Blocking CCR5 activity by maraviroc augmentation in post-stroke depression: a proof-of-concept clinical trial.

BACKGROUND: Post-stroke depression (PSD) is a significant impediment to successful rehabilitation and recovery after a stroke. Current therapeutic options are limited, leaving an unmet demand for specific and effective therapeutic options. Our objective was to investigate the safety of Maraviroc, a CCR5 antagonist, as a possible mechanism-based add-on therapeutic option for PSD in an open-label proof-of-concept clinical trial. METHODS: We conducted a 10-week clinical trial in which ten patients with subcortical and cortical stroke, suffering from PSD. were administered a daily oral dose of 300 mg Maraviroc. Participants were then monitored for an additional eight weeks. The primary outcome measure was serious treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. The secondary outcome measure was a change in the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Maraviroc was well tolerated, with no reports of serious adverse events or discontinuations due to intolerance. The MADRS scores substantially reduced from baseline to week 10 (mean change: -16.4 ± 9.3; p < 0.001). By the conclusion of the treatment phase, a favorable response was observed in five patients, with four achieving remission. The time to response was relatively short, approximately three weeks. After the cessation of treatment, MADRS scores increased at week 18 by 6.1 ± 9.6 points (p = 0.014). CONCLUSIONS: Our proof-of-concept study suggests that a daily dosage of 300 mg of Maraviroc may represent a well-tolerated and potentially effective pharmacological approach to treating PSD. Further comprehensive placebo-controlled studies are needed to assess the impact of Maraviroc augmentation on PSD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05932550, Retrospectively registered: 28/06/2023.

CCR5-Δ32 polymorphism-a possible protective factor from gait impairment amongst post-stroke patients.

BACKGROUND AND PURPOSE: Stroke and small vessel disease cause gait disturbances and falls. The naturally occurring loss-of-function mutation in the C-C chemokine receptor 5 gene (CCR5-Δ32) has recently been reported as a protective factor in post-stroke motor and cognitive recovery. We sought to examine whether it also influences gait and balance measures up to 2 years after stroke. METHOD: Participants were 575 survivors of first-ever, mild-moderate ischaemic stroke or transient ischaemic attack from the TABASCO prospective study, who underwent a 3 T magnetic resonance imaging at baseline and were examined by a multi-professional team 6, 12 and 24 months after the event, using neurological, neuropsychological and mobility examinations. Gait rhythm and the timing of the gait cycle were measured by force-sensitive insoles. CCR5-Δ32 status and gait measures were available for 335 patients. RESULTS: CCR5-Δ32 carriers (16.4%) had higher gait speed and decreased (better) stride and swing time variability 6 and 12 months after the index event compared to non-carriers (p < 0.01 for all). The association remained significant after adjustment for age, gender, education, ethnicity and stroke severity. CONCLUSIONS: Significant associations were found between gait measurements and CCR5-Δ32 loss-of-function mutation amongst stroke survivors. This is the first study showing that genetic predisposition may predict long-term gait function after ischaemic stroke.

Posttraumatic Stress Symptoms After Stroke: The Effects of Anatomy and Coping Style.

BACKGROUND: Posttraumatic stress disorder (PTSD) can be triggered by life-threatening medical emergencies, such as stroke. Data suggest that up to 25% of stroke survivors will develop PTSD symptomatology, but little is known about predisposing factors. We sought to examine whether neuroimaging measures and coping styles are related to PTSD symptoms after stroke. METHODS: Participants were survivors of first-ever, mild-moderate ischemic stroke, or transient ischemic attack from the TABASCO study (Tel Aviv Brain Acute Stroke Cohort). All participants underwent a 3T magnetic resonance imaging at baseline and were examined 6, 12, and 24 months thereafter, using neurological, neuropsychological, and functional evaluations. At baseline, coping styles were evaluated by a self-reported questionnaire. PTSD symptoms were assessed using the PTSD checklist. Data were available for 436 patients. RESULTS: Forty-eight participants (11%) developed probable PTSD (PTSD checklist ≥44) during the first year after the stroke/transient ischemic attack. Stroke was more likely to cause PTSD than transient ischemic attack. Stroke severity, larger white matter lesion volume, and worse hippocampal connectivity were associated with PTSD severity, while infarct volume or location was not. In a multivariate analysis, high-anxious and defensive coping styles were associated with a 6.66-fold higher risk of developing poststroke PTSD ([95% CI, 2.08-21.34]; P<0.01) compared with low-anxious and repressive coping styles, after adjusting for age, education, stroke severity, brain atrophy, and depression. CONCLUSIONS: In our cohort, PTSD was a common sequela among stroke survivors. We suggest that risk factors for PTSD development include stroke severity, white matter damage, and premorbid coping styles. Early identification of at-risk patients is key to effective treatment.

