The German trial on Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE): a multicenter, randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Comprehensive treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major clinical challenge. The current therapy gold standard is aciclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains around 20% and a majority of survivors suffer from severe disability. Experimental research and recent retrospective clinical observations suggest a favourable therapy response to adjuvant dexamethasone. Currently there is no randomized clinical trial evidence, however, to support the routine use of adjuvant corticosteroid treatment in HSVE. METHODS: The German trial of Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE) studied the effect of adjuvant dexamethasone versus placebo on top of standard aciclovir treatment in adult patients aged 18 up to 85 years with proven HSVE in German academic centers of Neurology in a randomized and double blind fashion. The trial was open from November 2007 to December 2012. The initially planned sample size was 372 patients with the option to increase to up to 450 patients after the second interim analysis. The primary endpoint was a binary functional outcome after 6 months assessed using the modified Rankin scale (mRS 0-2 vs. 3-6). Secondary endpoints included mortality after 6 and 12 months, functional outcome after 6 months measured with the Glasgow outcome scale (GOS), functional outcome after 12 months measured with mRS and GOS, quality of life as measured with the EuroQol 5D instrument after 6 and 12 months, neuropsychological testing after 6 months, cranial magnetic resonance imaging findings after 6 months, seizures up to day of discharge or at the latest at day 30, and after 6 and 12 months. RESULTS: The trial was stopped prematurely for slow recruitment after 41 patients had been randomized, 21 of them treated with dexamethasone and 20 with placebo. No difference was observed in the primary endpoint. In the full analysis set (n = 19 in each group), 12 patients in each treatment arm achieved a mRS of 0-2. Similarly, we did not observe significant differences in the secondary endpoints (GOS, mRS, quality of life, neuropsychological testing). CONCLUSION: GACHE being prematurely terminated demonstrated challenges encountered performing randomized, placebo-controlled trials in rare life threatening neurological diseases. Based upon our trial results the use of adjuvant steroids in addition to antiviral treatment remains experimental and is at the decision of the individual treating physician. Unfortunately, the small number of study participants does not allow firm conclusions. TRIAL REGISTRATION: EudraCT-Nr. 2005-003201-81.

Early Quantification of Hematoma Hounsfield Units on Noncontrast CT in Acute Intraventricular Hemorrhage Predicts Ventricular Clearance after Intraventricular Thrombolysis.

BACKGROUND AND PURPOSE: Thrombolytic efficacy of intraventricular rtPA for acute intraventricular hemorrhage may depend on hematoma composition. We assessed whether hematoma Hounsfield unit quantification informs intraventricular hemorrhage clearance after intraventricular rtPA. MATERIALS AND METHODS: Serial NCCT was performed on 52 patients who received intraventricular rtPA as part of the Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage trial and 12 controls with intraventricular hemorrhage, but no rtPA treatment. A blinded investigator calculated Hounsfield unit values for intraventricular hemorrhage volumes on admission (t0), days 3-4 (t1), and days 6-9 (t2). Controls were matched uniquely to 12 rtPA-treated patients for comparison. RESULTS: Median intraventricular hemorrhage volume on admission for patients treated with intraventricular rtPA was 31.9 mL (interquartile range, 34.1 mL), and it decreased to 4.9 mL (interquartile range, 14.5 mL) (t2). Mean (±standard error of the mean) Hounsfield unit for intraventricular hemorrhage was 52.1 (0.59) at t0 and decreased significantly to 50.1 (0.63) (t1), and to 45.1 (0.71) (t2). Total intraventricular hemorrhage Hounsfield unit count was significantly correlated with intraventricular hemorrhage volume at all time points (t0: P = .002; t1: P < .001; t2: P < .001). On serologic and CSF analysis at t0, only higher CSF protein was positively correlated with intraventricular hemorrhage Hounsfield units (P = .03). In 24 matched patients treated with rtPA and controls, total intraventricular hemorrhage Hounsfield units were significantly lower in patients treated with rtPA at t2 (P = .02). Higher Hounsfield unit quantification of fourth ventricle hematomas independently predicted slower clearance of this ventricle (95% CI, 0.02-0.14; P = .02), along with higher intraventricular hemorrhage volume (95% CI, 0.02-0.41; P = .03) and lower CSF protein levels (95% CI, -0.003 to -0.002; P < .001). CONCLUSIONS: Intraventricular hemorrhage Hounsfield unit counts decrease significantly in the acute phase and to a greater extent with intraventricular rtPA treatment. Intraventricular hemorrhage Hounsfield units are correlated significantly with CSF protein and not with serum erythrocyte or platelet concentrations. Hounsfield unit counts may reflect intraventricular hemorrhage clot composition and rtPA sensitivity.

