Atrial Fibrillation Detected before or after Stroke: Role of Anticoagulation.

BACKGROUND: Atrial fibrillation (AF) known before ischemic stroke (KAF) has been postulated to be an independent category with a recurrence risk higher than that of AF detected after stroke (AFDAS). However, it is unknown whether this risk difference is confounded by pre-existing anticoagulation, which is most common in KAF and also indicates a high ischemic stroke recurrence risk. METHODS: Individual patient data analysis from 5 prospective cohorts of anticoagulated patients following AF-associated ischemic stroke. We compared the primary (ischemic stroke recurrence) and secondary outcome (all-cause death) among patients with AFDAS versus KAF and among anticoagulation-naïve versus previously anticoagulated patients using multivariable Cox, Fine-Gray models, and goodness-of-fit statistics to investigate the relative independent prognostic importance of AF-category and pre-existing anticoagulation. RESULTS: Of 4,357 patients, 1,889 (43%) had AFDAS and 2,468 (57%) had KAF, while 3,105 (71%) were anticoagulation-naïve before stroke and 1,252 (29%) were previously anticoagulated. During 6,071 patient-years of follow-up, we observed 244 recurrent strokes and 661 deaths. Only pre-existing anticoagulation (but not KAF) was independently associated with a higher hazard for stroke recurrence in both Cox and Fine-Gray models. Models incorporating pre-existing anticoagulation showed better fit than those with AF category; adding AF-category did not result in better model fit. Neither pre-existing anticoagulation nor KAF were independently associated with death. CONCLUSION: Our findings challenge the notion that KAF and AFDAS are clinically relevant and distinct prognostic entities. Instead of attributing an independently high stroke recurrence risk to KAF, future research should focus on the causes of stroke despite anticoagulation to develop improved preventive treatments. ANN NEUROL 2023;94:43-54.

The course of tumor-related epilepsy in glioblastoma patients: A retrospective analysis.

PURPOSE: Many patients with glioblastoma suffer from tumor-related seizures. However, there is limited data on the characteristics of tumor-related epilepsy achieving seizure freedom. The aim of this study was to characterize the course of epilepsy in patients with glioblastoma and the factors that influence it. METHODS: We retrospectively analyzed the medical records of glioblastoma patients treated at the University Hospital Erlangen between 01/2006 and 01/2020. RESULTS: In the final cohort of patients with glioblastoma (n = 520), 292 patients (56.2 %) suffered from tumor-related epilepsy (persons with epilepsy, PWE). Levetiracetam was the most commonly used first-line antiseizure medication (n = 245, 83.9 % of PWE). The onset of epilepsy was preoperative in 154/292 patients (52.7 %). 136 PWE (46.6 %) experienced only one single seizure while 27/292 PWE (9.2 %) developed drug-resistant epilepsy. Status epilepticus occurred in 48/292 patients (16.4 %). Early postoperative onset (within 30 days of surgery) of epilepsy and total gross resection (compared with debulking) were independently associated with a lower risk of further seizures. We did not detect dose-dependent pro- or antiseizure effects of radiochemotherapy. CONCLUSION: Tumor-related epilepsy occurred in more than 50% of our cohort, but drug-resistant epilepsy developed in less than 10% of cases. Epilepsy usually started before tumor surgery.

Oral Anticoagulants in the Oldest Old with Recent Stroke and Atrial Fibrillation.

OBJECTIVE: To investigate the safety and effectiveness of direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA) after recent stroke in patients with atrial fibrillation (AF) aged ≥85 years. METHODS: Individual patient data analysis from seven prospective stroke cohorts. We compared DOAC versus VKA treatment among patients with AF and recent stroke (<3 months) aged ≥85 versus <85 years. Primary outcome was the composite of recurrent stroke, intracranial hemorrhage (ICH) and all-cause death. We used simple, adjusted, and weighted Cox regression to account for confounders. We calculated the net benefit of DOAC versus VKA by balancing stroke reduction against the weighted ICH risk. RESULTS: In total, 5,984 of 6,267 (95.5%) patients were eligible for analysis. Of those, 1,380 (23%) were aged ≥85 years and 3,688 (62%) received a DOAC. During 6,874 patient-years follow-up, the impact of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome did not differ between patients aged ≥85 (HR≥85y  = 0.65, 95%-CI [0.52, 0.81]) and < 85 years (HR<85y  = 0.79, 95%-CI [0.66, 0.95]) in simple (pinteraction  = 0.129), adjusted (pinteraction  = 0.094) or weighted (pinteraction  = 0.512) models. Analyses on recurrent stroke, ICH and death separately were consistent with the primary analysis, as were sensitivity analyses using age dichotomized at 90 years and as a continuous variable. DOAC had a similar net clinical benefit in patients aged ≥85 (+1.73 to +2.66) and < 85 years (+1.90 to +3.36 events/100 patient-years for ICH-weights 1.5 to 3.1). INTERPRETATION: The favorable profile of DOAC over VKA in patients with AF and recent stroke was maintained in the oldest old. ANN NEUROL 2022;91:78-88.