Endovascular thrombectomy is beneficial for functional nonagenarians - a multicenter cohort analysis.

INTRODUCTION: The use of endovascular thrombectomy (EVT) has dramatically increased in recent years. However, most existing studies used an upper age limit of 80 and data regarding the safety and efficacy of EVT among nonagenarians is still lacking. METHODS: 767 consecutive patients undergoing EVT for large vessel occlusion (LVO) in three participating centers were recruited into a prospective ongoing database. Demographic, clinical and imaging characteristics were documented. Statistical analysis was done to evaluate EVT outcome among nonagenarians compared to younger patients. RESULTS: The current analysis included 41 (5.4%) patients older than 90 years. Compared to younger patients, nonagenarians were more often female (78% versus 50.3%, p ≤ 0.001), had worse baseline mRS scores (2 [0-3] versus 0 [0-2], p < 0.001), higher rates of hypertension and hyperlipidemia and a higher admission NIHSS (20 [14-23] versus 16 [11-20], p < 0.001). No differences were found between groups regarding the involved vessel, stroke etiology, time from symptoms to door or symptoms to EVT, successful recanalization rates and hemorrhagic transformation rates. Nonagenarians had worse mRS at 90 days (5 [3-6] versus 3 [2-5], p = 0.001), similar discharge NIHSS (5 [1-11] versus 4 [1-11], p = 0.78) and higher mortality rates (36.6% versus 15.8%, p < 0.001). All nonagenarians with baseline mRS 4 have died within 90 days. 36.4% of nonagenarian patients with baseline MRS of 3 or less had favorable outcome. DISCUSSION: This study demonstrates that nonagenarian stroke patients with baseline mRS of 3 or less benefit from EVT with no significant difference in the rate of favorable outcome compared to octogenarians.

Clinical and MRI characteristics of multiple sclerosis in patients of Middle Eastern and North African ancestry residing in Ontario, Canada.

BACKGROUND: Multiple sclerosis (MS) incidence is rising in traditionally low-burden regions, including the Middle East and North Africa (MENA). OBJECTIVES: Our objective was to evaluate disease characteristics in MS patients of MENA descent (MENA-MS). METHODS: MENA-MS patients and age- and sex-matched MS patients of European descent (EUR-MS) were identified through the MS Clinic Registry of St. Michael's Hospital in Toronto, Canada. Disease activity and severity were evaluated by the annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, change in the Expanded Disability Status Scale (EDSS), progression index (PI), and MS Severity Score (MSSS). RESULTS: All MS patients within the registry identified to be of MENA origin (n = 192), and age- and sex-matched EUR-MS patients were included. Mean age was 42.9 years, 67% female. A total of 25% and 24% of EUR-MS and MENA-MS had progressive disease, with similar mean disease durations (11.5 and 11.4 years, respectively). Clinical and radiological disease activity (ARR, proportion with new/enlarging MRI lesions) was similar. MENA-MS showed greater disability progression over time (EDSS change = 0.24 vs. 0.06, p = 0.01), a higher MSSS (3.12 vs. 2.67, p = 0.04), and higher PI (0.34 vs. 0.27, p = 0.07). CONCLUSION: MENA-MS patients demonstrate higher disease severity compared to EUR-MS patients, despite having similar inflammatory measures of disease activity, with disability progression in the absence of relapses. These observations illustrate the importance of the intersections of environmental, socioeconomic, and genetic determinants in optimizing individualized MS care.

Five-year longitudinal changes in quantitative spinal cord MRI in multiple sclerosis.

