Neurocritical Care

Background: There are currently no therapies proven to accelerate recovery of consciousness for patient with acute severe traumatic brain injury (TBI) in the intensive care unit (ICU). Methods: We performed an open-label, Phase 1 safety and dose-finding study of intravenous methylphenidate (IV MPH) in ICU patients with acute disorders of consciousness (DoC) caused by severe TBI. IV MPH was administered in daily doses of 0.5, 1.0, and 2.0 mg/kg. The primary outcome measure was the number of adverse events (AEs) at each dose. IV MPH pharmacokinetics were measured for 24 hours after each dose. The effect of IV MPH on brain networks was measured using EEG and resting-state functional MRI (rs-fMRI). A pharmacodynamic response was defined by change-point analysis of EEG and rs-fMRI time-series data. Behavioral responses were assessed using the Coma Recovery Scale-Revised (CRS-R). Findings: Between August 24, 2020, and April 1, 2024, we screened 488 ICU patients with TBI and enrolled 9 males (age 23-79 years) with acute traumatic DoC: coma (n=3), vegetative state/unresponsive wakefulness syndrome (n=3), and minimally conscious state (n=3). There were no serious AEs at any dose. Mild-moderate AEs observed at 1.0 mg/kg or 2.0 mg/kg included insomnia, emesis, paroxysmal sympathetic hyperactivity, and transaminitis. Maximum plasma MPH concentration ranged from mean (SD) 312.7 (100.6) ng/mL to 1319.5 (433.8) ng/mL and occurred within a median of 7-14 minutes across doses. Pharmacodynamic responses were observed via EEG in 7/8 participants who received 0.5 mg/kg (1/9 did not undergo EEG), 6/9 who received 1.0 mg/kg, and 4/6 who received 2.0 mg/kg. One of two patients who completed rs-fMRI showed a pharmacodynamic response. CRS-R level of arousal increased within 15 min of the IV MPH bolus for 6/9 participants at 0.5 mg/kg, 5/9 at 1.0 mg/kg, and 0/6 at 2.0 mg/kg. Interpretation: For patients with acute severe TBI, IV MPH may be safe at doses of 0.5-2.0 mg/kg. Pharmacodynamic and behavioral responses suggest that IV MPH promotes recovery of arousal, a prerequisite of consciousness, in the ICU.

Background: Aneurysmal subarachnoid haemorrhage (aSAH) is frequently complicated by delayed cerebral ischaemia (DCI), for which current therapies incompletely target the underlying multifactorial pathophysiology. Transauricular vagus nerve stimulation (taVNS) modulates inflammatory, vasoactive and autonomic pathways and may attenuate secondary brain injury after aSAH. Methods: We conducted a prospective, single-centre, single-blind, randomised, sham-controlled pilot trial in adults within 5 days of aneurysm securing for non-traumatic aSAH. Participants were allocated 1:1 to active taVNS (left tragus) or sham (left earlobe) using a portable device delivered for 45 minutes twice daily over 5 days. Primary outcomes were safety (taVNS-related serious adverse events), acceptability, and compliance; secondary outcomes included inflammatory biomarkers, DCI, in-hospital complications, and functional outcomes to 1 month. Results: Thirty patients were randomised (16 taVNS, 14 sham), with numerically more severe aSAH at baseline in the taVNS arm. No taVNS-related serious adverse events occurred; side effects were generally mild and transient, and over 80% of planned sessions were completed. TaVNS produced greater reductions in serum tumour necrosis factor- and trends towards reductions in interleukin-1{beta} and interleukin-10, with numerically fewer DCI events (6.6% vs 35.7%) and neurological impairments (16.7% vs 53.8%), although functional outcomes were not statistically different at 1 month. Conclusions: Early taVNS after aSAH is safe, acceptable, and feasible in the neurocritical care setting and shows biologically plausible signals warranting evaluation in larger multi-centre trials.

Purpose. Prognostic assessments after acute brain injury are largely narrative, and how prognostic language relates to subsequent care has not been measured at scale. We quantified where it is written and its association with a subsequent code-status limitation. Materials and Methods. Multidatabase observational study of adults with acute brain injury or a related neurologic emergency, using MIMIC-IV (2008-2019; discharge summaries and radiology reports) and a timestamped MIMIC-III cohort (notes and code-status orders). The exposure was documented prognostic language; outcomes were its association with a subsequent full-code-to-limitation transition, note-stream location, and completeness of documented command-following relative to structured Glasgow Coma Scale (GCS) motor scores. Results. Among 31,993 admissions (27,054 patients; median age, 69 years; 54.9% male), prognostic language in the timestamped cohort (MIMIC-III) was associated with a subsequent code-status limitation after multivariable adjustment (adjusted hazard ratio, 4.3; 95% CI, 2.9-6.5; unadjusted 14-day cumulative incidence, 40% vs 8.5%), including the comfort-measures component (3.9), a higher-risk subgroup (4.4), and after acute-physiology adjustment (4.1); the association was concentrated in the first 3 days. Non-prognostic severity language showed no comparable association (hazard ratios, 1.1-1.3). Prognostic language localized almost entirely to the narrative (4.9% of discharge summaries vs 0.015% of radiology reports); command-following was undocumented in 55.7% of summaries, and no final-24-hour GCS motor score was charted in 72.8%. Conclusions. Documented prognostic language after acute brain injury was written in the narrative, not structured fields, and was associated with a subsequent code-status limitation after multivariable adjustment. This observational association cannot establish causation but warrants prospective study.

