Bedside quantitative electroencephalography improves assessment of consciousness in comatose subarachnoid hemorrhage patients.

OBJECTIVE: Accurate behavioral assessments of consciousness carry tremendous significance in guiding management, but are extremely challenging in acutely brain-injured patients. We evaluated whether electroencephalography (EEG) and multimodality monitoring parameters may facilitate assessment of consciousness in patients with subarachnoid hemorrhage. METHODS: A retrospective analysis was performed of 83 consecutively treated adults with subarachnoid hemorrhage. All patients were initially comatose and had invasive brain monitoring placed. Behavioral assessments were performed during daily interruption of sedation and categorized into 3 groups based on their best examination as (1) comatose, (2) arousable (eye opening or attending toward a stimulus), and (3) aware (command following). EEG features included spectral power and complexity measures. Comparisons were made using bootstrapping methods and partial least squares regression. RESULTS: We identified 389 artifact-free EEG clips following behavioral assessments. Increasing central gamma, posterior alpha, and diffuse theta-delta oscillations differentiated patients who were arousable from those in coma. Command following was characterized by a further increase in central gamma and posterior alpha, as well as an increase in alpha permutation entropy. These EEG features together with basic neurological examinations (eg, pupillary light reflex) contributed heavily to a linear model predicting behavioral state, whereas brain physiology measures (eg, brain oxygenation), structural injury, and clinical course added less. INTERPRETATION: EEG measures of behavioral states provide distinctive signatures that complement behavioral assessments of patients with subarachnoid hemorrhage shortly after the injury. Our data support the hypothesis that impaired connectivity of cortex with both central thalamus and basal forebrain underlies decreasing levels of consciousness. Ann Neurol 2016;80:541-553.

Brain injury visible on early MRI after subarachnoid hemorrhage might predict neurological impairment and functional outcome.

BACKGROUND: In subarachnoid hemorrhage (SAH), brain injury visible within 48 h of onset may impact on admission neurological disability and 3-month functional outcome. With volumetric MRI, we measured the volume of brain injury visible after SAH, and assessed the association with admission clinical grade and 3-month functional outcome. METHODS: Retrospective cohort study conducted in the Neurocritical Care Division, Columbia University Medical Center, New York, USA. On brain MRI acquired within 48 h of SAH-onset and before aneurysm-securing (n = 27), two blinded readers measured DWI and FLAIR-lesion volumes using semi-automated, computer segmentation software. RESULTS: Compared to post-resuscitation Hunt-Hess grade 1-3 (70 %), high-grade patients (30 %) had higher lesion volumes on DWI (34 ml [IQR: 0-64] vs. 2 ml [IQR: 0.5-7], P = 0.02) and on FLAIR (81 ml [IQR: 24-127] vs. 3 ml [IQR: 0-27], P = 0.02). On DWI, each 10 ml increase in lesion volume was associated with a 101 %-increase in the odds of presenting with 1 grade more in the Hunt-Hess scale (aOR 2.01, 95 % CI 1.10-3.68, P = 0.02), but was not significantly associated with 3-month outcome. On FLAIR, each 10 ml increase in lesion volume was associated with 34 % higher odds of a 1-point increase on the Hunt-Hess scale (aOR 1.34, 95 % CI 1.06-1.68, P = 0.01) and 139 % higher odds of a 1-point increase on the 3-month mRS (aOR 2.39, 95 % CI 1.13-5.07, P = 0.02). CONCLUSION: The volume of brain injury visible on DWI and FLAIR within 48 h after SAH is proportional to neurological impairment on admission. Moreover, FLAIR-imaging implicates chronic brain injury-predating SAH-as potentially relevant cause of poor functional outcome.

Impact of premorbid hypertension on haemorrhage severity and aneurysm rebleeding risk after subarachnoid haemorrhage.