BACKGROUND: The spinal cord (SC) is highly relevant to disability in multiple sclerosis (MS), but few studies have evaluated longitudinal changes in quantitative spinal cord magnetic resonance imaging (SC-MRI). OBJECTIVES: The aim of this study was to characterize the relationships between 5-year changes in SC-MRI with disability in MS. METHODS: In total, 75 MS patients underwent 3 T SC-MRI and clinical assessment (expanded disability status scale (EDSS) and MS functional composite (MSFC)) at baseline, 2 and 5 years. SC-cross-sectional area (CSA) and diffusion-tensor indices (fractional anisotropy (FA), mean, perpendicular, parallel diffusivity (MD, λ⊥, λ||) and magnetization transfer ratio (MTR)) were extracted at C3-C4. Mixed-effects regression incorporating subject-specific slopes assessed longitudinal change in SC-MRI measures. RESULTS: SC-CSA and MTR decreased (p = 0.009, p = 0.03) over 5.1 years. There were moderate correlations between 2- and 5-year subject-specific slopes of SC-MRI indices and follow-up EDSS scores (Pearson's r with FA = -0.23 (p < 0.001); MD = 0.31 (p < 0.001); λ⊥ = 0.34 (p < 0.001); λ|| = -0.12 (p = 0.05), MTR = -0.37 (p < 0.001); SC-CSA = -0.47 (p < 0.001) at 5 years); MSFC showed similar trends. The 2- and 5-year subject-specific slopes were robustly correlated (r = 0.93-0.97 for FA, λ⊥, SC-CSA and MTR, all ps < 0.001). CONCLUSION: In MS, certain quantitative SC-MRI indices change over 5 years, reflecting ongoing tissue changes. Subject-specific trajectories of SC-MRI index change at 2 and 5 years are strongly correlated and highly relevant to follow-up disability. These findings suggest that individual dynamics of change should be accounted for when interpreting longitudinal SC-MRI measures and that measuring short-term change is predictive of long-term clinical disability.

CCR5-Δ32 polymorphism: a possible protective factor for post-stroke depressive symptoms.

Background: A naturally occurring loss-of-function mutation in the gene for C-C chemokine receptor type 5 (CCR5-Δ32) has recently been reported as a protective factor in post-stroke motor and cognitive recovery. We sought to examine whether this mutation also prevented the development of depressive symptoms up to 2 years after a stroke. Methods: Participants were survivors of a first-ever mild to moderate ischemic stroke or transient ischemic attack from the TABASCO prospective study who underwent a 3 T MRI at baseline and were examined by a multiprofessional team 6, 12 and 24 months after the event, including an evaluation of depressive symptoms using the Geriatric Depression Scale. Results: CCR5-Δ32 status and a baseline depression evaluation were available for 435 patients. Compared with noncarriers, CCR5-Δ32 carriers (16.1%) had fewer depressive symptoms at admission (p = 0.035) and at 6 months (p < 0.001), 12 months (p < 0.001) and 24 months (p = 0.006) after the index event. This association remained significant at 6 and 12 months after adjustment for age, sex, education, antidepressant use, ethnicity and the presence of cortical infarcts. These findings were more robust in women. Compared to baseline, depressive symptoms in CCR5-Δ32 noncarriers tended to remain stable or grow worse over time, but in CCR5-Δ32 carriers, symptoms tended to improve. Limitations: A limitation of this study was the exclusion of patients who had a severe stroke or who had pre-stroke depression. Conclusion: Carriers of the CCR5-Δ32 allele had a lower tendency to develop depressive symptoms post-stroke, and this phenomenon was more prominent in women. These findings could have clinical implications; they suggest a mechanism-based treatment target for post-stroke depression. Drugs mimicking this loss-of-function mutation exist and could serve as a novel antidepressant therapy.

Working status is related to post stroke/TIA cognitive decline: data from the TABASCO study.

BACKGROUND AND AIMS: Occupational status may influence physical and mental post-stroke outcomes. We aimed to evaluate the association between occupational status and type, or engagement in social and family activities, neuroimaging measures and cognitive decline (CD) in a prospective cohort of stroke patients. METHODS: We included 273 first-ever stroke survivors at working age. All patients underwent 3T MRI at admission, as well as clinical and cognitive assessments at admission, 6, 12 and 24 months thereafter. RESULTS: Ninty nine (36.3%) of the participants were unemployed prior to the stroke. Age, sex, work type, other comorbidities, stroke severity or location were not associated with return to work. Patients who returned to work (87.4%) had better cognitive results and less depressive symptoms than those who retired after the event. Pre-stroke unemployment was associated with diabetes mellitus, hypertension, dyslipidemia, depression, poorer cognitive scores and brain atrophy. During the follow-up, 11% developed CD. CD was more common among previously unemployed than employed participants (19.2% vs. 6.3%, p = 0.001). Multiple regression adjusted for risk factors, revealed that pre-stroke unemployment was an independent predictor of CD (HR, 3.0; 95% CI: 1.06-8.44). Furthermore, engagement in mentally stimulating jobs decreased the risk for CD. CONCLUSIONS: Pre-stroke unemployment and post-stroke work disruption were each associated with depression and poorer cognitive performance up to two years post-stroke, as well as with brain atrophy at admission. Retirement after the stroke may increase the risk of developing CD. These results highlight the importance of continued employment in preserving cognitive abilities among stroke survivors.

