Early plasma biomarker dynamic profiles are associated with acute ischemic stroke outcomes.

BACKGROUND: Early outcome prediction after acute ischemic stroke (AIS) might be improved with blood-based biomarkers. We investigated whether the longitudinal profile of a multi-marker panel could predict the outcome of successfully recanalized AIS patients. METHODS: We used ultrasensitive single-molecule array (Simoa) to measure glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), total-tau (t-tau) and ELISA for brevican in a prospective study of AIS patients with anterior circulation large vessel occlusion successfully submitted to thrombectomy. Plasma was obtained at admission, upon treatment, 24 h and 72 h after treatment. Clinical and neuroimaging outcomes were assessed independently. RESULTS: Thirty-five patients (64.8%) had good early clinical or neuroimaging outcome. Baseline biomarker levels did not distinguish between outcomes. However, longitudinal intra-individual biomarker changes followed different dynamic profiles with time and according to outcome. GFAP levels exhibited an early and prominent increase between admission and just after treatment. NfL increase was less pronounced between admission and up to 24 h. T-tau increased between treatment and 24 h. Interestingly, GFAP rate-of-change (pg/ml/h) between admission and immediately after recanalization had a good discriminative capacity between clinical outcomes (AUC = 0.88, p < 0.001), which was higher than admission CT-ASPECTS (AUC = 0.75, p < 0.01). T-tau rate-of-change provided moderate discriminative capacity (AUC = 0.71, p < 0.05). Moreover, in AIS patients with admission CT-ASPECTS <9 both GFAP and NfL rate-of-change were good outcome predictors (AUC = 0.82 and 0.77, p < 0.05). CONCLUSION: Early GFAP, t-tau and NfL rate-of-change in plasma can predict AIS clinical and neuroimaging outcome after successful recanalization. Such dynamic measures match and anticipate neuroimaging predictive capacity, potentially improving AIS patient stratification for treatment, and targeting individualized stroke care.

Fluid biomarkers in stroke: From animal models to clinical care.

Stroke is a leading cause of death and disability worldwide. Stroke prevention, early diagnosis, and efficient acute treatment are priorities to successfully impact stroke death and disability. Fluid biomarkers may improve stroke differential diagnostic, patient stratification for acute treatment, and post-stroke individualized rehabilitation. In the present work, we characterized the use of stroke animal models in fluid biomarker research through a systematic review of PubMed and Scopus databases, followed by a literature review on the translation to the human stroke care setting and future perspectives in the field. We found increasing numbers of publications but with limited translation to the clinic. Animal studies are very heterogeneous, do not account for several human features present in stroke, and, importantly, only a minority of such studies used human cohorts to validate biomarker findings. Clinical studies have found appealing candidates, both protein and circulating nucleic acids, to contribute to a more personalized stroke care pathway. Still, brain tissue complexity and the fact that different brain pathologies share lesion biomarkers make this task challenging due to biomarker low specificity. Moreover, the study design and lack of validation cohorts may have precluded a formal integration of biomarkers in different steps of stroke diagnosis and treatment. To overcome such issues, recent pivotal studies on biomarker dynamics in individual patients are providing added value to diagnosis and anticipating patients' early prognosis. Presently, the most consistent protein biomarkers for stroke diagnosis and short- and long-term prognosis are associated with tissue damage at neuronal (TAU), axonal (NFL), or astroglial (GFAP and S100ß) levels. Most promising nucleic acids are microRNAs (miR), due to their stability in plasma and ease of access. Still, clinical validation and standardized quantitation place them a step behind compared protein as stroke biomarkers. Ultimately, the definition of clinically relevant biomarker panels and optimization of fast and sensitive biomarker measurements in the blood, together with their combination with clinical and neuroimaging data, will pave the way toward personalized stroke care.

Posterior Circulation Stroke: Coma (More Than Time) is Brain.