Attitudes toward persons with epilepsy as friends: Results of a factorial survey.

OBJECTIVE: Discrimination against persons with epilepsy (PWEs) may persist. The aim of this study was to examine whether epilepsy is an obstacle to desired friendship. METHODS: A factorial survey (vignettes), which is less biased by social desirability, was applied to PWEs, their relatives, and lay persons. The vignettes described a person who was varied by the dimensions of age (younger, same age, older), gender (male, female), disease (healthy, mild epilepsy, severe epilepsy [generalized tonic-clonic seizures], diabetes), origin (German, non-German), contact (phone/internet, activities at home, activities outside), frequency of contacts (weekly, monthly), and distance (around the corner, 10 km away). Respondents rated their willingness to befriend the person on a 10-point Likert scale. Multivariate regression determined the contribution of each dimension on the judgment. RESULTS: Participants were 64 PWEs (age = 37.1 ± 14.0 years), 64 relatives of PWEs (age = 45.1 ± 13.6 years), and 98 controls without contact with PWEs (age = 24.4 ± 10.1 years). Controls were less interested in a friendship with a PWE with mild epilepsy (-3.4%) and even more avoided PWEs with severe epilepsy (-11.7%), whereas in PWEs with tonic-clonic seizures, a mild form of epilepsy was actually conducive to friendship (+7.0%). Controls preferred females (+5.0%) and disliked younger people (-12.3%) and contacts via the internet or telephone (-7.3%). PWEs were also less interested in younger people (-5.8%), and relatives of PWEs had a lower preference for friendships with longer distance (-2.3%). SIGNIFICANCE: PWEs still suffer from a risk of social avoidance, and this becomes more evident with generalized motor seizures.

Time-dependent risk factors for epileptic seizures in glioblastoma patients: A retrospective analysis of 520 cases.

OBJECTIVE: Epilepsy is a common comorbidity of glioblastoma. Seizures may occur in various phases of the disease. We aimed to assess potential risk factors for seizures in accordance with the point in time at which they occurred. METHODS: We retrospectively analyzed medical files of adult patients with de novo glioblastoma treated at our institution between January 2006 and January 2020. We categorized seizures as preoperative seizures (POS), early postoperative seizures (EPS; before initiation of radio[chemo]therapy [RCT]), seizures during radiotherapy (SDR; during or <30 days after RCT), and posttherapeutic seizures (PTS; ≥30 days after completion of RCT). We addressed associations between patients' characteristics and their seizures. RESULTS: In the final cohort (N = 520), 292 patients experienced seizures. POS, EPS, SDR, and/or PTS occurred in 29.6% (154/520), 6.0% (31/520), 13.8% (70/509), and 36.1% (152/421) of patients, respectively. POS occurred more frequently in patients with higher Karnofsky Performance Scale scores (odds ratio [OR] = 3.27, p = .001) and tumor location in the temporal lobe (OR = 1.51, p = .034). None of the parameters we analyzed was related to the occurrence of EPS. SDR were independently associated with tumor location (parietal lobe, OR = 1.86, p = .027) and POS, but not EPS, and were independent of RCT. PTS were independently associated with tumor progression (OR = 2.32, p < .001) and with occurrence of SDR (OR = 3.36, p < .001), and negatively correlated with temporal lobe location (OR = .58, p < .014). In patients with tumors exclusively located in the temporal lobe, complete tumor resection was associated with a decreased risk of postoperative seizures. SIGNIFICANCE: Seizures in glioblastoma patients have various, time-dependent risk factors. Temporal lobe localization was a risk factor for preoperative seizures; surgery may have had a protective effect in these patients. RCT did not have dose-dependent pro- or anticonvulsive effects. PTS were associated with tumor progression.

Trends in the neurological emergency room, focusing on persons with seizures.

