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- Cerebrospinal Fluid Cytokines in Multiple System Atrophy: a Cross-Sectional Catalan MSA Registry StudyPublication . Compta, Y; Dias, S; Giraldo, D; Pérez-Soriano, A; Muñoz, E; Saura, J; Fernández, M; Bravo, P; Cámara, A; Pulido-Salgado, M; Painous, C; Ríos, J; Martí, MJIntroduction: Neuroinflammation is a potential player in neurodegenerative conditions, particularly the aggressive ones, such as multiple system atrophy (MSA). Previous reports on cytokine levels in MSA using serum or cerebrospinal fluid (CSF) have been inconsistent, including small samples and a limited number of cytokines, often without comparison to Parkinson's disease (PD), a main MSA differential diagnosis. Methods: Cross-sectional study of CSF levels of 38 cytokines using a multiplex assay in 73 participants: 39 MSA patients (19 with parkinsonian type [MSAp], 20 with cerebellar type [MSAc]; 31 probable, 8 possible), 19 PD patients and 15 neurologically unimpaired controls. None of the participants was under non-steroidal anti-inflammatory drugs at the time of the lumbar puncture. Results: There were not significant differences in sex and age among participants. In global non-parametric comparisons FDR-corrected for multiple comparisons, CSF levels of 5 cytokines (FGF-2, IL-10, MCP-3, IL-12p40, MDC) differed among the three groups. In pair-wise FDR-corrected non-parametric comparisons 12 cytokines (FGF-2, eotaxin, fractalkine, IFN-α2, IL-10, MCP-3, IL-12p40, MDC, IL-17, IL-7, MIP-1β, TNF-α) were significantly higher in MSA vs. non-MSA cases (PD + controls pooled together). Of these, MCP-3 and MDC were the most significant ones, also differed in MSA vs. PD, and were significant MSA-predictors in binary logistic regression models and ROC curves adjusted for age. CSF levels of fractalkine and MIP-1α showed a strong and significant positive correlation with UMSARS-2 scores. Conclusion: Increased CSF levels of cytokines such as MCP-3, MDC, fractalkine and MIP-1α deserve consideration as potential diagnostic or severity biomarkers of MSA.
- Characteristics and Outcomes of Patients With Cerebral Venous Sinus Thrombosis in SARS-CoV-2 Vaccine–Induced Immune Thrombotic ThrombocytopeniaPublication . Sánchez van Kammen, M; Aguiar de Sousa, D; Poli, S; Cordonnier, C; Heldner, M; van de Munckhof, A; Krzywicka, K; van Haaps, T; Ciccone, A; Middeldorp, S; Levi, M; Kremer Hovinga, J; Silvis, S; Hiltunen, S; Mansour, M; Arauz, A; Barboza, M; Field, T; Tsivgoulis, G; Nagel, S; Lindgren, E; Tatlisumak, T; Jood, K; Putaala, J; Ferro, J; Arnold, M; Coutinho, J; Sharma, A; Elkady, A; Negro, A; Günther, A; Gutschalk, A; Schönenberger, S; Buture, A; Murphy, S; Paiva Nunes, A; Tiede, A; Puthuppallil Philip, A; Mengel, A; Medina, A; Hellström Vogel, Å; Tawa, A; Aujayeb, A; Casolla, B; Buck, B; Zanferrari, C; Garcia-Esperon, C; Vayne, C; Legault, C; Pfrepper, C; Tracol, C; Soriano, C; Guisado-Alonso, D; Bougon, D; Zimatore, D; Michalski, D; Blacquiere, D; Johansson, E; Cuadrado-Godia, E; De Maistre, E; Carrera, E; Vuillier, F; Bonneville, F; Giammello, F; Bode, F; Zimmerman, J; d’Onofrio, F; Grillo, F; Cotton, F; Caparros, F; Puy, L; Maier, F; Gulli, G; Frisullo, G; Polkinghorne, G; Franchineau, G; Cangür, H; Katzberg, H; Sibon, I; Baharoglu, I; Brar, J; Payen, JF; Burrow, J; Fernandes, J; Schouten, J; Althaus, K; Garambois, K; Derex, L; Humbertjean, L; Lebrato Hernandez, L; Kellermair, L; Morin Martin, M; Petruzzellis, M; Cotelli, M; Dubois, MC; Carvalho, M; Wittstock, M; Miranda, M; Skjelland, M; Bandettini di Poggio, M; Scholz, M; Raposo, N; Kahnis, R; Kruyt, N; Huet, O; Sharma, P; Candelaresi, P; Reiner, P; Vieira, R; Acampora, R; Kern, R; Leker, R; Coutts, S; Bal, S; Sharma, S; Susen, S; Cox, T; Geeraerts, T; Gattringer, T; Bartsch, T; Kleinig, T; Dizonno, V; Arslan, YImportance: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson). Objective: To describe the clinical characteristics and outcome of patients with cerebral venous sinus thrombosis (CVST) after SARS-CoV-2 vaccination with and without TTS. Design, setting, and participants: This cohort study used data from an international registry of consecutive patients with CVST within 28 days of SARS-CoV-2 vaccination included between March 29 and June 18, 2021, from 81 hospitals in 19 countries. For reference, data from patients with CVST between 2015 and 