Research and technology in neurocritical care.

The daily practice of neurointensivists focuses on the recognition of subtle changes in the neurological examination, interactions between the brain and systemic derangements, and brain physiology. Common alterations such as fever, hyperglycemia, and hypotension have different consequences in patients with brain insults compared with patients of general medical illness. Various technologies have become available or are currently being developed. The session on "research and technology" of the first neurocritical care research conference held in Houston in September of 2009 was devoted to the discussion of the current status, and the research role of state-of-the art technologies in neurocritical patients including multi-modality neuromonitoring, biomarkers, neuroimaging, and "omics" research (proteomix, genomics, and metabolomics). We have summarized the topics discussed in this session. We have provided a brief overview of the current status of these technologies, and put forward recommendations for future research applications in the field of neurocritical care.

Treatment of unruptured intracranial aneurysms: a nationwide assessment of effectiveness.

BACKGROUND AND PURPOSE: With advances in neuroimaging, unruptured cerebral aneurysms are being diagnosed more frequently. Until 1995, surgical clipping of the aneurysm was the only treatment available. Since then, a less invasive endovascular technique has been found effective in a trial of ruptured aneurysms. No efficacy studies comparing the 2 procedures for unruptured aneurysms exist to guide clinical decisions. The objective of this study was to assess effectiveness and outcomes of endovascular versus neurosurgical treatment for unruptured intracranial aneurysms. METHODS: This was a retrospective cohort study, using data collected over a 1-year time interval (between 1998 and 2000), from 429 hospitals, in 18 states, and representing 58% of the US population. A total of 2535 treated, unruptured cerebral aneurysm cases were evaluated. The measurements used were effectiveness as measured by hospital discharge outcomes: 1) mortality (in-hospital death), 2) adverse outcomes (death or discharge to a rehabilitation or nursing facility), 3) length of stay, and 4) hospital charges. Univariate analyses compared endovascular versus neurosurgical discharge outcomes. Multivariable models were adjusted for age, sex, region, Medicaid insurance status, year, hospital case volume, comorbidity score, and admission source. RESULTS: Endovascular treatment was associated with fewer adverse outcomes (6.6% versus 13.2%), decreased mortality (0.9% versus 2.5%), shorter lengths of stay (4.5 versus 7.4 days), and lower hospital charges (42,044 dollars versus 47,567 dollars) compared with neurosurgical treatment (P < .05). After multivariable adjustment, neurosurgical cases had 70% greater odds of an adverse outcome, 30% increased hospital charges, and 80% longer length of stay compared with endovascular cases (P < .05). CONCLUSIONS: The current analysis indicates that endovascular therapy is associated with significantly less morbidity, less mortality, and decreased hospital resource use at discharge, compared with conventional neurosurgical treatment for all unruptured aneurysms. Endovascular therapy, as a treatment alternative to surgical clipping, should be offered as a viable therapeutic option for all patients considering treatment of an unruptured cerebral aneurysm.

Prevalence and knowledge of transient ischemic attack among US adults.

