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Pre-clinical studies of traumatic brain injury (TBI) show that glyburide reduces edema and hemorrhagic progression of contusions. We conducted a small Phase II, three-institution, randomized placebo-controlled trial of subjects with TBI to assess the safety and efficacy of intravenous (IV) glyburide. Twenty-eight subjects were randomized and underwent a 72-h infusion of IV glyburide or placebo, beginning within 10 h of trauma. Of the 28 subjects, 25 had Glasgow Coma Scale (GCS) scores of 6-10, and 14 had contusions. There were no differences in adverse events (AEs) or severe adverse events (ASEs) between groups. The magnetic resonance imaging (MRI) percent change at 72-168 h from screening/baseline was compared between the glyburide and placebo groups. Analysis of contusions (7 per group) showed that lesion volumes (hemorrhage plus edema) increased 1036% with placebo versus 136% with glyburide (p = 0.15), and that hemorrhage volumes increased 11.6% with placebo but decreased 29.6% with glyburide (p = 0.62). Three diffusion MRI measures of edema were quantified: mean diffusivity (MD), free water (FW), and tissue MD (MDt), corresponding to overall, extracellular, and intracellular water, respectively. The percent change with time for each measure was compared in lesions (n = 14) versus uninjured white matter (n = 24) in subjects receiving placebo (n = 20) or glyburide (n = 18). For placebo, the percent change in lesions for all three measures was significantly different compared with uninjured white matter (analysis of variance [ANOVA], p

Background Magnetic resonance imaging-guided focused ultrasound thalamotomy is approved by the U.S. Food and Drug Administration for treatment of essential tremor. Although this incisionless technology creates an ablative lesion, it potentially avoids serious complications of open stereotactic surgery. Objective To determine the safety profile of magnetic resonance imaging-guided focused ultrasound unilateral thalamotomy for essential tremor, including frequency, and severity of adverse events, including serious adverse events. Methods Analysis of safety data for magnetic resonance imaging-guided focused ultrasound thalamotomy (186 patients, five studies). Results Procedure-related serious adverse events were very infrequent (1.6%), without intracerebral hemorrhages or infections. Adverse events were usually transient and were commonly rated as mild (79%) and rarely severe (1%). As previously reported, abnormalities in sensation and balance were the commonest thalamotomy-related adverse events. Conclusion The overall safety profile of magnetic resonance imaging-guided focused ultrasound thalamotomy supports its role as a new option for patients with medically refractory essential tremor. © 2018 International Parkinson and Movement Disorder Society.

OBJECTIVE Magnetic resonance guided focused ultrasound (MRgFUS) has recently been investigated as a new treatment modality for essential tremor (ET), but the durability of the procedure has not yet been evaluated. This study reports results at a 2- year follow-up after MRgFUS thalamotomy for ET. METHODS A total of 76 patients with moderate-to-severe ET, who had not responded to at least two trials of medical therapy, were enrolled in the original randomized study of unilateral thalamotomy and evaluated using the clinical rating scale for tremor. Sixty-seven of the patients continued in the open-label extension phase of the study with monitoring for 2 years. Nine patients were excluded by 2 years, for example, because of alternative therapy such as deep brain stimulation (n = 3) or inadequate thermal lesioning (n = 1). However, all patients in each follow-up period were analyzed. RESULTS Mean hand tremor score at baseline (19.8 ± 4.9; 76 patients) improved by 55% at 6 months (8.6 ± 4.5; 75 patients). The improvement in tremor score from baseline was durable at 1 year (53%; 8.9 ± 4.8; 70 patients) and at 2 years (56%; 8.8 ± 5.0; 67 patients). Similarly, the disability score at baseline (16.4 ± 4.5; 76 patients) improved by 64% at 6 months (5.4 ± 4.7; 75 patients). This improvement was also sustained at 1 year (5.4 ± 5.3; 70 patients) and at 2 years (6.5 ± 5.0; 67 patients). Paresthesias and gait disturbances were the most common adverse effects at 1 year-each observed in 10 patients with an additional 5 patients experiencing neurological adverse effects. None of the adverse events worsened over the period of follow-up, and 2 of these resolved. There were no new delayed complications at 2 years. INTERPRETATION Tremor suppression after MRgFUS thalamotomy for ET is stably maintained at 2 years. Latent or delayed complications do not develop after treatment. Ann Neurol 2018;83:107-114.

