulants, as well as cervical artery dissection. We included relevant randomized trials and included observational studies of dissection unrelated to major trauma. Where studies were sufficiently similar, we performed meta-analyses for efficacy (ischemic stroke) and safety (major hemorrhage, symptomatic intracranial hemorrhage, and death) outcomes using relative risks. RESULTS: We identified 11 studies (2 randomized trials and 9 observational studies) that met the inclusion criteria. These included 5039 patients (30% [1512] treated with anticoagulation and 70% [3527]) treated with antiplatelets]. In meta-analysis, anticoagulation was associated with a lower ischemic stroke risk (relative risk, 0.63 [95% CI, 0.43 to 0.94]; P=0.02; I2=0%) but higher major bleeding risk (relative risk, 2.25 [95% CI, 1.07 to 4.72]; P=0.03, I2=0%). The risks of death and symptomatic intracranial hemorrhage were similar between the 2 treatments. Effect sizes were larger in randomized trials. There are insufficient data on the efficacy and safety of dual antiplatelet therapy or direct oral anticoagulants. CONCLUSIONS: In this study of patients with cervical artery dissection, anticoagulation was superior to antiplatelet therapy in reducing ischemic stroke but carried a higher major bleeding risk. This argues for an individualized therapeutic approach incorporating the net clinical benefit of ischemic stroke reduction and bleeding risks. Large randomized clinical trials are required to clarify optimal antithrombotic strategies for management of cervical artery dissection.

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.

Direct Oral Anticoagulants Versus Vitamin K Antagonists in Cerebral Venous Thrombosis: A Systematic Review and Meta-Analysis.

BACKGROUND: High level evidence for direct oral anticoagulants (DOACs) in patients with cerebral venous thrombosis is lacking. We performed a systematic review and meta-analysis to assess the efficacy and safety of DOACs versus vitamin K antagonists in patients with cerebral venous thrombosis. METHODS: This systematic review was registered in PROSPERO (CRD42021228800). We searched MEDLINE (via Ovid), EMBASE, CINAHL, and the Web of Science Core Collection between January 1, 2007 and Feb 22, 2022. Search terms included a combination of keywords and controlled vocabulary terms for cerebral venous thrombosis, vitamin K antagonists/warfarin, and DOACs. We included both randomized and nonrandomized studies that compared vitamin K antagonists and DOACs in 5 or more patients with cerebral venous thrombosis. Where studies were sufficiently similar, we performed meta-analyses for efficacy (recurrent venous thromboembolism and complete recanalization) and safety (major hemorrhage) outcomes, using relative risks (RRs). RESULTS: Out of 10 665 records identified, we screened 254 as potentially eligible. Nineteen studies (16 observational studies [n=1735] and 3 randomized controlled trials [n=215]) met the inclusion criteria. All 3 randomized controlled trials had some concerns, and all 16 observational studies had at least moderate risk of bias. When compared with vitamin K antagonist treatment, DOAC had comparable risks of recurrent venous thromboembolism (relative risk [RR], 0.85 [95% CI, 0.52-1.37], I2=0%), major hemorrhage (RR, 0.70 [95% CI, 0.40-1.21], I2=0%), intracranial hemorrhage (RR, 0.58 [95% CI, 0.30-1.12]; I2=0%), death (RR, 1.14 [95% CI, 0.54-2.43], I2=1%), and complete venous recanalization (RR, 0.98 [95% CI, 0.87-1.11]; I2=0%). CONCLUSIONS: This systematic review and meta-analysis suggest that in patients with cerebral venous thrombosis, DOACs, and warfarin may have comparable efficacy and safety. Given the limitations of the studies included (low number of randomized controlled trials, modest total sample size, rare outcome events), our findings should be interpreted with caution pending confirmation by ongoing randomized controlled trials and large, prospective, observational studies.

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.

Adaptive Approach to Endovascular Management of Large Vessel Occlusion During the COVID-19 Pandemic.

