Endovascular Versus Medical Therapy in Posterior Cerebral Artery Stroke: Role of Baseline NIHSS Score and Occlusion Site.

BACKGROUND: Acute ischemic stroke with isolated posterior cerebral artery occlusion (iPCAO) lacks management evidence from randomized trials. We aimed to evaluate whether the association between endovascular treatment (EVT) and outcomes in iPCAO acute ischemic stroke is modified by initial stroke severity (baseline National Institutes of Health Stroke Scale [NIHSS]) and arterial occlusion site. METHODS: Based on the multicenter, retrospective, case-control study of consecutive iPCAO acute ischemic stroke patients (PLATO study [Posterior Cerebral Artery Occlusion Stroke]), we assessed the heterogeneity of EVT outcomes compared with medical management (MM) for iPCAO, according to baseline NIHSS score (≤6 versus >6) and occlusion site (P1 versus P2), using multivariable regression modeling with interaction terms. The primary outcome was the favorable shift of 3-month modified Rankin Scale (mRS). Secondary outcomes included excellent outcome (mRS score 0-1), functional independence (mRS score 0-2), symptomatic intracranial hemorrhage, and mortality. RESULTS: From 1344 patients assessed for eligibility, 1059 were included (median age, 74 years; 43.7% women; 41.3% had intravenous thrombolysis): 364 receiving EVT and 695 receiving MM. Baseline stroke severity did not modify the association of EVT with 3-month mRS distribution (Pinteraction=0.312) but did with functional independence (Pinteraction=0.010), with a similar trend on excellent outcome (Pinteraction=0.069). EVT was associated with more favorable outcomes than MM in patients with baseline NIHSS score >6 (mRS score 0-1, 30.6% versus 17.7%; adjusted odds ratio [aOR], 2.01 [95% CI, 1.22-3.31]; mRS score 0 to 2, 46.1% versus 31.9%; aOR, 1.64 [95% CI, 1.08-2.51]) but not in those with NIHSS score ≤6 (mRS score 0-1, 43.8% versus 46.3%; aOR, 0.90 [95% CI, 0.49-1.64]; mRS score 0-2, 65.3% versus 74.3%; aOR, 0.55 [95% CI, 0.30-1.0]). EVT was associated with more symptomatic intracranial hemorrhage regardless of baseline NIHSS score (Pinteraction=0.467), while the mortality increase was more pronounced in patients with NIHSS score ≤6 (Pinteraction=0.044; NIHSS score ≤6: aOR, 7.95 [95% CI, 3.11-20.28]; NIHSS score >6: aOR, 1.98 [95% CI, 1.08-3.65]). Arterial occlusion site did not modify the association of EVT with outcomes compared with MM. CONCLUSIONS: Baseline clinical stroke severity, rather than the occlusion site, may be an important modifier of the association between EVT and outcomes in iPCAO. Only severely affected patients with iPCAO (NIHSS score >6) had more favorable disability outcomes with EVT than MM, despite increased mortality and symptomatic intracranial hemorrhage.

Anisocoria After Direct Light Stimulus is Associated with Poor Outcomes Following Acute Brain Injury.