BACKGROUND: Little information is available about public knowledge of TIA and prevalence of a TIA diagnosis. METHODS: The National Stroke Association sponsored a telephone survey by single-stage random-digit dialing of noninstitutionalized US residents > or =18 years old, which was conducted in 1999. Demographic characteristics of participants were compared to the US population to produce weights for projections. Independent predictors of knowledge and diagnosis of TIA were determined by including all demographic characteristics in logistic regression models. RESULTS: Among 10,112 participants, 2.3% reported having been told by a physician that they had a TIA. Older age, lower income, and fewer years of education were independently associated with a diagnosis of TIA. Of those with TIA, only 64% saw a physician within 24 hours of the event. A physician diagnosis of stroke was reported by 2.3% of participants, of whom 19% recalled having had a TIA before the stroke. An additional 3.2% of participants recalled symptoms consistent with TIA but did not seek medical attention. Only 8.2% correctly related the definition of TIA and 8.6% could identify a typical symptom. Men, nonwhites, and those with lower income and fewer years of education were less likely to be knowledgeable about TIA. CONCLUSIONS: An estimated 4.9 million people in the US report a diagnosis of TIA, and many more recall symptoms consistent with TIA but do not seek medical attention. Reducing stroke risk after TIA could have substantial impact on public health but will require public education about the importance of having stroke symptoms evaluated, even if they resolve.

Vulnerability of the thalamic somatosensory pathway after prolonged global hypoxic-ischemic injury.

The aim of this study was to test the hypothesis that under prolonged global ischemic injury, the somatosensory thalamus and the cortex would manifest differential susceptibility leading to varying degrees of thalamo-cortical dissociation. The thalamic electrical responses displayed increasing suppression with longer durations of ischemia leading to a significant thalamo-cortical electrical dissociation. The data also point to a selective vulnerability of the network oscillations involving the thalamic relay and reticular thalamic neurons. An adult rat model of asphyxial cardiac arrest involving three cohorts with 3 min (G1, n=5), 5 min (G2, n=5) and 7 min (G3, n=5) of asphyxia respectively was used. The cortical evoked response, as quantified by the peak amplitude at 20 ms in the cortical evoked potential, recovers to more than 60% of baseline in all the cases. The multi-unit responses to the somatosensory stimuli recorded from the thalamic ventral posterior lateral (VPL) nuclei consists typically of three components: (1). the ON response (<30 ms after stimulus), (2). the OFF response (period of inhibition, from 30 ms to 100 ms after stimulus) and (3). rhythmic spindles (beyond 100 ms after stimulus). Asphyxia has a significant effect on the VPL ON response at 30 min (P<0.025), 60 min (P<0.05) and 90 min (P<0.05) after asphyxia. Only animals in G3 show a significant suppression (P<0.05) of the VPL ON response when compared to the sham group at 30 min, 60 min and 90 min after asphyxia. There was no significant reduction in somatosensory cortical N20 (negative peak in the cortical response at 20 ms after stimulus) amplitude in any of the three groups with asphyxia indicating a thalamo-cortical dissociation in G3. Further, rhythmic spindle oscillations in the thalamic VPL nuclei that normally accompany the ON response recover either slowly after the recovery of ON response (in the case of G1 and G2) or do not recover at all (in the case of G3).We conclude that there is strong evidence for selective vulnerability of thalamic relay neurons and its network interactions with the inhibitory interneurons in the somatosensory pathway leading to a thalamo-cortical dissociation after prolonged durations of global ischemia.

Intra-arterial papaverine-induced seizures: case report and review of the literature.