BACKGROUND AND PURPOSE: Previous studies in neurological emergency rooms (nERs) have reported many non-acute, self-presenting patients, patients with delayed presentation of stroke, and frequent visits of persons with seizures (PWS). The aim of this study was to evaluate trends during the last decade, with special focus on PWS. METHODS: We retrospectively analyzed patients who presented to our specialized nER during the course of 5 months in 2017 and 2019, and included information on admission/referral, hospitalization, discharge diagnosis, and diagnostic tests/treatment in the nER. RESULTS: A total of 2791 patients (46.6% male, mean age 57 ± 21 years) were included. The most common diagnoses were cerebrovascular events (26.3%), headache (14.1%), and seizures (10.5%). Most patients presented with symptoms lasting >48 h (41.3%). The PWS group included the largest proportion of patients presenting within 4.5 h of symptom onset (171/293, 58.4%), whereas only 37.1% of stroke patients presented within this time frame (273/735). Self-presentation was the most common admission pathway (31.1%), followed by emergency service referral (30.4%, including the majority of PWS: 197/293, 67.2%). Despite known diagnosis of epilepsy in 49.2%, PWS more often underwent accessory diagnostic testing including cerebral imaging, compared to the overall cohort (accessory diagnostics 93.9% vs. 85.4%; cerebral imaging 70.1% vs. 64.1%). Electroencephalography in the nER was only performed in 20/111 patients (18.0%) with a first seizure. Nearly half of the patients (46.7%) were discharged home after nER work-up, including most self-presenters (632/869, 72.7%) and headache patients (377/393, 88.3%), as well as 37.2% (109/293) of PWS. CONCLUSION: After 10 years, nER overuse remains a problem. Stroke patients still do not present early enough, whereas PWS, even those with known epilepsy, often seek acute and extensive assessment, indicating gaps in pre-hospital management and possible over-assessment.

Surgical hematoma evacuation of cortical intracerebral hemorrhage ≥10 ml reduces risk of subsequent epilepsy by more than 70%: A retrospective monocenter study.

AIM: The aim of this study was to re-evaluate risk factors for post-ICH epilepsy (PICHE) and examine the impact of surgical hematoma evacuation on epilepsy development after ICH. BACKGROUND AND PURPOSE: Epilepsy is a common complication after intracerebral hemorrhage (ICH). Information on risk factors is still scarce and the role of ICH evacuation remains uncertain. METHODS: We retrospectively included patients with spontaneous ICH treated in our hospital in 2006-2019. Patients' medical records were analyzed. In addition, mailed questionnaires and telephone interviews were used to complete the dataset. Uni- and multivariable hazard ratios (HRs) were applied to investigate risk factors for PICHE and the impact of surgical ICH evacuation. RESULTS: Among 587 ICH patients available for analyses, 139 (23.7%) developed PICHE (mean follow-up 1795 ± 1378 days). The median time of epilepsy onset was 7 months after ICH (range 1-132 months). Risk factors associated with PICHE were cortical hemorrhage (multivariable HR 1.65 [95% CI 1.14-2.37]; p = 0.008), ICH volume > 10 ml (multivariable HR 1.91 [95% CI 1.33-2.73]; p < 0.001) and acute symptomatic seizures (multivariable HR 1.81 [95% CI 1.20-2.75]; p = 0.005). Patients with cortical ICH > 10 ml who underwent surgical hematoma evacuation were less likely to develop epilepsy than those with conservative treatment alone (multivariable HR 0.26 [95% CI 0.08-0.84]; p = 0.025). CONCLUSIONS: Post-ICH epilepsy is frequent and predicted by large cortical ICH and acute symptomatic seizures. Hematoma evacuation reduced the risk of PICHE by more than 70% in patients with large cortical ICH. This finding could be considered in the clinical decision making on the acute treatment of ICH.

Can flat-detector CT after successful endovascular treatment predict long-term outcome in patients with large vessel occlusion? An Alberta Stroke Programme Early CT Score-based study.