Introduction and objectives Hydrocephalus is a common complication of aneurysmal subarachnoid haemorrhage. This is one of several standard indications for the insertion of an external ventricular drain, but there are no standard guidelines for timing of extraventricular drain discontinuation in this population. Therefore, the study aims were to examine the 1) factors associated with extraventricular drain duration in aneurysmal subarachnoid haemorrhage and 2) association between extraventricular drain duration and clinical and resource-based outcomes. Methods In this single centre retrospective cohort study, data for adult patients treated in the ICU between 2015-2023 with aneurysmal subarachnoid haemorrhage and requiring an extraventricular drain were analysed. Data were extracted from both a prospective patient registry and the electronic medical record. Linear regression modelling was used to identify the factors associated with extraventricular drain duration. Measures used to examine the association between extraventricular drain duration, and the outcomes of interest included hazard ratio, relative risk, and mean differences as appropriate for a specific outcome. Results Of the participants (n=205), 68% (n = 140) were female, mean age was 60.7 (SD 13.3) years and 71% (n = 145) had a modified Fisher score of 4. Mean extraventricular drain duration was 15.3 (SD 8.6) days. The number of days mechanically ventilated and extraventricular drain challenge by clamp trial were associated with an increased duration of extraventricular drain treatment. Increased extraventricular drain duration was associated with an increased incidence of ventriculoperitoneal shunt insertion, and an increase in ICU and hospital length of stay when extraventricular drain duration exceeded 20 days. Conclusion The factors associated with an increased duration of extraventricular drain treatment were a longer duration of mechanical ventilation. The outcomes associated with an increased duration of extraventricular drain treatment were an increased incidence of ventriculoperitoneal shunt insertion, an increased incidence of ventriculitis when extraventricular drain duration exceeded 20 days, and an increase in ICU length of stay. These study findings may inform the conduct of a larger multi-centre study to examine the factors associated with duration of treatment with extraventricular drain, and outcomes associated with extraventricular drain duration.

BACKGROUND Children receiving extracorporeal membrane oxygenation (ECMO) are at high risk for focal cerebral injury (FCI). There is emerging evidence that electroencephalography (EEG) may aid FCI detection. The EEG Correlate of Injury to the Nervous System (COIN) index quantifies and displays focal background asymmetries. We evaluated whether COIN is associated with FCI in pediatric ECMO. METHODS Retrospective, cross-sectional study of patients age 28 days to 21 years, on venoarterial ECMO at a tertiary children's hospital, who received EEG monitoring and neuroimaging during ECMO. COIN was calculated from all available EEG data. COIN of 0 implies a symmetric EEG and negative COIN values are observed with FCI. Median COIN values near FCI recognition time were compared to median COIN values from randomly selected control EEG batches using logistic regression. A receiver operator characteristic curve was used to identify multilevel FCI test ranges. Likelihood ratios were calculated to estimate the posttest FCI probability for each COIN range. RESULTS During the 8-year study period (2015-2023), 33 of 142 ECMO runs met study criteria for COIN analysis. Twelve patients (36%) had FCI. The COIN cutoff of -13.3 had 92% sensitivity and 67% specificity for FCI. The COIN cutoff of -27.7 had 67% sensitivity and 90% specificity. Likelihood ratios were 0.13 for COIN (0 to -13.3), 1.1 for COIN (-13.3 to -27.7), and 7.0 for COIN (< -27.7). Posttest probability was 0.02, 0.13, 0.49 in each respective range. CONCLUSION FCI on ECMO is associated with COIN-measured EEG asymmetry. COIN may support FCI risk-stratification during ECMO.

