Geoffrey T. Manley

The ICH Score A Simple, Reliable Grading Scale for Intracerebral Hemorrhage

BACKGROUND AND PURPOSE Intracerebral hemorrhage (ICH) constitutes 10% to 15% of all strokes and remains without a treatment of proven benefit. Despite several existing outcome prediction models for ICH, there is no standard clinical grading scale for ICH analogous to those for traumatic brain injury, subarachnoid hemorrhage, or ischemic stroke. METHODS Records of all patients with acute ICH presenting to the University of California, San Francisco during 1997-1998 were reviewed. Independent predictors of 30-day mortality were identified by logistic regression. A risk stratification scale (the ICH Score) was developed with weighting of independent predictors based on strength of association. RESULTS Factors independently associated with 30-day mortality were Glasgow Coma Scale score (P<0.001), age >/=80 years (P=0.001), infratentorial origin of ICH (P=0.03), ICH volume (P=0.047), and presence of intraventricular hemorrhage (P=0.052). The ICH Score was the sum of individual points assigned as follows: GCS score 3 to 4 (=2 points), 5 to 12 (=1), 13 to 15 (=0); age >/=80 years yes (=1), no (=0); infratentorial origin yes (=1), no (=0); ICH volume >/=30 cm(3) (=1), <30 cm(3) (=0); and intraventricular hemorrhage yes (=1), no (=0). All 26 patients with an ICH Score of 0 survived, and all 6 patients with an ICH Score of 5 died. Thirty-day mortality increased steadily with ICH Score (P<0.005). CONCLUSIONS The ICH Score is a simple clinical grading scale that allows risk stratification on presentation with ICH. The use of a scale such as the ICH Score could improve standardization of clinical treatment protocols and clinical research studies in ICH.

Classification of Traumatic Brain Injury for Targeted Therapies

The heterogeneity of traumatic brain injury (TBI) is considered one of the most significant barriers to finding effective therapeutic interventions. In October, 2007, the National Institute of Neurological Disorders and Stroke, with support from the Brain Injury Association of America, the Defense and Veterans Brain Injury Center, and the National Institute of Disability and Rehabilitation Research, convened a workshop to outline the steps needed to develop a reliable, efficient and valid classification system for TBI that could be used to link specific patterns of brain and neurovascular injury with appropriate therapeutic interventions. Currently, the Glasgow Coma Scale (GCS) is the primary selection criterion for inclusion in most TBI clinical trials. While the GCS is extremely useful in the clinical management and prognosis of TBI, it does not provide specific information about the pathophysiologic mechanisms which are responsible for neurological deficits and targeted by interventions. On the premise that brain injuries with similar pathoanatomic features are likely to share common pathophysiologic mechanisms, participants proposed that a new, multidimensional classification system should be developed for TBI clinical trials. It was agreed that preclinical models were vital in establishing pathophysiologic mechanisms relevant to specific pathoanatomic types of TBI and verifying that a given therapeutic approach improves outcome in these targeted TBI types. In a clinical trial, patients with the targeted pathoanatomic injury type would be selected using an initial diagnostic entry criterion, including their severity of injury. Coexisting brain injury types would be identified and multivariate prognostic modeling used for refinement of inclusion/exclusion criteria and patient stratification. Outcome assessment would utilize endpoints relevant to the targeted injury type. Advantages and disadvantages of currently available diagnostic, monitoring, and assessment tools were discussed. Recommendations were made for enhancing the utility of available or emerging tools in order to facilitate implementation of a pathoanatomic classification approach for clinical trials.

Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema

Aquaporin‐4 (AQP4) is the major water channel in the brain, expressed predominantly in astroglial cell membranes. Initial studies in AQP4‐deficient mice showed reduced cellular brain edema following water intoxication and ischemic stroke. We hypothesized that AQP4 deletion would have the opposite effect (increased brain swelling) in vasogenic (noncellular) edema because of impaired removal of excess brain water through glial limitans and ependymal barriers. In support of this hypothesis, we found higher intracranial pressure (ICP, 52±6 vs. 26±3 cm H2O) and brain water content (81.2±0.1 vs. 80.4±0.1%) in AQP4‐deficient mice after continuous intraparenchymal fluid infusion. In a freeze‐injury model of vasogenic brain edema, AQP4‐deficient mice had remarkably worse clinical outcome, higher ICP (22±4 vs. 9±1 cm H2O), and greater brain water content (80.9±0.1 vs. 79.4±0.1%). In a brain tumor edema model involving stereotactic implantation of melanoma cells, tumor growth was comparable in wild‐ type and AQP4‐deficient mice. However, AQP4‐deficient mice had higher ICP (39±4 vs. 19±5 cm H2O at seven days postimplantation) and corresponding accelerated neurological deterioration. Thus, AQP4‐mediated transcellular water movement is crucial for fluid clearance in vasogenic brain edema, suggesting AQP4 activation and/or up‐regulation as a novel therapeutic option in vasogenic brain edema.