BACKGROUND: Microcatheter-guided intra-arterial (IA) papaverine infusion in conjunction with balloon angioplasty is an available therapy for patients with symptomatic vasospasm after subarachnoid hemorrhage (SAH) that is refractory to hypertensive, hypervolemic therapy. However, side effects and complications have been reported in association with its use. CASE DESCRIPTION: We report on a patient who developed symptomatic vasospasm after subarachnoid hemorrhage due to rupture of a left terminal internal carotid artery (ICA) saccular aneurysm. Seven days after the hemorrhage and 4 days after surgical clipping, the patient developed aphasia and right hemiparesis due to vasospasm, which was refractory to maximal medical treatment with volume and blood pressure elevation. Cerebral angiography identified severe narrowing of distal ICA and proximal middle cerebral artery segments bilaterally. These findings partially resolved after balloon angioplasty. However, after 300 mg of IA papaverine, the patient developed generalized convulsions. This occurred despite therapeutic serum levels of phenytoin. Twenty-four hours later, after brief neurologic improvement, recurrent neurologic deficits prompted repeat papaverine administration. Seizures again occurred after the administration of 240 mg of IA papaverine and prevented administration of the full dose. The patient did not develop further seizures and her neurologic deficits continue to resolve. CONCLUSIONS: IA papaverine-induced seizures are infrequently reported. This potential complication should be considered when papaverine administration is entertained in the treatment of anterior circulation refractory symptomatic vasospasm after SAH.

Blood clot resolution in human cerebrospinal fluid: evidence of first-order kinetics.

OBJECTIVE: To determine the kinetics of blood clot resolution in human cerebrospinal fluid. METHODS: Computed tomographic scans of 17 adult patients with intraventricular hemorrhages were analyzed. Intraventricular clot volume was determined and analyzed over time to determine both a standardized percentage rate and an absolute rate of clot resolution. Results were analyzed by use of regression for cross sectional time-series data. To determine the kinetics of intraventricular clot resolution, the effect of the clot volume on the percentage rate of clot resolution, clot half-life, and absolute rate of clot resolution was analyzed. The potential effect of age, sex, type of hemorrhage, and treatment with external ventricular drainage on the percentage rate of clot resolution was assessed. RESULTS: The percentage rate of clot resolution was 10.8% per day (95% confidence interval, 9.05-12.61 %), and it was independent of initial clot volume, age, sex, type of underlying hemorrhage, and use of external ventricular drainage. The absolute rate of clot resolution varied directly with the maximal clot volume (R2 = 0.88; P < 0.001). The percentage clot resolution data are consistent with events during the first 24 to 48 hours that antagonize clot resolution. CONCLUSION: These findings demonstrate that intraventricular blood clot resolution in patients with intraventricular hemorrhage follows first-order kinetics. The thrombolytic enzyme system responsible for intraventricular clot resolution seems to be saturated at 24 to 48 hours after the initial hemorrhage.

Transcranial magnetic stimulation in the rat.

Transcranial magnetic stimulation (TMS) allows for quantification of motor system excitability. While routinely used in humans, application in other species is rare and little is known about the characteristics of animal TMS. The unique features of TMS, i.e., predominantly interneuronal stimulation at low intensity and non-invasiveness, are particularly useful in evaluating injury and recovery in animal models. This study was conducted to characterize the rodent motor evoked potential to TMS (MEPTMS) and to develop a methodology for reproducible assessment of motor excitability in the rat. MEPTMS were compared with responses evoked by electrical stimulation of cervical spinal cord (MEPCES) and peripheral nerve. MEP were recorded by subcutaneous electrodes implanted bilaterally over the calf. Animals remained under propofol infusion and restrained in a stereotactic frame while TMS followed by CES measurements were obtained before and after 2 h of idle time. TMS was applied using a 5-cm-diameter figure-of-eight coil. MEPTMS had onset latencies of 6.7+/-1.3 ms. Latencies decreased with higher stimulation intensity (r=-0.7, P<0.05). Two morphologies, MEPTMS, 1 and MEPTMS, 2, were distinguished by latency of the first negative peak (N1), overall shape, and amplitude. MEPTMS, 2 were more frequent at higher stimulation intensity. While recruitment curves for MEPTMS, 1 followed a sigmoid course, no supramaximal response was reached for MEPTMS, 2. Mid-cervical spinal transection completely abolished any response to TMS. MEPCES showed a significantly shorter latency (5.29+/-0.24, P<0.0001). Two types of MEPCES resembling MEPTMS, 1 and 2 were observed. Neither MEPTMS nor MEPCES changed on repeat assessment after 2 h. This study demonstrates the feasibility and reproducibility of TMS in the rat. Sigmoid recruitment curves for MEPTMS, 1 suggest input-output properties similar to those of the human corticospinal system. Latency differences between CES and TMS point to a supraspinal origin of the MEPTMS. The two morphologies likely reflect different cortical or subcortical origins of MEPTMS.