2018 were derived from an existing international registry. Clinical characteristics and mortality rate were described for adults with (1) CVST in the setting of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after SARS-CoV-2 vaccination not fulling criteria for TTS, and (3) CVST unrelated to SARS-CoV-2 vaccination. Exposures: Patients were classified as having TTS if they had new-onset thrombocytopenia without recent exposure to heparin, in accordance with the Brighton Collaboration interim criteria. Main outcomes and measures: Clinical characteristics and mortality rate. Results: Of 116 patients with postvaccination CVST, 78 (67.2%) had TTS, of whom 76 had been vaccinated with ChAdOx1 nCov-19; 38 (32.8%) had no indication of TTS. The control group included 207 patients with CVST before the COVID-19 pandemic. A total of 63 of 78 (81%), 30 of 38 (79%), and 145 of 207 (70.0%) patients, respectively, were female, and the mean (SD) age was 45 (14), 55 (20), and 42 (16) years, respectively. Concomitant thromboembolism occurred in 25 of 70 patients (36%) in the TTS group, 2 of 35 (6%) in the no TTS group, and 10 of 206 (4.9%) in the control group, and in-hospital mortality rates were 47% (36 of 76; 95% CI, 37-58), 5% (2 of 37; 95% CI, 1-18), and 3.9% (8 of 207; 95% CI, 2.0-7.4), respectively. The mortality rate was 61% (14 of 23) among patients in the TTS group diagnosed before the condition garnered attention in the scientific community and 42% (22 of 53) among patients diagnosed later. Conclusions and relevance: In this cohort study of patients with CVST, a distinct clinical profile and high mortality rate was observed in patients meeting criteria for TTS after SARS-CoV-2 vaccination.
- Dabigatran Initiation in Patients with Non-Valvular AF and First Acute Ischaemic Stroke: a Retrospective Observational Study from the SITS RegistryPublication . Escudero-Martinez, I; Mazya, M; Teutsch, C; Lesko, N; Gdovinova, Z; Barbarini, L; Fryze, W; Karlinski, M; Kobayashi, A; Krastev, G; Paiva Nunes, A; Pasztoova, K; Peeters, A; Sobolewski, P; Vilionskis, A; Toni, D; Ahmed, NBackground and objective: The optimal timing for initiation of dabigatran after acute ischaemic stroke (AIS) is not established. We aimed to evaluate initiation timing and clinical outcomes of dabigatran in AIS patients with non-valvular atrial fibrillation (NVAF). Design: Retrospective study based on prospectively collected data in SITS (Safe Implementation of Treatment in Stroke) Thrombolysis and Thrombectomy Registry from July 2014 to July 2018. Participants: European NVAF patients (≥18 years) hospitalised after first-ever ischaemic stroke. Setting: A multinational, observational monitoring register. Intervention: Dabigatran initiation within 3 months after the ischaemic stroke. Primary and secondary outcomes: The primary outcome was time from first-ever ischaemic stroke (index event) to dabigatran initiation. Additional outcomes included physicians' reasons for delaying dabigatran initiation beyond acute hospital discharge and outcomes within 3 months of index event. Methods: We identified patients with NVAF who received dabigatran within 3 months of the index event. We performed descriptive statistics for baseline and demographic data and clinical outcomes after dabigatran initiation. Results: In total, 1489 patients with NVAF received dabigatran after AIS treated with thrombolysis and/or thrombectomy. Of these, 1240 had available initiation time. At baseline, median age was 75 years; 53% of patients were women, 15% were receiving an oral anticoagulant, 29% acetylsalicylic acid and 4% clopidogrel. Most patients (82%) initiated dabigatran within 14 days after the index event. Patients initiating earlier had lower stroke severity from median NIHSS 8 (IQR 6-13) if initiated within 7 days to NIHSS 15 (9-19) if initiated between 28 days and 3 months. Most common reasons for delaying initiation were haemorrhagic transformation or intracranial haemorrhage, stroke severity and infarct size. Few thrombotic/haemorrhagic events occurred within 3 months after the index event (20 of 926 patients, 2.2% with the available data). Conclusions: Our findings, together with previous observational studies, indicate that dabigatran initiated within the first days after an AIS is safe in patients treated with intravenous thrombolysis, endovascular thrombectomy or both.
