Ictal Electroencephalographic Characteristics of Nodding Syndrome: A Comparative Case-Series from South Sudan, Tanzania, and Uganda.

Nodding syndrome (NS) is a poorly understood form of childhood-onset epilepsy that is characterized by the pathognomonic ictal phenomenon of repetitive vertical head drops. To evaluate the underlying ictal neurophysiology, ictal EEG features were evaluated in nine participants with confirmed NS from South Sudan, Tanzania, and Uganda and ictal presence of high frequency gamma oscillations on scalp EEG were assessed. Ictal EEG during the head nodding episode predominantly showed generalized slow waves or sharp-and-slow wave complexes followed by electrodecrement. Augmentation of gamma activity (30-70 Hz) was seen during the head nodding episode in all the participants. We confirm that head nodding episodes in persons with NS from the three geographically distinct regions in sub-Saharan Africa share the common features of slow waves with electrodecrement and superimposed gamma activity. ANN NEUROL 2022;92:75-80.

Consensus Clinical Guidance for Diagnosis and Management of Adult COVID-19 Encephalopathy Patients.

Encephalopathy, a common condition among patients hospitalized with COVID-19, can be a challenge to manage and negatively affect prognosis. While encephalopathy may present clinically as delirium, subsyndromal delirium, or coma and may be a result of systemic causes such as hypoxia, COVID-19 has also been associated with more prolonged encephalopathy due to less common but nevertheless severe complications, such as inflammation of the brain parenchyma (with or without cerebrovascular involvement), demyelination, or seizures, which may be disproportionate to COVID-19 severity and require specific management. Given the large number of patients hospitalized with severe acute respiratory syndrome coronavirus-2 infection, even these relatively unlikely complications are increasingly recognized and are particularly important because they require specific management. Therefore, the aim of this review is to provide pragmatic guidance on the management of COVID-19 encephalopathy through consensus agreement of the Global COVID-19 Neuro Research Coalition. A systematic literature search of MEDLINE, medRxiv, and bioRxiv was conducted between January 1, 2020, and June 21, 2021, with additional review of references cited within the identified bibliographies. A modified Delphi approach was then undertaken to develop recommendations, along with a parallel approach to score the strength of both the recommendations and the supporting evidence. This review presents analysis of contemporaneous evidence for the definition, epidemiology, and pathophysiology of COVID-19 encephalopathy and practical guidance for clinical assessment, investigation, and both acute and long-term management.

Does the presence of a specialist doctor reduce the burden of disease in people with epilepsy in low-resource settings? A comparison of two epilepsy clinics in rural Tanzania.

BACKGROUND: With an estimated lifetime prevalence of epilepsy of 7.6 per 1,000 people, epilepsy represents one of the most common neurological disorders worldwide, with the majority of people with epilepsy (PWE) living in low-income and middle-income countries (LMICs). Adequately treated, up to 70 % of PWE will become seizure-free, however, as many as 85% of PWE worldwide, mostly from LMICs, do not receive adequate treatment. OBJECTIVE: To assess the impact of the presence of a neurologist on the management of PWE in Tanzania. METHODS: Two epilepsy clinics in rural Tanzania, one continuously attended by a neurologist, and one mainly attended by nurses with training in epilepsy and supervised intermittently by specialist doctors (neurologists/psychiatrists) were comparatively analyzed by multivariable linear and logistic regression models with regard to the outcome parameters seizure frequency, the occurrence of side effects of antiepileptic medication and days lost after a seizure. RESULTS: The presence of a neurologist significantly reduced the mean number of seizures patients experienced per month by 4.49 seizures (p < 0.01) while leading to an increase in the occurrence of reported side effects (OR: 2.15, p = 0.02). CONCLUSION: The presence of a neurologist may play a substantial role in reducing the burden of the disease of PWE in LMICs. Hence, specialist training should be encouraged, and relevant context-specific infrastructure established.

The Loss of Temporal Muscle Volume is Associated with Poor Outcome in Patients with Subarachnoid Hemorrhage: An Observational Cohort Study.