OBJECTIVE: Arterial hypertension (HTN) is a risk factor for subarachnoid haemorrhage (SAH). We aimed to assess the impact of premorbid HTN on the severity of initial bleeding and the risk of aneurysm rebleeding after SAH. DESIGN: Retrospective analysis of a prospective cohort study of all SAH patients admitted to Columbia University Medical Center between 1996 and 2012. RESULTS: We enrolled 1312 consecutive patients with SAH; 643 (49%) had premorbid HTN. Patients with premorbid HTN presented more frequently as Hunt-Hess Grade IV or V (36% vs 25%, p<0.001) and World Federation of Neurosurgical Societies (WFNS) Grade 4 or 5 (42.6% vs 28.2%, p<0.001), with larger amounts of subarachnoid (Hijdra Sum Score 17 vs 14, p<0.001) and intraventricular blood (median IVH sum score 2 vs 1, p<0.001), and more often with intracerebral haemorrhage (20% vs 13%, p=0.002). In multivariate analysis, patients with premorbid HTN had a higher risk of in-hospital aneurysm rebleeding (11.8% vs 5.5%, adjusted OR 1.67, 95% CI 1.02 to 2.74, p=0.04) after adjusting for age, admission, Hunt-Hess grade, size and site of the ruptured aneurysm. CONCLUSIONS: Premorbid HTN is associated with increased severity of the initial bleeding event and represents a significant risk factor for aneurysm rebleeding. Given that aneurysm rebleeding is a potentially fatal-but preventable-complication, these findings are of clinical relevance.

Qualitative feasibility study of the mobile app Destroke for clinical stroke monitoring based on the NIH stroke scale.

Background: Stroke is a leading cause of severe disability in the United States, but there is no effective method for patients to accurately detect the signs of stroke at home. We developed a mobile app, Destroke, that allows remote performance of a modified NIH stroke scale (NIHSS) by patients. Aims: To assess the feasibility of a mobile app for stroke monitoring and education by patients with a history of stroke. Materials and methods: We enrolled 25 patients with a history of stroke in a prospective open-label study to evaluate the feasibility of the Destroke app in patients with stroke. Nineteen patients completed all study assessments, with a median time from stroke onset to enrollment of 5.6 years (range 0.1-12 years). We designed a modified NIHSS that assessed 12 out of 16 tasks on the NIHSS. Patients completed this test eight times over a 28-day period. We conducted pre-study surveys that assessed demographic information, stroke and cardiovascular history, baseline NIHSS, and experience using mobile technologies, and mid- and post-study surveys that assessed patient satisfaction on app usage and confidence in stroke detection. Results: Ten men and nine women participated in this study (median age of 64 (33-76)), representing ten US states and Washington D.C. Median baseline NIHSS was 0 (0-4). 15 patients reported using health apps. On a 5-point Likert scale, patients rated the app as 4.2 on being able to understand and use the app and 4.3 on using the app when instructed by their doctor. For eight patients with poor confidence in detecting the signs of a stroke before the study, six showed higher confidence after the study. Conclusions: The use of an at-home stroke monitoring app is feasible by patients with a history of stroke and improves confidence in detecting the signs of stroke.

Agrin expression during synaptogenesis induced by traumatic brain injury.

Interaction between extracellular matrix proteins and regulatory proteinases can mediate synaptic integrity. Previously, we documented that matrix metalloproteinase 3 (MMP-3) expression and activity increase following traumatic brain injury (TBI). We now report protein and mRNA analysis of agrin, a MMP-3 substrate, over the time course of trauma-induced synaptogenesis. Agrin expression during the successful synaptic reorganization of unilateral entorhinal cortical lesion (UEC) was compared with expression when normal synaptogenesis fails (combined fluid percussion TBI and bilateral entorhinal lesion [BEC]). We observed that agrin protein was increased in both models at 2 and 7 days postinjury, and immuohistochemical (IHC) co-localization suggested reactive astrocytes contribute to that increase. Agrin formed defined boundaries for sprouting axons along deafferented dendrites in the UEC, but failed to do so after combined insult. Similarly, Western blot analysis revealed greater increase in UEC agrin protein relative to the combined TBI+BEC model. Both models showed increased agrin transcription at 7 days postinjury and mRNA normalization by 15 days. Attenuation of synaptic pathology with the NMDA antagonist MK-801 reduced 7-day UEC agrin transcript to a level not different from unlesioned controls. By contrast, MK-801 in the combined insult failed to significantly change 7-day agrin transcript, mRNA levels remaining elevated over uninjured sham cases. Together, these results suggest that agrin plays an important role in the sprouting phase of reactive synaptogenesis, and that both its expression and distribution are correlated with extent of successful recovery after TBI. Further, when pathogenic conditions which induce synaptic plasticity are reduced, increase in agrin mRNA is attenuated.