Diagnostic impact of early transcranial Doppler ultrasonography on the TOAST classification subtype in acute cerebral ischemia.

OBJECTIVE: The impact of early transcranial Doppler ultrasonography (TCD) upon stroke subtype diagnosis is unknown and may affect therapeutic strategies. In this study, the diagnostic usefulness of TCD in stroke subtype diagnosis according to the criteria of the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) study was investigated in patients with acute cerebral ischemia. METHODS: TCD examination within 24 h of symptom onset was performed in 50 consecutive patients with acute cerebral ischemia. Of these 54% were female. Sixty percent of patients were black, 36% white, and 4% Asian. Initial TOAST stroke subtype diagnosis (ITSSD) was based upon clinical presentation and initial brain imaging studies. Modified TOAST stroke subtype diagnosis was determined subsequently after additional review of the TCD examination. Final TOAST stroke subtype diagnosis was determined at hospital discharge, incorporating all diagnostic studies. Using final TOAST stroke subtype diagnosis as the 'gold standard' ITSSD and modified TOAST stroke subtype diagnosis were compared in order to determine additional benefit from the information obtained by TCD. Data were collected retrospectively by a single investigator. RESULTS: ITSSD classified 23 of 50 (46%) patients correctly. After TCD, 30 of 50 (60%) patients were classified correctly, for an absolute benefit of 14% and a relative benefit of 30% (p = 0.018). Most benefit from TCD was observed in the TOAST stroke subtype category large-artery atherosclerosis, in particular in patients with intracranial vascular disease. In this category, ITSSD had a sensitivity of 27% which increased to 64% after TCD (p = 0.002). CONCLUSION: TCD within 24 h of symptom onset improves the accuracy of early stroke subtype diagnosis in patients with acute cerebral ischemia due to large-artery atherosclerosis. This may have clinical implications for early therapeutic interventions.

Cerebral hemodynamics changes during retrograde brain perfusion in dogs.

The objective of this study was to examine cerebral hemodynamics changes during hypothermic circulatory arrest (HCA) with and without retrograde cerebral perfusion (RCP). Thirteen colony-bred hound dogs were placed on cardiopulmonary bypass (CPB) and cooled to 18 degrees C. Five dogs underwent 2 hours of HCA without RCP and 8 with RCP. The animals were then rewarmed on CPB until normothermic and weaned. Cerebral blood flow velocity (CBFV) and Gosling Pulsatility Index (PI) in the middle cerebral artery (MCA) were studied using trans-cranial Doppler ultrasound (TCD). At baseline and during pre- and postarrest CPB, there was anterograde direction of blood flow in the MCA. During HCA with RCP, there was retrograde direction of blood flow in the MCA. There was no difference in CBFV between pre-, during, and postarrest CPB in the group with RCP; however, there was significantly increased CBFV during postarrest CPB in the group without RCP compared to the dogs with RCP. Later, at 3 hours after postarrest CPB, there was decreased CBFV in all animals accompanied by increased PI (2.4 +/- 0.4 and 2.2 +/- 0.6 for animals with RCP and without RCP, respectively) and abnormal TCD waveform changes including decreased diastolic compartment and sharp systolic peak. During hypothermic circulatory arrest, RCP provides CBFV in the MCA comparable to MCA CBFV during CPB. HCA dogs without RCP showed immediate hyperemia on reperfusion. The decreased CBFV and increased PI at 1 hour after postarrest CPB could be an indicator of progressive ischemic injury due to the increased intracranial pressure despite the implementation of RCP.