INTRODUCTION: The COVID-19 pandemic has resulted in unprecedented strain on the health care system. An adaptive strategy for the handling of thrombectomy for patients with large vessel occlusion has evolved at our center to optimize patient care while also minimizing risk of virus transmission. The purpose of this study was to evaluate the effects of the new thrombectomy protocol by comparing thrombectomy times and patient outcomes during the pandemic and pre pandemic period. METHODS: A retrospective cohort study was conducted on patients who underwent emergent thrombectomy from April 4th, 2020 to August 25th, 2020 (pandemic period) and between December 2nd, 2019 to April 3rd, 2020 (pre-pandemic period). The new protocol centered on a standardized approach to airway management in patients considered 'high-risk' for infection. An array of patient-specific factors and outcomes were compared between the two groups. RESULTS: A total of 126 patients were included in the study. There was no significant difference in door-to-recanalization or other time parameters between the two groups (138 minutes during the pandemic vs. 129 minutes pre-pandemic; p=0.37). However, outcomes measured as discharge modified Rankin Scale (mRS) were worse for patients during the pandemic (mRS ≤ 2, 10/58; 17.2% during pandemic vs. 24/68; 35.3% pre-pandemic, p = 0.02). No neurointerventional providers have been found to contract COVID-19. CONCLUSION: Our approach to mechanical thrombectomy during the COVID-19 era was associated with similar recanalization rates but worse clinical outcomes compared to pre pandemic period. Further studies are necessary to identify factors contributing to worse outcomes during this ongoing pandemic.

Migraine History: A Predictor of Negative Diffusion-Weighted Imaging in IV-tPA-Treated Stroke Mimics.

BACKGROUND: Migraine, seizures, and psychiatric disorders are frequently reported as "stroke mimics" in patients with negative diffusion-weighted imaging (DWI) after IV-tPA. We sought to determine predictors of negative DWI in suspected stroke patients treated with IV-tPA. METHOD: A retrospective case-control study encompassing all acute stroke patients treated with IV-tPA (at our hospital or "dripped and shipped") from January 2013 to December 2014 was con- ducted. A total of 275 patients were identified with 47 negative DWI cases and 228 positive DWI controls. Variables including demographic factors, stroke characteristics, and clinical comorbidities were analyzed for statistical significance. A multivariate logistic regression was performed (SPSS-24) to identify predictors of negative DWI. RESULTS: Approximately 17% of patients had negative DWI after IV-tPA. Compared to controls, migraine history independently predicted negative DWI (odds ratio [OR] 5.0 95% confidence interval [CI] 1.03-24.6, P = .046). Increasing age (OR .97 95% CI .94-.99, P = .02) and atrial fibrillation (OR .25 95% CI .08-.77, P = .01) predicted lower probability of negative DWI. Gender, admission NIHSS, treatment location, preadmission modified Rankin scale, diabetes mellitus, hypertension, hyperlipidemia, symptom side, seizure history, and psychiatric history did not predict negative DWI status. CONCLUSIONS: In our study, roughly 1 in 6 patients treated with IV-tPA were later found to be stroke mimics with negative DWI. Despite a high proportion of suspected stroke mimics in our study, only preexisting migraine history independently predicted negative DWI status after IV-tPA treatment in suspected stroke patients.

Misdiagnosis of Cerebral Vein Thrombosis in the Emergency Department.