Desmopressin administration and rebleeding in subarachnoid hemorrhage: analysis of an observational prospective database.

OBJECTIVERebleeding remains a frequent and catastrophic event leading to poor outcome after subarachnoid hemorrhage (SAH). Reduced platelet function after the initial bleed is associated with higher risk of early rebleeding. Desmopressin (DDAVP) is a well-known hemostatic agent, and recent guidelines already suggest its use in individuals exposed to antiplatelet drugs. The authors hypothesized that DDAVP administration in patients with SAH at admission would be associated with lower risks of rebleeding.METHODSThe authors performed an observational cohort study of patients enrolled in the Columbia University SAH Outcome Project between August 1996 and July 2015. The authors compared the rate of rebleeding between patients who were and those who were not treated with DDAVP. After adjustment for known predictors, logistic regression was used to measure the association between treatment with DDAVP and risks of rebleeding.RESULTSAmong 1639 patients with SAH, 12% were treated with DDAVP. The main indication for treatment was suspected exposure to an antiplatelet agent. The overall incidence of rebleeding was 9% (1% among patients treated with DDAVP compared with 8% among those not treated). After adjustment for antiplatelet use and known predictors, treatment with DDAVP was associated with a 45% reduction in the risks of rebleeding (adjusted OR 0.55, 95% CI 0.27-0.97). DDAVP was associated with a higher incidence of hyponatremia but not with thrombotic events or delayed cerebral ischemia.CONCLUSIONSTreatment with DDAVP was associated with a lower risk of rebleeding among patients with SAH. These findings support further study of DDAVP as first-line therapy for medical hemostasis in patients with SAH.

Does the obesity paradox predict functional outcome in intracerebral hemorrhage?

OBJECTIVEBeing overweight or mildly obese has been associated with a decreased risk of death or hospitalization in patients with cardiovascular disease. Similarly, overweight patients admitted to an intensive care unit (ICU) have improved survival up to 1 year after admission. These counterintuitive observations are examples of the "obesity paradox." Does the obesity paradox exist in patients with intracerebral hemorrhage (ICH)? In this study the authors examined whether there was an association between obesity and functional outcome in patients with ICH.METHODSThe authors analyzed 202 patients admitted to the neurological ICU (NICU) who were prospectively enrolled in the Columbia University ICH Outcomes Project between September 2009 and December 2012. Patients were categorized into 2 groups: overweight (body mass index [BMI] ≥ 25 kg/m2) and not overweight (BMI < 25 kg/m2). The primary outcome was defined as survival with favorable outcome (modified Rankin Scale [mRS] score 0-3) versus death or severe disability (mRS score 4-6) at 3 months.RESULTSThe mean age of the patients in the study was 61 years. The mean BMI was 28 ± 6 kg/m2. The mean Glasgow Coma Scale score was 10 ± 4 and the mean ICH score was 1.9 ± 1.3. The overall 90-day mortality rate was 41%. Among patients with a BMI < 25 kg/m2, 24% (17/70) had a good outcome, compared with 39% (52/132) among those with a BMI ≥ 25 kg/m2 (p = 0.03). After adjusting for ICH score, sex, do-not-resuscitate code status, and history of hypertension, being overweight or obese (BMI ≥ 25 kg/m2) was associated with twice the odds of having a good outcome compared with patients with BMI < 25 kg/m2 (adjusted odds ratio 2.05, 95% confidence interval 1.03-4.06, p = 0.04).CONCLUSIONSIn patients with ICH admitted to the NICU, being overweight or obese (BMI ≥ 25 kg/m2) was associated with favorable outcome after adjustment for established predictors. The reason for this finding requires further study.