Background Spontaneous intracerebral hemorrhage (ICH) is the most devastating type of stroke but lacks the established time-critical treatment guidelines available for acute ischemic stroke. This study investigated the impact of Code Stroke activation and warfarin use on anticoagulation reversal times to identify opportunities for quality improvement. Methods We retrospectively assessed patients with anticoagulation-associated ICH admitted to our medical center between January 1, 2020, and December 31, 2025. Patients with warfarin- or direct oral anticoagulant (DOAC)-associated ICH were identified from our ICH clinical trial screening log, Vizient, and AHA's Get With The Guidelines-Stroke registry. Code Stroke activation, warfarin or DOAC use, anticoagulation reversal times, causes of delay, and clinical outcomes at hospital discharge were analyzed. Results Of 892 ICH admissions, 50 patients had confirmed anticoagulation-associated ICH. Among those who underwent reversed at our center (n=34), Code Stroke activation (n=24) significantly reduced door-to-CT time (16.5 [12.8-22.0] vs 172.5 [49.0-261.5] minutes, p <0.001), reversal agent order-to-needle time (37.5 [24.7-56.9] vs 57.0 [39.0-85.0] minutes, p <0.001), and door-to-treatment (DTT) time (64 [48-98] vs 277 [159-305] minutes, p <0.001) compared to non-activation (n=10). Conversely, warfarin use was associated with higher international normalized ratios (INR) (2.7 [2.2-3.6] vs 1.3 [1.2-1.9], p =0.003) and significantly longer DTT time (95 [51-108] vs 64 [48-77] minutes, p =0.007). Primary DTT delays stemmed from the absence of a time-critical treatment protocol, weight-based dosing for 4F-PCC, waiting for INR results, and a lack of Code Stroke activation for patients with mild symptoms, trauma or unexplained unresponsiveness. Conclusions Our findings suggest that Code Stroke activation for all suspected cases of ICH, a time-critical emergency department algorithm targeting a DTT time of less than 60 minutes, and immediate anticoagulation reversal with fixed-dose 4F-PCC without waiting for INR results may optimize the acute management of anticoagulation-associated ICH.

Background: Spontaneous intracerebral hemorrhage (ICH) has high disability and mortality. Accurate early prognostication remains challenging in routine practice. Conventional CT assessment relies mainly on hematoma volume and rough anatomical location, limiting individualized prognosis. Radiomics combined with machine learning may improve prognostic assessment by extracting quantitative texture and heterogeneity features.Methods: In this retrospective multicenter study, we included 2,680 consecutive patients with spontaneous ICH: training (n=1,876), internal validation (n=804), and independent external validation (n=196). Deep learning automatically segmented hematomas, and 1,690 radiomics features were extracted from admission non-contrast CT (NCCT). After reproducibility assessment, univariate screening, and LASSO selection, 42 features were integrated into a Rad-score. The Rad-score was combined with demographic, clinical, and conventional CT variables to construct two complementary machine learning models for functional outcome prediction and comprehensive prognostic stratification. Performance was assessed using R2, mean squared error (MSE), area under the receiver operating characteristic curve (AUC), calibration, decision curve analysis, and external validation. Both models were internally and externally validated. Ambient temperature variation at symptom onset was explored as a potential prognostic modifier. Results: Forty-two reproducible radiomics features constituted the Rad-score. Adding radiomics substantially improved performance over conventional clinical and imaging models. For functional outcome prediction, the integrated model increased R2 from 0.35 to 0.93 and reduced MSE from 387 to 61. For prognostic risk stratification, the clinical-only model achieved an AUC of 0.59, whereas the fully integrated model achieved 0.95 and maintained robust external performance (AUC=0.86). Conclusions: We developed and validated a machine learning-based clinical decision support system integrating conventional CT radiomics and clinical variables for prognostic prediction and risk stratification in ICH. By capturing quantitative imaging information beyond conventional CT markers, this framework improved prognostic discrimination and generalizability. These findings support integrating quantitative imaging biomarkers into clinical decision-making for spontaneous ICH. The association between ambient temperature variation and disease progression warrants prospective investigation. Further prospective validation is warranted.

BACKGROUND. After aneurysmal subarachnoid hemorrhage (aSAH), erythrocyte lysis within cerebrospinal fluid (CSF) releases cell-free hemoglobin, a potential driver of secondary brain injury (SBI). Whether hemolysis precedes SBI and how its temporal associations compare with those of inflammation and neuroglial injury remain unclear. METHODS. In this biomarker profiling study of the prospective multicenter HeMoVal cohort, 259 patients with aSAH requiring external ventricular drainage contributed 2,411 serial CSF samples over days 1-4 after hemorrhage. We quantified 22 analytes using spectrophotometry, immunoassay, and mass spectrometry; 19 were assigned to five prespecified disease pathway composites. Day- and site-adjusted generalized estimating equations estimated associations with same-day SBI and future first SBI (angiographic vasospasm, delayed cerebral ischemia, or delayed ischemic neurological deficit); a day-wise landmark analysis assessed robustness. RESULTS. On the day of sampling, SBI was associated with four pathways, with the largest estimates for inflammation and neuroglial injury. Within the prespecified +72-hour horizon, only hemolysis (OR 1.40 per SD; 95% CI, 1.17-1.68) and the erythrophagocyte response (OR 1.28; 1.07-1.54) had FDR-significant forward associations with first SBI. Hemolysis had the largest forward estimate at every horizon; landmark analysis was concordant (pooled OR 1.86; 95% bootstrap CI, 1.37-2.65). The protective scavenger proteins haptoglobin and hemopexin declined to fitted plateaus of 2.4% and 12.5% of day-1 concentrations, versus ~36% for plasma-protein references. CONCLUSION. In a scavenger-depleted CSF compartment, hemolysis and the erythrophagocyte response were associated with subsequent SBI. These findings identify hemolysis as a candidate upstream process and support testing sustained CSF hemoglobin scavenging to prevent SBI. TRIAL REGISTRATION. ClinicalTrials.gov NCT04998370. FUNDING. CSL Behring; Swiss National Science Foundation; University of Zurich