BACKGROUND AND PURPOSE: Rates of cerebral venous thrombosis (CVT) misdiagnosis in the emergency department and outcomes associated with misdiagnosis have been underexplored. METHODS: Using administrative data, we identified adults with CVT at New York, California, and Florida hospitals from 2005 to 2013. Our primary outcome was probable misdiagnosis of CVT, defined as a treat-and-release emergency department visit for headache or seizure within 14 days before CVT. In addition, logistic regression was used to compare rates of clinical outcomes in patients with and without probable CVT misdiagnosis. We performed a confirmatory study at 2 tertiary care centers. RESULTS: We identified 5966 patients with CVT in whom 216 (3.6%; 95% confidence interval [CI], 1.1%-4.1%) had a probable misdiagnosis of CVT. After adjusting for demographics, risk factors for CVT, and the Elixhauser comorbidity index, probable CVT misdiagnosis was not associated with in-hospital mortality (odds ratio, 0.14; 95% CI, 0.02-1.05), intracerebral hemorrhage (odds ratio, 0.97; 95% CI, 0.57-1.65), or unfavorable discharge disposition (odds ratio, 0.90; 95% CI, 0.61-1.32); a longer length of hospital stay was seen among misdiagnosed patients with CVT (odds ratio, 1.62; 95% CI, 1.04-2.50). In our confirmatory cohort, probable CVT misdiagnosis occurred in 8 of 134 patients with CVT (6.0%; 95% CI, 2.6%-11.4%). CONCLUSIONS: In a large, heterogeneous multistate cohort, probable misdiagnosis of CVT occurred in 1 of 30 patients but was not associated with the adverse clinical outcomes included in our study.

Diagnostic Error in Stroke-Reasons and Proposed Solutions.

PURPOSE OF REVIEW: We discuss the frequency of stroke misdiagnosis and identify subgroups of stroke at high risk for specific diagnostic errors. In addition, we review common reasons for misdiagnosis and propose solutions to decrease error. RECENT FINDINGS: According to a recent report by the National Academy of Medicine, most people in the USA are likely to experience a diagnostic error during their lifetimes. Nearly half of such errors result in serious disability and death. Stroke misdiagnosis is a major health care concern, with initial misdiagnosis estimated to occur in 9% of all stroke patients in the emergency setting. Under- or missed diagnosis (false negative) of stroke can result in adverse patient outcomes due to the preclusion of acute treatments and failure to initiate secondary prevention strategies. On the other hand, the overdiagnosis of stroke can result in inappropriate treatment, delayed identification of actual underlying disease, and increased health care costs. Young patients, women, minorities, and patients presenting with non-specific, transient, or posterior circulation stroke symptoms are at increased risk of misdiagnosis. Strategies to decrease diagnostic error in stroke have largely focused on early stroke detection via bedside examination strategies and a clinical decision rules. Targeted interventions to improve the diagnostic accuracy of stroke diagnosis among high-risk groups as well as symptom-specific clinical decision supports are needed. There are a number of open questions in the study of stroke misdiagnosis. To improve patient outcomes, existing strategies to improve stroke diagnostic accuracy should be more broadly adopted and novel interventions devised and tested to reduce diagnostic errors.

Cerebral Hyperperfusion Syndrome After Carotid Revascularization and Acute Ischemic Stroke.

PURPOSE OF REVIEW: Cerebral hyperperfusion syndrome (CHS) is a rare but significant complication after carotid revascularization and is increasingly recognized after acute stroke treatments. In this review, we discuss the epidemiology and pathophysiology of CHS, clinical presentation including ipsilateral headache, seizures, and focal neurological deficits, and radiographic presentation. We propose preventive therapies with emphasis on acute stroke post-thrombectomy hyperperfusion. RECENT FINDINGS: CHS was first described after carotid revascularization but is now also reported in patients with acute ischemic stroke. Proposed criteria involve a combination of new clinical symptoms, radiographic evidence of hyperperfusion, and/or presence of intracerebral hemorrhage occurring within 30 days after the carotid or intracranial vessel manipulation. Strongest risk factors include reduced cerebral vasoreactivity, contralateral stenosis of ≥ 70%, post-procedure hypertension, and recent ipsilateral stroke. Pathophysiology is incompletely understood but is likely due to increase in cerebral blood flow and impaired cerebral autoregulation, particularly in the areas of disrupted blood-brain barrier, as well as baroreceptor dysfunction during carotid surgery. Strict blood pressure control pre-, during, and post-procedure is recommended, depending on the recanalization status of the vessel. However, there is no randomized data regarding the goal blood pressure to prevent cerebral hyperperfusion syndrome. With technical advances, carotid or intracranial vessel manipulation is increasingly common. CHS is a likely under-recognized and serious complication of carotid revascularization and intracranial thrombectomy. Awareness of and surveillance for CHS is important to reduce morbidity and mortality. Future research should focus on validation of proposed diagnostic criteria and determining optimal post-procedure hemodynamic management to prevent CHS.