Summary of evidence-based guideline update: Evaluation and management of concussion in sports Report of the Guideline Development Subcommittee of the American Academy of Neurology

Objective: To update the 1997 American Academy of Neurology (AAN) practice parameter regarding sports concussion, focusing on 4 questions: 1) What factors increase/decrease concussion risk? 2) What diagnostic tools identify those with concussion and those at increased risk for severe/prolonged early impairments, neurologic catastrophe, or chronic neurobehavioral impairment? 3) What clinical factors identify those at increased risk for severe/prolonged early postconcussion impairments, neurologic catastrophe, recurrent concussions, or chronic neurobehavioral impairment? 4) What interventions enhance recovery, reduce recurrent concussion risk, or diminish long-term sequelae? The complete guideline on which this summary is based is available as an online data supplement to this article. Methods: We systematically reviewed the literature from 1955 to June 2012 for pertinent evidence. We assessed evidence for quality and synthesized into conclusions using a modified Grading of Recommendations Assessment, Development and Evaluation process. We used a modified Delphi process to develop recommendations. Results: Specific risk factors can increase or decrease concussion risk. Diagnostic tools to help identify individuals with concussion include graded symptom checklists, the Standardized Assessment of Concussion, neuropsychological assessments, and the Balance Error Scoring System. Ongoing clinical symptoms, concussion history, and younger age identify those at risk for postconcussion impairments. Risk factors for recurrent concussion include history of multiple concussions, particularly within 10 days after initial concussion. Risk factors for chronic neurobehavioral impairment include concussion exposure and APOE ε4 genotype. Data are insufficient to show that any intervention enhances recovery or diminishes long-term sequelae postconcussion. Practice recommendations are presented for preparticipation counseling, management of suspected concussion, and management of diagnosed concussion.

Extent of Microstructural White Matter Injury in Postconcussive Syndrome Correlates with Impaired Cognitive Reaction Time: A 3T Diffusion Tensor Imaging Study of Mild Traumatic Brain Injury

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) may be a useful index of microstructural changes implicated in diffuse axonal injury (DAI) linked to persistent postconcussive symptoms, especially in mild traumatic brain injury (TBI), for which conventional MR imaging techniques may lack sensitivity. We hypothesized that for mild TBI, DTI measures of DAI would correlate with impairments in reaction time, whereas the number of focal lesions on conventional 3T MR imaging would not. MATERIALS AND METHODS: Thirty-four adult patients with mild TBI with persistent symptoms were assessed for DAI by quantifying traumatic microhemorrhages detected on a conventional set of T2*-weighted gradient-echo images and by DTI measures of fractional anisotropy (FA) within a set of a priori regions of interest. FA values 2.5 SDs below the region average, based on a group of 26 healthy control adults, were coded as exhibiting DAI. RESULTS: DTI measures revealed several predominant regions of damage including the anterior corona radiata (41% of the patients), uncinate fasciculus (29%), genu of the corpus callosum (21%), inferior longitudinal fasciculus (21%), and cingulum bundle (18%). The number of damaged white matter structures as quantified by DTI was significantly correlated with mean reaction time on a simple cognitive task (r = 0.49, P = .012). In contradistinction, the number of traumatic microhemorrhages was uncorrelated with reaction time (r = −0.08, P = .71). CONCLUSION: Microstructural white matter lesions detected by DTI correlate with persistent cognitive deficits in mild TBI, even in populations in which conventional measures do not. DTI measures may thus contribute additional diagnostic information related to DAI.

Involvement of aquaporin-4 in astroglial cell migration and glial scar formation

Aquaporin-4, the major water-selective channel in astroglia throughout the central nervous system, facilitates water movement into and out of the brain. Here, we identify a novel role for aquaporin-4 in astroglial cell migration, as occurs during glial scar formation. Astroglia cultured from the neocortex of aquaporin-4-null mice had similar morphology, proliferation and adhesion, but markedly impaired migration determined by Transwell migration efficiency (18±2 vs 58±4% of cells migrated towards 10% serum in 8 hours; P<0.001) and wound healing rate (4.6 vs 7.0 μm/hour speed of wound edge; P<0.001) compared with wild-type mice. Transwell migration was similarly impaired (25±4% migrated cells) in wild-type astroglia after ∼90% reduction in aquaporin-4 protein expression by RNA inhibition. Aquaporin-4 was polarized to the leading edge of the plasma membrane in migrating wild-type astroglia, where rapid shape changes were seen by video microscopy. Astroglial cell migration was enhanced by a small extracellular osmotic gradient, suggesting that aquaporin-4 facilitates water influx across the leading edge of a migrating cell. In an in vivo model of reactive gliosis and astroglial cell migration produced by cortical stab injury, glial scar formation was remarkably impaired in aquaporin-4-null mice, with reduced migration of reactive astroglia towards the site of injury. Our findings provide evidence for the involvement of aquaporin-4 in astroglial cell migration, which occurs during glial scar formation in brain injury, stroke, tumor and focal abscess.

Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1

Aquaporin‐1 (AQP1) is a water channel expressed strongly at the ventricular‐facing surface of choroid plexus epithelium. We developed novel methods to compare water permeability in isolated choroid plexus of wild‐type vs. AQP1 null mice, as well as intracranial pressure (ICP) and cerebrospinal fluid (CSF) production and absorption. Osmotically induced water transport was rapid in choroid plexus from wild‐type mice and reduced by fivefold by AQP1 deletion. AQP1 deletion did not affect choroid plexus size or structure. By stereotaxic puncture of the lateral ventricle with a microneedle, ICP was 9.5 ± 1.4 cm H2O in wild‐type mice and 4.2 ± 0.4 cm H2O in AQP1 null mice. CSF production, an isosmolar fluid secretion process, was measured by a dye dilution method involving fluid collections using a second microneedle introduced into the cisterna magna. CSF production in wild‐type mice was (in µl min–1) 0.37 ± 0.04 (control), 0.16 ± 0.03 (acetazolamide‐treated), and 1.14 ± 0.15 (forskolin‐treated), and reduced by ~25% in AQP1 null mice. Pressure‐dependent CSF outflow, measured from steady‐state ICP at different ventricular infusion rates, was not affected by AQP1 deletion. In a model of focal brain injury, AQP1 null mice had remarkably reduced ICP and improved survival compared with wild‐type mice. The reduced ICP and CSF production in AQP1 null mice provides direct functional evidence for the involvement of AQP1 in CSF dynamics, suggesting AQP1 inhibition as a novel option for therapy of elevated ICP.

Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels

The glial water channel aquaporin‐4 (AQP4) has been hypothesized to modulate water and potassium fluxes associated with neuronal activity. In this study, we examined the seizure phenotype of AQP4 −/− mice using in vivo electrical stimulation and electroencephalographic (EEG) recording. AQP4 −/− mice were found to have dramatically prolonged stimulation‐evoked seizures after hippocampal stimulation compared to wild‐type controls (33 ± 2 s vs. 13 ± 2 s). In addition, AQP4 −/− mice were found to have a higher seizure threshold (167 ± 17 μA vs. 114 ± 10 μA). To assess a potential effect of AQP4 on potassium kinetics, we used in vivo recording with potassium‐sensitive microelectrodes after direct cortical stimulation. Although there was no significant difference in baseline or peak [K+]o, the rise time to peak [K+]o (t1/2, 2.3 ± 0.5 s) as well as the recovery to baseline [K+]o (t1/2, 15.6 ± 1.5 s) were slowed in AQP4 −/− mice compared to WT mice (t1/2, 0.5 ± 0.1 and 6.6 ± 0.7 s, respectively). These results implicate AQP4 in the expression and termination of seizure activity and support the hypothesis that AQP4 is coupled to potassium homeostasis in vivo.

NEW INSIGHTS INTO WATER TRANSPORT AND EDEMA IN THE CENTRAL NERVOUS SYSTEM FROM PHENOTYPE ANALYSIS OF AQUAPORIN-4 NULL MICE

Aquaporin-4 (AQP4) is the major water channel in the CNS. Its expression at fluid-tissue barriers (blood-brain and brain-cerebrospinal fluid barriers) throughout the brain and spinal cord suggests a role in water transport under normal and pathological conditions. Phenotype studies of transgenic mice lacking AQP4 have provided evidence for a role of AQP4 in cerebral water balance and neural signal transduction. Primary cultures of astrocytes from AQP4-null mice have greatly reduced osmotic water permeability compared with wild-type astrocytes, indicating that AQP4 is the principal water channel in these cells. AQP4-null mice have reduced brain swelling and improved neurological outcome following water intoxication and focal cerebral ischemia, establishing a role of AQP4 in the development of cytotoxic (cellular) cerebral edema. In contrast, brain swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid leak) edema caused by freeze-injury and brain tumor, probably due to impaired AQP4-dependent brain water clearance. AQP4-null mice also have markedly reduced acoustic brainstem response potentials and significantly increased seizure threshold in response to chemical convulsants, implicating AQP4 in modulation of neural signal transduction. Pharmacological modulation of AQP4 function may thus provide a novel therapeutic strategy for the treatment of stroke, tumor-associated edema, epilepsy, traumatic brain injury, and other disorders of the CNS associated with altered brain water balance.

Very Early Administration of Progesterone for Acute Traumatic Brain Injury

BACKGROUND Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI. METHODS We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score. RESULTS A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes. CONCLUSIONS This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.).