Background: Unruptured intracranial aneurysms (UIAs) are increasingly identified incidentally, and management balances rupture risk against treatment risk. UIA diagnosis has been linked to psychological distress, but psychotropic medication initiation after UIA discovery has not been compared across the full UIA management spectrum. Methods: We conducted a retrospective cohort study using IBM MarketScan claims (CCAE, MDCD, and MDCR; 2009-2023) among adults with a UIA diagnosis, continuous enrollment for 365 days before and after the index date, and no SAH/rupture on or before the index date. We compared the prevalence of 6 mental-health diagnoses before versus after UIA discovery and used adjusted logistic regression to examine psychotropic medication initiation within 365 days by management strategy (untreated observation as the reference). Results: Among 54,945 patients (untreated, 78.5%; endovascular, 11.3%; clipping, 3.0%; other/uncertain, 7.2%), prevalence of every mental-health diagnosis was higher after UIA discovery, most for depression (+4.6 percentage points) and anxiety (+4.5 points). Medication initiation was most common for benzodiazepines (8.7%). Endovascular treatment was associated with higher adjusted odds of benzodiazepine (aOR, 1.21), SSRI (aOR, 1.20), and sedative-hypnotic (aOR, 1.25) initiation.Surgical clipping demonstrated the broadest association, with higher odds across 5 of 6 classes, including benzodiazepines (aOR, 1.71) and sedative-hypnotics (aOR, 1.86). Benzodiazepines had the lowest 1-year persistence (10.5%) despite being the most commonly initiated class. Findings were consistent across sensitivity analyses, with the exception of the increase in panic disorder, which was no longer observed after applying a 30-day post-index lag. Conclusions: Mental-health diagnoses and psychotropic medication initiation increased after UIA discovery, and medication initiation was most pronounced among patients treated with surgical clipping. These findings support psychological assessment as part of aneurysm management regardless of strategy.

Introduction Post-cardiac arrest brain injury (PCABI) patterns across patients are heterogeneous, and conventional clinical variables incompletely capture in vivo injury severity. Here, we evaluated whether anatomically resolved diffusion-weighted MRI (DWI) lesion patterns identify biologically distinct PCABI phenotypes. Methods We conducted a retrospective study of patients with PCABI who underwent brain MRI and intraparenchymal PbtO2; monitoring (n = 24). Ischemic lesion burden was quantified using an MNI atlas-based apparent diffusion coefficient pipeline with a voxel intensity threshold of <650 x 10-6 mm2/s and was summarized at whole-brain, hemispheric, tissue-class, and segment levels. Principal component analysis (PCA) and k-means clustering were used to identify MRI-derived injury patterns for downstream physiological analysis. Results Greater whole-brain lesion burden was associated with lower mean PbtO2 (r = -0.49, p = 0.014), with concurrent associations in the left hemisphere (r = -0.50, p = 0.012), right hemisphere (r = -0.48, p = 0.019), grey matter (r = -0.48, p = 0.018), and white matter (r = -0.49, p = 0.016). PCA identified a dominant lesion-pattern axis associated with PbtO2; (r = 0.48, p = 0.0169). K-means clustering in PC1-PC2 space identified three MRI-derived injury patterns with distinct regional signatures and progressively greater whole-brain lesion burden (p < 0.001). Discussion Greater MRI-defined lesion burden was associated with lower PbtO2 post-cardiac arrest. Anatomically resolved DWI/ADC lesion mapping identified three MRI-derived injury patterns that differed in cerebrovascular physiology, lesion patterning and whole-brain injury burden. Integrating quantitative MRI, intraparenchymal neuromonitoring, and blood biomarkers improved the characterization of the heterogeneity observed in PCABI patients.