- Influence of Weather on Seizure Frequency - Clinical Experience in the Emergency Room of a Tertiary HospitalPublication . Brás, P; Barros, A; Vaz, S; Sequeira, J; Melancia, D; Fernandes, A; de Sousa, A; Dias, S; Menezes Cordeiro, I; Manita, M
- Intensive Blood Pressure Treatment Reduced Stroke Risk in Patients With Albuminuria in the SPRINT TrialPublication . Leitão, L; Soares-Dos-Reis, R; Neves, JS; Baptista, RB; Bigotte Vieira, M; Mc Causland, FRBackground and Purpose- Albuminuria is associated with stroke risk among individuals with diabetes. However, the association of albuminuria with incident stroke among nondiabetic patients is less clear. Methods- We performed a post hoc analysis of the SPRINT (Systolic Blood Pressure Intervention Trial), which examined the effect of higher versus lower intensity blood pressure management on mortality in 8913 participants without diabetes. We fit unadjusted and adjusted Cox proportional hazards models to estimate the association of baseline albuminuria (urinary albumin-to-creatinine ratio ≥30 mg/g versus<30 mg/g) with stroke risk. We also assessed effect modification according to treatment arms. Results- Mean age was 68±9 years, 35% were female, and 30% were black. Median follow-up was 3.2 years, and 19% patients had baseline albuminuria. Incident stroke occurred in 129 individuals during follow-up. Albuminuria was associated with increased stroke risk (unadjusted hazard ratio, 2.24; 95% CI, 1.55-3.23; adjusted hazard ratio 1.73; 95% CI, 1.17-2.56). The association of albuminuria with incident stroke differed according to the randomized treatment arm (P interaction=0.03). In the intensive treatment arm, the association of albuminuria and stroke was nonsignificant (unadjusted hazard ratio, 1.25; 95% CI, 0.69-2.28), whereas, in the standard treatment arm, it was significant (unadjusted hazard ratio, 3.44; 95% CI, 2.11-5.61). Conclusions- In a post hoc analysis of SPRINT, baseline albuminuria (versus not) was associated with a higher risk of incident stroke, but this relationship appeared to be restricted to those in the standard treatment arm. Further studies are required to conclusively determine if reduction of albuminuria in itself is beneficial in reducing stroke risk. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062.
- Language Improvement One Week After Thrombolysis in Acute StrokePublication . Martins, IP; Fonseca, J; Morgado, J; Leal, G; Farrajota, L; Fonseca, AC; Melo, TPOBJECTIVES: Language recovery following acute stroke is difficult to predict due to several evaluation factors and time constraints. We aimed to investigate the predictors of aphasia recovery and to identify the National Institute of Health and Stroke Scale (NIHSS) items that best reflect linguistic performance, 1 week after thrombolysis. MATERIALS AND METHODS: We retrieved data from a prospective registry of patients with aphasia secondary to left middle cerebral artery (MCA) stroke treated with intravenous thrombolysis. Complete recovery at day 7 (D7) was measured in a composite verbal score (CVS) (Σ Language+Questions+Commands NIHSS scores). Lesion size was categorized by the Alberta Stroke Program Early CT score (ASPECTS) and vascular patency by ultrasound. CVS was correlated with standardized aphasia testing if both were performed within a two-day interval. RESULTS: Of 228 patients included (age average 67.32 years, 131 men), 72% presented some language improvement that was complete in 31%. Total recovery was predicted by ASPECTS (OR=1.65; 95% CI, 1.295-2.108; P < 0.00) and baseline aphasia severity (OR=0.439; 95% CI, 0.242-0.796; P < 0.007). CVS correlated better with standardized aphasia measures (aphasia quotient, severity, comprehension) than NIHSS_Language item. CONCLUSIONS: Lesion size and initial aphasia severity are the main predictors of aphasia recovery one week after thrombolysis. A NIHSS composite verbal score seems to capture the global linguistic performance better than the language item alone.