BACKGROUND: Assessing pupil size and reactivity is the standard of care in neurocritically ill patients. Anisocoria observed in critically ill patients often prompts further investigation and treatment. This study explores anisocoria at rest and after light stimulus determined using quantitative pupillometry as a predictor of discharge modified Rankin Scale (mRS) scores. METHODS: This analysis includes data from an international registry and includes patients with paired (left and right eye) quantitative pupillometry readings linked to discharge mRS scores. Anisocoria was defined as the absolute difference in pupil size using three common cut points (> 0.5 mm, > 1 mm, and > 2 mm). Nonparametric models were constructed to explore patient outcome using three predictors: the presence of anisocoria at rest (in ambient light); the presence of anisocoria after light stimulus; and persistent anisocoria (present both at rest and after light). The primary outcome was discharge mRS score associated with the presence of anisocoria at rest versus after light stimulus using the three commonly defined cut points. RESULTS: This analysis included 152,905 paired observations from 6,654 patients with a mean age of 57.0 (standard deviation 17.9) years, and a median hospital stay of 5 (interquartile range 3-12) days. The mean admission Glasgow Coma Scale score was 12.7 (standard deviation 3.5), and the median discharge mRS score was 2 (interquartile range 0-4). The ranges for absolute differences in pupil diameters were 0-5.76 mm at rest and 0-6.84 mm after light. Using an anisocoria cut point of > 0.5 mm, patients with anisocoria after light had worse median mRS scores (2 [interquartile range 0-4]) than patients with anisocoria at rest (1 [interquartile range 0-3]; P < .0001). Patients with persistent anisocoria had worse median mRS scores (3 [interquartile range 1-4]) than those without persistent anisocoria (1 [interquartile range 0-3]; P < .0001). Similar findings were observed using a cut point for anisocoria of > 1 mm and > 2 mm. CONCLUSIONS: Anisocoria after light is a new biomarker that portends worse outcome than anisocoria at rest. After further validation, anisocoria after light should be considered for inclusion as a reported and trended assessment value.

Endovascular Versus Medical Management of Posterior Cerebral Artery Occlusion Stroke: The PLATO Study.

BACKGROUND: The optimal management of patients with isolated posterior cerebral artery occlusion is uncertain. We compared clinical outcomes for endovascular therapy (EVT) versus medical management (MM) in patients with isolated posterior cerebral artery occlusion. METHODS: This multinational case-control study conducted at 27 sites in Europe and North America included consecutive patients with isolated posterior cerebral artery occlusion presenting within 24 hours of time last well from January 2015 to August 2022. Patients treated with EVT or MM were compared with multivariable logistic regression and inverse probability of treatment weighting. The coprimary outcomes were the 90-day modified Rankin Scale ordinal shift and ≥2-point decrease in the National Institutes of Health Stroke Scale. RESULTS: Of 1023 patients, 589 (57.6%) were male with median (interquartile range) age of 74 (64-82) years. The median (interquartile range) National Institutes of Health Stroke Scale was 6 (3-10). The occlusion segments were P1 (41.2%), P2 (49.2%), and P3 (7.1%). Overall, intravenous thrombolysis was administered in 43% and EVT in 37%. There was no difference between the EVT and MM groups in the 90-day modified Rankin Scale shift (aOR, 1.13 [95% CI, 0.85-1.50]; P=0.41). There were higher odds of a decrease in the National Institutes of Health Stroke Scale by ≥2 points with EVT (aOR, 1.84 [95% CI, 1.35-2.52]; P=0.0001). Compared with MM, EVT was associated with a higher likelihood of excellent outcome (aOR, 1.50 [95% CI, 1.07-2.09]; P=0.018), complete vision recovery, and similar rates of functional independence (modified Rankin Scale score, 0-2), despite a higher rate of SICH and mortality (symptomatic intracranial hemorrhage, 6.2% versus 1.7%; P=0.0001; mortality, 10.1% versus 5.0%; P=0.002). CONCLUSIONS: In patients with isolated posterior cerebral artery occlusion, EVT was associated with similar odds of disability by ordinal modified Rankin Scale, higher odds of early National Institutes of Health stroke scale improvement, and complete vision recovery compared with MM. There was a higher likelihood of excellent outcome in the EVT group despite a higher rate of symptomatic intracranial hemorrhage and mortality. Continued enrollment into ongoing distal vessel occlusion randomized trials is warranted.

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.

Peak Edema Extension Distance: An Edema Measure Independent from Hematoma Volume Associated with Functional Outcome in Intracerebral Hemorrhage.

