The effectiveness and safety of clazosentan in treating aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a severe event often complicated by cerebral vasospasm (CV). This study aimed to assess the efficacy and safety of clazosentan, an endothelin receptor antagonist, in reducing CV, delayed cerebral ischemia (DCI), and the need for rescue therapy in aSAH patients, while evaluating its impact on functional outcomes and mortality. METHODS: We conducted a literature search across multiple databases to identify relevant studies evaluating the effects of clazosentan in aSAH patients. Both cohort studies and randomized controlled trials (RCTs) were included. The primary outcomes were vasospasm incidence, moderate to severe vasospasm, DCI, and the need for rescue therapy. Secondary outcomes included functional outcomes, mortality, and adverse events. The data were pooled as Risk ratios (R/R) with 95 % confidence intervals (CI) using RevMan 5.4 software. RESULTS: A total of 11 studies, including 10 published and one unpublished, comprising 8,469 patients were included in the meta-analysis. Clazosentan significantly reduced the incidence of vasospasm (R/R = 0.49: 0.34-0.70), moderate to severe vasospasm (R/R = 0.53: 0.46-0.61), DCI (R/R = 0.70: 0.59-0.82), and the need for rescue therapy (R/R = 0.65: 0.52-0.83) compared to placebo. However, no significant improvement in functional outcomes or mortality rates was observed. Clazosentan was associated with increased rates of pulmonary adverse events (R/R = 1.89: 1.64-2.18), hypotension (R/R = 2.47: 1.79-3.42), and anemia (R/R = 1.49: 1.23-1.79) but no increased risk of hepatobiliary adverse events or cerebral hemorrhage. CONCLUSIONS: Clazosentan demonstrates efficacy in reducing vasospasm, moderate to severe vasospasm, DCI, and the need for rescue therapy in aSAH patients, but does not significantly improve functional outcomes or mortality rates. While associated with specific adverse events, clazosentan may be a valuable adjunctive therapy in the management of aSAH, particularly in a high-risk population for vasospasm.

Clinical Characteristics as Predictors of Early and Delayed Cerebral Infarction in Aneurysmal Subarachnoid Hemorrhage Patients: A Meta-Analysis of 4527 Cases.

BACKGROUND: Predictors of delayed cerebral infarction (DCI) and early cerebral infraction (ECI) among aneurysmal subarachnoid hemorrhage (aSAH) patients remain unclear. We aimed to systematically review and synthesize the literature on predictors of ECI and DCI among aSAH patients. METHODS: We systematically searched PubMed, EMBASE, Cochrane Library, and Scopus databases comprehensively from inception through January 2024 for observational cohort studies examining predictors of DCI or ECI following aneurysmal SAH. Studies were screened, reviewed, and meta-analyzed, adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane guidelines. The data were pooled as Odds ratios (OR) with 95% confidence intervals using Review Manager 5.4 software. Methodologic quality was assessed with the Newcastle-Ottawa Scale. RESULTS: Our meta-analysis included 12 moderate to high-quality cohort studies comprising 4527 patients. Regarding DCI predictors, Higher severity scores (OR = 1.49, 95% confidence interval [1.12, 1.97], P = 0.005) and high Fisher scores (OR = 2.23, 95% confidence interval [1.28, 3.89], P = 0.005) on presentation were significantly associated with an increased risk of DCI. Also, the female sex and the presence of vasospasm were significantly associated with an increased risk of DCI (OR = 3.04, 95% confidence interval [1.35, 6.88], P = 0.007). In contrast, preexisting hypertension (P = 0.94), aneurysm treatment (P = 0.14), and location (P = 0.16) did not reliably predict DCI risk. Regarding ECI, the pooled analysis demonstrated no significant associations between sex (P = 0.51), pre-existing hypertension (P = 0.63), severity (P = 0.51), or anterior aneurysm location versus posterior (P = 0.86) and the occurrence of ECI. CONCLUSION: Female sex, admission disease severity, presence of vasospasm and Fisher grading can predict DCI risk post-aSAH. Significant knowledge gaps exist for ECI predictors. Further large standardized cohorts are warranted to guide prognosis and interventions.

COVID-19 Associated Wake-Up Stroke Treated With DWI/FLAIR Mismatch Guided Intravenous Alteplase: A Case Report.