PURPOSE: Recent studies postulate a high prognostic value of the Alberta Stroke Programme Early CT Score (ASPECTS) applied on non-contrast whole-brain flat-detector CT (FDCT) after successful endovascular treatment (EVT). The aim of this study was the evaluation of long-term patient outcome after endovascular treatment using postinterventional FDCT. METHODS: Using a local database (Stroke Research Consortium in Northern Bavaria, STAMINA), 517 patients with successful endovascular treatment (modified Thrombolysis in Cerebral Infarction (mTICI) ≥ 2B) due to acute ischaemic stroke (AIS) and large vessel occlusion (LVO) of the anterior circulation were recruited retrospectively. In all cases, non-contrast FDCT after EVT was analysed with special focus at ASPECTS. These results were correlated with the functional outcome in long-term (modified Rankin Scale (mRS) shift from pre-stroke to 90 days after discharge). RESULTS: A significant difference in FDCT-ASPECTS compared to the subgroup of favourable vs. unfavourable outcome (Δ mRS) (median ASPECTS 10 (10-9) vs. median ASPECTS 9 (10-7); p = 0,001) could be demonstrated. Multivariable regression analysis revealed FDCT-ASPECTS (OR 0.234, 95% CI - 0.102-0.008, p = 0.022) along with the NHISS at admission (OR 0.169, 95% CI 0.003-0.018, p = 0.008) as independent factors for a favourable outcome. Cut-off point for a favourable outcome (Δ mRS) was identified at an ASPECTS ≥ 8 (sensitivity 90.6%, specificity 35%). CONCLUSION: For patients with LVO and successful EVT, FDCT-ASPECTS was found to be highly reliable in predicting long-term outcome.

Extended Multimodal Flat Detector CT Imaging in Acute Ischemic Stroke: A Pilot Study.

By using Flat detector computed tomography (FD-CT), a one-stop-shop approach in the diagnostic workup of acute ischemic stroke (AIS) might be achieved. Although information on upstream vessels is warranted, dedicated FD-CT protocols which include the imaging of the cervical vasculature are still lacking. We aimed to prospectively evaluate the implementation of a new multimodal FD-CT protocol including cervical vessel imaging in AIS patients. In total, 16 patients were included in this study. Eight patients with AIS due to large vessel occlusion (LVO) prospectively received a fully multimodal FD-CT imaging, including non-enhanced flat detector computed tomography (NE-FDCT), dynamic perfusion flat detector computed tomography (FD-CTP) and flat detector computed tomography angiography (FD-CTA) including cervical imaging. For comparison of time metrics and image quality, eight AIS patients, which received multimodal CT imaging, were included retrospectively. Although image quality of NE-FDCT and FD-CTA was rated slightly lower than NE-CT and CTA, all FD-CT datasets were of diagnostic quality. Intracerebral hemorrhage exclusion and LVO detection was reliably possible. Median door-to-image time was comparable for the FD-CT group and the control group (CT:30 min, IQR27-58; FD-CT:44.5 min, IQR31-55, p = 0.491). Door-to-groin-puncture time (CT:79.5 min, IQR65-90; FD-CT:59.5 min, IQR51-67; p = 0.016) and image-to-groin-puncture time (CT:44 min, IQR30-50; FD-CT:14 min, IQR12-18; p < 0.001) were significantly shorter, when patients were directly transferred to the angiosuite, where FD-CT took place. Our study indicates that using a new fully multimodal FD-CT approach including imaging of cervical vessels for first-line imaging in AIS patients is feasible and comparable to multimodal CT imaging with substantial potential to streamline the stroke workflow.

Prediction of Recurrent Ischemic Stroke Using Registry Data and Machine Learning Methods: The Erlangen Stroke Registry.

BACKGROUND: There have been multiple efforts toward individual prediction of recurrent strokes based on structured clinical and imaging data using machine learning algorithms. Some of these efforts resulted in relatively accurate prediction models. However, acquiring clinical and imaging data is typically possible at provider sites only and is associated with additional costs. Therefore, we developed recurrent stroke prediction models based solely on data easily obtained from the patient at home. METHODS: Data from 384 patients with ischemic stroke were obtained from the Erlangen Stroke Registry. Patients were followed at 3 and 12 months after first stroke and then annually, for about 2 years on average. Multiple machine learning algorithms were applied to train predictive models for estimating individual risk of recurrent stroke within 1 year. Double nested cross-validation was utilized for conservative performance estimation and models' learning capabilities were assessed by learning curves. Predicted probabilities were calibrated, and relative variable importance was assessed using explainable artificial intelligence techniques. RESULTS: The best model achieved the area under the curve of 0.70 (95% CI, 0.64-0.76) and relatively good probability calibration. The most predictive factors included patient's family and housing circumstances, rehabilitative measures, age, high calorie diet, systolic and diastolic blood pressures, percutaneous endoscopic gastrotomy, number of family doctor's home visits, and patient's mental state. CONCLUSIONS: Developing fairly accurate models for individual risk prediction of recurrent ischemic stroke within 1 year solely based on registry data is feasible. Such models could be applied in a home setting to provide an initial risk assessment and identify high-risk patients early.