BACKGROUND: Our objective was to test the association between hematoma volume and long-term (> 72 h) edema extension distance (EED) evolution and the association between peak EED and early EED increase with functional outcome at 3 months in patients with intracerebral hemorrhage (ICH). METHODS: This retrospective cohort study included patients with spontaneous supratentorial ICH between January 2006 and January 2014. EED, an edema measure defined as the distance between the hematoma border and the outer edema border, was calculated by using absolute hematoma and edema volumes. We used multivariable logistic regression accounting for age, ICH volume, and location and receiver operating characteristic analysis for assessing measures associated with functional outcome and EED evolution. Functional outcome after 3 months was assessed by using the modified Rankin Scale (0-3 = favorable, 4-6 = unfavorable). To identify properties associated with peak EED multivariable linear and logistic regression analyses were conducted. RESULTS: A total of 292 patients were included. Median age was 70 years (interquartile range [IQR] 62-78), median ICH volume on admission 17.7 mL (IQR 7.9-40.2), median peak perihemorrhagic edema (PHE) volume was 37.5 mL (IQR 19.1-60.6), median peak EED was 0.67 cm (IQR 0.51-0.84) with an early EED increase up to 72 h (EED72-0) of 0.06 cm (- 0.02 to 0.15). Peak EED was found to be independent of ICH volume (R2 = 0.001, p = 0.6). In multivariable analyses, peak EED (odds ratio 0.224, 95% confidence interval [CI] [0.071-0.705]) and peak PHE volume (odds ratio 0.984 [95% CI 0.973-0.994]) were inversely associated with favorable functional outcome at 3 months. Receiver operating characteristic analysis identified a peak PHE volume of 26.8 mL (area under the curve 0.695 [95% CI 0.632-0.759]; p ≤ 0.001) and a peak EED of 0.58 cm (area under the curve 0.608 [95% CI 0.540-0.676]; p = 0.002) as best predictive values for outcome discrimination. CONCLUSIONS: Compared with absolute peak PHE volume, peak EED represents a promising edema measure in patients with ICH that is largely hematoma volume-independent and nevertheless associated with functional outcome.

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.

Thrombocytopenia and Clinical Outcomes in Intracerebral Hemorrhage: A Retrospective Multicenter Cohort Study.

BACKGROUND AND PURPOSE: The impact of platelets on hematoma enlargement (HE) of intracerebral hemorrhage (ICH) is not yet sufficiently elucidated. Especially the role of reduced platelet counts on HE and clinical outcomes is still poorly understood. This study investigated the influence of thrombocytopenia on HE, functional outcome, and mortality in patients with ICH with or without prior antiplatelet therapy (APT). METHODS: Individual participant data of multicenter cohort studies (multicenter RETRACE program [German-Wide Multicenter Analysis of Oral Anticoagulation-Associated Intracerebral Hemorrhage] and single-center UKER-ICH registry [Universitätsklinikum Erlangen Cohort of Patients With Spontaneous ICH]) were grouped into APT and non-APT ICH patients according to the platelet count, that is, with or without thrombocytopenia (cells <150×109/L). Of all patients, 51.5% (1124 of 2183) were on vitamin K antagonist. Imbalances in baseline characteristics including proportions of vitamin K antagonist patients were addressed using propensity score matching. Outcome analyses included HE (>33%), as well as mortality and functional outcome, after 3 months using the modified Rankin Scale, dichotomized into favorable (modified Rankin Scale score, 0-3) and unfavorable (modified Rankin Scale score, 4-6). RESULTS: Of overall 2252 ICH patients, 11.4% (52 of 458) under APT and 14.0% (242 of 1725) without APT presented with thrombocytopenia on admission. The proportion of patients with HE was not significantly different between patients with or without thrombocytopenia among APT and non-APT ICH patients after propensity score matching (HE: APT patients: 9 of 40 [22.5%] thrombocytopenia versus 27 of 115 [23.5%] nonthrombocytopenia, P=0.89; non-APT patients: 54 of 174 [31.0%] thrombocytopenia versus 106 of 356 [29.8%] nonthrombocytopenia, P=0.77). In both (APT and non-APT) propensity score matching cohorts, there were no significant differences regarding functional outcome. Mortality after 3 months did not differ among non-APT patients, whereas the mortality rate was significantly higher for APT patients with thrombocytopenia versus APT patients with normal platelet count (APT: 29 of 46 [63.0%] thrombocytopenia versus 58 of 140 [41.4%] nonthrombocytopenia, P=0.01; non-APT: 95 of 227 [41.9%] thrombocytopenia versus 178 of 455 [39.1%] nonthrombocytopenia, P=0.49). CONCLUSIONS: Our study implies that thrombocytopenia does not affect rates of HE and functional outcome among ICH patients, neither in patients with nor without APT. In light of increased mortality, the significance of platelet transfusions for ICH patients with thrombocytopenia and previous APT should be explored in future studies.