INTRODUCTION: Wake-up strokes are challenging to manage due to unknown time of onset. Recently, the wake-up trial demonstrated that recombinant tissue plasminogen activator (rtPA) could be administered based on the magnetic resonance imaging (MRI)- diffusion weighted imaging/fluid attenuated inversion recovery mismatch. Many still doubt the safety results due to the higher rate of hemorrhagic conversion reported. Although it was statistically insignificant, the study was terminated early. Furthermore, Corona virus disease-19 is associated with coagulopathy and a higher risk of hemorrhagic conversion. CASE REPORT: A 46-year-old fully functioning male presented with a wake-up right hemiparesis, right facial droop, and expressive aphasia. His National Institute of Health Stroke Scale was 4 upon arrival. Last known well state was >4.5 hours. He tested positive for SARS-CoV-2 viral infection. He had left distal-M2 occlusion. He was deemed not a candidate for rtPA. Hyperacute-MRI protocol showed diffusion weighted imaging/fluid attenuated inversion recovery mismatch. The patient received rtPA at 6.5 hours from the last knwn well state. Follow-up MRI-susceptibility weighted imaging revealed fragmented clot. The stroke burden was less than that shown on the initial computed tomography-perfusion scans implying saved penumbra. There was no hemorrhagic conversion despite low fibrinogen levels. CONCLUSION: The hyperacute-MRI protocol for wake-up COVID-19 associated strokes might be a safe option.

Covid-19 systemic infection exacerbates pre-existing acute disseminated encephalomyelitis (ADEM).

Acute disseminated encephalomyelitis (ADEM) is an uncommon diagnosis in adults. It is known to be due to an abnormal immune response to a systemic infection rather than direct viral invasion to the central nervous system. There have been few reports of ADEM diagnosed in the setting of COVID-19 systemic infection. However, we report a case of Coxsackie induced ADEM that remitted but got exacerbated by COVID-19 infection. The patient contracted the COVID-19 infection shortly after being discharged to a rehabilitation facility. Direct COVID-19 neuroinvasion was ruled out via CSF PCR testing for the virus. The patient responded well to pulse steroid therapy and plasmapheresis in both occasions. We hypothesize that COVID-19 infection can flare-up a recently remitted ADEM via altering the immune responses. It is known now that COVID-19 infection can produce cytokine storming. Cytokine pathway activation is known to be involved in the pathology of ADEM. Caution regarding discharging immune suppressed patient to the inpatient rehabilitation facility should be made in the era of COVID-19 pandemic.

Role of Non-Perfusion Factors in Mildly Symptomatic Large Vessel Occlusion Stroke.

INTRODUCTION: Uncertainty regarding reperfusion of mildly-symptomatic (minor) large vessel occlusion (LVO)-strokes exists. Recently, benefits from reperfusion were suggested. However, there is still no strong data to support this. Furthermore, a proportion of those patients don't improve even after non-hemorrhagic reperfusion. Our study evaluated whether or not non-perfusion factors account for such persistent deconditioning. METHODS: Patients with identified minor LVO-strokes (NIHSS ≤ 8) from our stroke alert registry between January-2016 and May-2018 were included. Variables/ predictors of outcome were tested using univariate/multivariate logistic and linear regression analyses. Three month-modified ranking scale (mRS) was used to differentiate between favorable (mRS = 0-2) and unfavorable outcomes (mRS = 3-6). RESULTS: Eighty-one patients were included. Significant differences between the two outcome groups regarding admission-NIHSS and discharge-NIHSS existed (OR = 0.47, 0.49 / p = 0.0005, <0.0001 respectively).The two groups had matching perfusion measures. In the poor outcome group, discharge-NIHSS was unchanged from the admission-NIHSS while in the good outcome group, discharge-NIHSS significantly improved. CONCLUSION: Admission and discharge NIHSS are independent predictors of outcome in patients with minor-LVO strokes. Unchanged discharge-NIHSS predicts worse outcomes while improved discharge-NIHSS predicts good outcomes. Unchanged NIHSS in the poor outcome group was independent of the perfusion parameters. In literature, complement activation and pro-inflammatory responses to ischemia might account for the progression of stroke symptoms in major-strokes. Our study concludes similar phenomena might be present in minor-strokes. Therefore, discharge-NIHSS may be useful as a clinical marker for future therapies.

Ipsilateral Vocal Cord Paralysis After Acute Anterior Ischemic Stroke.