Comparison of Two Automated Computed Tomography Perfusion Applications to Predict the Final Infarct Volume After Thrombolysis in Cerebral Infarction 3 Recanalization.

BACKGROUND: Several automated computed tomography perfusion software applications have been developed to provide support in the definition of ischemic core and penumbra in acute ischemic stroke. However, the degree of interchangeability between software packages is not yet clear. Our study aimed to evaluate 2 commonly used automated perfusion software applications (Syngo.via and RAPID) for the indication of ischemic core with respect to the follow-up infarct volume (FIV) after successful recanalization and with consideration of the clinical impact. METHODS: Retrospectively, 154 patients with large vessel occlusion of the middle cerebral artery or the internal carotid artery, who underwent endovascular therapy with a consequent Thrombolysis in Cerebral Infarction 3 result within 2 hours after computed tomography perfusion, were included. Computed tomography perfusion core volumes were assessed with both software applications with different thresholds for relative cerebral blood flow (rCBF). The results were compared with the FIV on computed tomography within 24 to 36 hours after recanalization. Bland-Altman was applied to display the levels of agreement and to evaluate systematic differences. RESULTS: Highest correlation between ischemic core volume and FIV without significant differences was found at a threshold of rCBF<38% for the RAPID software (r=0.89, P<0.001) and rCBF<25% for the Syngo software (r=0.87, P<0.001). Bland-Altman analysis revealed best agreement in these settings. In the vendor default settings (rCBF<30% for RAPID and rCBF<20% for Syngo) correlation between ischemic core volume and FIV was also high (RAPID: r=0.88, Syngo: r=0.86, P<0.001), but mean differences were significant (P<0.001). The risk of critical overestimation of the FIV was higher with rCBF<38% (RAPID) and rCBF<25% (Syngo) than in the default settings. CONCLUSIONS: By adjusting the rCBF thresholds, comparable results with reliable information on the FIV after complete recanalization can be obtained both with the RAPID and Syngo software. Keeping the software specific default settings means being more inclusive in patient selection, but forgo the highest possible accuracy in the estimation of the FIV.

Hematoma Expansion and Clinical Outcomes in Patients With Factor-Xa Inhibitor-Related Atraumatic Intracerebral Hemorrhage Treated Within the ANNEXA-4 Trial Versus Real-World Usual Care.

BACKGROUND AND PURPOSE: It is unestablished whether andexanet alfa, compared with guideline-based usual care including prothrombin complex concentrates, is associated with reduced hematoma expansion (HE) and mortality in patients with factor-Xa inhibitor-related intracerebral hemorrhage (ICH). We compared the occurrence of HE and clinical outcomes in patients treated either with andexanet alfa or with usual care during the acute phase of factor-Xa inhibitor-related ICH. METHODS: Data were extracted from the multicenter, prospective, single-arm ANNEXA-4 trial (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) and a multicenter observational cohort study, RETRACE-II (German-Wide Multicenter Analysis of Oral Anticoagulant-Associated Intracerebral Hemorrhage - Part Two). HE was based on computed tomography scans performed within 36 hours from baseline imaging. Inverse probability of treatment weighting was performed to adjust for baseline comorbidities and ICH severity. Patients presenting with atraumatic ICH while receiving apixaban or rivaroxaban within 18 hours of admission were included. Patients with secondary ICH or not fulfilling the inclusion criteria for the ANNEXA-4 trial were excluded. We compared ANNEXA-4 patients, who received andexanet alfa for hemostatic treatment, with RETRACE-II patients who were treated with usual care, primarily administration of prothrombin complex concentrates. Primary outcome was rate of HE defined as relative increase of ≥35%. Secondary outcomes comprised mean absolute change in hematoma volume, as well as in-hospital mortality and functional outcome. RESULTS: Overall, 182 patients with factor-Xa inhibitor-related ICH (85 receiving andexanet alfa versus 97 receiving usual care) were selected for analysis. There were no relevant differences regarding demographic or clinical characteristics between both groups. HE occurred in 11 of 80 (14%) andexanet alfa patients compared with 21 of 67 (36%) usual care patients (adjusted relative risk, 0.40 [95% CI, 0.20-0.78]; P=0.005), with a reduction in mean overall hematoma volume change of 7 mL. There were no statistically significant differences among in-hospital mortality or functional outcomes. Sensitivity analysis including only usual care patients receiving prothrombin complex concentrates demonstrated consistent results. CONCLUSIONS: As compared with usual care, andexanet alfa was associated with a lower rate of HE in atraumatic factor-Xa inhibitor-related ICH, however, without translating into significantly improved clinical outcomes. A comparative trial is needed to confirm the benefit on limiting HE and to explore clinical outcomes across patient subgroups and by time to treatment. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT02329327 and NCT03093233.