BACKGROUND: Intensive care unit (ICU) acquired weakness is a major contributor to poor functional outcome of ICU patients. Quantification of temporal muscle volume assessed on routine computed tomography (CT) scans may serve as a biomarker for muscle wasting in patients suffering from acute brain injury. METHODS: This is a retrospective analysis of prospectively collected data. Temporal muscle volume was assessed on head CT scans of consecutive patients with spontaneous subarachnoid hemorrhage within prespecified time frames (on admission, then weekly ± 2 days). Whenever possible, temporal muscle volume was assessed bilaterally and averaged for the analysis. Poor functional outcome was defined as a 3-month modified Rankin Scale Score ≥ 3. Statistical analysis was performed using generalized estimating equations to handle repeated measurements within individuals. RESULTS: The analysis comprised 110 patients with a median Hunt & Hess score of 4 (interquartile range 3-5). Median age was 61 (50-70) years, 73 patients (66%) were women. Baseline temporal muscle volume was 18.5 ± 0.78 cm3 and significantly decreased over time (p < 0.001) by a mean of 7.9% per week. Higher disease severity (p = 0.002), hydrocephalus (p = 0.020), pneumonia (p = 0.032), and bloodstream infection (p = 0.015) were associated with more pronounced muscle volume loss. Patients with poor functional outcome had smaller muscle volumes 2 and 3 weeks after subarachnoid hemorrhage compared with those with good outcome (p = 0.025). The maximum muscle volume loss during ICU stay was greater in patients with poor functional outcome (- 32.2% ± 2.5% vs. - 22.7% ± 2.5%, p = 0.008). The hazard ratio for poor functional outcome was 1.027 (95% confidence interval 1.003-1.051) per percent of maximum muscle volume loss. CONCLUSIONS: Temporal muscle volume, which is easily assessable on routine head CT scans, progressively decreases during the ICU stay after spontaneous subarachnoid hemorrhage. Because of its association with disease severity and functional outcome, it may serve as a biomarker for muscle wasting and outcome prognostication.

Characteristics of people with epilepsy in three Eastern African countries - a pooled analysis.

BACKGROUND: Epilepsy is one of the most common neurological disorders worldwide. Yet, its treatment gap is large in some areas and especially in sub-Saharan Africa data on clinical, radiological and semiological characteristics, as well as on treatment of persons with epilepsy (PWE) are still scarce. METHODS: We pooled data from four cross-sectional studies on epilepsy in eastern Africa. Two studies from Malawi and Uganda were community-based; two studies in Tanzania (urban Dar es Salaam and rural Haydom) were hospital-based. Clinical characteristics of PWE were assessed by the same questionnaire. Additionally, data on treatment were collected and computed tomography (CT) scans were performed. RESULTS: Overall, 1179 PWE were included in our analysis (581 (49.3%) female, median age 22 years (IQR 15-32 years)). Up to 25% of the patients had focal onset seizures. Those showed a higher rate of remarkable CT scan findings, with especially post-ischaemic and neurocysticercosis-associated lesions, compared to PWE with generalized onset seizures (35.1% vs. 20%). The majority of the patients experienced tonic-clonic seizures (70-85%). Only 67-78% of PWE received anti-seizure medication (ASM) treatment in the community-based studies, mostly monotherapy with phenobarbital, phenytoin or carbamazepine. Yet, underdosage was frequent and a large proportion of PWE received alternative non-ASM treatment consisting of herbal treatment (up to 83%) and/or scarification (up to 20%). CONCLUSIONS: Epilepsy is common in sub-Saharan Africa, often caused by neurocysticercosis or ischaemic strokes. PWE suffer from high seizure rates and subsequent injuries, as well as from socio-economic consequences due to insufficient ASM treatment. This pooled analysis illustrates the need for structural programmes for adequate identification, education, assessment and treatment of PWE in sub-Saharan Africa.

Intracerebral Iron Accumulation may be Associated with Secondary Brain Injury in Patients with Poor Grade Subarachnoid Hemorrhage.