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.

Cross-Sectional Retrospective Study to Identify Clinical and Radiographic Features Associated With VZV Reactivation in Cryptogenic Stroke Patients With CSF Testing.

Background and Purpose: A large proportion of ischemic stroke patients lack a definitive stroke etiology despite extensive diagnostic testing. Varicella-Zoster Virus (VZV) can directly invade blood vessels causing vasculitis and may be associated with cryptogenic stroke (CS). Methods: We conducted a retrospective cross-sectional study of CS patients tested for VZV. The following were considered evidence of VZV reactivation (VZV+): positive CSF VZV PCR, anti-VZV IgM in CSF, or anti-VZV IgG CSF/serum ratio of 1:10 or higher. We describe the cohort, report VZV+ proportion with 95% confidence intervals (CI) determined with the Wald method, and compare patient groups using standard statistical tests. Results: A total of 72 CS patients met full study inclusion criteria. Most of the patients were <65 years old, had few traditional vascular risk factors, and had multifocal infarcts. Mean age was 49 years (SD ±13) and 47% were women. A total of 14 patients (19.4%; CI: 11.4-30.8%) had evidence of CNS VZV reactivation. There was no difference in evaluated demographic or radiographic features between those with versus without evidence of VZV reactivation. History of ischemic stroke in the past year (11/14 vs 25/43, P<.05) and hypertension (13/14 vs 35/58 and P<.05) were associated with VZV+. Conclusion: We found a high proportion of CNS VZV reactivation in a cross-sectional cohort of CS patients selected for CSF testing. Testing for VZV might be reasonable in CS patients who are young, have multifocal infarcts, or had an ischemic stroke within the past year, but additional research is needed.

Endovascular Therapy for Cerebral Vein Thrombosis: A Propensity-Matched Analysis of Anticoagulation in the Treatment of Cerebral Venous Thrombosis.

BACKGROUND: Endovascular treatment (EVT) for cerebral vein thrombosis (CVT) has not been proven to be more effective than anticoagulation based on recent results of the Thrombolysis or Anticoagulation for Cerebral Venous Thrombosis (TO-ACT) randomized clinical trial. OBJECTIVE: To compare outcomes of EVT vs medical management in CVT. METHODS: We compared EVT vs medical management in a retrospective multinational cohort of consecutive patients with CVT across 4 countries (USA, Italy, Switzerland, and New Zealand) and 27 sites (2015-2020), using propensity score matching (PSM) and inverse probability treatment weighting (IPTW), and meta-analyzed these results with the TO-ACT trial. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] 0-1) at 90 days. RESULTS: Of the 987 patients, the mean age was 45.7 ± 16.9 years and 79 (8%) underwent EVT. With PSM (n = 124), there were no major differences in clinical or imaging features between groups other than a higher proportion of female patients receiving EVT (81% vs 65%, P = .04). There was no difference in the primary outcome with PSM (odds ratio [OR] 1.48, 95% CI, 0.55-3.96) or IPTW (OR 1.02, 95% CI, 0.34-3.06). EVT was associated with a higher 90-day shift in modified Rankin Scale (OR 2.00, 95% CI, 1.01-3.98) and mortality with IPTW (OR 4.60, 95% CI, 1.10-19.23) but no other differences in secondary outcomes with PSM or IPTW. A meta-analysis of primary and secondary outcomes from TO-ACT and PSM patients from anticoagulation in the treatment of cerebral venous thrombosis also showed no significant association with EVT in primary or secondary outcomes. CONCLUSION: In this large observational cohort, there was no evidence of benefit with EVT for CVT. These findings corroborate the results from the TO-ACT trial.

