Early brain injury and cognitive impairment after aneurysmal subarachnoid haemorrhage.

The first 72 h following aneurysm rupture play a key role in determining clinical and cognitive outcomes after subarachnoid haemorrhage (SAH). Yet, very little is known about the impact of so called "early brain injury" on patents with clinically good grade SAH (as defined as World Federation of Neurosurgeons Grade 1 and 2). 27 patients with good grade SAH underwent MRI scanning were prospectively recruited at three time-points after SAH: within the first 72 h (acute phase), at 5-10 days and at 3 months. Patients underwent additional, comprehensive cognitive assessment 3 months post-SAH. 27 paired healthy controls were also recruited for comparison. In the first 72 h post-SAH, patients had significantly higher global and regional brain volume than controls. This change was accompanied by restricted water diffusion in patients. Persisting abnormalities in the volume of the posterior cerebellum at 3 months post-SAH were present to those patients with worse cognitive outcome. When using this residual abnormal brain area as a region of interest in the acute-phase scans, we could predict with an accuracy of 84% (sensitivity 82%, specificity 86%) which patients would develop cognitive impairment 3 months later, despite initially appearing clinically indistinguishable from those making full recovery. In an exploratory sample of good clinical grade SAH patients compared to healthy controls, we identified a region of the posterior cerebellum for which acute changes on MRI were associated with cognitive impairment. Whilst further investigation will be required to confirm causality, use of this finding as a risk stratification biomarker is promising.

New-onset super refractory status epilepticus: A case-series.

INTRODUCTION: Literature on New-Onset Refractory Status Epilepticus (NORSE) is scarce and management is guided mainly by retrospective reports, short case series or expert opinions. We aimed to add to the pool of the available data by retrospectively reviewing seven cases of NORSE cases admitted to our hospital over the last five years between January 2014 and March 2019. METHODS: Fully anonymised data from medical charts, EEG reports, imaging reports, laboratory test results, types of antiepileptic medications, intravenous anaesthetic therapy, and immune therapies received was collected, along with response to treatment, length of hospital stay and outcome at discharge. RESULTS: The mean age was 43.5 ±â€¯23.8 years (range 18-75) and three patients were females. Prodromal symptoms consisted mainly of fever (4/7), headache (4/7) and self terminating seizures (7/7), before presenting with status epilepticus. Initial imaging findings were abnormal in 3/7 and CSF analysis in 3/7. All patients underwent intermittent EEG recordings, mainly for titration or tapering of the anaesthetic agents, with the initial goal of achieving burst suppression and cessation of electrographic seizures. Our index case spent the longest time in therapeutic burst suppression (102 days) and remained on thiopentone for 214 days. The mean duration of NICU stay was 88 ±â€¯85.4 days (range 4-225 days) while the mean duration of hospital stay was 113.8 ±â€¯111.2 days (range 17-292). CONCLUSIONS: The management of patients with NORSE remains challenging, often requiring multiple intravenous anaesthetic treatments, leading to complicated and prolonged hospital and intensive care unit stays but good outcome remains possible.

Calcium channel blockade with nimodipine reverses MRI evidence of cerebral oedema following acute hypoxia.

Acute cerebral hypoxia causes rapid calcium shifts leading to neuronal damage and death. Calcium channel antagonists improve outcomes in some clinical conditions, but mechanisms remain unclear. In 18 healthy participants we: (i) quantified with multiparametric MRI the effect of hypoxia on the thalamus, a region particularly sensitive to hypoxia, and on the whole brain in general; (ii) investigated how calcium channel antagonism with the drug nimodipine affects the brain response to hypoxia. Hypoxia resulted in a significant decrease in apparent diffusion coefficient (ADC), a measure particularly sensitive to cell swelling, in a widespread network of regions across the brain, and the thalamus in particular. In hypoxia, nimodipine significantly increased ADC in the same brain regions, normalizing ADC towards normoxia baseline. There was positive correlation between blood nimodipine levels and ADC change. In the thalamus, there was a significant decrease in the amplitude of low frequency fluctuations (ALFF) in resting state functional MRI and an apparent increase of grey matter volume in hypoxia, with the ALFF partially normalized towards normoxia baseline with nimodipine. This study provides further evidence that the brain response to acute hypoxia is mediated by calcium, and importantly that manipulation of intracellular calcium flux following hypoxia may reduce cerebral cytotoxic oedema.

Acute impairment of saccadic eye movements is associated with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