Coherence-weighted Wiener filtering of somatosensory evoked potentials.

In this paper, we present a Wiener filtering (WF) approach for extraction of somatosensory evoked potentials (SEPs) from the background electroencephalogram (EEG), with sweep-to-sweep variations in its signal power. To account for the EEG power variations, WF is modified by iteratively weighting the power spectrum using the coherence function. Coherence-weighted Wiener filtering (CWWF) is able to extract SEP waveforms, which have a greater level of detail as compared with conventional time-domain averaging (TDA). Using CWWF, the components of the SEP show significantly less variability. As such, CWWF should be useful as an important diagnostic tool able to detect minimal changes in the SEP. In an experimental study of cerebral hypoxia, CWWF is shown to be more responsive to detection of injury than WF or TDA.

A novel quantitative EEG injury measure of global cerebral ischemia.

OBJECTIVE: To develop a novel quantitative EEG (qEEG) based analysis method, cepstral distance (CD) and compare it to spectral distance (SD) in detecting EEG changes related to global ischemia in rats. METHODS: Adult Wistar rats were subjected to asphyxic-cardiac arrest for sham, 1, 3, 5 and 7 min (n=5 per group). The EEG signal was processed and fitted into an autoregressive (AR) model. A pre-injury baseline EEG was compared to selected data segments during asphyxia and recovery. The dissimilarities in the EEG segments were measured using CD and SD. A segment measured was considered abnormal when it exceeded 30% of baseline and its duration was used as the index of injury. A comprehensive Neurodeficit Score (NDS) at 24 h was used to assess outcome and was correlated with CD and SD measures. RESULTS: A higher correlation was found with CD and asphyxia time (r=0.81, P<0.001) compared to SD and asphyxia time (r=0.69, P<0.001). Correlation with cardiac arrest time (MAP<10 mmHg) showed that CD was superior (r=0.71, P<0.001) to SD (r=0.52, P=0.002). CD obtained during global ischemia and 90 min into recovery correlated significantly with NDS at 24 h after injury (Spearman coefficient=-0.83, P<0.005), and was more robust than the traditional SD (Spearman coefficient=-0.63, P<0.005). CONCLUSION: The novel qEEG-based injury index from CD was superior to SD in quantifying early cerebral dysfunction after cardiac arrest and in providing neurological prognosis at 24 h after global ischemia in adult rats. Studying early qEEG changes after asphyxic-cardiac arrest may provide new insights into the injury and recovery process, and present opportunities for therapy.

Optical light scatter imaging of cellular and sub-cellular morphology changes in stressed rat hippocampal slices.

Optical imaging, such as transmission imaging, is used to study brain tissue injury. Transmission imaging detects cellular swelling via an increase in light transmitted by tissue slices due to a decrease in scattering particle concentration. Transmission imaging cannot distinguish sub-cellular particle size changes from cellular swelling or shrinkage. We present an optical imaging method, based on Mie scatter theory, to detect changes in sub-cellular particle size and concentration. The system uses a modified inverted microscope and a 16-bit cooled CCD camera to image tissue light scatter at two angles. Dual-angle scatter ratio imaging successfully discriminated latex microsphere suspensions of differing sizes (0.6, 0.8, 1 and 2 microm) and concentrations. We applied scatter imaging to hippocampal slices treated with 100 microM N-methyl-D-aspartate (NMDA) to model excitotoxic injury or -40 mOsm hypotonic perfusion solution to cause edema injury. We detected light scatter decreases similar to transmission imaging in the CA1 region of the hippocampus for both treatments. Using our system, we could distinguish between NMDA and hypotonic treatments on the basis of statistically significant (P<0.0003) differences in the scatter ratio measured in CA1. Scatter imaging should be useful in studying tissue injuries or activity resulting in brain tissue swelling as well as morphological changes in sub-cellular organelles such as mitochondrial swelling.