Background: Serial glial fibrillary acidic protein (GFAP) trajectories have become an important framework for contextualizing evolving secondary-injury pathophysiology after moderate-to-severe traumatic brain injury (msTBI). However, total GFAP pools release and clearance signals that may be less useful for longitudinal bedside decisions than a proteoform-resolved assay. We compared total GFAP with neoGFAP, defined here as calpain-generated GFAP proteoforms intended to index active astroglial proteolysis during the subacute phase. Methods: We analyzed 651 serial serum samples from 95 msTBI patients from a previously described single-site cohort. Total GFAP and neoGFAP were measured on the same MSD platform from 6 to 240 hours after injury. Early (6 to 72 h) and late (96 to 240 h) windows, data-derived tertiles, and serial trajectory summaries were calculated directly from serial samples. Models were benchmarked against age plus admission post-resuscitation Glasgow Coma Scale (GCS) and the admission IMPACT extended risk score using five-fold stratified cross-validation. Outcomes were unfavorable outcome (GOSE 1 to 4), less-than-good recovery (GOSE 1 to 6), Disability Rating Scale (DRS) [&ge;]15, mortality, and neuroimaging worsening at 6 months. Results: The cohort contributed 95 serial biomarker profiles, with 90 participants evaluable for 6-month GOSE and 89 for DRS. Unfavorable outcome occurred in 57/90 (63.3%), and less-than-good recovery in 79/90 (87.8%). For unfavorable outcome, IMPACT plus early neoGFAP reached AUROC 0.85 versus 0.84 for IMPACT plus early total GFAP and 0.81 for IMPACT alone. For less-than-good recovery, IMPACT plus late neoGFAP achieved AUROC 0.90 versus 0.84 for late total GFAP and 0.82 for IMPACT alone. Secondary analyses for DRS, mortality, and neuroimaging worsening showed smaller differences. Conclusions: In this retrospective analysis, neoGFAP provided clearer incremental value than total GFAP for recovery-oriented monitoring, especially when late-window reassessment of patients who remained at risk for less-than-good recovery was required. Results support prospective testing of neoGFAP as a pathophysiology-informed adjunct to serial bedside decision making, repeat-assessment thresholds, and recovery stratification.

OBJECTIVE: Sepsis-associated encephalopathy (SAE) and sepsis-associated delirium (SAD) lack confirmatory laboratory tests or biomarkers. We evaluated whether the Th17/interleukin (IL)-17 axis or neuroglial-injury biomarkers reflect acute brain dysfunction beyond systemic inflammation and whether biomarker profiles differ between these phenotypes. DATA SOURCES: EMBASE, MEDLINE/PubMed, and the Cochrane Library from inception to August 1, 2026, supplemented by backward and forward citation searching, following PRISMA 2020. STUDY SELECTION: Observational studies of adults with sepsis classified by SAE or SAD status and reporting circulating biomarker concentrations by neurological group or biomarker-outcome associations. Eighteen studies (2,388 participants; 1,863 with sepsis) were included. DATA EXTRACTION: Two reviewers independently extracted study, phenotype, assay, and outcome data. Risk of bias was assessed with the Newcastle-Ottawa Scale and certainty with GRADE. DATA SYNTHESIS: Random-effects models pooled standardized mean differences (SMDs) separately against non-septic and septic controls and odds ratios (ORs) for biomarker-outcome associations. IL-6 was the only mediator elevated in both comparative frameworks and associated with outcomes (non-septic controls: SMD, 0.54 [0.25-0.82]; septic controls: SMD, 1.05 [0.51-1.59]; OR, 1.85 [1.50-2.29]). S100B, neuron-specific enolase, IL-10, tumor necrosis factor; and interferon-gamma; were elevated versus septic controls, whereas IL-17 was modestly elevated only versus non-septic controls (SMD, 0.37 [0.01-0.73]). The IL-6 septic-control effect was concentrated in SAE (p<0.0001) and remained robust in leave-one-out and risk-of-bias sensitivity analyses. Certainty was low to very low, and all 14 computable prediction intervals included the null. CONCLUSIONS: IL-6 emerges as the leading circulating candidate biomarker of sepsis-associated brain dysfunction, while S100B and NSE capture neuroglial injury beyond sepsis. Current evidence does not establish a discriminating role for the Th17 axis. Future studies require standardized neurological phenotyping and appropriately matched septic controls to establish diagnostic value.