- Nivolumab-Induced Seronegative EncephalitisPublication . Cabral, G; Ladeira, F; Gil, NImmune checkpoint inhibitors (ICIs) have emerged as a new therapeutic tool for numerous types of cancer. Neurological complications have been reported in 1% of patients who have undergone checkpoint inhibition therapy. ICIs-induced encephalitides occur in 0.1-0.2% of patients within weeks after ICIs initiation; are usually seronegative and have nonspecific changes on imaging, CSF and electroencephalogram (EEG) studies. Early recognition and prompt treatment are important to prevent significant morbidity and mortality. We present a case of nivolumab-induced encephalitis with very subtle clinical symptoms and full recovery following ICIs suspension and steroids.
- OCT in Alzheimer's Disease: Thinning of the RNFL and Superior HemiretinaPublication . Cunha, JP; Proença, R; Dias-Santos, A; Almeida, R; Águas, H; Alves, M; Papoila, AL; Louro, C; Castanheira-Dinis, ABACKGROUND: Peripapillary retinal nerve fiber layer (pRNFL) and internal macular layer thinning have been demonstrated in Alzheimer's disease (AD) with optical coherence tomography (OCT) studies. The purpose of this study is to compare the pRNFL thickness and overall retinal thickness (RT) in AD patients with non-AD patients, using spectral domain optical coherence tomography (SD-OCT) and determine the sectors most characteristically affected in AD. METHODS: A cross-sectional study was performed to determine the pRNFL and overall macular RT thicknesses in AD and non-AD patients, attending a tertiary hospital center. For pRNFL, the global and six peripapillary quadrants were calculated, and for overall RT values, the nine Early Treatment Diabetic Retinopathy Study (ETDRS) areas were used. A multiple regression analysis was applied to assess the effects of disease, age, gender, spherical equivalent, visual acuity, intraocular pressure, axial length and blood pressure on pRNFL and overall macular RT. RESULTS: A total of 202 subjects, including 50 eyes of 50 patients with mild AD (mean age 73.10; SD = 5.36 years) and 152 eyes of 152 patients without AD (mean age 71.03; SD = 4.62 years). After Bonferroni correction, the pRNFL was significantly thinner for the AD group globally and in the temporal superior quadrant (10.76 μm and 20.09 μm mean decrease, respectively). The RT thickness was also decreased in superior sectors S3 and S6 (mean thinning of 9.92 μm and 11.65 μm, respectively). Spearman's correlation coefficient showed a direct association between pRNFL in the temporal superior quadrant and RT in superior S6 and S3 sectors (rS = 0.41; p < 0.001 and rS = 0.28; p < 0.001, respectively). CONCLUSIONS: Patients with AD showed a significant thickness reduction in global and temporal superior quadrants in pRNFL and in superior pericentral and peripheral sectors of RT. These findings may reflect a peripapillary and retinal changes characteristic of AD, suggesting the importance of SD-OCT as a potential adjuvant in early diagnosis of AD. Further studies are needed to understand which retinal layers and macular sectors are more useful as potential ocular biomarker over time in AD.