Background Magnetic resonance-guided focused ultrasound ablation of the thalamic ventral intermediate nucleus is a safe and effective treatment for medically refractory essential tremor. However, indirect targeting of the ventral intermediate nucleus using stereotactic coordinates from normal neuroanatomy can be inefficient. We therefore evaluated the feasibility of supplementing this method with direct targeting of the dentato-rubro-thalamic tract. Methods We retrospectively identified four patients undergoing magnetic resonance-guided focused ultrasound ablation for essential tremor in which preoperative diffusion tractography imaging of the dentato-rubro-thalamic tract was fused with T2 weighted-imaging and utilized for intra-procedural targeting. The size and location of the dentato-rubro-thalamic tract and 24-hour lesion, as well as the center of the stereotactic coordinates, was evaluated. Finally, the amount of overlap between the dentato-rubro-thalamic tract and the lesion was calculated. Results The 24-hour lesion size was homogeneous in the cohort (mean 31.3 mm2, range 30–32 mm2), while there was substantial variation in the dentato-rubro-thalamic tract area (mean 14.3 mm2, range 3–24 mm2). The center of the stereotactic coordinates and dentato-rubro-thalamic tract diverged by more than 1 mm in mediolateral and anterposterior directions in all patients, while the dentato-rubro-thalamic tract and lesion centers were in close proximity (mean mediolateral separation 1 mm, range 0.1–2.2 mm; mean anteroposterior separation 0.75 mm, range 0.4–1.2 mm). There was greater than 50% coverage of the dentato-rubro-thalamic tract by the lesion in all patients (mean 82.9%, range 66.7–100%). All patients experienced durable tremor relief. Conclusion Direct targeting of the dentato-rubro-thalamic tract using diffusion tractography imaging fused to T2 weighted-imaging may be a useful strategy for focused ultrasound treatment of essential tremor. Further investigation of the technique is warranted.

ObjectiveTo test the hypothesis that transcranial magnetic resonance–guided focused ultrasound (tcMRgFUS) thalamotomy is effective, durable, and safe for patients with medication-refractory essential tremor (ET), we assessed clinical outcomes at 3-year follow-up of a controlled multicenter prospective trial.MethodsOutcomes were based on the Clinical Rating Scale for Tremor, including hand combined tremor–motor (scale of 0–32), functional disability (scale of 0–32), and postural tremor (scale of 0–4) scores, and total scores from the Quality of Life in Essential Tremor Questionnaire (scale of 0–100). Scores at 36 months were compared with baseline and at 6 months after treatment to assess for efficacy and durability. Adverse events were also reported.ResultsMeasured scores remained improved from baseline to 36 months (allp< 0.0001). Range of improvement from baseline was 38%–50% in hand tremor, 43%–56% in disability, 50%–75% in postural tremor, and 27%–42% in quality of life. When compared to scores at 6 months, median scores increased for hand tremor (95% confidence interval [CI] 0–2,p= 0.0098) and disability (95% CI 1–4,p= 0.0001). During the third follow-up year, all previously noted adverse events remained mild or moderate, none worsened, 2 resolved, and no new adverse events occurred.ConclusionsResults at 3 years after unilateral tcMRgFUS thalamotomy for ET show continued benefit, and no progressive or delayed complications. Patients may experience mild degradation in some treatment metrics by 3 years, though improvement from baseline remains significant.Clinicaltrials.gov identifierNCT01827904.Classification of evidenceThis study provides Class IV evidence that for patients with severe ET, unilateral tcMRgFUS thalamotomy provides durable benefit after 3 years.