Treatment of status epilepticus with midazolam in the critical care setting.

Status epilepticus (SE) is a potentially life-threatening condition that requires prompt and aggressive treatment. Prolonged status seizures are associated with significant physiological sequelae and neurological deficits. Although systemic events such as hyperthermia and anoxia contribute to neuronal damage, SE in and of itself can induce cell death. In general, the sooner it is brought under control, the more favourable is the prognosis. Benzodiazepines, as a group, are the most frequently used anticonvulsants in the management of status seizures. Midazolam, a water-soluble benzodiazepine, is a potent anticonvulsant that offers many advantages over typical benzodiazepines. Because of its stability in aqueous media, midazolam dissolves in common diluents such as normal saline or dextrose water. Consequently, midazolam both intravenously (i.v.) and intramuscularly (i.m.) is well tolerated locally and is associated with less venoirritation than benzodiazepines or antiepileptics that require organic solvents. The water solubility of midazolam also allows rapid and reliable absorption of the drug from the i.m. injection site. Because it is rapidly metabolised and its metabolites are pharmacologically inactive, midazolam has a short duration of action. Most patients regain full conscious state and can be evaluated soon after the cessation of treatment. Midazolam by continuous i.v. infusion and by the i.m. route has been successfully used in the treatment of SE. Although some respiratory and haemodynamic side-effects have been associated with midazolam, no clinically significant side-effects were observed with its use for the indication of SE. It is suggested that midazolam is a safe and rapidly effective treatment option in the management of SE in the critical care setting.

Early electrophysiological and histologic changes after global cerebral ischemia in rats.

INTRODUCTION: Cerebral anoxia is fundamental to morbidity and mortality after resuscitation from cardiac arrest. With no proven effective primary therapy for post-anoxic brain injury, the goal of neurologic care are supportive, to provide prognosis and prevention of further complications. With the multifaceted approach using electroencephalography (EEG), somatosensory evoked potentials (SEP), multiunit recordings, behavioral and histologic assessment, we investigated the hyperacute recovery period after resuscitation from cardiac arrest in a rat model to define the value of EEG and SEP in assessing neurologic injury. METHODS: Two cohorts of rats were subjected to sham and graded asphyxic-cardiac arrest. EEG was collected during baseline, at injury, and 90 minutes into recovery in the first rat cohort. EEG bursting during the first 90 minutes of recovery was visually analyzed and correlated with the neurologic recovery at 24 hours after injury. The neurologic recovery was assessed using a neurodeficit score (NDS) with 80 as normal and 0 as brain dead. The next rat cohort subjected to asphyxic-cardiac arrest was studied using SEP and multiunit recording in the VPL; brain histologic studies were performed at 4 hours after the asphyxia. RESULTS: The first rat cohort subjected to graded asphyxic-cardiac arrest emerged from EEG isoelectricity by burst-suppression pattern during the first 90 minutes after asphyxia. Six rats in the good outcome group (NDS >60) showed increased frequency of bursting, leading to return of EEG background activity. Six rats with a bad outcome (NDS <60) had low-intensity and persistent bursting without return of EEG background activity within 90 minutes of observation. Visual assessment showed increased EEG peak burst counts during the first 90 minutes of recovery for the rats with a good outcome compared with the rats with a bad outcome. In the second cohort, the rats were subjected to 3 minutes, 5 minutes, and 7 minutes of asphyxia. The N20 recovered to 60% of baseline in all three cases. The recovery profile of VPL is similar to that of cortical N2O for the animal with 3 minutes of asphyxia. However, VPL response is suppressed after 7 minutes of asphyxia leading to a divergence in the rate of recovery of the cortical N20 and VPL response. In both the animals (with mild and intermediate injury) in which the early response in VPL recovered to more than 50% of baseline, the recovery profile was similar to the N20 in cortical evoked potential (EP). The rats were killed 4 hours after asphyxia and the hematoxylin and eosin stain performed on the brains showed evidence of neuronal injury in the thalamic reticular nucleus (TRN) which seemed to correlate with the duration of asphyxia. CONCLUSION: We present a multimodality assessment of early neurologic recovery following resuscitation from cardiac arrest. The recovery of bursting and high-frequency oscillations may be regulated by interneurons in the TRN. The early selective vulnerability of these interneurons in the TRN may be crucial to the early neurologic recovery as assessed by EP, multiunit recording, EEG, and neurologic behavioral recovery.