Association of Intraventricular Fibrinolysis With Clinical Outcomes in Intracerebral Hemorrhage: An Individual Participant Data Meta-Analysis.

BACKGROUND: In patients with intracerebral hemorrhage (ICH), the presence of intraventricular hemorrhage constitutes a promising therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes. METHODS: This individual participant data meta-analysis pooled 1501 patients from 2 randomized trials and 7 observational studies enrolled during 2004 to 2015. We compared IVF versus standard of care (including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH with intraventricular hemorrhage. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS; range: 0-6, lower scores indicating less disability) at 6 months, dichotomized into mRS score: 0 to 3 versus mRS: 4 to 6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random effects and doubly robust models to calculate odds ratios and absolute treatment effects (ATE). RESULTS: Comparing treatment of 596 with IVF to 905 with standard of care resulted in an ATE to achieve the primary outcome of 9.3% (95% CI, 4.4-14.1). IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common odds ratio, 1.75 (95% CI, 1.39-2.17), reduced mortality, odds ratio, 0.47 (95% CI, 0.35-0.64), without increased adverse events, absolute difference, 1.0% (95% CI, -2.7 to 4.8). Exploratory analyses provided that early IVF treatment (≤48 hours) after symptom onset was associated with an ATE, 15.2% (95% CI, 8.6-21.8) to achieve the primary outcome. CONCLUSIONS: As compared to standard of care, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage was significantly associated with improved functional outcome at 6 months. The treatment effect was linked to an early time window <48 hours, specifying a target population for future trials.

Multicenter Validation of the max-ICH Score in Intracerebral Hemorrhage.

OBJECTIVE: Outcome prognostication unbiased by early care limitations (ECL) is essential for guiding treatment in patients presenting with intracerebral hemorrhage (ICH). The aim of this study was to determine whether the max-ICH (maximally treated ICH) Score provides improved and clinically useful prognostic estimation of functional long-term outcomes after ICH. METHODS: This multicenter validation study compared the prognostication of the max-ICH Score versus the ICH Score regarding diagnostic accuracy (discrimination and calibration) and clinical utility using decision curve analysis. We performed a joint investigation of individual participant data of consecutive spontaneous ICH patients (n = 4,677) from 2 retrospective German-wide studies (RETRACE I + II; anticoagulation-associated ICH only) conducted at 22 participating centers, one German prospective single-center study (UKER-ICH; nonanticoagulation-associated ICH only), and 1 US-based prospective longitudinal single-center study (MGH; both anticoagulation- and nonanticoagulation-associated ICH), treated between January 2006 and December 2015. RESULTS: Of 4,677 included ICH patients, 1,017 (21.7%) were affected by ECL (German cohort: 15.6% [440 of 2,377]; MGH: 31.0% [577 of 1,283]). Validation of long-term functional outcome prognostication by the max-ICH Score provided good and superior discrimination in patients without ECL compared with the ICH Score (area under the receiver operating curve [AUROC], German cohort: 0.81 [0.78-0.83] vs 0.74 [0.72-0.77], p < 0.01; MGH: 0.85 [0.81-0.89] vs 0.78 [0.74-0.82], p < 0.01), and for the entire cohort (AUROC, German cohort: 0.84 [0.82-0.86] vs 0.80 [0.77-0.82], p < 0.01; MGH: 0.83 [0.81-0.85] vs 0.77 [0.75-0.79], p < 0.01). Both scores showed no evidence of poor calibration. The clinical utility investigated by decision curve analysis showed, at high threshold probabilities (0.8, aiming to avoid false-positive poor outcome attribution), that the max-ICH Score provided a clinical net benefit compared with the ICH Score (14.1 vs 2.1 net predicted poor outcomes per 100 patients). INTERPRETATION: The max-ICH Score provides valid and improved prognostication of functional outcome after ICH. The associated clinical net benefit in minimizing false poor outcome attribution might potentially prevent unwarranted care limitations in patients with ICH. ANN NEUROL 2021;89:474-484.

Amantadine treatment is associated with improved consciousness in patients with non-traumatic brain injury.