Objectives: Aneurysmal subarachnoid haemorrhage is a life-threatening emergency that commonly presents with a sudden, severe headache. The diagnosis is usually confirmed on CT imaging, however a small subset of patients demonstrate normal imaging, particularly if presentation is delayed - in which case spectrophotometric analysis of cerebrospinal fluid (CSF) is undertaken. Nevertheless, thunderclap headache is a common presentation and the vast majority of investigated patients do not have aneurysmal subarachnoid haemorrhage. This ten-year service evaluation at a tertiary neurosurgery centre aims to estimate the utility of lumbar puncture in the diagnostic work-up of these patients. Methods: All instances of CSF spectrophotometry between 01/01/2011 and 31/12/2020 were evaluated. Clinical records of patients with positive spectrophotometry were analysed. A second method identified all coded diagnoses of non-traumatic subarachnoid haemorrhage over the same time period, with review of clinical records in cases of negative imaging. Results: Of 2158 instances of CSF spectrophotometry performed at the tertiary neurosurgery centre, four aneurysms were identified and treated by coiling or clipping, resulting in a number needed to treat of 540 patients to diagnose one case of aneurysmal subarachnoid haemorrhage. Of 648 patients with a coded diagnosis of non-traumatic subarachnoid haemorrhage (including local patients and transfers from satellite hospitals), 27 patients displayed initial negative imaging, of which 9 were found to have aneurysms and underwent neuro-intervention. Lumbar puncture was instrumental in the diagnosis and led to intervention in three patients identified by this method. Conclusion: CSF analysis resulted in diagnosis and intervention for missed (CT-negative) aneurysmal subarachnoid haemorrhage in approximately 1/540 tested patients. The estimated yield in a real-world setting may be useful for clinicians or provide a basis for discussion when counselling patients on benefit and risk.

Background: Glial fibrillary acidic protein (GFAP) is a promising blood biomarker that can distinguish intracerebral hemorrhage (ICH) from acute ischemic stroke (AIS). We aimed to summarize the existing evidence regarding: 1) the diagnostic accuracy of GFAP to differentiate ICH from AIS, and from undifferentiated suspected stroke, and 2) characterize GFAP's diagnostic accuracy across time strata from stroke onset. As a secondary objective, associations between GFAP and clinical and radiological outcomes were narratively summarized. Methods: Five databases [(MEDLINE/EMBASE/EBM Reviews/CINAHL Complete/Google Scholar] were searched (03/2026) for studies reporting blood GFAP levels in acute stroke. GFAP levels were analyzed according to time from onset to sampling. Risk of bias was assessed using QUADAS-2 for studies reporting diagnostic accuracy data. Forest plots, pooled sensitivities and specificities were calculated. Results: Two reviewers independently screened 6,336 studies; 64 were included for systematic review and 18 for meta-analysis. Risk of bias was low overall among diagnostic studies. For differentiating ICH from AIS, pooled AUC was 0.86 (95% CI: 0.76-0.92), pooled sensitivity 74.4% (95% CI:63.2-84.2%) and pooled specificity 87.2% (95% CI:77.0-94.7%). For ICH versus undifferentiated suspected stroke, pooled AUC was 0.88 (95% CI: 0.79-0.95), pooled sensitivity 75.4% (95% CI: 63.6-83.3%) and pooled specificity 90.5% (95% CI:88.0-96.2%). Diagnostic precision improved in earlier time strata: <6h: AUC 0.91, sensitivity 75.0%, specificity 92.7%; <2h: AUC 0.96, sensitivity 76.7%, specificity 96.4%. GFAP correlated with ICH volume in 11/12 studies, although smaller hematomas (<10 mL) were frequently associated with GFAP values below limits of detection. Few studies (n=3) suggest higher GFAP levels correlate with greater ischemic injury in AIS. Conclusions: As a blood biomarker in acute stroke, GFAP has strong rule-in value (i.e. high specificity) for ICH, which is preserved in earlier time windows. Nevertheless, sensitivity remains limited, restricting its use as a rule-out test, particularly for smaller ICH volumes. Knowledge gaps remain regarding GFAP's potential in assessing ischemic injury extent in AIS.

Endovascular thrombectomy (EVT) improves outcomes in acute ischemic stroke caused by large vessel occlusion. Despite successful recanalization, early neurological deterioration (END) remains frequent and predicts poor outcomes. Disturbances in cerebral autoregulation may contribute to END, yet reliable bedside predictors are limited. Transcranial Doppler (TCD) provides noninvasive bedside assessment of cerebral blood flow velocities and may identify hemodynamic patterns associated with post-EVT deterioration. PRECISE-TCD is a prospective, single-center observational study enrolling 180-300 patients undergoing EVT for anterior circulation large vessel occlusion at a tertiary academic medical center. TCD examinations will be performed as soon as feasible after EVT, daily through 72 hours, and near END events. Hemodynamic parameters including peak systolic velocity (PSV), end-diastolic velocity (EDV), mean flow velocity (MFV), and pulsatility index (PI) will be measured in bilateral MCA, ACA, PCA, carotid siphon, vertebrobasilar, and ophthalmic artery territories. The primary outcome is the association between TCD-derived parameters and END within 72 hours, defined as an increase of [&ge;]4 points in total NIHSS score, an increase of [&ge;]1 point in NIHSS subcategory 1a, radiologic evidence of intracranial hemorrhage within 72 hours, or any neurological change prompting emergent head CT at clinician discretion. Secondary outcomes include NIHSS at 24 hours and discharge, discharge disposition, and modified Rankin Scale (mRS) at 90 {+/-} 10 days after hospital discharge. Joint models for longitudinal and time-to-event data will determine the association between TCD parameter trajectories and time to END. Unsupervised clustering will identify TCD-based hemodynamic phenotypes using vessel velocities, pulsatility indices, hemispheric asymmetry measures, collateral flow, and temporal trajectory patterns. We hypothesize that abnormal post-EVT hemodynamic phenotypes will correlate with END and hemorrhagic transformation. Identifying such signatures may support development of TCD-guided, individualized blood pressure strategies to reduce secondary injury after reperfusion and inform future interventional trials. The study is registered at ClinicalTrials.gov (NCT07013396).