Transcranial focused ultrasound (FUS) can noninvasively transmit acoustic energy with a high degree of accuracy and safety to targets and regions within the brain. Technological advances, including phased-array transducers and real-time temperature monitoring with magnetic resonance thermometry, have created new opportunities for FUS research and clinical translation. Neuro-oncology, in particular, has become a major area of interest because FUS offers a multifaceted approach to the treatment of brain tumors. FUS has the potential to generate cytotoxicity within tumor tissue, both directly via thermal ablation and indirectly through radiosensitization and sonodynamic therapy; to enhance the delivery of therapeutic agents to brain tumors by transiently opening the blood-brain barrier or improving distribution through the brain extracellular space; and to modulate the tumor microenvironment to generate an immune response. In this review, we describe each of these applications for FUS, the proposed mechanisms of action, and the preclinical and clinical studies that have set the foundation for using FUS in neuro-oncology. ABBREVIATIONS BBB, blood-brain barrierCED, convection-enhanced delivery5-Ala, 5-aminolevulinic acidFUS, focused ultrasoundGBM, glioblastoma multiformeHSP, heat shock proteinMRgFUS, magnetic resonance-guided focused ultrasoundpFUS, pulsed focused ultrasound.

Background Magnetic resonance-guided focused ultrasound thalamotomy (FUS-T) is an emerging treatment for essential tremor (ET). Objective To determine the predictors of outcomes after FUS-T. Methods Two treatment groups were analyzed: 75 ET patients enrolled in the pivotal trial, between 2013 and 2015; and 114 patients enrolled in the postpivotal trials, between 2015 and 2016. All patients had medication-refractory, disabling ET, and underwent unilateral FUS-T. The primary outcome (hand tremor score, 32-point scale with higher scores indicating worse tremor) and the secondary outcome variables (Clinical Rating Scale for Tremor Part C score: 32-point scale with higher scores indicating more disability) were assessed at baseline and 1, 3, 6, and 12 mo. The operative outcome variables (ie, peak temperature, number of sonications) were analyzed. The results between the 2 treatment groups, pivotal and postpivotal, were compared with repeated measures analysis of variance and adjusted for confounding variables. Results A total of 179 patients completed the 12-mo evaluation. The significant predictors of tremor outcomes were patient age, disease duration, peak temperature, and number of sonications. A greater improvement in hand tremor scores was observed in the postpivotal group at all time points, including 12 mo (61.9% ± 24.9% vs 52.1% ± 24.9%, P = .009). In the postpivotal group, higher energy was used, resulting in higher peak temperatures (56.7 ± 2.5 vs 55.6 ± 2.8°C, P = .004). After adjusting for age, years of disease, number of sonications, and maximum temperature, the treatment group was a significant predictor of outcomes (F = 7.9 [1,165], P = .005). Conclusion We observed an improvement in outcomes in the postpivotal group compared to the pivotal group potentially reflecting a learning curve with FUS-T. The other associations of tremor outcomes included patient age, disease duration, peak temperature, and number of sonications.

To compare the performance of five prognostic models [RTOG recursive partitioning analysis (RPA), Score Index for Radiosurgery in Brain Metastases (SIR), Barnholtz-Sloan–Kattan nomogram (BSKN), diagnosis-specific Graded Prognostic Assessment (dsGPA), and Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA)] against actual survival in patients with brain metastases treated with SRS +/− WBRT. 100 consecutive patients treated with SRS +/− WBRT between January 2006 and July 2012 were retrospectively analyzed. Patients were binned according to 33 percentiles of the predicted survival distribution for the BSKN and dsGPA models to compare with LungmolGPA, RPA and SIR. Pearson’s correlation coefficients between predicted and observed survival were estimated to quantify the proportion of variance in observed survival. Median survival for the entire cohort was 13.5 months, with predicted vs actual MS by BSKN, SIR, dsGPA, RPA, adenocarcinoma Lung-molGPA, and nonadenocarcinoma Lung-molGPA was 3.8 vs 15.6 months, 7 vs 13.5 months, 9.4 vs 13.5 months, 10.3 vs 13.5 months, 13.7 vs 13.7 months, and 9.8 vs 9.7 months, respectively. The BSKN model and adenocarcinoma LungmolGPA created three groups with a statistically significantly different MS (p = 0.002 and p = 0.01, respectively). All models under-predicted MS and only the BSKN and Lung-molGPA model stratified patients into three risk groups with statistically significant actual MS. The prognostic groupings of the adenocarcinoma Lung-molGPA group was the best predictor of MS, and showed that we are making improvements in our prognostic ability by utilizing molecular information that is much more widely available in the current treatment era.