Assessment of carotid artery ultrasonography in the presence of an acoustic shadow artifact.

BACKGROUND: B-mode and Color Doppler ultrasonography (CDUS) are the methods of choice for screening and determining the degree of Carotid artery stenosis. The evaluation of stenosis with calcification may be hampered by a common CDUS artifact known as acoustic shadow (AS). Our objective was to assess the change in reliability of CDUS readings in the presence of an AS artifact. METHODS: Single center retrospective observational study. Included were patients with either an AS artifact or high-grade stenosis (defined by peak systolic velocity (PSV) > 240 cm/s) demonstrated in CDUS, and had a CT angiography (CTA) done within 6 months of the sonographic exam. All subjects were identified through the Tel-Aviv Sorasky medical center (TASMC) CDUS unit registry from which clinical information was extracted. CDUS images were manually reviewed grading AS magnitude. All CTAs were reviewed and reconstructed for accurate assessment of percent stenosis and were used as gold standard. RESULTS: The study cohort included 227 consecutive patients (corresponding with 454 internal carotid arteries) meeting inclusion criteria. 43.2% of the arteries (n = 195) had an AS artifact present on CDUS, regardless of percent stenosis, with a large artifact present in 6.7% arteries (n = 30). Older age was significantly related to the presence of AS artifact (p < 0.001). In the study cohort as a whole there was a strong correlation between percent stenosis on CTA and PSV values (Pearson's r 0.672, p < 0.001) regardless of AS existence. The CDUS sensitivity and specificity for predicting severe stenosis were 82 and 73% respectively. The presence of a small AS slightly diminished the correlation between CDUS and CTA results without compromising CDUS reliability. A large AS severely affected the correlation between CDUS and CTA exams (Pearson's r = 0.24, p = 0.27) and reduced CDUS reliability with a sensitivity and specificity of 62%. CONCLUSION: The presence of a large AS severely degrades the accuracy of the routine CDUS measurements. In these cases, the patient should be referred to a CDUS exam including doppler-measurement of periorbital arteries and intracranial arteries in addition to other imaging modalities such as CTA or MRA in order to assess future stroke risk.

The collateral circulation determines cortical infarct volume in anterior circulation ischemic stroke.

BACKGROUND: Acute ischemic stroke (AIS) is a common neurological event that causes varying degrees of disability. AIS outcome varies considerably, from complete recovery to complete loss of tissue and function. This diversity is partly explained by the compensatory ability of the collateral circulation and the ensuing cerebral flow grade. The collateral flow to the anterior circulation largely supplies the cortical areas. The deep brain tissue is supplied by penetrating arteries and has little or no collateral supply. Although these brain compartments differ substantially in their collateral supply, there are no published data on the different effects the collateral circulation has on them. In addition, the influence of baseline collateral flow on the final infarct size following endovascular or reperfusion therapies remains unknown. This study was designed to determine the effect of the collateral circulation on cortical infarct volume and deep infarct volume, and to investigate the relation between the collateral grade, response to reperfusion therapy and clinical outcome. METHODS: We studied consecutive patients presenting to our medical center between April 2008 and April 2012 with AIS and anterior proximal artery occlusion. To be included patients had to undergo a computerized tomographic angiographic study within 12 h of symptom onset demonstrating the occlusion. Imaging data and clinical and laboratory values were extracted retrospectively from the original scans and medical records. Cortical infarct volume (CIV) and deep infarct volume (DIV) were calculated as well as collateral grade. Clinical outcome was assessed at discharge using the modified Rankin Scale (mRS). RESULTS: Of the 51 study patients, 13 were treated conservatively, 22 received intravenous recombinant tissue plasminogen activator, and 16 received intra-arterial thrombolysis. The collateral grading was similar for all three treatment groups. While there was a moderate inverse correlation between the collateral grade and CIV (Spearman's rho = -0.49, P < 0.001), no comparable correlation was observed between the collateral grade and DIV (Spearman's rho =0.03, P = 0.85). Clinical outcome was significantly related to CIV but not to DIV (Spearman's rho =0.6 P < 0.001 versus Spearman's rho =0.09 P = 0.54, respectively). The correlation between the collateral grade and CIV was greatly diminished and lost its statistical significance in patients with successful recanalization (Spearman's rho = 0.2, p = 0.3). CONCLUSIONS: Our data shows that the collateral circulation is an important determinant of cortical infarct volume and, in turn, of clinical outcome in the setting of anterior circulation major artery occlusion. Our findings further demonstrate the benefit of recanalization in sparing cortical tissue from injury. Additional studies are needed to determine the impact of stroke therapy on the final infarct volume in relation to the collateral grade.