Patient-Powered Reporting of Modified Rankin Scale Outcomes Via the Internet.

BACKGROUND AND PURPOSE: The modified Rankin Scale (mRS) is a common and resource-intensive measure of functional outcome in stroke-related conditions. In this observational prospective cohort feasibility study, mRS scores are generated using a patient-powered online survey and compared to scores obtained by structured telephonic interview. MATERIALS AND METHODS: Fifty-one patients with subarachnoid hemorrhage (SAH) or their surrogates responded to an online survey following discharge from the hospital. These responses were used to generate an mRS score and then compared to blinded telephonic assessments by trained personnel. A weighted kappa (Kw) with confidence intervals (CIs) was calculated. RESULTS: The Kw between the patient/surrogate and the trained personnel scores was 0.85 (95% CI, 0.74-0.95, P < .001). CONCLUSION: This study provides first evidence that patient/surrogate survey responses may be an efficient and reliable alternative to generate mRS scores compared to trained personnel after SAH.

Seizure burden in subarachnoid hemorrhage associated with functional and cognitive outcome.

OBJECTIVE: To assess the relationship between seizure burden on continuous EEG (cEEG) and functional as well as cognitive outcome 3 months after subarachnoid hemorrhage (SAH). METHODS: The study included all consecutive patients with a spontaneous SAH admitted to the Columbia University Medical Center Neurological Intensive Care Unit and monitored with cEEG between 1996 and 2013. Seizure burden was defined as the duration, in hours, of seizures on cEEG. Cognitive outcomes were measured with the Telephone Interview for Cognitive Status (TICS, ranging from 0 to 51, indicating poor to good global mental status). RESULTS: Overall, 402 patients with SAH were included with a median age of 58 years (interquartile range [IQR] 46-68 years). The median duration of cEEG monitoring was 96 hours (IQR 48-155 hours). Seizures were recorded in 50 patients (12%), in whom the median seizure burden was 6 hours (IQR 1-13 hours). At 3 months, in multivariate analysis, seizure burden was associated with unfavorable functional and cognitive outcome. Every hour of seizure on cEEG was associated with an odds ratio of 1.10 (95% confidence interval [CI] 1.01-1.21, p = 0.04) to 3-month disability and mortality, and the TICS-score decreased, on average, by 0.16 points (adjusted coefficient -0.19, 95% CI -0.33 to -0.05, p = 0.01). CONCLUSION: In this study, after adjusting for established predictors, seizure burden was associated with functional outcome and cognitive impairment 3 months after SAH.

Intraventricular hemorrhage expansion in patients with spontaneous intracerebral hemorrhage.

OBJECTIVE: To evaluate whether delayed appearance of intraventricular hemorrhage (dIVH) represents an independent entity from intraventricular hemorrhage (IVH) present on admission CT or is primarily related to the time interval between symptom onset and admission CT. METHODS: A total of 282 spontaneous intracerebral hemorrhage (ICH) patients, admitted February 2009-March 2014 to the neurological intensive care unit of a tertiary care university hospital, were prospectively enrolled in the ICH Outcomes Project. Multivariate logistic regression was used to determine associations with acute mortality and functional long-term outcome (modified Rankin Scale). RESULTS: A cohort of 282 ICH patients was retrospectively studied: 151 (53.5%) had intraventricular hemorrhage on initial CT scan (iIVH). Of the remaining 131 patients, 19 (14.5%) developed IVH after the initial CT scan (dIVH). The median times from symptom onset to admission CT were 1.1, 6.0, and 7.4 hours for the dIVH, iIVH, and no IVH groups (Mann-Whitney U test, dIVH vs iIVH, p < 0.001) and median time from onset to dIVH detection was 7.2 hours. The increase in ICH volume following hospital admission was larger in dIVH than in iIVH and no IVH patients (mean 17.6, 0.2, and 0.4 mL). After controlling for components of the ICH score and hematoma expansion, presence of IVH on initial CT was associated with discharge mortality and poor outcome at 3, 6, and 12 months, but dIVH was not associated with any of the outcome measures. CONCLUSIONS: In ICH patients, associated IVH on admission imaging is commonly encountered and is associated with poor long-term outcome. In contrast, dIVH on subsequent scans is far less common and does not appear to portend worse outcome.