BACKGROUND AND PURPOSE: Contrary to anterior circulation, the legitimacy of endovascular treatment in posterior circulation stroke is still being questioned. Finding reliable prognostic factors and determining how patient selection should be done has become top priority. METHODS: Observational and retrospective study from two Portuguese hospitals, including all consecutive patients with posterior circulation occlusions who underwent thrombectomy between January 1st 2015 and December 31st 2019. RESULTS: Out of a total of 126 patients, the median age was 74 (IQR 61-80) and 39.7% were female. A good clinical outcome (mRS ≤2) was associated with a lower incidence of coma (24,2% vs 66,7%, p < 0,001) and of sudden onset coma (3% vs 18%,=0,04), a lower NIHSS at admission (14 vs 19, p < 0,001), a higher pc-ASPECTS at admission (10 vs 9, p < 0,001) and at 24 h (8 vs 6, p < 0,001) and a higher BATMAN score (7 vs 6, p = 0,017). Differences in the times of symptom-onset-to-recanalization (496 vs 536, p = 0,19) and symptom-onset-to-coma (130 vs 195, p = 0,52) were not remarkable. When excluding NIHSS and pc-ASPECTS at 24 h, coma (p = 0,003; OR=0,22; 95% CI: 0,08-0,59) and the pc-ASPECTS at admission (p = 0,037; OR=1,63; 95% CI: 1,03-2,57) become independent predictors of good outcome. CONCLUSIONS: In strokes from the posterior circulation, coma, more than time, appears to be an important prognostic factor. The BATMAN and the pc-ASPECTS scores were also associated with clinical outcome and coma.

Early Recanalization in Patients With Cerebral Venous Thrombosis Treated With Anticoagulation.

Background and Purpose- The hypothesis that venous recanalization prevents progression of venous infarction is not established in patients with cerebral venous thrombosis (CVT). Evidence is also scarce on the association between residual symptoms, particularly headache, and the recanalization grade. We aimed to assess, in patients with CVT treated with standard anticoagulation, (1) the rate of early venous recanalization, (2) whether lack of early recanalization was predictor of parenchymal brain lesion progression, and (3) the prevalence and features of persistent headache according to the recanalization grade achieved. Methods- PRIORITy-CVT (Pathophysiology of Venous Infarction - Prediction of Infarction and Recanalization in CVT) was a multicenter, prospective, cohort study including patients with newly diagnosed CVT. Standardized magnetic resonance imaging was performed at inclusion (≤24 hours of therapeutic anticoagulation), days 8 and 90. Potential imaging predictors of recanalization were predefined and analyzed at each anatomical segment. Primary outcomes were rate of early recanalization and brain lesion progression at day 8. Secondary outcomes were headache (days 8 and 90) and functional outcome (modified Rankin Scale at days 8 and 90). Results- Sixty eight patients with CVT were included, of whom 30 (44%) had parenchymal lesions. At the early follow-up (n=63; 8±2 days), 68% (n=43) of patients had partial recanalization and 6% (n=4) full recanalization. Early recanalization was associated both with early regression (P=0.03) and lower risk of enlargement of nonhemorrhagic lesions (P=0.02). Lesions showing diffusion restriction (n=12) were fully reversible in 66% of cases, particularly in patients showing early venous recanalization. Evidence of new or enlarged hemorrhagic lesions, headache at days 8 and 90, and unfavorable functional outcome at days 8 and 90 were not significantly different in patients achieving recanalization. Conclusions- Venous recanalization started within the first 8 days of therapeutic anticoagulation in most patients with CVT and was associated with early regression of nonhemorrhagic lesions, including venous infarction. There was an association between persistent venous occlusion at day 8 and enlargement of nonhemorrhagic lesions.

Social impairment and stigma in genetic generalized epilepsies.

INTRODUCTION: Patients with epilepsy have poor social outcome. Multifactorial factors are usually involved, but among them, stigma features may have an important role. Genetic generalized epilepsies (GGEs) were previously considered "benign" syndromes. The aim of our study was to assess social impairment and stigma in GGE and to evaluate differences between the following GGE subsyndromes: juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and generalized tonic-clonic seizures alone (GTCSA). Additionally, we compared these outcomes with outcomes from a cohort of patients with epilepsy with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS), a severe and difficult-to-treat syndrome. Results were compared with social data from the general population. METHODS: Adult patients with epilepsy with a previously classified GGE or MTLE-HS were consecutively invited to fill in a sociodemographic and stigma questionnaire in outpatient clinic. Clinical data and psychiatric comorbidities were retrieved from clinical notes. RESULTS: Questionnaires from 333 patients were obtained: 226/67% from patients with GGE (JME: 106/31.8%, GTCSA: 74/22.2%, and JAE: 46/13.8%) and 107/32.1% from patients with MTLE-HS. We found that patients with GGE have a good academic achievement but they have increased difficulties in finding a partner, higher rates of divorce, and a reduced number of children per woman and per man when compared with general population. We also observed that patients with GGE have higher rates of unemployment (22.6%) and lower monthly income than general population. Severe problems in housing were only seen in GGEs. Of these, 3 patients (1.3%) were in homeless condition. Over half (52%) of patients with MTLE-HS and over a quarter (28%) of patients with GGE experienced felt stigma. Psychiatric comorbidity was highly prevalent among GGE (34.1%), especially in patients with refractory epilepsy. Mood and anxiety disorders were the most prevalent conditions. No other significant differences were found between GGE subsyndromes. DISCUSSION: We found an impairment in every social domain assessed (except in level of education) when compared with general population. Most of the social outcome parameters were unexpectedly close or similar to MTLE-HS or even worse as it was the prevalence of homelessness among GGE. Social impairment is underdiagnosed and might be considered in clinical practice even in syndromes for some time considered benign such as GGE.