Case report: Cerebral sinus vein thrombosis in VEXAS syndrome.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic) syndrome is a newly described hemato-inflammatory acquired monogenic entity that presents in adulthood. One of the main features of VEXAS syndrome is a high venous thromboembolism (VTE) burden, with approximately 30-40% experiencing lower extremity deep vein thrombosis and a lower incidence of pulmonary embolism at approximately 10%. To date, VEXAS syndrome has not been associated with rarer forms of VTE such as cerebral sinus vein thrombosis (CSVT) and Budd-Chiari syndrome, which are well-recognized vascular manifestations in Behcet's disease, another autoinflammatory vasculitic disease. Herein, we describe a case of acute severe extensive and fatal CSVT in a patient with VEXAS syndrome. The event occurred during a period of apparently quiescent inflammatory status, while the patient was receiving tocilizumab and a low dose of glucocorticoids. Despite treatment with anticoagulation, high-dose glucocorticoids, endovascular thrombectomy, and intracranial pressure-lowering agents, the patient suffered severe neurologic damage and ultimately succumbed to the condition 3 weeks after the onset of CSVT. To the best of our knowledge, this is the first reported case of CVST in a patient with VEXAS syndrome.

Circle of Willis integrity in acute middle cerebral artery occlusion: does the posterior communicating artery matter?

BACKGROUND: Collateral circulation is an important determinant of outcome in people with acute ischemic stroke due to large vessel occlusion (LVO). OBJECTIVE: To explore the impact of the circle of Willis (CW) anatomical characteristics ipsilateral to the occlusion site, particularly the posterior communicating artery (PComA) and the A1-portion of the anterior cerebral artery (A1-ACA), on stroke outcomes in a cohort of patients with LVO and middle cerebral artery (MCA) occlusion, undergoing endovascular thrombectomy (EVT). METHODS: This is a retrospective cohort study performed in a comprehensive tertiary stroke center. The study population consisted of consecutive patients with LVO with proximal MCA occlusion (M1) between June 2016 and April 2021, undergoing EVT. Demographic, clinical, and imaging information was extracted from patient files. Patency and diameters of ipsilateral A1-ACA and PComA were manually measured on admission CT angiography images in the core laboratory. RESULTS: One hundred and five patients with LVO comprised the study cohort, mean age 72.3 years, 43.8% were male, mean National Institutes of Health Stroke Scale score at admission 15.2. The cohort was grouped according to CW vessel characteristics. On univariate analysis, a well-developed PComA was associated with lower rates of hemorrhagic transformation (1.8% vs 14.3%, P=0.01) and a trend towards lower mortality rates (8.9% vs 20.4%, P=0.08).On multivariable regression analysis a well-developed PComA emerged as an independent predictor for survival (aOR=0.09, 95% CI 0.01 to 0.4 for survival at discharge, P=0.009, aOR=0.22, 95% CI 0.05 to 0.8 for survival at 90 days, P=0.02). CONCLUSIONS: In a cohort of patients with LVO due to M1 occlusion undergoing EVT, a well-developed PComA was associated with significantly lower hemorrhagic transformation rates, a trend towards better functional outcomes, and independently predicted survival. Larger studies are needed to understand the differential effect of CW collateral conduits on stroke outcome and evaluate the practicality of incorporating such factors in the clinical decision-making process prior to EVT.

Association between intracranial vessel calcifications, structural brain damage, and cognitive impairment after minor strokes: a prospective study.