Predictors of Recurrent Venous Thrombosis After Cerebral Venous Thrombosis: Analysis of the ACTION-CVT Study.

BACKGROUND AND OBJECTIVE: Cerebral venous thrombosis (CVT) is a rare cause of stroke carrying a nearly 4% risk of recurrence after 1 year. There are limited data on predictors of recurrent venous thrombosis in patients with CVT. In this study, we aim to identify those predictors. METHODS: This is a secondary analysis of the ACTION-CVT study which is a multicenter international study of consecutive patients hospitalized with a diagnosis of CVT over a 6-year period. Patients with cancer-associated CVT, CVT during pregnancy, or CVT in the setting of known antiphospholipid antibody syndrome were excluded per the ACTION-CVT protocol. The study outcome was recurrent venous thrombosis defined as recurrent venous thromboembolism (VTE) or de novo CVT. We compared characteristics between patients with vs without recurrent venous thrombosis during follow-up and performed adjusted Cox regression analyses to determine important predictors of recurrent venous thrombosis. RESULTS: Nine hundred forty-seven patients were included with a mean age of 45.2 years, 63.9% were women, and 83.6% had at least 3 months of follow-up. During a median follow-up of 308 (interquartile range 120-700) days, there were 5.05 recurrent venous thromboses (37 VTE and 24 de novo CVT) per 100 patient-years. Predictors of recurrent venous thrombosis were Black race (adjusted hazard ratio [aHR] 2.13, 95% CI 1.14-3.98, p = 0.018), history of VTE (aHR 3.40, 95% CI 1.80-6.42, p < 0.001), and the presence of one or more positive antiphospholipid antibodies (aHR 3.85, 95% CI 1.97-7.50, p < 0.001). Sensitivity analyses including events only occurring on oral anticoagulation yielded similar findings. DISCUSSION: Black race, history of VTE, and the presence of one or more antiphospholipid antibodies are associated with recurrent venous thrombosis among patients with CVT. Future studies are needed to validate our findings to better understand mechanisms and treatment strategies in patients with CVT.

Assessing diagnostic error in cerebral venous thrombosis via detailed chart review.

Background Diagnostic error in cerebral venous thrombosis (CVT) has been understudied despite the harm associated with misdiagnosis of other cerebrovascular diseases as well as the known challenges of evaluating non-specific neurological symptoms in clinical practice. Methods We conducted a retrospective cohort study of CVT patients hospitalized at a single center. Two independent reviewers used a medical record review tool, the Safer Dx Instrument, to identify diagnostic errors. Demographic and clinical factors were abstracted. We compared subjects with and without a diagnostic error using the t-test for continuous variables and the chi-square (χ2) test or Fisher's exact test for categorical variables; an alpha of 0.05 was the cutoff for significance. Results A total of 72 CVT patients initially met study inclusion criteria; 19 were excluded due to incomplete medical records. Of the 53 patients included in the final analysis, the mean age was 48 years and 32 (60.4%) were women. Diagnostic error occurred in 11 cases [20.8%; 95% confidence interval (CI) 11.8-33.6%]. Subjects with diagnostic errors were younger (42 vs. 49 years, p = 0.13), more often women (81.8% vs. 54.8%, p = 0.17), and were significantly more likely to have a past medical history of a headache disorder prior to the index CVT visit (7.1% vs. 36.4%, p = 0.03). Conclusions Nearly one in five patients with complete medical records experienced a diagnostic error. Prior history of headache was the only evaluated clinical factor that was more common among those with an error in diagnosis. Future work on distinguishing primary from secondary headaches to improve diagnostic accuracy in acute neurological disease is warranted.