BACKGROUND: The amount of intracranial blood is a strong predictor of poor outcome after subarachnoid hemorrhage (SAH). Here, we aimed to measure iron concentrations in the cerebral white matter, using the cerebral microdialysis (CMD) technique, and to associate iron levels with the local metabolic profile, complications, and functional outcome. METHODS: For the observational cohort study, 36 patients with consecutive poor grade SAH (Hunt & Hess grade of 4 or 5, Glasgow Coma Scale Score ≤ 8) undergoing multimodal neuromonitoring were analyzed for brain metabolic changes, including CMD iron levels quantified by graphite furnace atomic absorption spectrometry. The study time encompassed 14 days after admission. Statistical analysis was performed using generalized estimating equations. RESULTS: Patients were admitted in a poor clinical grade (n = 26, 72%) or deteriorated within 24 h (n = 10, 28%). The median blood volume in the subarachnoid space was high (SAH sum score = 26, interquartile range 20-28). Initial CMD iron was 44 µg/L (25-65 µg/L), which significantly decreased to a level of 25 µg/L (14-30 µg/L) at day 4 and then constantly increased over the remaining neuromonitoring days (p < 0.01). A higher intraventricular hemorrhage sum score (≥ 5) was associated with higher CMD iron levels (Wald-statistic = 4.1, df = 1, p = 0.04) but not with the hemorrhage load in the subarachnoid space (p = 0.8). In patients developing vasospasm, the CMD iron load was higher, compared with patients without vasospasm (Wald-statistic = 4.1, degree of freedom = 1, p = 0.04), which was not true for delayed cerebral infarction (p = 0.4). Higher iron concentrations in the brain extracellular fluid (34 µg/L, 36-56 µg/L vs. 23 µg/L, 15-37 µg/L) were associated with mitochondrial dysfunction (CMD lactate to pyruvate ratio > 30 and CMD-pyruvate > 70 µM/L, p < 0.001). Brain extracellular iron load was not associated with functional outcome after 3 months (p > 0.5). CONCLUSIONS: This study suggests that iron accumulates in the cerebral white matter in patients with poor grade SAH. These findings may support trials aiming to scavenger brain extracellular iron based on the hypothesis that iron-mediated neurotoxicity may contribute to acute and secondary brain injury following SAH.

Febrile seizures in an urban Tanzanian population: lessons learned from a community-based random cluster survey.

OBJECTIVE: To analyse the cumulative incidence of febrile seizures, to evaluate the accuracy of our screening questionnaire and to describe clinical characteristics of children with febrile seizure in an urban population in Tanzania. METHODS: A large random cluster sampled population was screened for a febrile seizure history as part of a larger epilepsy study using a standardised questionnaire in a two-stage door-to-door survey in Tanzania. A subset of screen positive participants was further examined for confirmation of diagnosis and evaluation of clinical characteristics. RESULTS: Overall, 49 697 people were screened for a febrile seizure history of whom 184 (0.4%) screened positive. Women more commonly screened positive than men (112 [0.4%] vs. 72 [0.3%]). There was no marked difference between age groups or education. The positive predictive value of the screening tool was 37% (95% CI 24-51%) but its accuracy varied with the age of interviewed individuals. Cumulative incidence rates were estimated between 1.1% and 2.0% after adjusting for the inaccuracy of the screening tool. Most febrile seizures occurred before the age of two (65%) and most children had more than one episode (80%). A large proportion of children had complex febrile seizure (65%), often caused by malaria or respiratory infections. CONCLUSIONS: The community-based cumulative incidence of a febrile seizure history in an urban Tanzanian population was similar to rates reported from other rural populations after adjusting for the inaccuracy of our screening tool. Based on the integrated nature of the febrile seizure questionnaire, screening positivity rates may have been too low. This has implications for the design of future studies. The majority of cases had complex febrile seizures often associated with malaria. This has implications for clinical case management.

The Importance of PbtO2 Probe Location for Data Interpretation in Patients with Intracerebral Hemorrhage.

BACKGROUND/OBJECTIVE: Monitoring of brain tissue oxygen tension (PbtO2) provides insight into brain pathophysiology after intracerebral hemorrhage (ICH). Integration of probe location is recommended to optimize data interpretation. So far, little is known about the importance of PbtO2 catheter location in ICH patients. METHODS: We prospectively included 40 ICH patients after hematoma evacuation (HE) who required PbtO2-monitoring. PbtO2-probe location was evaluated in all head computed tomography (CT) scans within the first 6 days after HE and defined as location in the healthy brain tissue or perilesional when the catheter tip was located within 1 cm of a focal lesion (hypodense or hyperdense). Generalized estimating equations were used to investigate levels of PbtO2 in relation to different probe locations. RESULTS: Patients were 60 [51-66] years old and had a median ICH-volume of 47 [29-60] mL. Neuromonitoring probes remained for a median of 6 [2-11] days. PbtO2-probes were located in healthy brain tissue in 18/40 (45%) patients and in perilesional brain tissue in 22/40 (55%) patients. In the acute phase after HE (0-72 h), PbtO2 levels were significantly lower (21 ± 12 mmHg vs. 29 ± 10 mmHg, p = 0.010) and brain tissue hypoxia (BTH) was more common in the perilesional area as compared to healthy brain tissue (46% vs. 19%, adjOR 4.0, 95% CI 1.54-10.58, p = 0.005). Episodes of BTH significantly decreased over time in patients with probes in perilesional location (p = 0.001) but remained stable in normal appearing area (p = 0.485). A significant association between BTH and poor functional outcome was only found when probes were located in the perilesional brain tissue (adjOR 6.6, 95% CI 1.3-33.8, p = 0.023). CONCLUSIONS: In the acute phase, BTH was more common in the perilesional area compared to healthy brain tissue. The improvement of BTH in the perilesional area over time may be the result of targeted treatment interventions and tissue regeneration. Due to the localized measurement of invasive neuromonitoring devices, integration of probe location in the clinical management of ICH patients and in research protocols seems mandatory.