Background: Vascular calcifications are a hallmark of atherosclerosis, and in the coronary arteries are routinely used as a prognostic marker. Calcifications of intracranial vessels (ICC) are frequently observed on non-contrast CT (NCCT) and their effect on post-stroke cognitive impairment (PSCI) remains unclear. Our aim was to explore the association of ICC with prospective long-term cognitive function and advanced MRI-measures in a large prospective cohort of cognitively intact mild stroke survivors. Methods: Data from the Tel-Aviv brain acute stroke cohort (TABASCO) study [ClinicalTrials.gov #NCT01926691] were analyzed. This prospective cohort study (n = 575) aimed to identify predictors of PSCI, in cognitively intact mild stroke survivors. A quantitative assessment of the intracranial calcium content - The ICC score (ICCS) was calculated semi-automatically on NCCT using a validated calcium quantification application. Participants underwent a 3 T-MRI and prospective comprehensive cognitive clinical and laboratory assessments at enrollment, 6, 12, and 24-months. Results: Data were available for 531 participants (67.4 years, 59.5% males). The incidence of PSCI at two-years doubled in the high ICCS group (26% vs. 13.7%, p < 0.001). The high ICCS group had significantly greater small-vessel-disease (SVD) tissue changes and reduced microstructural-integrity assessed by Diffusion-Tensor-Imaging (DTI) maps (p < 0.05 for all). In multivariate analysis, a higher ICCS was independently associated with brain atrophy manifested by lower normalized white and gray matter, hippocampal and thalamic volumes (ß = -0.178, ß = -0.2, ß = -0.137, ß = -0.157; p < 0.05) and independently predicted PSCI (OR 1.83, 95%CI 1.01-3.35). Conclusion: Our findings suggest that the ICCS, which is a simple and readily available imaging marker on NCCT, is associated with brain atrophy, microstructural damage, the extent of SVD, and may predict PSCI. This finding has implications for identifying individuals at risk for PSCI and implementing targeted interventions to mitigate this risk.

Systemic Lupus Erythematous and Obstructive Sleep Apnea: A Possible Association.

Marked fatigue is common in patients with systemic lupus erythematosus (SLE). This study aimed to assess the association of sleep disorders, including obstructive sleep apnea (OSA), with SLE. Forty-two consecutive patients with SLE and 20 healthy controls were recruited and underwent a one-night ambulatory sleep examination. They completed questionnaires, including the Pittsburgh Sleep Quality Index (PSQI) and Functional Assessment of Chronic Illness Therapy (FACIT). SLE disease activity and damage were assessed by the SLE Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI). A significantly increased apnea/hypopnea index was noted in the SLE group compared to healthy controls (p = 0.004). SLE patients had higher rates of moderate-to-severe OSA (p = 0.04), PSQI (p = 0.001), and FACIT scores (p = 0.0008). Multivariate analysis revealed that the SDI was associated with OSA (p = 0.03). There was a positive association between SLEDAI-2K and moderate-to-severe OSA (p = 0.03). Patients with SLE had an increased prevalence of OSA and poorer quality of sleep compared to healthy controls. Our findings suggest that active disease and accumulated damage may be associated with OSA. These findings highlight the importance of identifying the presence of OSA in patients with SLE.

Characteristics of patients with cerebral sinus venous thrombosis and JAK2 V617F mutation.

OBJECTIVES: Janus kinase 2 (JAK2-V617F) mutations can cause thrombocytosis, polycythemia and hyper viscosity leading to cerebral sinus venous thrombosis (CSVT). However, data regarding the characteristics and prevalence of JAK2-V617F mutation in patients with CSVT are currently lacking. We aimed to evaluate the characteristics of CSVT patients that carry the JAK2 mutation. MATERIALS AND METHODS: Data of consecutive patients with CSVT, admitted to three large academic medical centers between 2010 and 2020, were retrospectively studied. Demographics, clinical presentations, radiological and clinical outcome parameters were compared between carriers of the JAK2-V617F mutation and controls. RESULTS: Out of 404 patients diagnosed with CSVT, 26 patients (6.5%) were carriers of the mutation. JAK2 mutation carriers more often had thrombocytosis (54% vs. 1%, p < 0.001). Furthermore, carriers of the JAK2 mutation less often had involvement of the transverse sinus (50% vs. 68%, p = 0.021). Finally, patients with the JAK2 mutation were more prone to have intracerebral hemorrhage (ICH, 31% vs. 17%, p = 0.044), but there was no significant difference between groups in terms of mortality nor functional outcome. CONCLUSIONS: JAK2 mutation is not uncommon in patients with CSVT and should be routinely screened for in this population. CSVT in JAK2 mutation carriers may have a tendency toward involving specific venous sinuses and is associated with a higher rate of ICH but similar overall prognosis.