Focused ultrasound (FUS) produces a region of high intensity at the focal zone of the beam but with minimal effects at adjacent areas, allowing the sonication of deep targets throughout the body. Despite early obstacles to transmitting ultrasound energy through the skull, recent advances in ultrasound technology, software, and real-time monitoring have resulted in a renewed interest in the clinical applications of transcranial FUS. Following extensive pre-clinical studies, ultrasound-induced thermal ablation has been approved by several countries for the treatment of essential tremor, Parkinson's disease, obsessive-compulsive disorder, depression, and neuropathic pain. Ongoing clinical trials involving patients with brain tumors, Alzheimer's disease, or epilepsy, and pre-clinical work involving stroke and hydrocephalus have the potential to significantly expand the possible indications for transcranial FUS in the future.

Traumatic brain injury (TBI) is a major cause of death and disability. In the United States alone approximately 1.4 million sustain a TBI each year, of which 50,000 people die, and over 200,000 are hospitalized. Despite numerous prior clinical trials no standard pharmacotherapy for the treatment of TBI has been established. Citicoline, a naturally occurring endogenous compound, offers the potential of neuroprotection, neurorecovery, and neurofacilitation to enhance recovery after TBI. Citicoline has a favorable side-effect profile in humans and several meta-analyses suggest a benefit of citicoline treatment in stroke and dementia. COBRIT is a randomized, double-blind, placebo-controlled, multi-center trial of the effects of 90 days of citicoline on functional outcome in patients with complicated mild, moderate, and severe TBI. In all, 1292 patients will be recruited over an estimated 32 months from eight clinical sites with random assignment to citicoline (1000 mg twice a day) or placebo (twice a day), administered enterally or orally. Functional outcomes are assessed at 30, 90, and 180 days after the day of randomization. The primary outcome consists of a set of measures that will be analyzed as a composite measure using a global test procedure at 90 days. The measures comprise the following core battery: the California Verbal Learning Test II; the Controlled Oral Word Association Test; Digit Span; Extended Glasgow Outcome Scale; the Processing Speed Index; Stroop Test part 1 and Stroop Test part 2; and Trail Making Test parts A and B. Secondary outcomes include survival, toxicity, and rate of recovery.