Background: Traumatic brain injury (TBI) increases long-term risk for cognitive decline and neurodegeneration, motivating objective blood biomarkers that can be measured repeatedly over time. However, reliance on venipuncture limits longitudinal monitoring, particularly outside clinic settings. Objective: We conducted a pilot feasibility study comparing fingerstick capillary blood collected as dried plasma spots (DPS) with matched venous EDTA plasma for quantification of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL). Methods: Paired samples were collected prospectively across matched time points spanning hours to decades post-injury and assayed using high-sensitivity immunoassays. Results: Absolute protein recovery from DPS was lower and more variable than venous plasma, but paired GFAP and NfL measurements remained well-correlated. We further evaluated the GFAP/NfL ratio as an internal, sample-based normalization strategy and observed improved concordance between capillary DPS and venous plasma compared with either analyte alone. Conclusions: These pilot findings support the analytical feasibility of capillary DPS sampling for GFAP and NfL measurement in TBI and identify the GFAP/NfL ratio as an exploratory internal-normalization approach. Formal analytical and clinical validation, including outcome linkage and prospective evaluation, will be required before capillary DPS can be considered for clinical monitoring applications.

Background: Evidence regarding delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) remains sparse. We aimed to identify its predictors and occurrence and evaluate its role in ischemic stroke and functional outcome under treatment with interventional rescue therapy (IRT). Methods: This retrospective single-center study included 628 adults with aSAH from 2014?2023. The primary endpoint was occurrence of refractory DCI (= refractory despite induced hypertension) treated with at least one IRT. Multivariable models evaluated refractory DCI, new ischemic stroke, and poor functional outcome (mRS 3?6) at 6?12 months. Results: Among 628 included patients, 61 who died within 3 days were excluded from DCI analysis; 166/567 (29%) developed refractory DCI. Younger age (OR = 0.98; P<0.001), female sex (OR = 0.57; P=0.007), and higher WFNS grade (OR = 1.18; P=0.011) were independently associated with refractory DCI. Earlier first IRT was associated with longer DCI duration (IRR = 0.88; P<0.001) and more required IRTs (IRR = 0.91; P<0.001). IRT was performed later than day 14 in 29/166 patients (17.5%); none was older than 70 years. Refractory DCI was associated with new ischemic stroke (OR = 4.68; P<0.001) and poor functional outcome (OR = 2.37; P<0.001); earlier first IRT was associated with poor outcome within the refractory DCI subgroup (OR = 0.86; P=0.03). Outcomes after 1?2 IRTs did not differ from those without refractory DCI (P=0.4), whereas ?3 IRTs were associated with poor outcome (P=0.04). Conclusions: Refractory DCI affected 29% of aSAH patients, predominantly younger women and patients with poorer initial neurological status, and extended beyond day 14 in nearly 20% of affected patients, none of whom was older than 70 years. Refractory DCI and earlier onset were associated with poorer radiological and functional outcomes. The absence of a detected outcome difference after 1?2 IRTs suggests that favorable outcomes may remain achievable despite refractory DCI.

Introduction: Hematoma expansion is a main cause of early worsening after spontaneous intracerebral hemorrhage (ICH). Many hospitals in low income countries have no invasive pressure monitoring and no automated pupillometer. Staff use the Glasgow Coma Scale (GCS) and a penlight to check the pupils, and pupil changes seen with a penlight usually come late. The speed of pupil constriction may change earlier, and smartphones record video fast enough to measure it. Methods and analysis: This will be a single-centre prospective cohort study of 120 adults with ICH on non-contrast computed tomography (NCCT) who arrive within 24 hours of symptom onset. At admission and every 6 hours until 48 hours, we will record a 6 second smartphone video of each eye reacting to a flash, using an eyecup that blocks ward light. Open-source software will measure the pupil diameter in every frame. The main measure is constriction velocity (CV). The primary outcome is hematoma expansion (an increase of more than 6 mL or more than 33%) on NCCT at 24 hours. Secondary outcomes are a fall of 2 or more GCS points within 48 hours and in-hospital death. The primary analysis estimates the area under the receiver operating characteristic curve for the percentage fall in CV from each patient's first recording. Ethics and dissemination: Patients or their legal representatives will give written consent. Results will be submitted to a peer-reviewed journal, and the analysis code will be made public.