Refractory myasthenia gravis: Characteristics of a portuguese cohort.

INTRODUCTION: Some myasthenia gravis (MG) patients are refractory to conventional treatments. METHODS: To describe the clinical features of refractory MG (RMG) and explore the association with human leukocyte antigen HLA-DRB1 alleles, a cohort study of 114 consecutive MG patients was performed. Patients were classified as RMG based on predefined criteria. RESULTS: Twenty-two patients were found to have RMG (19.3%). There were no differences between non-RMG and RMG patients with respect to sex, age of onset, abnormal 3-Hz repetitive nerve stimulation, anti-acetylcholine receptor antibody positivity, thymectomy, thymoma or thymic hyperplasia, and polyautoimmunity. HLA-DRB1*03 was more frequent in the non-RMG vs. control population (P = 3 × 10-6 ). The HLA-DRB1*13 allele was less frequent in non-RMG patients compared with controls (P = 0.002), and less frequent in the non-RMG group compared with the RMG group (P = 0.003). DISCUSSION: HLA-DRB1*03 was more common in non-RMG, and the HLA-DRB1*13 allele appeared to have a protective role, as reported previously in other autoimmune disorders. Muscle Nerve 60: 188-191, 2019.

Nationwide Access to Endovascular Treatment for Acute Ischemic Stroke in Portugal.

INTRODUCTION: Since the publication of endovascular treatment trials and European Stroke Guidelines, Portugal has re-organized stroke healthcare. The nine centers performing endovascular treatment are not equally distributed within the country, which may lead to differential access to endovascular treatment. Our main aim was to perform a descriptive analysis of the main treatment metrics regarding endovascular treatment in mainland Portugal and its administrative districts. MATERIAL AND METHODS: A retrospective national multicentric cohort study was conducted, including all ischemic stroke patients treated with endovascular treatment in mainland Portugal over two years (July 2015 to June 2017). All endovascular treatment centers contributed to an anonymized database. Demographic, stroke-related and procedure-related variables were collected. Crude endovascular treatment rates were calculated per 100 000 inhabitants for mainland Portugal, and each district and endovascular treatment standardized ratios (indirect age-sex standardization) were also calculated. Patient time metrics were computed as the median time between stroke onset, first-door, and puncture. RESULTS: A total of 1625 endovascular treatment procedures were registered. The endovascular treatment rate was 8.27/100 000 inhabitants/year. We found regional heterogeneity in endovascular treatment rates (1.58 to 16.53/100 000/year), with higher rates in districts closer to endovascular treatment centers. When analyzed by district, the median time from stroke onset to puncture ranged from 212 to 432 minutes, reflecting regional heterogeneity. DISCUSSION: Overall endovascular treatment rates and procedural times in Portugal are comparable to other international registries. We found geographic heterogeneity, with lower endovascular treatment rates and longer onset-to-puncture time in southern and inner regions. CONCLUSION: The overall national rate of EVT in the first two years after the organization of EVT-capable centers is one of the highest among European countries, however, significant regional disparities were documented. Moreover, stroke-onset-to-first-door times and in-hospital procedural times in the EVT centers were comparable to those reported in the randomized controlled trials performed in high-volume tertiary hospitals.