Impact of Statins on Hematoma, Edema, Seizures, Vascular Events, and Functional Recovery After Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: The impact of statins on hematoma characteristics, perihemorrhagic edema (PHE), cardiovascular events, seizures, and functional recovery in patients with intracerebral hemorrhage (ICH) is insufficiently studied. METHODS: Patients with ICH of the prospective UKER-ICH (Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage) study (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03183167) were analyzed by multivariable regression modeling and propensity score matching, and PHE volumes were volumetrically assessed. Outcomes comprised hematoma characteristics, the impact of continuation, discontinuation, and initiation of statins on peak PHE extent, and the influence of statin treatment on the occurrence of seizures, cardiovascular adverse events, and functional recovery after ICH. RESULTS: A total of 1275 patients with ICH with information on statin treatment were analyzed. Statin treatment on hospital admission (21.7%) was associated with higher rates of lobar versus nonlobar ICH (odds ratio, 1.57 [1.03-2.40]; P=0.038). Initiation of statins after ICH was associated with increased peak PHE (ß=0.12, SE=0.06, P=0.008), whereas continuation versus discontinuation of prior statin treatment was not significantly associated with edema formation (P>0.10). There were no significant differences in the incidence of remote symptomatic seizures according to statin exposure during follow-up (statins: 11.5% versus no statins: 7.8%, subdistribution hazard ratio: 1.15 [0.80-1.66]; P=0.512). Patients on statins revealed less cardiovascular adverse events and more frequently functional recovery after 12 months (functional recovery: 57.7% versus 45.0%, odds ratio 1.67 [1.09-2.56]; P=0.019). CONCLUSIONS: Among statin users, lobar ICH occurs more frequently as compared with nonstatin users. While continuation of prior statin treatment appears to be safe regarding PHE formation, the initiation of statins during the first days after ICH may increase PHE extent. However, statins should be initiated thereafter (eg, at hospital discharge) to prevent cardiovascular events and potentially improve functional recovery.

Beyond Functional Impairment: Redefining Favorable Outcome in Patients with Subarachnoid Hemorrhage.

BACKGROUND: For outcome assessment in patients surviving subarachnoid hemorrhage (SAH), the modified Rankin scale (mRS) represents the mostly established outcome tool, whereas other dimensions of outcome such as mood disorders and impairments in social life remain unattended so far. OBJECTIVE: The aim of our study was to correlate 12-month functional and subjective health outcomes in SAH survivors. METHODS: All SAH patients treated over a 5-year period received outcome assessment at 12 months, including functional scores (mRS and Barthel Index [BI]), subjective health measurement (EQ-5D), and whether they returned to work. Analyses - including utility-weighted mRS - were conducted to detect associations and correlations among different outcome measures, especially in patients achieving good functional outcome (i.e., mRS 0-2) at 12 months. RESULTS: Of 351 SAH survivors, 287 (81.2%) achieved favorable functional outcome at 12 months. Contrary to the BI, the EQ-5D visual analog scale (VAS) showed a strong association with different mRS grades, accentuated in patients with favorable functional outcome. Despite favorable functional outcome, patients reported a high rate of impairments in activities (24.0%), pain (33.4%), and anxiety/depression (42.5%). Further, multivariable analysis revealed (i) impairments in activities (odds ratio [OR] [95% confidence interval {CI}]: 0.872 [0.817-0.930]), (ii) presence of depression or anxiety (OR [95% CI]: 0.836 [0.760-0.920]), and (iii) return to work (OR [95% CI]: 1.102 [0.1.013-1.198]) to be independently associated with self-reported subjective health. CONCLUSION: Established stroke scores mainly focusing on functional outcomes do poorly reflect the high rate of subjective impairments reported in SAH survivors, specifically in those achieving good functional outcome. Further studies are needed to investigate whether psychoeducational approaches aiming at improving coping mechanisms and perceived self-efficacy may result in higher subjective health in these patients.