OBJECTIVE: This study was conducted to evaluate outcome after decompressive craniectomy (DC) in the setting of mass evacuation with or without intracranial pressure (ICP) monitoring. METHODS: Over a 48-month period (March 2000 to March 2004), 54 of 967 consecutive head injury patients underwent DC for evacuation of a mass lesion. DC was performed without ICP monitoring in 27 patients who required urgent decompression (group A) and in 27 patients who did not require urgent surgery and who had their ICP monitored for 1 to 14 days before surgery (group B). RESULTS: In group A, the mean Glasgow Coma Scale score was 6.0; 80% had computed tomographic evidence of a shift greater than 5 mm; and 25 patients underwent DC immediately after resuscitation. In group B, the mean Glasgow Coma Scale score was 7.3; 40% had computed tomographic evidence of shift; and 75% underwent DC 24 hours or longer after presentation. Overall, 22 patients died (12 in group A and 10 in group B), 11 remained vegetative or severely disabled (3 in group A and 8 in group B), and 19 had good recovery (11 in group A and 8 in group B). Two patients were lost to follow-up. In 18 group B patients with ICP greater than 20 mm Hg before mass evacuation, ICP dropped an average of 13 mm Hg (P < 0.001 A mass lesion greater than 50 mL (odds ratio [OR], 2.86; 95% confidence interval [Cl], 1.04-7.89) and evidence of low attenuation on computed tomography before (OR, 3.3; 95% Cl, 1.1-10.3) or after (OR, 2.92; 95% Cl, 1.02-8.34) DC were predictors of death. A good outcome occurred in 42% of patients with and in 63% of patients without delayed traumatic injury (OR, 0.3; 95% Cl, 0.1-1.1 Outcome was favorable in 78.6% of patients who had no ICP monitoring before DC versus 47.1 % of patients with ICP monitoring (OR, 0.2; 95% Cl, 0.1-1.2). CONCLUSION: In this study, mortality after DC for mass lesion was greater than expected, and outcome did not differ between patients with or without ICP monitoring.

One hundred and ninety-three patients with brain metastases from various primary sites received Gamma Knife radiosurgery (GKR) from July 1992 to August 1997 and were reviewed to evaluate their clinical outcome. Survival follow-up was available on 173 patients. Whole-brain radiation therapy was also administered to 148 of these patients. The median survival was 13.1 months from initial detection of brain metastases, and 7.5 months from GKR. Univariate and multivariate analyses were performed to determine prognostic factors that influenced survival following GKR. Enhanced survival is observed in patients with radiosensitive tumor types, supratentorial tumor, history of brain tumor resection, controlled primary site, and absent extracranial metastases. Local lesion control was obtained in 82% of the patients according to their last follow-up MRI scan. GKR is an effective means of treating patients with brain metastases.

The capacity of adult human microglia to activate memory T-lymphocyte responses to recall viral antigens in autologous peripheral blood lymphocytes (PBL) was examined using measles and influenza viruses. Microglia and peripheral blood macrophages were isolated form 6 patients who underwent surgical brain biopsies. Microglial cultures readily expressed high levels of HLA class II molecules under basal culture conditions. However, compared to macrophages, microglia appeared to express much lower levels of CD45, a phenotype that has been associated with the ability of rat brain macrophage/microglia to present antigen. PBL were depleted of macrophages (D-PBL) and the efficacy of the depletion was assessed by a reduction in the T-cell response to concanavalin A. D-PBL were reconstituted with macrophages, microglia, or in some cases microglia pretreated with interferon-gamma (IFN gamma). It was observed that microglia were as efficient as macrophages in presenting viral antigens. Pretreatment of microglia with IFN gamma did not enhance further antigen presentation. Oligodendrocytes which lack constitutive or inducible HLA class II molecules failed to present viral antigens. The results have implications of the direct function of microglia as perpetuators and possibly initiators of immune responses to virus infection in the central nervous system compartment.

In view of the pathophysiology and biomechanics of severe closed head injury (CHI) in children, we postulated that the frontal lobes sustain diffuse injury, even in the absence of focal brain lesions detected by magnetic resonance imaging (MRI). This study quantitated the morphological effects of CHI on the frontal lobes in children who sustained head trauma of varying severity. The MRI findings of 14 children who had sustained severe CHIs (Glasgow Coma Scale score of < or = 8) were compared with the findings in a matched group of 14 children having sustained mild head injuries (Glasgow Coma Scale score of 13-15). The patients ranged in age from 5 to 15 years at the time of their MRIs, which were acquired at least 3 months postinjury. MRI findings revealed no focal areas of abnormal signal in the frontal lobes. Volumetric analysis disclosed that the total prefrontal cerebrospinal fluid increased and the gray matter volume decreased in the patients with severe CHI, relative to the mildly injured comparison group. Gray matter volume was also reduced in the orbitofrontal and dorsolateral regions of the brains of children with severe CHI, relative to the children who sustained mild head trauma. These volumetric findings indicate that prefrontal tissue loss occurs after severe CHI in children, even in the absence of focal brain lesions in this area. Nearly two-thirds of the children who sustained severe CHIs were moderately disabled after an average postinjury interval of 3 years or more, whereas 12 of the 14 patients with mild CHIs attained a good recovery (2 were moderately disabled) by the time of study.(ABSTRACT TRUNCATED AT 250 WORDS)