Single-Dose Intraventricular Nimodipine Microparticles Versus Oral Nimodipine for Aneurysmal Subarachnoid Hemorrhage.

Background and Purpose- EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine. Methods- Subjects were World Federation of Neurological Surgeons grades 2-4, modified Fisher grades 2-4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6-8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated. Results- The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83-1.22], P=0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P=0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3-4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94-1.58], P=0.13). No safety concerns were identified that halted the study or that preclude further development. Conclusions- There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02790632.

Hemodynamic response during endotracheal suctioning predicts awakening and functional outcome in subarachnoid hemorrhage patients.

BACKGROUND: Endotracheal suctioning (ES) provokes a cumulative hemodynamic response by activation of sympathetic and parasympathetic circuits in the central nervous system. In this proof-of-concept study, we aimed to analyze hemodynamic changes during ES in ventilated subarachnoid hemorrhage (SAH) patients and investigated whether the associated hemodynamic changes relate to the time to arousal and functional outcome. METHODS: For the current observational study, 191 SAH patients admitted to the neurological intensive care unit of a tertiary hospital requiring mechanical ventilation were included. One thousand eighty ES episodes during the first 72 h of admission were analyzed. Baseline median heart rate (HR) and mean arterial pressure (MAP) were compared to peak HR and MAP during ES based on 5-min averaged data (ΔHR and ΔMAP). Multivariable analysis to assess associations between ΔHR and ΔMAP and time to arousal (time to Richmond Agitation Sedation Scale ≥ 0, RASS) and poor functional outcome (modified Rankin Scale Score > 2, mRS) was performed using generalized estimating equations. RESULTS: Patients were 59 (IQR, 50-70) years old and presented with a median admission H&H grade of 4 (IQR, 3-5). In-hospital mortality was 22% (25% at 3 months) and median time to arousal was 13 (IQR, 4-21) days. HR increased by 2.3 ± 7.1 beats per minute (bpm) from 75.1 ± 14.8 bpm at baseline. MAP increased by 3.2 ± 7.8 mmHg from baseline 80.9 ± 9.8 mmHg. In multivariable analysis, ΔHR (p < 0.001) was significantly lower in patients who regained consciousness at a later time point and a lower ΔHR was associated with poor functional 3-month outcome independent of RASS (adjOR = 0.95; 95% CI = 0.93-0.98) or midazolam dose (adjOR = 0.96; 95% CI = 0.94-0.98). ΔMAP was neither associated with the time to regain consciousness (p = 0.087) nor with functional outcome (p = 0.263). CONCLUSION: Augmentation in heart rate may quantify the hemodynamic response during endotracheal suctioning in brain-injured patients. The value as a biomarker to early discriminate the time to arousal and functional outcome in acutely brain-injured patients needs prospective confirmation.

The Importance of Probe Location for the Interpretation of Cerebral Microdialysis Data in Subarachnoid Hemorrhage Patients.