INTRODUCTION: The vocal cord is innervated by the recurrent laryngeal nerve and the superior laryngeal nerve, which are branches of the vagus nerve. The nucleus ambiguous is a motor nucleus of the vagus nerve and it is located in the medulla. It receives supratentorial upper motor regulatory fibers. Commonly, this regulation is bilaterally represented in the brain. Less commonly, it is contralaterally represented. This case describes a rare presentation. CASE PRESENTATION: We present a female patient in her early sixties with a past medical history significant for hypertension who presented with acute right-sided weakness and expressive aphasia (National Institutes of Health Stroke Scale = 20). Computed tomography (CT)-head was unremarkable but she was outside the window for chemical thrombolytic therapy. CT-angiogram revealed occlusion of the left extracranial and intracranial internal carotid artery and, thus, she was deemed not a candidate for mechanical thrombectomy. CT-perfusion scans (Rapid software) showed a large penumbra within the respective vascular territory affected including the operculum and the insula. The core infarction was relatively small and located in the left basal ganglia. After inducing therapeutic hypertension, the patient's aphasia improved. Surprisingly, this unmasked a moderate to severe hypophonic voice. The patient underwent flexible fiberoptic laryngoscopy which showed a paralyzed left vocal cord but without signs of inflammation. CONCLUSION: Our case is a rare case of transient ipsilateral vocal cord paralysis associated with anterior unilateral cerebral ischemia. The paralysis resolved with improvement of the cerebral ischemic penumbra.

The Significance of Contrast Density of the Computed Tomography-Angiographic Spot Sign and its Correlation with Hematoma Expansion.

BACKGROUND AND PURPOSE: The computed tomography angiographic (CTA) spot sign has been shown to predict hematoma expansion in patients with intracranial hemorrhage (ICH), but the significance of the spot sign density (SSD) and the spot sign ratio (SSR) has not yet been explored. METHODS: Using the institutional Neurocritical care and Stroke registry, we retrospectively reviewed patients with ICH from January-2013 to June-2017. We selected patients who had baseline CT-head (CTH), CTA with positive-spot sign within 6 hours of last known well and at least one follow-up CTH within 24 hours. Baseline demographics and variables known to affect hematoma-volume were collected. Hematoma-volumes and SSR were calculated using computer-assisted 3D-volumetric measurement and the average of the surrounding hematoma density divided by the SSD, respectively. The 2-sample t test and the area-under-the-curve (receiver operating characteristic) were used to detect the association between hematoma expansion and outcome at discharge. RESULTS: A total of 320 patients were reviewed; 22 met the inclusion criteria. Significant hematoma expansion (volume expansion ≥12.5 cc or ≥33% compared to baseline) was noted in 14 (64%) subjects. SSD was significantly higher in subjects with hematoma expansion (216 ± 66) than those without (155 ± 52, P = .036). With a cut-off SSD of ≥150 HU, we had sensitivity of 86% and specificity of 75%. For SSR, lower ratios suggested a trend toward hematoma expansion, although it was not statistically significant (P = .12). There was no significant correlation between SSD or SSR and modified ranking scale at discharge and after 3-6 months. CONCLUSION: SSD might be a good predictor of hematoma growth. Although SSR showed a trend toward expansion, results were not statistically significant.

The intraventricular-spot sign: prevalence, significance, and relation to hematoma expansion and outcomes.

BACKGROUND: The presence of the spot sign on computed tomography angiogram (CTA) is considered a sign of active bleeding, and studies have shown it can predict hematoma expansion in intraparenchymal hemorrhage (IPH). The spot sign in intraventricular hemorrhage (IVH) has not been explored yet. The purpose of this study is to estimate the prevalence of the intraventricular-spot sign, and its prediction of hematoma expansion and clinical outcomes. METHODS: We retrieved data of hemorrhagic stroke patients seen at our medical center from January 2013 to January 2018. A total of 321 subjects were filtered for the prevalence analysis (PA). We further excluded 114 subjects without a follow-up CT-head for the hematoma expansion analysis (HEA). Patients were grouped based on the location of hemorrhage into three groups: isolated IPH with the spot sign always in IPH (i-IPH), isolated IVH with the spot sign always in IVH (i-IVH), and combined IPH and IVH which would be further sub-grouped according to the location of the spot sign: in IPH only (IPH+/IVH) and in IVH only (IPH/IVH+). The prevalence, demographics, and incidence of hematoma expansion were compared between the groups using Pearson's chi-square test and Student's t test. RESULTS: The prevalence of the spot sign was 8, 20, 17, 5% in (i-IPH), (i-IVH), (IPH+/IVH), and (IPH/IVH+) groups, respectively. The rate of hematoma expansion were (42 vs. 13%), (33 vs. 31%), (80 vs. 22%), and (25 vs. 22%) in spot sign positive vs. negative subjects in each group, respectively (p values = 0.023, = 1, <0.001, and = 1). CONCLUSION: We studied the prediction of spot sign on hematoma expansion and clinical outcomes in the different subtypes of ICH. Our study showed that spot sign is a good predictor in IPH but not IVH. Despite the rarity of IVH; the prevalence of spot sign was higher in IVH than IPH. This might be due to anatomical and physiological variations.