Automated Pupillometry Identifies Absence of Intracranial Pressure Elevation in Intracerebral Hemorrhage Patients.

INTRODUCTION: Although automated pupillometry is increasingly used in critical care settings, predictive value of automatically assessed pupillary parameters during different intracranial pressure (ICP) levels and possible clinical implications are unestablished. METHODS: This retrospective cohort study at the neurocritical care unit of the University of Erlangen-Nuremberg (2016-2018) included 23 nontraumatic supratentorial (intracerebral hemorrhage) ICH patients without signs of abnormal pupillary function by manual assessment, i.e., absent light reflex. We assessed ICP levels by an external ventricular drain simultaneously with parameters of pupillary reactivity [i.e., maximum and minimum apertures, light reflex latency (Lat), constriction and redilation velocities (CV, DV), and percentage change of apertures (per-change)] using a portable pupillometer (NeurOptics®). Computed tomography (CT) scans were analyzed to determine lesion location, size, intraventricular hemorrhage, hydrocephalus, midline shift, and compression or absence of the basal cisterns. We performed receiver operating characteristics analysis to investigate associations of ICP levels with pupillary parameters and to determine best cutoff values for prediction of ICP elevation. After dichotomization of assessments according to ICP values (normal: < 20 mmHg, elevated: ≥ 20 mmHg), prognostic performance of the determined cutoff parameters of pupillary function versus of CT-imaging findings was analyzed by calculating sensitivity, specificity, positive and negative predictive values (logistic regression, corresponding ORs with 95% CIs). RESULTS: In 23 patients (11 women, median age 59.0 (51.0-69.0) years), 1,934 assessments were available for analysis. A total of 74 ICP elevations ≥ 20 mmHg occurred in seven patients. Best discriminative thresholds for ICP elevation were: CV < 0.8 mm/s (AUC 0.740), per-change < 10% (AUC 0.743), DV < 0.2 mm/s (AUC 0.703), and Lat > 0.3 s (AUC 0.616). Positive predictive value of all four parameters to indicate ICP elevation ranged between 7.2 and 8.3% only and was similarly low for CT abnormalities (9.1%). We found high negative predictive values of pupillary parameters [CV: 99.2% (95% CI 98.3-99.6), per-change: 98.7% (95% CI 97.8-99.2), DV: 98.0% (95% CI 97.0-98.7), Lat: 97.0% (95% CI 96.0-97.7)], and CT abnormalities [99.7% (95% CI 99.2-99.9)], providing evidence that both techniques adequately identified ICH patients without ICP elevation. CONCLUSIONS: Our data suggest an association between noninvasively detected changes in pupillary reactivity and ICP levels in sedated ICH patients. Although automated pupillometry and neuroimaging seem not sufficient to noninvasively indicate ICP elevation, both techniques, however, adequately identified ICH patients without ICP elevation. This finding may facilitate routine management by saving invasive ICP monitoring or repeated CT controls in patients with specific automated pupillometry readings.

Blood Pressure and Anticoagulation Reversal Management during Off-Hours in Oral Anticoagulation-Associated Intracerebral Hemorrhage.