Tonic-clonic activity at subarachnoid hemorrhage onset: impact on complications and outcome.

OBJECTIVE: Tonic-clonic activity (TCA) at onset complicates 3% to 21% of cases of subarachnoid hemorrhage (SAH). The impact of onset TCA on in-hospital complications, including seizures, remains unclear. One study associated onset TCA with poor clinical outcome at 6 weeks after SAH, but to our knowledge no other studies have confirmed this relationship. This study aims to assess the impact of onset TCA on in-hospital complications, poor functional outcome, mortality, and epilepsy at 3 months. METHODS: Analysis of a prospective study cohort of 1479 SAH patients admitted to Columbia University Medical Center between 1996 and 2012. TCA within 6 hours of hemorrhage onset was identified based on accounts of emergency care providers or family witnesses. RESULTS: TCA at onset was described in 170 patients (11%). Patients with onset TCA were younger (P = 0.002), presented more often with poor clinical grade (55% vs. 26%, P<0.001) and had larger amounts of cisternal, intraventricular, and intracerebral blood than those without onset TCA (all, P<0.001). After adjusting for known confounders, onset TCA was significantly associated with in-hospital seizures (OR 3.80, 95%-CI: 2.43-5.96, P<0.001), in-hospital pneumonia (OR 1.56, 95%-CI: 1.06-2.31, p = 0.02), and delayed cerebral ischemia (OR 1.77, 95%-CI: 1.21-2.58, P = 0.003). At 3 months, however, onset TCA was not associated with poor functional outcome, mortality, and epilepsy after adjusting for age, admission clinical grade, and cisternal blood volume. CONCLUSIONS: Onset TCA is not a rare event as it complicates 11% of cases of SAH. New and clinically relevant findings are the association of onset TCA with in-hospital seizures, pneumonia and delayed cerebral ischemia. Despite the increased risk of in-hospital complications, onset TCA is not associated with disability, mortality, and epilepsy at 3 months.

Deficits in ERK and CREB activation in the hippocampus after traumatic brain injury.

Traumatic brain injury (TBI) activates several protein kinase signaling pathways in the hippocampus that are critical for hippocampal-dependent memory formation. In particular, extracellular signal-regulated kinase (ERK), a protein kinase activated during and necessary for hippocampal-dependent learning, is transiently activated after TBI. However, TBI patients experience hippocampal-dependent cognitive deficits that occur for several months to years after the initial injury. Although basal activation levels of ERK return to sham levels within hours after TBI, we hypothesized that activation of ERK may be impaired after TBI. Adult male Sprague-Dawley rats received either sham surgery or moderate parasagittal fluid-percussion brain injury. At 2, 8, or 12 weeks after surgery, the ipsilateral hippocampi of sham surgery and TBI animals were sectioned into transverse slices. After 2h of recovery in oxygenated artificial cerebrospinal fluid, the hippocampal slices were stimulated with glutamate or KCl depolarization, then analyzed by western blotting for phosphorylated, activated ERK and one of its downstream effectors, the transcription factor cAMP response element-binding protein (CREB). We found that activation of ERK (p<0.05) and CREB (p<0.05) after 30s of glutamate stimulation or KCl depolarization was decreased in hippocampal slices from animals at 2, 8, or 12 weeks after TBI as compared to sham animals. Basal levels of phosphorylated or total ERK were not significantly altered at 2, 8, or 12 weeks after TBI, although basal levels of phosphorylated CREB were decreased 12 weeks post-trauma. These results suggest that TBI results in chronic signaling deficits through the ERK-CREB pathway in the hippocampus.