BACKGROUND: There is no uniform definition for cerebral microdialysis (CMD) probe location with respect to focal brain lesions, and the impact of CMD-probe location on measured molecule concentrations is unclear. METHODS: We retrospectively analyzed data of 51 consecutive subarachnoid hemorrhage patients with CMD-monitoring between 2010 and 2016 included in a prospective observational cohort study. Microdialysis probe location was assessed on all brain computed tomography (CT) scans performed during CMD-monitoring and defined as perilesional in the presence of a focal hypodense or hyperdense lesion within a 1-cm radius of the gold tip of the CMD-probe, or otherwise as normal-appearing brain tissue. RESULTS: Probe location was detected in normal-appearing brain tissue on 53/143 (37%) and in perilesional location on 90/143 (63%) CT scans. In the perilesional area, CMD-glucose levels were lower (p = 0.003), whereas CMD-lactate (p = 0.002), CMD-lactate-to-pyruvate-ratio (LPR; p < 0.001), CMD-glutamate (p = 0.002), and CMD-glycerol levels (p < 0.001) were higher. Neuroglucopenia (CMD-glucose < 0.7 mmol/l, p = 0.002), metabolic distress (p = 0.002), and mitochondrial dysfunction (p = 0.005) were more common in perilesional compared to normal-appearing brain tissue. Development of new lesions in the proximity of the CMD-probe (n = 13) was associated with a decrease in CMD-glucose levels, evidence of neuroglucopenia, metabolic distress, as well as increasing CMD-glutamate and CMD-glycerol levels. Neuroglucopenia was associated with poor outcome independent of probe location, whereas elevated CMD-lactate, CMD-LPR, CMD-glutamate, and CMD-glycerol levels were only predictive of poor outcome in normal-appearing brain tissue. CONCLUSIONS: Focal brain lesions significantly impact on concentrations of brain metabolites assessed by CMD. With the exception of CMD-glucose, the prognostic value of CMD-derived parameters seems to be higher when assessed in normal-appearing brain tissue. CMD was sensitive to detect the development of new focal lesions in vicinity to the neuromonitoring probe. Probe location should be described in the research reporting brain metabolic changes measured by CMD and integrated in statistical models.

Risk Factors for Dysphagia and the Impact on Outcome After Spontaneous Subarachnoid Hemorrhage.

BACKGROUND: Despite the tremendous impact of swallowing disorders on outcome following ischemic stroke, little is known about the incidence of dysphagia after subarachnoid hemorrhage (SAH) and its contribution to hospital complications, length of intensive care unit stay, and functional outcome. METHODS: This is a retrospective analysis of an ongoing prospective cohort study. Swallowing ability was assessed in consecutive non-traumatic SAH patients admitted to our neurological intensive care unit using the Bogenhausen Dysphagia Score (BODS). A BODS > 2 points indicated dysphagia. Functional outcome was assessed 3 months after the SAH using the modified Rankin Scale with a score > 2 defined as poor functional outcome. RESULTS: Two-hundred and fifty consecutive SAH patients comprising all clinical severity grades with a median age of 57 years (interquartile range 47-67) were eligible for analysis. Dysphagia was diagnosed in 86 patients (34.4%). Factors independently associated with the development of dysphagia were poor clinical grade on admission (Hunt & Hess grades 4-5), SAH-associated parenchymal hematoma, hydrocephalus, detection of an aneurysm, and prolonged mechanical ventilation (> 48 h). Dysphagia was independently associated with a higher rate of pneumonia (OR = 4.32, 95% CI = 2.35-7.93), blood stream infection (OR = 4.3, 95% CI = 2.0-9.4), longer ICU stay [14 (8-21) days versus 29.5 (23-45) days, p < 0.001], and poor functional outcome after 3 months (OR = 3.10, 95% CI = 1.49-6.39). CONCLUSIONS: Dysphagia is a frequent complication of non-traumatic SAH and associated with poor functional outcome, infectious complications, and prolonged stay in the intensive care unit. Early identification of high-risk patients is needed to timely stratify individual patients for dysphagia treatment.

[Imported infections of the central nervous system : Migration and travel neurology]. / Importierte Infektionen des Zentralnervensystems : Migrations- und Reise-Neurologie.

The numbers of migrants, refugees and asylum seekers reached an unprecedented high in Europe in 2015 and 2016 but in 2019 they are back to the average numbers of the last 30 years. In contrast, frequencies of international and intercontinental travelers have continuously increased over the past decades and will continue to do so in the coming years. In 2018 more than 1.35 billion incoming travelers were reported worldwide by international organizations. Detailed knowledge of the epidemiology, transmission types, risk behavior and clinical presentation of acute and chronic central nervous system (CNS) infections enables timely diagnosis and initiation of potentially life-saving emergency treatment. Acute infections of the CNS, e.g. cerebral Plasmodium falciparum malaria or arboviral encephalitis, are seen most frequently and almost exclusively in travelers returning from tropical countries, whereas chronic CNS infections, e.g. tuberculous meningitis or neurocysticercosis, are typically seen in migrants and refugees. Beside CNS infections genetic diseases, environment-associated, nutrition-related, metabolic or cerebrovascular diseases also need to be considered when discussing differential diagnostic possibilities.