- Prognostic Factors Associated with Disability in a Cohort of Neuromyelitis Optica Spectrum Disorder and MOG-Associated Disease from a Nationwide Portuguese Registry.Publication . Moura, João; Samões, Raquel; Sousa, Ana Paula; Figueiroa, Sónia; Mendonça, Teresa; Abreu, Pedro; Guimarães, Joana; Melo, Claúdia; Sousa, Raquel; Soares, Mafalda; Correia, Ana Sofia; Marques, Inês Brás; Perdigão, Sandra; Alves, Ivânia; Felgueiras, Helena; Nzwalo, Hipólito; Mendes, Irene; Almeida, Vânia; Boleixa, Daniela; Carneiro, Paula; Neves, Esmeralda; Silva, Ana Martins; Sá, Maria José; Santos, ErnestinaIntroduction: Neuromyelitis optica spectrum disorders (NMOSD) and MOG-associated disease (MOGAD) are an increasingly recognized group of demyelinating disorders of the central nervous system. Previous studies suggest that prognosis is predicted by older age at onset, number of relapses, the severity of the first attack and autoantibody status. Objective: To study prognostic factors associated with disability progression and additional relapses in the 3-year follow-up of a national NMOSD/MOGAD cohort. Results: Out of 180 of the initial Portuguese cohort, data on 82 patients was available at the end of the follow-up period (2019-2022). Two patients died. Twenty (24.4%) patients had one or more attack in this period (25 attacks in total), mostly transverse myelitis (TM) (56.0%) or optic neuritis (32.0%). MOGAD was significantly associated with a monophasic disease course (p = 0.03), with milder attacks (p = 0.01), while AQP4 + NMOSD was associated with relapses (p = 0.03). The most common treatment modalities were azathioprine (38.8%) and rituximab (18.8%). AQP4 + NMOSD more frequently required chronic immunosuppressive treatment, particularly rituximab (p = 0.01). Eighteen (22.5%) had an EDSS ≥6 at the end of the follow-up. AQP4 + NMOSD (p < 0.01) and the occurrence of transverse myelitis (TM) during disease (p = 0.04) correlated with an EDSS≥6 at the end of the follow-up period. MOGAD was significantly associated with an EDSS<6 (p < 0.01), and MOG+ cases that reached an EDSS>6 were significantly older (64.0 ± 2.8 versus 31.0 ± 17.1, p = 0.017). A bivariate logistic regression model including the serostatus and TM attacks during disease history successfully predicted 72.2% of patients that progressed to an EDSS≥6. Conclusion: This study highlights that myelitis predict increased disability (EDSS≥6) in NMOSD/MOGAG and AQP4 positivity is associated with increased disability.
- Quality of Life in Subjects with Upper- and Lower-Limb Spasticity Treated with IncobotulinumtoxinAPublication . Fheodoroff, K; Rekand, T; Medeiros, L; Koßmehl, P; Wissel, J; Bensmail, D; Scheschonka, A; Flatau-Baqué, B; Simon, O; Dressler, D; Simpson, DMBackground: We evaluated quality of life among subjects with upper- and lower-limb spasticity who received escalating doses of incobotulinumtoxinA (total body doses up to 800 U) in the prospective, single-arm, dose-titration TOWER study. Methods: In this exploratory trial, subjects (N = 155; 18-80 years of age) with upper- and lower-limb spasticity due to cerebral causes who were deemed to require total body doses of up to 800 U incobotulinumtoxinA received three consecutive injection cycles of incobotulinumtoxinA (400, 600, and up to 800 U), each with 12 to 16 weeks' follow-up. QoL was assessed using the EuroQol 5-dimensions questionnaire, three-level (EQ-5D), before and 4 weeks post-injection in each injection cycle and at the end of injection cycle 3. Results: The mean EQ-5D visual analog scale scores of 155 participants continuously improved from study baseline to 4 weeks post-injection in all injection cycles (mean [standard deviation] change 6.7 [14.1], 9.6 [16.3], and 8.6 [17.0] for injection cycles 1, 2, and 3, respectively; p < 0.0001 for all, paired sample t-test). In general, among those with a change in the EQ-5D rating of their condition, the proportion of subjects with 'improvement' was greater than that with 'worsening' for individual EQ-5D dimensions across all injection cycles. At the end of injection cycle 3, the proportion of subjects rating their condition as 'normal' increased from study baseline for all dimensions, and there was a ≥ 46% reduction in the proportion of subjects with a rating of 'severe impairment'. Conclusion: These preliminary results suggest that escalating incobotulinumtoxinA doses up to 800 U are associated with improvement in quality of life ratings in subjects with multifocal upper- and lower-limb spasticity, and form a basis for future comparator studies.