Mitochondrial dysfunction may be central to the pathophysiology of traumatic brain injury (TBI) and often can be recognized cytologically by changes in mitochondrial ultrastructure. This study is the first to broadly characterize and quantify mitochondrial morphologic alterations in surgically resected human TBI tissues from three contiguous cortical injury zones. These zones were designated as injury center (Near), periphery (Far), and Penumbra. Tissues from 22 patients with TBI with varying degrees of damage and time intervals from TBI to surgical tissue collection within the first week post-injury were rapidly fixed in the surgical suite and processed for electron microscopy. A large number of mitochondrial structural patterns were identified and divided into four survival categories: normal, normal reactive, reactive degenerating, and end-stage degenerating profiles. A tissue sample acquired at 38 hours post-injury was selected for detailed mitochondrial quantification, because it best exhibited the wide variation in cellular and mitochondrial changes consistently noted in all the other cases. The distribution of mitochondrial morphologic phenotypes varied significantly between the three injury zones and when compared with control cortical tissue obtained from an epilepsy lobectomy. This study is unique in its comparative quantification of the mitochondrial ultrastructural alterations at progressive distances from the center of injury in surviving TBI patients and in relation to control human cortex. These quantitative observations may be useful in guiding the translation of mitochondrial-based neuroprotective interventions to clinical implementation.

The present study was conducted to further our understanding of the relationship between performance on neuropsychological tests and functional status after head injury and to provide information on the relative usefulness of neuropsychological tests as outcome measures in clinical trials of brain injury. We sought to select the fewest number of 19 neuropsychological tests administered to 110 patients that, in combination, were most closely related to outcome (as measured by the Glasgow Outcome Scale (GOS) and to the remaining neuropsychological measures. The relationship of memory and intellectual deficits to functional status was also considered. To address these questions, we analyzed 19 neuropsychological measures and GOS scores of 110 severely brain injured patients from the Traumatic Coma Data Bank. Of 19 neuropsychological measures compared with GOS at 3 and 6 months, four tests (Controlled Oral Word Association, Grooved Pegboard, Trailmaking Part B, and Rey-Osterrieth Complex Figure Delayed Recall) provided the closest relationship to GOS and to the remaining 15 tests. Similar analyses were performed on 30 moderately injured patients to test the generality of our findings across different levels of patient severity. The same four tests were found to be highly predictive of GOS. Grooved Pegboard, a test of fine motor coordination, accounted for 80% of the variation in GOS. Fifteen percent of 116 patients with severe brain injury could not complete a neuropsychological battery and 39% were excluded because of previous brain injury or known substance abuse. Language: en

Evoked magnetic fields to randomized infrequent omissions of visual stimuli resulted in a magnetic field pattern over the right hemisphere consistent with a dipolar source and led to localization of this source within the superior temporal sulcus. Previous investigations using implanted microelectrodes, ablation/lesion procedures in monkeys and observations of behavioral anomalies following injury in humans have already indicated the importance of the inferior portions of the temporal lobe in visual processing. However, until now, no method was available to study noninvasively the role of temporal cortex during visual processing.