Fluid Intake But Not Fluid Balance Is Associated With Poor Outcome in Nontraumatic Subarachnoid Hemorrhage Patients.

OBJECTIVES: Optimal fluid management is important in patients with acute brain injury, including subarachnoid hemorrhage. We aimed to examine the relationship between daily fluid intake and fluid balance with hospital complications and functional outcome. DESIGN: Retrospective observational cohort study. SETTING: Neurocritical care unit at a tertiary academic medical center. PATIENTS: Two-hundred thirty-seven consecutive nontraumatic subarachnoid hemorrhage patients admitted to the neurologic ICU between 2010 and 2016. INTERVENTIONS: Total daily amount of fluids and fluid balance were calculated over 15 days. Using multivariate generalized estimating equation models the association of daily fluid intake and fluid balance with disease severity, hospital complications and poor functional outcome (3-mo modified Rankin Score ≥ 3) was investigated. Additionally, we described the composition of fluids given. MEASUREMENTS AND MAIN RESULTS: Patients presented with a median admission Hunt and Hess grade of 3 (interquartile range, 1-5) and were 57 years old (interquartile range, 47-67 yr old). A higher daily fluid intake was associated with higher admission Hunt and Hess grade (odds ratio, 1.61; 95% CI, 1.47-1.76; p < 0.001), increased pulmonary fluid accumulation (adjusted odds ratio, 1.11; 95% CI, 1.01-1.21; p = 0.033), prolonged mechanical ventilation (Wald statistic = 20.08; degrees of freedom = 1; p < 0.001), higher daily Subarachnoid hemorrhage Early Brain Edema Score (adjusted odds ratio, 1.11; 95% CI, 1.01-1.22; p = 0.034), occurrence of anemia (adjusted odds ratio, 1.36; 95% CI, 1.20-1.54; p < 0.001), delayed cerebral ischemia (adjusted odds ratio, 1.31; 95% CI, 1.14-1.51; p < 0.001), and poor functional outcome (adjusted odds ratio, 1.25; 95% CI, 1.10-1.41; p < 0.001). Daily fluid balance was associated with higher admission Hunt and Hess grade (odds ratio, 1.09; 95% CI, 1.05-1.13; p < 0.001) and anemia (adjusted odds ratio, 1.17; 95% CI, 1.03-1.33; p = 0.019). The main contributors to fluids were nutritional compounds (31%), IV drugs (30%), and volume substitution (17%). CONCLUSIONS: Our study demonstrates a significant association of fluid intake but not fluid balance with hospital complications and poor functional outcome in subarachnoid hemorrhage patients. A larger prospective study is needed to confirm our results.

A long-term follow-up study on otoacoustic emissions testing in paediatric patients with severe malaria in Gabon.

BACKGROUND: In a previous study, severe and cerebral malaria have been connected with acute cochlear malfunction in children, demonstrated by a decrease of transitory evoked otoacoustic emissions (TEOAEs) reproducibility. This study aims to determine whether cochlear malfunction persists for 4 years after recovery from severe malaria in a subset of the previous study's collective. Follow-up TEOAEs were performed on site (CERMEL, Hôpital Albert Schweitzer, Lambaréné, Gabon) or at the participants' homes; 33 out of 90 participants included in the initial investigation by Schmutzhard et al. could be retrieved and were re-examined, 31/33 could be included. Of the 57 missing participants, 51 could not be contacted, 1 had moved away, 4 refused to cooperate, and 1 had died. METHODS: As in the initial investigation, participants of this prospective follow-up study were subjected to TEOAE examination on both ears separately. A wave correlation rate of > 60% on both ears was considered a "pass"; if one ear failed to pass, the examination was considered a "fail". The results were compared to the primary control group. Additionally, a questionnaire has been applied focusing on subsequent malaria infections between the primary inclusion and follow-up and subjective impairment of hearing and/or understanding. RESULTS: The cohort's mean age was 9 years, 14 children were female, 18 male. 31 had been originally admitted with severe, one with cerebral malaria. 83.8% of participants (n = 26) presented with a TEOAE correlation rate of > 60% on both ears (the cut-off for good cochlear function); in the control group, 92.2% (n = 83) had passed TEOAE examination on both ears. Recurrent severe malaria was associated with a worse TEOAE correlation rate. Age at infection and gender had no influence on the outcome. CONCLUSIONS: Cochlear malfunction seems to be persistent after 4 years in more than 16% of children hospitalized for malaria. In a healthy control group, this proportion was 7.8%. Yet, the severity of the initial TEOAE-decrease did not predict a worse outcome.