Introdução: A aprovação do tratamento endovascular para o acidente vascular cerebral isquémico obrigou à reorganização dos cuidados de saúde em Portugal. Os nove centros que realizam tratamento endovascular não estão distribuídos equitativamente pelo território, o que poderá causar acesso diferencial a tratamento. O principal objetivo deste estudo é realizar uma análise descritiva da frequência e métricas temporais do tratamento endovascular em Portugal continental e seus distritos. Material e Métodos: Estudo de coorte nacional multicêntrico, incluindo todos os doentes com acidente vascular cerebral isquémico submetidos a tratamento endovascular em Portugal continental durante um período de dois anos (julho 2015 a junho 2017). Foram colhidos dados demográficos, relacionados com o acidente vascular cerebral e variáveis do procedimento. Taxas de tratamento endovascular brutas e ajustadas (ajuste indireto a idade e sexo) foram calculadas por 100 000 habitantes/ano para Portugal continental e cada distrito. Métricas de procedimento como tempo entre instalação, primeira porta e punção foram também analisadas. Resultados: Foram registados 1625 tratamentos endovasculares, indicando uma taxa bruta nacional de tratamento endovascular de 8,27/100 000 habitantes/ano. As taxas de tratamento endovascular entre distritos variaram entre 1,58 e 16,53/100 000/ano, com taxas mais elevadas nos distritos próximos a hospitais com tratamento endovascular. O tempo entre sintomas e punção femural entre distritos variou entre 212 e 432 minutos. Discussão: A análise nacional a taxas de tratamento endovascular e tempos de atuação é comparável a outros registos internacionais. Verificaram-se heterogeneidades geográficas, com taxas de tratamento endovascular menores e maior tempo para tratamento nos distritos do sul e interior. Conclusão: Portugal continental apresenta uma taxa nacional de tratamento endovascular elevada, apresentando, contudo, assimetrias regionais no acesso. As métricas temporais foram comparáveis com as observadas nos ensaios clínicos piloto.

Female preponderance in genetic generalized epilepsies.

INTRODUCTION: Epilepsy is more prevalent in men but Genetic Generalized Epilepsies (GGE) seem to be more common in women. A predominant maternal inheritance has been previously described in GGE. Our objective was to determine sex and inheritance patterns in a GGE population compared to mesial temporal lobe epilepsy with hippocampal sclerosis (MTLEHS). METHODS: We performed a prospective observational study including adult GGE and MTLEHS patients followed up at a tertiary epilepsy center from January 2016 to December 2019. Patients' familial history was obtained by a detailed questionnaire. Clinical and demographic data was retrieved from clinical notes. RESULTS: A cohort of 641 patients, 403 with GGE and 238 with MTLEHS, was analyzed. GGE was more common in women than MTLEHS (58.8% vs 44.5%, OR=1.63, p = 0.004). Compared to MTLEHS patients, more GGE patients had familial history of epilepsy (45.4% vs 25.2%; p<0.001). The GGE group had a higher percentage of female relatives with epilepsy (55% vs 37%; p = 0.006). The prevalence of maternal inheritance was not different between GGE and MTLEHS groups (62.9% vs 57.7%; p = 0.596). Photosensitivity was more common in females than in males (44.7% vs 34.3%, p = 0.036). CONCLUSION: There is a female preponderance in GGE when compared to MTLEHS, as both GGE patients and their affected relatives are more frequently women. The prevalence of maternal inheritance was not higher in GGE than in MTLEHS.

Matrix Metalloproteinase-9 Levels are Associated with Brain Lesion and Persistent Venous Occlusion in Patients with Cerebral Venous Thrombosis.

BACKGROUND: Elucidating mechanisms of brain damage in cerebral venous thrombosis (CVT) would be instrumental to develop targeted therapies and improve prognosis prediction. Matrix metalloproteinase-9 (MMP-9), a gelatinase that degrades major components of the basal lamina, has been associated to blood-brain barrier disruption. We aimed to assess, in patients with CVT, the temporal change in serum concentrations of MMP-9 and its association with key imaging and clinical outcomes. METHODS: Pathophysiology of Venous Infarction-PRediction of InfarctiOn and RecanalIzaTion in CVT (PRIORITy-CVT) was a multicenter prospective cohort study of patients with newly diagnosed CVT. Serial collection of peripheral blood samples performed on day 1, 3, and 8, and standardized magnetic resonance imaging on day 1, 8, and 90. MMP-9 was quantified using enzyme-linked immunosorbent assay in 59 patients and 22 healthy controls. Primary outcomes were parenchymal brain lesion, early evolution of brain lesion, early recanalization, and functional outcome on day 90. RESULTS: CVT patients with parenchymal brain lesion had higher baseline concentrations of MMP-9 compared with controls (adjusted p = 0.001). The area under receiver operating characteristic curve value for MMP-9 for predicting brain lesion was 0.71 (95% confidence interval [CI]: 0.57-0.85, p = 0.009). Patients with venous recanalization showed early decline of circulating MMP-9 and significantly lower levels on day 8 (p = 0.021). Higher MMP-9 on day 8 was associated with persistent venous occlusion (odds ratio: 1.20 [per 20 ng/mL], 95% CI: 1.02-1.43, p = 0.030). CONCLUSION: We report a novel relationship among MMP-9, parenchymal brain damage, and early venous recanalization, suggesting that circulating MMP-9 is a dynamic marker of brain tissue damage in patients with CVT.