OBJECTIVE: This study determined the effect of amantadine treatment on consciousness in patients with non-traumatic brain injury. METHODS: We pooled individual patient data of five single-centre observational studies to determine the effect of amantadine treatment among patients with ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, community-acquired bacterial meningitis and status epilepticus, admitted between January 2012 and December 2015 and ventilated ≥7 days. Patient selection and multivariable regression modelling were used to adjust for differences in intergroup comparison and for parameters associated with consciousness. Improvement of consciousness 5 days after treatment initiation was defined as primary outcome. Secondary outcomes included Glasgow Coma Scale (GCS) at day 5 and GCS at day 10, rate of ICU delirium, epileptic seizures and all-cause mortality at 90 days. RESULTS: Overall, 84 of 294 (28.6%) eligible patients received amantadine. Amantadine treatment was associated with improvement of consciousness at day 5 (amantadine: 86.9% vs control: 54.0%; absolute difference: 32.9 (20.0-44.2); adjusted OR (aOR): 5.71 (2.50-13.05), p<0.001). Secondary outcomes showed differences in GCS 5 days (9 (8-11) vs 6 (3-9), p<0.001) and GCS 10 days (10(8-11) vs 9(6-11),p=0.003) after treatment initiation. There were no significant differences regarding all-cause mortality (aOR: 0.89 (0.44-1.82), p=0.758) and ICU delirium (aOR: 1.39 (0.58-3.31), p=0.462). Rate of epileptic seizures after initiation of amantadine treatment was numerically higher in the amantadine group (amantadine: 10.7% vs control: 3.0%; absolute difference: 7.7 (0.3-16.4); aOR: 3.68 (0.86-15.71), p=0.079). CONCLUSIONS: Amantadine treatment is associated with improved consciousness among patients with different types of non-traumatic brain injury in this observational cohort analysis. Epileptic seizures should be considered as potential side effects and randomised controlled trials are needed to confirm these findings.

Antiseizure medication and perceived "fair" cost allocation: A factorial survey among neurologists, persons with epilepsy, their relatives, and a control group.

OBJECTIVE: Because resources are limited in modern health care systems, the decision on the allocation of expensive drugs can be supported by a public consent. This study examines how various factors influence subjectively perceived "fair" pricing of antiseizure medication (ASM) among four groups including physicians, persons with epilepsy (PWEs), their relatives, and a control group. METHODS: We conducted a factorial survey. Vignettes featured a fictional PWE receiving a fictional ASM. The characteristics of the fictional PWE, ASM, and epilepsy varied. Participants were asked to assess the subjectively appropriate annual cost of ASM treatment per year for each scenario. RESULTS: Fifty-seven PWEs (mean age (SD) 37.7 ± 12.3, 45.6% female), 44 relatives (age 48.4 ± 15.7, 51.1% female), 46 neurologists (age 37.1 ± 9.6, 65.2% female), and 47 persons in the control group (age 31.2 ± 11.2, 68.1% female) completed the questionnaire. The amount of money that respondents were willing to spend for ASM treatment was higher than currently needed in Germany and increased with disease severity among all groups. All groups except for PWEs accepted higher costs of a drug with better seizure control. Physicians and the control group, but not PWEs and their relatives, tended to do so also for minor or no side effects. Physicians reduced the costs for unemployed patients and the control group spent less money for older patients. SIGNIFICANCE: ASM effectiveness appears to justify higher costs. However, the control group attributed less money to older PWEs and physicians allocated fewer drug costs to unemployed PWEs.

Posterior circulation ischemic stroke not involving the brainstem is associated with cardiovascular autonomic dysfunction.

BACKGROUND AND PURPOSE: Ischemic stroke may induce cardiovascular autonomic dysfunction, but most previous studies have included patients with anterior circulation ischemic stroke or brainstem stroke. It remains unclear whether posterior circulation ischemic stroke (PCIS) without brainstem involvement also compromises cardiovascular autonomic modulation (CAM). Therefore, we aimed to assess CAM in PCIS patients with and without brainstem involvement. METHODS: In four subgroups of 61 PCIS patients (14 occipital lobe, 16 thalamic, 12 cerebellar, and 19 brainstem strokes) and 30 healthy controls, we recorded RR intervals (RRIs), systolic (SBP) and diastolic blood pressure (DBP), and respiration at supine rest during the first week after stroke onset. We calculated parameters reflecting total CAM (RRI-standard deviation [RRI-SD], RRI-total powers), predominantly sympathetic CAM (RRI-low-frequency [LF] powers and SBP-LF powers] and parasympathetic CAM (root mean square of successive RRI differences [RMSSD], RRI-high-frequency [HF] powers), sympathetic-parasympathetic balance (RRI-LF/HF ratios), and baroreflex sensitivity (BRS). Values were compared among the four PCIS groups and controls using one-way ANOVA Kruskal-Wallis tests, with post-hoc analyses. Significance was assumed for p < 0.05. RESULTS: In each PCIS subgroup, values for RRI, RRI-SD, RMSSD, RRI-HF powers, and BRS were significantly lower, while SBP-LF powers were higher than in the controls. Only in patients with occipital lobe stroke were RRI-LF/HF ratios significantly higher than in controls. Otherwise, autonomic variables did not differ among the four PCIS subgroups. CONCLUSIONS: During the first week after stroke onset, our PCIS patients with occipital lobe, thalamic, cerebellar, or brainstem strokes all had reduced cardiovagal modulation, compromised baroreflex, and increased peripheral sympathetic modulation. The RRI-LF/HF ratios suggest that sympathetic predominance is slightly more prominent after occipital lobe stroke. PCIS may trigger cardiovascular autonomic dysfunction even without brainstem involvement.