Clinical Trial Protocol: Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy, and Safety Study Comparing EG-1962 to Standard of Care Oral Nimodipine in Adults with Aneurysmal Subarachnoid Hemorrhage [NEWTON-2 (Nimodipine Microparticles to Enhance Recovery While Reducing TOxicity After SubarachNoid Hemorrhage)].

BACKGROUND: Nimodipine is the only drug approved in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) in many countries. EG-1962, a product developed using the Precisa™ platform, is an extended-release microparticle formulation of nimodipine that can be administered intraventricularly or intracisternally. It was developed to test the hypothesis that delivering higher concentrations of extended-release nimodipine directly to the cerebrospinal fluid would provide superior efficacy compared to systemic administration. RESULTS: A Phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation study determined the maximum tolerated dose and supported the safety and tolerability of EG-1962 in patients with aSAH. EG-1962, 600 mg, was selected for a pivotal, Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy, and safety study comparing it to standard of care oral nimodipine in adults with aSAH. Key inclusion criteria are patients with a ruptured saccular aneurysm repaired by clipping or coiling, World Federation of Neurological Surgeons grade 2-4, and modified Fisher score of > 1. Patients must have an external ventricular drain as part of standard of care. Patients are randomized to receive intraventricular investigational product (EG-1962 or NaCl solution) and an oral placebo or oral nimodipine in the approved dose regimen (active control) within 48 h of aSAH. The primary objective is to determine the efficacy of EG-1962 compared to oral nimodipine. CONCLUSIONS: The primary endpoint is the proportion of subjects with favorable outcome (6-8) on the Extended Glasgow Outcome Scale assessed 90 days after aSAH. The secondary endpoint is the proportion of subjects with favorable outcome on the Montreal Cognitive Assessment 90 days after aSAH. Data on safety, rescue therapy, delayed cerebral infarction, and health economics will be collected. Trail registration NCT02790632.

Cerebral Autoregulation in the Prediction of Delayed Cerebral Ischemia and Clinical Outcome in Poor-Grade Aneurysmal Subarachnoid Hemorrhage Patients.

OBJECTIVES: Pressure reactivity index and oxygen reactivity index are used to assess cerebral autoregulation after acute brain injury. The value of autoregulation indices in the prediction of delayed cerebral ischemia and outcome in patients with subarachnoid hemorrhage is still inconclusive. In this study, we aimed to focus on the predictive value of the first 72 hours commonly referred to as "early brain injury" in comparison to the overall monitoring period. DESIGN: Retrospective observational cohort study. SETTING: Neurocritical care unit at a tertiary academic medical center. PATIENTS: Forty-three consecutive poor-grade patients with nontraumatic subarachnoid hemorrhage admitted between 2012 and 2016 undergoing continuous high-frequency monitoring. INTERVENTIONS: High-frequency monitoring includes arterial blood pressure, intracranial pressure, and brain tissue oxygen tension. Pressure reactivity index and oxygen reactivity index were evaluated as moving correlation coefficient between mean arterial pressure/intracranial pressure and cerebral perfusion pressure/brain tissue oxygen tension, respectively. MEASUREMENTS AND MAIN RESULTS: Median autoregulation monitoring time was 188 ± 91 hours per patient. Initial pressure reactivity index was 0.31 ± 0.02 and decreased significantly to 0.01 ± 0.01 (p < 0.001) 3 days after admission with a second peak 10 days after admission (0.18 ± 0.14; p = 0.001). Admission oxygen reactivity index was high, 0.25 ± 0.03, and decreased to a minimum of 0.11 ± 0.02 eight days after admission (p = 0.008). Patients with delayed cerebral ischemia had significantly higher overall mean pressure reactivity index values (p < 0.04), which were more pronounced during the first 72 hours, reflecting early brain injury (p < 0.02). High pressure reactivity index during the first 72 hours was associated with poor functional outcome (p < 0.001). No association between oxygen reactivity index and delayed cerebral ischemia or clinical outcome was observed (p = 0.8/0.78). CONCLUSIONS: High initial pressure reactivity index, presumably reflecting early brain injury, but not oxygen reactivity index, was associated with delayed cerebral ischemia and worse clinical outcome in poor-grade subarachnoid hemorrhage patients. Our data indicate that autoregulation indices should be interpreted cautiously when used in these patients and that timing is crucial when autoregulation indices are evaluated as predictor for delayed cerebral ischemia and outcome.