Dysfunctions in mice by NMDA receptor point mutations NR1(N598Q) and NR1(N598R).

NMDA receptors in mice were mutated by gene targeting to substitute asparagine (N) in position 598 of the NR1 subunit to glutamine (Q) or arginine (R). Animals expressing exclusively the mutated NR1 alleles, NR1(Q/Q) and NR1(-/R) mice, developed a perinatally lethal phenotype mainly characterized by respiratory failure. The dysfunctions were partially rescued in heterozygous mice by the presence of pure wild-type receptors. Thus, NR1(+/Q) mice exhibited reduced life expectancy, with females being impaired in nurturing; NR1(+/R) mice displayed signs of underdevelopment such as growth retardation and impaired righting reflex, and died before weaning. We analyzed the key properties of NMDA receptors, high Ca(2+) permeability, and voltage-dependent Mg(2+) block, in the mutant mice. Comparison of the complex physiological and phenotypical changes observed in the different mutants indicates that properties controlled by NR1 subunit residue N598 are important for autonomic brain functions at birth and during postnatal development. We conclude that disturbed NMDA receptor signaling mediates a variety of neurological phenotypes.

Diffusion-weighted MRI and proton MR spectroscopic imaging in the study of secondary neuronal injury after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Cerebral ischemia has been proposed as contributing mechanism to secondary neuronal injury after intracerebral hemorrhage (ICH). Possible tools for investigating this hypothesis are diffusion-weighted (DWI) and proton magnetic resonance spectroscopic imaging ((1)H-MRSI). However, magnetic field inhomogeneity induced by paramagnetic blood products may prohibit the application of such techniques on perihematoma tissue. We report on the feasibility of DWI and (1)H-MRSI in the study of human ICH and present preliminary data on their contribution to understanding perihematoma tissue functional and metabolic profiles. METHODS: Patients with acute supratentorial ICH were prospectively evaluated using DWI and (1)H-MRSI. Obscuration of perihematoma tissue with both sequences was assessed. Obtainable apparent diffusion coefficient (Dav) and lactate spectra in perihematoma brain tissue were recorded and analyzed. RESULTS: Nine patients with mean age of 63.4 (36 to 87) years were enrolled. Mean time from symptom onset to initial MRI was 3.4 (1 to 9) days; mean hematoma volume was 35.4 (5 to 80) cm(3). Perihematoma diffusion values were attainable in 9 of 9 patients, and (1)H-MRSI measures were obtainable in 5 of 9 cases. Dav in perihematoma regions was 172.5 (120.0 to 302.5)x10(-5) mm(2)/s and 87.6 (76.5 to 102.1)x10(-5) mm(2)/s in contralateral corresponding regions of interest (P=0.002). One patient showed an additional area of reduced Dav with normal T(2) intensity, which suggests ischemia. (1)H-MRSI revealed lactate surrounding the hematoma in 2 patients. CONCLUSIONS: DWI and (1)H-MRSI can be used in the study of ICH patients. Our preliminary data are inconsistent with ischemia as the primary mechanism for perihematoma tissue injury. Further investigation with advanced MRI techniques will give a clearer understanding of the role that ischemia plays in tissue injury after ICH.