BACKGROUND: Prevention of hematoma enlargement in oral anticoagulation-associated intracerebral hemorrhage (OAC-ICH) focuses on blood pressure (BP) reduction and OAC reversal. We investigated whether treatment efficiency and clinical outcomes differ between OAC-ICH patients admitted outside versus during regular working hours. METHODS: Based on pooled data of multicenter cohort studies, we grouped OAC-ICH patients (vitamin K antagonist [VKA], non-vitamin K oral anticoagulant [NOAC]) according to on- vs. off-hour admission. Primary outcome was the functional outcome using the modified Rankin scale (mRS) dichotomized into favorable (mRS 0-3) and unfavorable (mRS 4-6) and mortality at 3 months. Secondary outcome measures included the occurrence of hematoma enlargement, the proportions of patients with systolic BP <140 mm Hg and with anticoagulation treatment achieving international normalized ratio (INR) levels <1.3 at 4 h. Propensity score matching (PSM) was performed to account for imbalances in baseline characteristics. RESULTS: The study population consisted of 76/126 NOAC-ICH patients and 1,005/1,470 VKA patients presenting during off-hours. Functional outcome and mortality rates were not significantly different among PSM patients with VKA-ICH and NOAC-ICH during on- vs. off-hours (mRS 4-6 VKA-ICH: on-hour: 239/357 [66.9%] vs. 253/363 [69.7%] off-hour; p = 0.43; NOAC-ICH: on-hour 26/42 [61.9%] vs. off-hour: 37/57 [64.9%]; p = 0.76; mRS 6 VKA-ICH: on-hour: 127/357 [35.6%] vs. off-hour: 148/363 [40.8%]; p = 0.15; -NOAC-ICH: on-hour 17/42 [40.5%] vs. off-hour: 16/57 [28.1%]; p = 0.20). There were no differences detectable regarding the secondary outcome measures (i.e., hematoma enlargement, the proportion of patients who achieved systolic BP levels <140 mm Hg at 4 h as well as anticoagulation treatment achieving INR levels <1.3 at 4 h) in OAC patients. CONCLUSION: Our study implies that BP reduction and anticoagulation reversal management are well established and associated with similar rates of hematoma enlargement and clinical outcomes in on- vs. off-hour admitted OAC-ICH patients.

Invasiveness and Clinical Outcomes of Off-Hour Admissions in Patients with Intracerebral Hemorrhage.

BACKGROUND: Whether time of hospital admission-during or outside regular working hours-affects functional outcome in intracerebral hemorrhage (ICH) is unestablished as previous analyses have focused on mortality only. We here investigate whether on- versus off-hour hospital admission in ICH is associated with levels of invasiveness and clinical outcomes. METHODS: Based on the UKER registry (NCT03183167) we grouped ICH-patients according to on- versus off-hour hospital admission. Primary outcome measures was functional outcome after 3 months using the modified Rankin scale (mRS) dichotomized into favorable (mRS = 0-3) and unfavorable (mRS = 4-6). Multivariate regression analyses were used to adjust for baseline imbalances, and subgroup analyses were performed to explore associations of on- versus off-hour admission with invasiveness of therapeutic interventions. RESULTS: A total of 438/1269 (34.5%) of ICH-patients were admitted during regular working hours. Mortality rates were not significantly different among patients with on- versus off-hour admission. On-hour patients showed a significantly larger proportion of patients with favorable outcome (on-hour: mRS = 0-3 after 3 months: 176/416 (42.3%) versus off-hour: 265/784 (33.8%); P = .004). Analysis of invasive therapeutic interventions revealed that likelihood of favorable outcome was significantly increased among on-hour admitted patients who did not require neurosurgical interventions (no external ventricular drain n = 349, OR: 1.67[1.13-2.48], P < .05; no hematoma evacuation surgery n = 423, OR: 1.51[1.07-2.14], P < .05). CONCLUSION: This study verified an "off-hour effect" in ICH that relates to functional outcome, rather than mortality, and which may be linked to different levels of invasive therapeutic interventions in patients admitted during off-hour.