Spontaneous systolic blood pressure drop early after mechanical thrombectomy predicts dramatic neurological recovery in ischaemic stroke patients.

INTRODUCTION: Spontaneous blood pressure drop within the first 24 h has been reported following arterial recanalisation in ischaemic stroke patients. We aimed to assess if spontaneous blood pressure drop within the first hour after mechanical thrombectomy is a marker of early neurological recovery. PATIENTS AND METHODS: Retrospective observational single-centre study including ischaemic stroke patients treated with mechanical thrombectomy. Blood pressure parameters from admission, mechanical thrombectomy start, mechanical thrombectomy end and hourly within 24 h after mechanical thrombectomy were reviewed. Primary outcome was early dramatic neurological recovery (8-point-reduction in NIHSS or NIHSS ≤ 2 at 24 h). Secondary outcome was functional independence at 90 days (mRankin 0-2). RESULTS: We included 458 patients in our analysis. Two-hundred (43.7%) patients achieved dramatic neurological recovery following mechanical thrombectomy. One hour after mechanical thrombectomy end, median systolic blood pressure was significantly different between outcome groups (129 vs. 138 mmHg, p = 0.005) and a higher drop in median systolic blood pressure was seen in the dramatic neurological recovery group (15 vs. 9 mmHg). Optimal cut-off for predicting dramatic neurological recovery was a systolic blood pressure drop of 10.5 mmHg (sensitivity 0.54, specificity 0.55, AUC 0.55). On multivariate analysis, spontaneous systolic blood pressure drop was associated with higher odds of achieving dramatic neurological recovery (OR for 10 mmHg blood pressure drop 1.14, 95% CI 1.01-1.29, p = 0.04). No significative association between any blood pressure parameter drop and functional independence at 90 days was found. DISCUSSION: We hypothesised that spontaneous systolic blood pressure drop is a marker of successful reperfusion and, therefore, a marker of improvement of cerebral autoregulation due to the reduced final ischaemic core. CONCLUSION: Spontaneous systolic blood pressure drop after mechanical thrombectomy is an early predictor of dramatic neurological recovery.

MuSK myasthenia gravis and pregnancy.

Muscle specific kinase (MuSK) myasthenia gravis (MG, MuSK-MG) is a rare subgroup of MG affecting mainly women during childbearing years. We investigated the influence of pregnancy in the course of MuSK-MG and pregnancy outcomes in females with MuSK-MG. A multicentre cohort of 17 women with MuSK-MG was studied retrospectively; 13 of them with ≥1 pregnancy. MuSK-MG onset age was 35,4 years; 23,0% had other autoimmune disorder; 46,2% were treatment refractory. Thirteen women experienced 27 pregnancies, either after MG onset (group I) (n = 4; maternal age at conception = 29.8 years) or before MG onset (group II) (n = 23; maternal age at conception = 26.2 years). In group I pregnancy occurred in average 9.8 years after the MG onset; it occurred in average 17.0 years before MG in group II. In group I, all were on steroids at time of conception, one on azathioprine and another receiving IVIG regularly. There were mild exacerbations that responded to treatment adjustments. There were no relapses in the 12 months following the delivery. There was no pre-eclampsia, birth defects or stillbirths in either group; 3 miscarriages in group II. One case of neonatal MG was recorded. In this small series, pregnancy did not seem to precipitate MuSK-MG or to have a major influence in the MuSK-MG course, and there was no apparent negative impact in pregnancy outcomes in those where pregnancy followed the MG onset. The weight was lower in the newborn of the group I mothers, although none had low birth weight.