Varicella Zoster Virus Vasculitis and Adult Cerebrovascular Disease.

The role of Varicella zoster virus (VZV) in neurological illness, particularly cerebrovascular disease, has been increasingly recognized. Primary infection by VZV causes varicella (chickenpox), after which the virus remains latent in neuronal ganglia. Later, during aging or immunosuppression, the virus can reactivate causing zoster (shingles). Virus reactivation can also spread to cerebral arteries causing vasculitis and stroke. Zoster is a recognized risk factor for stroke, but stroke can occur without preceding zoster rash. The diagnosis of VZV cerebral vasculitis is established by abnormal brain imaging and confirmed by presence of viral DNA or anti-VZV antibodies in cerebrospinal fluid. Treatment with acyclovir with or without prednisone is usually recommended. VZV vasculitis is a unique and uncommon stroke mechanism that has been under recognized. Careful diagnostic investigation may be warranted in a subgroup of patients with ischemic stroke to detect VZV vasculitis and initiate appropriate therapy. In the following review, we detail the clinical presentation of VZV vasculitis, diagnostic challenges in VZV detection, and suggest the ways to enhance recognition and treatment of this uncommon disease.

Dysregulation of system xc(-) expression induced by mutant huntingtin in a striatal neuronal cell line and in R6/2 mice.

Oxidative stress has been implicated in the pathogenesis of Huntington's disease (HD), however, the origin of the oxidative stress is unknown. System xc(-) plays a role in the import of cystine to synthesize the antioxidant glutathione. We found in the STHdh(Q7/Q7) and STHdh(Q111/Q111) striatal cell lines, derived from neuronal precursor cells isolated from knock-in mice containing 7 or 111 CAG repeats in the huntingtin gene, that there is a decrease in system xc(-) function. System xc(-) is composed of two proteins, the substrate specific transporter, xCT, and an anchoring protein, CD98. The decrease in function in system xc(-) that we observed is caused by a decrease in xCT mRNA and protein expression in the STHdh(Q111/Q111) cells. In addition, we found a decrease in protein and mRNA expression in the transgenic R6/2 HD mouse model at 6weeks of age. STHdh(Q111/Q111) cells have lower basal levels of GSH and higher basal levels of ROS. Acute inhibition of system xc(-) causes greater increase in oxidative stress in the STHdh(Q111/Q111) cells than in the STHdh(Q7/Q7) cells. These results suggest that a defect in the regulation of xCT may be involved in the pathogenesis of HD by compromising xCT expression and increasing susceptibility to oxidative stress.

Glutamate transporter expression and function in a striatal neuronal model of Huntington's disease.

Excitotoxicity may contribute to the pathogenesis of Huntington's disease. High affinity Na+ dependent glutamate transporters, residing in the plasma membrane, clear glutamate from the extracellular space and are the primary means of protection against excitotoxicity. Many reports suggest that Huntington's disease is associated with a decrease in the expression and function of glutamate transporters. We studied the expression and function of these transporters in a cellular model of Huntington's disease, STHdh(Q111/Q111) and STHdh(Q7/Q7) cells. We found that only GLT-1b and EAAC1 were expressed in these cell lines and only EAAC1 significantly contributed to the glutamate uptake. Surprisingly, there was an increase in Na+-dependent glutamate uptake in STHdh(Q111/Q111) cells accompanied by an increase in surface expression of EAAC1. We studied the influence of the Akt pathway on EAAC1 mediated uptake, since EAAC1 surface expression is influenced by Akt and previous studies have shown increased Akt expression in STHdh(Q111/Q111) cells. Glutamate uptake was inhibited by Akt pathway inhibitors in both the STHdh(Q7/Q7) and the STHdh(Q111/Q111) cell lines. We found no difference in Akt activation between the two cell lines under our conditions of culture. Therefore a difference in Akt activation does not seem to explain the increase in EAAC1 mediated uptake in the STHdh(Q111/Q111) cells.