OBJECTIVE Delayed cerebral ischemia (DCI) causing cerebral infarction remains a significant cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH). Early brain injury in the first 72 hours following rupture is likely to play a key role in the pathophysiology underlying DCI but remains difficult to quantify objectively. Current diagnostic modalities are based on the concept of vasoconstriction causing cerebral ischemia and infarction and are either invasive or have a steep learning curve and user variability. The authors sought to determine whether saccadic eye movements are impaired following aSAH and whether this measurement in the acute period is associated with the likelihood of developing DCI. METHODS As part of a prospective, observational cohort study, 24 male and female patients (mean age 53 years old, range 31-70 years old) were recruited. Inclusion criteria included presentation with World Federation of Neurosurgical Societies (WFNS) Grades 1 or 2 ("good grade") aSAH on admission and endovascular treatment within 72 hours of aneurysmal rupture. DCI and DCI-related cerebral infarction were defined according to consensus guidelines. Saccadometry data were collected at 3 time points in patients: in the first 72 hours, between Days 5 and 10, and at 3 months after aSAH. Data from 10 healthy controls was collected on 1 occasion for comparison. RESULTS Age-adjusted saccadic latency in patients was significantly prolonged in the first 72 hours following aSAH when compared with controls (188.7 msec [95% CI 176.9-202.2 msec] vs 160.7 msec [95% CI 145.6-179.4 msec], respectively; p = 0.0054, t-test). By 3 months after aSAH, there was no significant difference in median saccadic latency compared with controls (188.7 msec [95% CI 176.9-202.2 msec] vs 180.0 msec [95% CI 165.1-197.8 msec], respectively; p = 0.4175, t-test). Patients diagnosed with cerebral infarction due to DCI had a significantly higher age-adjusted saccadic latency in the first 72 hours than those without infarction (240.6 msec [95% CI 216.7-270.3 msec] vs 204.1 msec [95% CI 190.7-219.5 msec], respectively; p = 0.0157, t-test). This difference was more pronounced during Days 5-10 following aSAH, the peak incidence for DCI (303.7 msec [95% CI 266.7-352.7 msec] vs 207.6 msec [95% CI 193.7-223.6 msec], respectively; p < 0.0001, t-test). A binary generalized linear model showed that latency in the first 72 hours was the only significant predictor of cerebral infarction (p = 0.0185). CONCLUSIONS This is the first study to use saccadometry to measure the saccadic latency of eye movements in patients with aSAH during the acute period following aneurysm rupture. The results showed that median saccadic latency is associated with the risk of developing cerebral infarction due to DCI and may act as a potential objective biomarker to guide the need for intensive care admission and treatment. Future studies will look to formally validate saccadic latency as a biomarker of DCI in a larger cohort and assess whether the addition of saccades improves current clinical models for predicting patients at risk.

Electroencephalographic Response to Sodium Nitrite May Predict Delayed Cerebral Ischemia After Severe Subarachnoid Hemorrhage.

OBJECTIVES: Aneurysmal subarachnoid hemorrhage often leads to death and poor clinical outcome. Injury occurring during the first 72 hours is termed "early brain injury," with disruption of the nitric oxide pathway playing an important pathophysiologic role in its development. Quantitative electroencephalographic variables, such as α/δ frequency ratio, are surrogate markers of cerebral ischemia. This study assessed the quantitative electroencephalographic response to a cerebral nitric oxide donor (intravenous sodium nitrite) to explore whether this correlates with the eventual development of delayed cerebral ischemia. DESIGN: Unblinded pilot study testing response to drug intervention. SETTING: Neuroscience ICU, John Radcliffe Hospital, Oxford, United Kingdom. PATIENTS: Fourteen World Federation of Neurosurgeons grades 3, 4, and 5 patients (mean age, 52.8 yr [range, 41-69 yr]; 11 women). INTERVENTIONS: IV sodium nitrite (10 µg/kg/min) for 1 hour. MEASUREMENTS AND MAIN RESULTS: Continuous electroencephalographic recording for 2 hours. The alpha/delta frequency ratio was measured before and during IV sodium nitrite infusion. Seven of 14 patients developed delayed cerebral ischemia. There was a +30% to +118% (range) increase in the alpha/delta frequency ratio in patients who did not develop delayed cerebral ischemia (p < 0.0001) but an overall decrease in the alpha/delta frequency ratio in those patients who did develop delayed cerebral ischemia (range, +11% to -31%) (p = 0.006, multivariate analysis accounting for major confounds). CONCLUSIONS: Administration of sodium nitrite after severe subarachnoid hemorrhage differentially influences quantitative electroencephalographic variables depending on the patient's susceptibility to development of delayed cerebral ischemia. With further validation in a larger sample size, this response may be developed as a tool for risk stratification after aneurysmal subarachnoid hemorrhage.

Pseudo-continuous arterial spin labelling MRI for non-invasive, whole-brain, serial quantification of cerebral blood flow following aneurysmal subarachnoid haemorrhage.

Delayed cerebral ischaemia (DCI) is the major cause of mortality and morbidity following aneurysmal subarachnoid haemorrhage (SAH). Recent experimental evidence from animal models has highlighted the need for non-invasive and robust measurements of brain tissue perfusion in patients in order to help understand the pathophysiology underlying DCI. Quantitative, serial, whole-brain cerebral perfusion measurements were obtained with pseudo-continuous arterial spin labelling (PCASL) magnetic resonance imaging (MRI) in six SAH patients acutely following endovascular coiling. This technique requires no injected contrast or radioactive isotopes. MRI scanning was well tolerated. Artefact from endovascular coils was minimal. PCASL MRI was able to detect time-dependent and patient-specific changes in voxel-wise and regional cerebral blood flow. These changes reflected changes in clinical condition. Data obtained in healthy controls using the same experimental protocol confirm the reliability and reproducibility of these results. This is the first study to use whole-brain, quantitative PCASL to identify time-dependent changes in cerebral blood flow at the tissue level in the acute period following SAH. This technique has the potential to better understand changes in cerebral pathophysiology as a consequence of aneurysm rupture.