Chronic Kidney Disease and Clinical Outcomes in Patients with Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: The influence of chronic kidney disease (CKD) on functional outcome in intracerebral hemorrhage (ICH) is scarcely investigated and reported findings are conflicting mostly because of nonaccounting for imbalances. Aim of the present study was to determine the impact of CKD on functional long-term outcome in ICH-patients. METHODS: In this observational cohort study of spontaneous ICH-patients admitted to our Department of Neurology between 2006 and 2015 we investigated retrospectively as primary outcome the dichotomized functional status (modified-Rankin-Scale = 0-3-versus-4-6) at 12 months according to renal function (CKD versus non-CKD), including categorial estimates of the glomerular filtration rate subanalyses. Confounding was addressed by propensity-score(ps)-matching and adjusted multivariable regression analyses. RESULTS: We identified 1076 eligible ICH-patients, of which 131 (12.2%) suffered from CKD on hospital admission. Confounders associated with CKD consisted of hypertension (P = .023), Diabetes mellitus (P = .001), prior ischemic stroke and/or transitory ischemic attack (TIA) (P = .021), congestive heart failure (P < .01), impaired liver function (P < .01), antiplatelet therapy (P = .01), poorer premorbid functional status (P < .01), and deep ICH-location (P = .006). After balancing for confounding, patients with CKD showed a significantly decreased rate of favorable functional outcome at 12 months (CKD:29 of 111(26.1%)-versus-non-CKD:78 of 206 (37.9%); P = .035). Subanalyses showed that stages of CKD were evenly associated with mortality at 12 months (GFR category G3a, OR:2.811; CI (1.130-6.994); P = .026; GFR category G3b, OR:1.874; CI (.694-5.058); P = .215; GFR category G4, OR:10.316; CI (1.976-53.856); P = .006; GFR category G5, OR:8.989; CI (1.900-42.518); P = .006). CONCLUSIONS: As compared to ICH-patients without CKD, those with CKD show increased rates of mortality and worse functional outcomes even after statistical correction for imbalanced baseline characteritsics. This finding is presumably linked to comorbidity and warrants further investigation in prospective studies.

Characteristics in Non-Vitamin K Antagonist Oral Anticoagulant-Related Intracerebral Hemorrhage.

Background and Purpose- Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non-vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods- Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation-associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake <12h/24h or NOAC level >30 ng/mL). Results- Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1-42.3] mL versus VKA, 16.4 [5.8-40.6] mL; P=0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P=0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4-6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P=0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P=0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P=0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions- If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.

Association of prothrombin complex concentrate administration and hematoma enlargement in non-vitamin K antagonist oral anticoagulant-related intracerebral hemorrhage.

OBJECTIVE: To investigate parameters associated with hematoma enlargement in non-vitamin K antagonist oral anticoagulant (NOAC)-related intracerebral hemorrhage (ICH). METHODS: This retrospective cohort study includes individual patient data for 190 patients with NOAC-associated ICH over a 5-year period (2011-2015) at 19 departments of neurology across Germany. Primary outcome was the association of prothrombin complex concentrate (PCC) administration with hematoma enlargement. Subanalyses were calculated for blood pressure management and its association with the primary outcome. Secondary outcomes include associations with in-hospital mortality and functional outcome at 3 months assessed using the modified Rankin Scale. RESULTS: The study population for analysis of primary and secondary outcomes consisted of 146 NOAC-ICH patients with available follow-up imaging. Hematoma enlargement occurred in 49/146 (33.6%) patients with NOAC-related ICH. Parameters associated with hematoma enlargement were blood pressure ≥ 160mmHg within 4 hours and-in the case of factor Xa inhibitor ICH-anti-Xa levels on admission. PCC administration prior to follow-up imaging was not significantly associated with a reduced rate of hematoma enlargement either in overall NOAC-related ICH or in patients with factor Xa inhibitor intake (NOAC: risk ratio [RR] = 1.150, 95% confidence interval [CI] = 0.632-2.090; factor Xa inhibitor: RR = 1.057, 95% CI = 0.565-1.977), regardless of PCC dosage given or time interval until imaging or treatment. Systolic blood pressure levels < 160mmHg within 4 hours after admission were significantly associated with a reduction in the proportion of patients with hematoma enlargement (RR = 0.598, 95% CI = 0.365-0.978). PCC administration had no effect on mortality and functional outcome either at discharge or at 3 months. INTERPRETATION: In contrast to blood pressure control, PCC administration was not associated with a reduced rate of hematoma enlargement in NOAC-related ICH. Our findings support the need of further investigations exploring new hemostatic reversal strategies for patients with factor Xa inhibitor-related ICH. Ann Neurol 2018;83:186-196.

Heparin for prophylaxis of venous thromboembolism in intracerebral haemorrhage.

OBJECTIVE: To determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH. METHODS: Retrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC. RESULTS: IHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04-1.93) vs non-LDSH: 1.32 (0.33-3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38-4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4-6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume <4.4 mL: 0.18 (0.04-0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS <4: 0.29 (0.11-0.78); p=0.014) were significantly associated with fewer IHC. CONCLUSIONS: Heparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.