The pivotal role of timing of intravenous thrombolysis bridging treatment prior to endovascular thrombectomy.

Background: The role of intravenous thrombolysis (IVT) as bridging treatment prior to endovascular thrombectomy (EVT) is under debate and better patient selection is needed. Objectives: As the efficacy and safety of IVT diminish with time, we aimed to examine the impact of bridging treatment within different time frames from symptom onset. Design: A retrospective registry study. Methods: Data were extracted from ongoing prospective EVT registries in two large tertiary centers. The current study included IVT-eligible patients with onset to door (OTD) < 4 h. We examined the efficacy and safety of bridging treatment through a comparison of the IVT + EVT group with the direct-EVT group by different time frames. Results: In all, 408 patients (age 71.1 ± 14.6, 50.6% males) were included, among them 195 received IVT + EVT and 213 underwent direct EVT. Both groups had similar characteristics. In the IVT + EVT group only, longer OTD was associated with lower rates of favorable outcome (p = 0.021) and higher rates of hemorrhagic transformation (HT; p = 0.001). In patients with OTD ⩽ 2 h, IVT + EVT compared to direct EVT had higher rates of TICI 2b-3 (86.2% versus 80.7%, p = 0.038). In patients with OTD > 2 h, IVT + EVT had lower rates of favorable outcome (33.3% versus 56.9%, p = 0.021), worse discharge National Institutes of Health Stroke Scale [7 (2-13) versus 3 (1-8), p = 0.024], and higher rates of HT (34.0% versus 8.5%, p < 0.001). Discussion: In this study, we found OTD times to have a significant effect on the impact of IVT bridging treatment. Our study shows that among patients with OTD < 2 h bridging treatment may be associated with higher rates of successful recanalization. By contrast, in patients with OTD > 2 h, bridging treatment was associated with worse outcomes. Further time-sensitive randomized trials are needed.

Quantitative spinal cord MRI and sexual dysfunction in multiple sclerosis.

Background: Sexual dysfunction (SD) is frequently reported in multiple sclerosis (MS) and is likely related to MS-related damage to the spinal cord (SC). Objective: To assess associations between SD and quantitative MRI measures in people with MS (pwMS). Methods: This pilot study included 17 pwMS with SD who completed questionnaires assessing SD, mood, and fatigue. All participants underwent brain, cervical, and thoracic SC-MRI at 3T. Quantitative brain and SC-MRI measures, including brain/SC atrophy, SC lesion count, diffusion-tensor imaging (DTI) indices (fractional anisotropy [FA], mean, perpendicular, parallel diffusivity [MD, λ⊥, λ||]) and magnetization-transfer ratio (MTR) were obtained. Associations between quantitative MRI measures and SD were assessed while controlling for the extent of mood and fatigue symptomatology. Results: Subjects were a mean age of 46.9 years and 29% female. All subjects had self-reported SD (MSISQ-19 = 40.7, SQoL: 55.9) and 65% had a concurrent psychiatric diagnosis. When correlations between SD severity were assessed with individual brain and SC-MRI measures while controlling for psychiatric symptomatology, no associations were found. The only variables showing independent associations with SD were anxiety (p = 0.03), depression (p = 0.05), and fatigue (p = 0.04). Conclusion: We found no correlations between quantitative MRI measures in the brain and SC and severity of SD in pwMS, but psychiatric symptomatology and fatigue severity demonstrated relationships with SD. The multifactorial nature of SD in pwMS mandates a multidisciplinary approach.

Safety and Efficacy of Intravenous Alteplase before Endovascular Thrombectomy: A Pooled Analysis with Focus on the Elderly.