Background: Optimal arterial oxygen targets after return of spontaneous circulation (ROSC) in pediatric out-of-hospital cardiac arrest (OHCA) remain uncertain. We examined whether arterial oxygen tension on the first arterial blood gas after ROSC is associated with neurological or survival outcomes. Methods: Using the Japanese Association for Acute Medicine OHCA Registry, we retrospectively studied pediatric patients (<18 years) with OHCA in whom ROSC was confirmed at or after hospital arrival. Patients were categorized by PaO? on the first arterial blood gas after ROSC as normoxemia (60?200 mmHg) or hyperoxemia (>200 mmHg). Missing covariate data were handled using multiple imputation, and associations were estimated using inverse probability-weighted logistic regression. Outcomes were favorable neurological status at 30 days, defined as a Pediatric Cerebral Performance Category score of 1?3, and 30-day survival. Multiple sensitivity analyses were performed, including analyses using an alternative PaO? threshold, restricting the timing of PaO? measurement, and excluding extracorporeal cardiopulmonary resuscitation cases. Results: A total of 189 patients were included (95 normoxemia, 94 hyperoxemia). A favorable neurological outcome occurred in 21 of 95 (22.1%) normoxemia and 13 of 94 (13.8%) hyperoxemia patients, and 30-day survival in 40 of 95 (42.1%) and 42 of 94 (44.7%), respectively. After weighting, covariate balance was achieved with standardized mean differences below 0.1. Hyperoxemia was not significantly associated with favorable neurological outcome (adjusted odds ratio [aOR] 0.94, 95% confidence interval [CI] 0.49?1.77) or 30-day survival (aOR 1.49, 95% CI 0.88?2.54). Sensitivity analyses yielded consistent results. Conclusions: Early hyperoxemia after ROSC was not significantly associated with neurological or survival outcomes in pediatric out-of-hospital cardiac arrest. These findings suggest that a single early PaO? measurement may be insufficient to characterize the clinical impact of oxygen exposure after resuscitation. Future research should focus on phase-specific and individualized oxygen management incorporating serial physiological assessment.

Importance There is an urgent need for objective blood tests to guide triage of suspected traumatic brain injury (TBI) in far-forward combat environments, where blast exposure is common and neuroimaging is frequently unavailable. Blood-based glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) are transforming triage of suspected TBI due to their 99% negative predictive value for ruling out acute intracranial trauma in civilian impact TBI. However, accuracy in military blast-dominant TBI is unclear. Objective To determine accuracy of day-of-injury serum or plasma GFAP and UCH-L1 levels for ruling-out acute intracranial trauma in a sequential real-world cohort of combat casualties. Design Retrospective cohort study leveraging existing data from a clinical laboratory validation protocol that processed and stored leftover day-of-injury clinical samples from evacuated combat casualties between January 1, 2024, and February 6, 2025 for subsequent analysis for GFAP and UCH-L1 using FDA-cleared assay thresholds. Setting Single-center, tertiary referral trauma center. Participants Day-of-injury plasma or serum GFAP and UCH-L1 levels were available for 137 combat casualties. The cohort was 99.3% male with a median age of 21.8 years; 75.2% sustained blast-related injuries. Most (92.7%) had blood collected within 6 hours of injury. Exposure Serum or plasma GFAP and UCH-L1 measured with Abbott Alinity-i or i-STAT TBI assays. Elevation was defined as GFAP [&ge;]35 pg/mL or UCH-L1 [&ge;]400 pg/mL on Alinity-i, and GFAP [&ge;]30 pg/mL or UCH-L1 [&ge;]360 pg/mL on i-STAT. Main Outcomes and Measures Accuracy of biomarker elevation for ruling-out intracranial trauma on head CT, including sensitivity, specificity, and negative predictive value (NPV). Results Among 137 casualties, 83 (60.6%) were biomarker-elevated. Sixteen participants (11.7%) had CT-confirmed intracranial trauma, of whom 15 were biomarker-elevated, yielding 93.8% sensitivity and 98.2% NPV, and 43.8% specificity. Twenty-three participants (16.8%) had intracranial trauma and/or head/face/c-spine fracture; 21 were biomarker-elevated, corresponding to 91.3% sensitivity, 96.3% NPV, and 45.6% specificity. Conclusions and Relevance In this real-world cohort of blast-dominant combat casualties, day-of-injury GFAP and UCH-L1 demonstrated high NPV and sensitivity for intracranial trauma, with modest specificity. These findings support the utility of GFAP and UCH-L1 to aid early triage and decision-making in blast-dominant military TBI.