Systemic Inflammatory Response Syndrome as Predictor of Poor Outcome in Nontraumatic Subarachnoid Hemorrhage Patients.

OBJECTIVES: Subarachnoid hemorrhage is a life-threatening disease associated with high mortality and morbidity. A substantial number of patients develop systemic inflammatory response syndrome. We aimed to identify risk factors for systemic inflammatory response syndrome development and to evaluate the role of systemic inflammatory response syndrome on patients' outcome. DESIGN: Retrospective observational cohort study of prospectively collected data. SETTING: Neurocritical care unit at a tertiary academic medical center. PATIENTS: Two-hundred and ninety-seven consecutive nontraumatic subarachnoid hemorrhage patients admitted to the neurologic ICU between 2010 and 2017. INTERVENTIONS: Systemic inflammatory response syndrome was diagnosed based on greater than or equal to two criteria (hypo-/hyperthermia, tachypnea, leukopenia/leukocytosis, tachycardia) and defined as early (≤ 3 d) and delayed (days 6-10) systemic inflammatory response syndrome burden (systemic inflammatory response syndrome positive days within the first 10 d). Using multivariate analysis, risk factors for the development of early and delayed systemic inflammatory response syndrome and the relationship of systemic inflammatory response syndrome with poor 3-month functional outcome (modified Rankin Scale score ≥ 3) were analyzed. MEASUREMENTS AND MAIN RESULTS: Seventy-eight percent of subarachnoid hemorrhage patients had early systemic inflammatory response syndrome, and 69% developed delayed systemic inflammatory response syndrome. Median systemic inflammatory response syndrome burden was 60% (interquartile range, 10-90%). Risk factors for early systemic inflammatory response syndrome were higher admission Hunt and Hess grade (odds ratio, 1.75; 95% CI, 1.09-2.83; p = 0.02), aneurysm clipping (odds ratio, 4.84; 95% CI, 1.02-23.05; p = 0.048), and higher modified Fisher Scale score (odds ratio, 1.88; 95% CI, 1.25-2.89; p = 0.003). Hunt and Hess grade and pneumonia were independently associated with delayed systemic inflammatory response syndrome development. Systemic inflammatory response syndrome burden (area under the curve, 0.84; 95% CI, 0.79-0.88) had a higher predictive value for 3-month poor outcome compared with early systemic inflammatory response syndrome (area under the curve, 0.76; 95% CI, 0.70-0.81; p < 0.001). CONCLUSIONS: Systemic inflammatory response syndrome is common after subarachnoid hemorrhage and independently contributes to poor functional outcome. Systemic inflammatory response syndrome burden more accurately predicts poor outcome than early systemic inflammatory response syndrome.

Autoantibodies against neuronal surface proteins in spontaneous subarachnoid and intracerebral haemorrhage.

BACKGROUND: Brain autoimmunity has been reported in patients with preceding infection of the central nervous system by herpesviridae. It has been hypothesized that neuronal damage releasing antigens might trigger secondary immune response. The objective of the study was to investigate whether brain damage due to spontaneous subarachnoid haemorrhage (SAH) or intracerebral haemorrhage (ICH) induces reactivity against neuronal surface proteins. METHODS: Patients with spontaneous SAH and ICH, who had cerebrospinal fluid (CSF) and serum sampling within 2 weeks after disease onset (baseline) and afterwards at least 10 days later (follow-up), were included. Antibodies against NMDA, GABA-B, AMPA-1/- 2 receptor, LGI1 and CASPR2 were determined by indirect immunofluorescence. RESULTS: A total of 43 SAH and 11 ICH patients aged 62 (±12) years (65% females) had simultaneous CSF/ serum sampling median 5 and 26.5 days after disease onset. At baseline, all CSF samples were collected via ventricular drainage, at follow-up 20 (37.0%) patients had CSF collection by lumbar puncture because ventricular drain had been already removed. All CSF and serum samples at baseline and follow-up tested negative for antibodies against NMDA, GABA-B, AMPA-1/- 2 receptor, LGI1 and CASPR2. CONCLUSIONS: Immunoreactivity against common neuronal surface proteins was not observed within the early disease course of spontaneous SAH and ICH.