Current guidelines advocate intravenous thrombolysis (IVT) prior to endovascular thrombectomy (EVT) for all patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO). We evaluated outcomes with and without IVT pretreatment. Our institutional protocols allow AIS patients presenting early (<4 h from onset or last seen normal) who have an Alberta Stroke Program Early CT Score (ASPECTS) ≥6 to undergo EVT without IVT pretreatment if the endovascular team is in the hospital (direct EVT). Rates of recanalization and hemorrhagic transformation (HT) and neurological outcomes were retrospectively compared in consecutive patients undergoing IVT+EVT vs. direct EVT with subanalyses in those ≥80 years and ≥85 years. In the overall cohort (IVT+EVT = 147, direct EVT = 162), and in subsets of patients ≥80 years (IVT+EVT = 51, direct EVT = 50) and ≥85 years (IVT+EVT = 19, direct EVT = 32), the IVT+EVT cohort and the direct EVT group had similar baseline characteristics, underwent EVT after a comparable interval from symptom onset, and reached similar rates of target vessel recanalization. No differences were observed in the HT frequency, or in disability at discharge or after 90 days. Patients receiving direct EVT underwent more stenting of the carotid artery due to stenosis during the EVT procedure (22% vs. 6%, p = 0.001). Direct EVT and IVT+EVT had comparable neurological outcomes in the overall cohort and in the subgroups of patients ≥80 and ≥85 years, suggesting that direct EVT should be considered in patients with an elevated risk for HT.

Characteristics of Cerebral Sinus Venous Thrombosis Patients Presenting with Intracerebral Hemorrhage.

Patients with cerebral venous sinus thrombosis (CVST) occasionally present with intracerebral hemorrhage (ICH). In this study, we aimed to identify predictors for ICH in CVST patients. Prospective CVST databases from three academic centers were retrospectively analyzed. CVST patients with and without ICH upon presentation were compared. Among the 404 included patients (mean age 41.8 years, 33% male), 74 (18.3%) had an ICH. The patients with ICH were older (45 ± 20.6 vs. 41.1 ± 18 years, p = 0.045), and were more often pregnant or postpartum women (15% vs. 6%, p = 0.011), or chronically hypertensive (15% vs. 5%, p = 0.001). The ICH patients had higher rates of seizures (60% vs. 15%, p < 0.001), and focal neurological deficits (53% vs. 23%, p < 0.001). The ICH group had lower rates of excellent outcome measured by 90-day mRS 0 (56.7% vs. 80.3%, p < 0.001) and higher rates of 90-day mortality (8% vs. 3%, p = 0.041). Radiological variables associated with ICH included superior sagittal sinus (SSS) thrombosis (63% vs. 36%), isolated cortical vein thrombosis (38% vs. 8%), and presence of venous infarction (34% vs. 7%) (p < 0.001 for all). Upon multivariate analysis, chronic hypertension (OR 3.7, p = 0.027), being either pregnant or postpartum (OR 4.3, p = 0.006), isolated cortical thrombosis (OR 3.5, p = 0.007), and SSS involvement (OR 3.4, p < 0.001) were independently associated with ICH upon admission. In conclusion, among CVST patients, the following present higher for ICH: pregnant or postpartum women, and individuals with chronic hypertension, cortical vein, or SSS involvement.

Preventing post-stroke dementia. The MARCH Trial. Protocol and statistical analysis plan of a randomized clinical trial testing the safety and efficacy of Maraviroc in post-stroke cognitive impairment.

Background: Current evidence suggest that 25%-33% of stroke-survivors develop post-stroke cognitive impairment (PSCI). The licensed drug Maraviroc, a CCR5-antagonist, is postulated to act via a neuroprotective mechanism that may offer the potential of preventing progression to vascular dementia. Our hypothesis: Maraviroc may have the potential to augment learning skills and cognitive performance by affecting synaptic plasticity, along with neuro-inflammatory modulation in patients with cerebral small vessel disease (SVD) and PSCI. Design: MARCH is a multi-center, double-blind randomized-control Phase-II trial of Maraviroc 150 or 600 mg/day versus placebo for 12-months in five stroke centers in Israel. Included are patients diagnosed with recent (1-24 months) subcortical stroke who experience mild PSCI and have evidence of white matter lesions and SVD on neuroimaging. Outcomes: Primary outcomes: 1. Change in cognitive scores. 2. Drug related adverse events. Secondary outcomes: change in functional and affective scores, MRI-derived measures, inflammatory markers, carotid atherosclerosis, cerebrospinal-fluid biomarkers in a sub-study. A sample size of 60 in each treatment group and 30 in the placebo group (total - 150 participants) provides 80% power between the treatment and the placebo groups. Conclusions: The results of this work could lead to a novel, readily available, therapeutic avenue to reduce PSCI, and possibly other pathologies. This study will test safety and effectiveness of Maraviroc in limiting cognitive deterioration and/or post stroke cognitive impairment in patients with cerebral small vessel disease. Schedule: First-patient first-visit was May 2021. Recruitment to complete in 2023, follow-up to complete in 2024.