Acute care and secondary prevention of stroke with newly detected versus known atrial fibrillation.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) in stroke patients can be classified as either "known AF" (KAF), defined as AF confirmed before stroke onset, or "AF detected after stroke" (AFDAS), defined as AF diagnosed after stroke onset. While KAF is considered primarily cardiogenic, AFDAS includes patients with stroke-triggered neurogenic arrhythmias. This study aimed to investigate the clinical course of stroke, functional outcomes and the value of oral anticoagulation (OAC) for secondary prevention according to AF subtype. METHODS: Acute ischemic stroke patients were consecutively enrolled and AF was classified as AFDAS or KAF. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and 3-month functional outcomes were measured on the modified Rankin scale. Inverse probability weighting was applied to adjust for baseline confounders in patients with AFDAS and KAF. Multivariate logistic regression models were calculated to investigate the value of OAC for secondary prevention. RESULTS: A total of 822 stroke patients with AF were included, of whom 234 patients (28.5%) had AFDAS. AFDAS patients had a lower prevalence of coronary artery disease, heart failure, and sustained AF, but higher rates of large vessel occlusion compared to KAF patients. NIHSS scores were lower in patients on pre-stroke anticoagulation. OAC for secondary prevention was associated with favorable 3-month functional outcome (odds ratio 7.60, 95% confidence interval 3.42-16.88) independently of AF subtype. The rate of stroke recurrence did not differ significantly. CONCLUSIONS: Clinical characteristics suggest that AFDAS might comprise a distinct pathophysiological and clinical entity among stroke patients with AF. The benefit of anticoagulation for secondary prevention was not affected by AF subtype.

Corticosteroids in patients with vestibular neuritis: An updated meta-analysis.

Vestibular neuritis is a common neuro-otological entity. Therapeutically, corticosteroids are advised, although the evidence is limited. The objective of this review is to update meta-analyses of clinical trials that address the question of whether patients with vestibular neuritis treated with corticosteroids show better recovery than control patients. The electronic databases Medline, Scopus and Cochrane were searched for clinical trials for the years 1970-2020 without language restriction. Data were extracted, and outcome parameters were subjected to conventional and cumulative meta-analysis using a commercially available software program (www.meta-analysis.com). Finally, 15 trials with 363 participants in the treatment and 489 in the control groups were identified and could be included. Eight studies were judged to be at high risk of bias. The odds ratio (OR) for good outcome in the acute phase was 3.1 (95% CI 1.2-7.8; p = .015) in favour of steroid treatment leading to the number needed to treat (NNT) = 6 (95% CI 4-23). The odds ratio (OR) for restoration of vestibular function in the follow-up was 2.4 (95% CI 1.3-4.4; p = .004) for the benefit of steroid treatment resulting in a NNT = 7 (95% CI 5-18). The results of the cumulative statistics did not differ. The risk of adverse effects was higher in patients treated with steroids with an OR of 10.9 (95% CI 1.3-93.8; p = .015) and an estimated number needed to harm (NNH) = 4 (95% CI 3-19). The advantage for corticosteroids remained when differentiating between patients who participated in randomized or non-randomized clinical trials. Steroid treatment in vestibular neuritis resulted in a statistically significant benefit compared to control therapies. However, broad heterogeneity of the studies, mostly low-grade quality of studies, high risk of bias and broad confidence intervals put the findings into perspective allowing only a careful judgement of some benefit of corticosteroids. The findings, however, support the call for an adequately powered and well-designed randomized controlled trial to re-evaluate the effectiveness of corticosteroids.

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.