Predictors of outcome were examined in this prospective study of 151 patients severely injured by civilian gunshot wounds. Of the 151 patients, 133 (88%) died. Of the 123 patients with an initial Glasgow Coma Scale score of 3-5, 116 (94%) died, whereas of the 20 with an initial Glasgow Coma Scale score of 6-8, 14 (70%) died. There were no good outcomes, and only three moderate recoveries in patients who had initial scores of 8 or less. In those patients who survived long enough for intracranial pressure monitoring, intracranial hypertension predicted a very poor outcome. Computed tomographic scan characteristics such as midline shift, compression or obliteration of the mesencephalic cisterns, the presence of subarachnoid blood, intraventricular hemorrhage, and the presence of hyperdense or mixed-density lesions greater than 15 mL, either bilateral or unilateral, were all associated with a poor outcome. However, neither the caliber of gun nor the distance of the gun from the head significantly affected the risk of dying.

Reversible cerebral atrophy in humans has been documented by computed tomography in alcoholics and has been described as an incidental finding after head injury in children. Two children were studied who had sustained a severe closed head injury, 1 and 5 years previously, after which cerebral atrophy had developed, according to subacute computed tomography. Reversible cerebral atrophy was seen on magnetic resonance images of both patients. Despite normal appearance on magnetic resonance images more than 1 year after injury, both patients exhibited residual neuropsychological impairment on a broad range of cognitive and memory tests.

Fifty patients who sustained mild to moderate closed head injury (CHI) underwent a CT scan, MRI, and neurobehavioural testing. At baseline 40 patients had intracranial hyperintensities detected by MRI which predominated in the frontal and temporal regions, whereas 10 patients had lesions detected by CT. Neurobehavioural data obtained during the first admission to hospital disclosed no distinctive pattern in subgroups of patients characterised by lesions confined to the frontal, temporal, or frontotemporal regions, whereas all three groups exhibited pervasive deficits in relation to normal control subjects. The size of extraparenchymal lesion was significantly related to the initial Glasgow Coma Scale score, whereas this relation was not present in parenchymal lesions. One and three month follow up MRI findings showed substantial resolution of lesion while neuropsychological data reflected impressive recovery. The follow up data disclosed a trend from pervasive deficits to more specific impairments which were inconsistently related to the site of brain lesion. These results corroborate and extend previous findings, indicating that intracranial lesions detected by MRI are present in most patients hospitalised after mild to moderate CHI. Individual differences in the relation between site of lesion and the pattern of neuropsychological findings, which persist over one to three months after mild to moderate CHI, remain unexplained.

Serial neuropsychological findings were obtained in a case of infantile right parietal injury who was studied over a 13 year follow-up period. Magnetic resonance imaging at age 13 years documented extensive injury to the right hemisphere, particularly the parietal region. Serial examinations at age 7 and 13 years showed intact visual attention, normal expression and processing of affect and variable visuospatial abilities. However, intellectual development was generally depressed. Implications of these findings for recovery from early brain injury are discussed.

The Children's Orientation and Amnesia Test (COAT) was developed to assess cognition serially during the early stage of recovery from traumatic brain injury in children and adolescents. The norms for the COAT, which is composed of 16 items evaluating general orientation, temporal orientation, and memory, were defined from data obtained from 146 children aged 3 to 15 years. In 37 patients with head injuries, the duration of posttraumatic amnesia, as indicated by the number of days COAT scores were in the impaired range, was significantly related to both verbal and nonverbal memory at the baseline and 6 and 12 months after injury. COAT scores were a better predictor of verbal and nonverbal memory performance than the Glasgow Coma Scale score at 6 and 12 months after the injury. This study shows that the COAT has adequate reliability and validity as a measure of the duration of posttraumatic amnesia in children and adolescents.

This article reports on a study in which the outcome of sober versus intoxicated traumatic brain injured (TBI) patients was evaluated, controlling for age and preinjury alcohol history. Levels of blood alcohol were evaluated for association with the intracranlal diagnosis, controlling for alcohol history and age. Also, intracranial diagnosis versus preinjury alcohol history were evaluated, controlling for blood alcohol level and age. The results showed an association between a history of excessive alcohol use and outcome that was reflected in poor outcome for all types of computed tomography diagnosis and a greater prevalence of mass lesions. Clinical consequences, as well as limitations of the study, are discussed.

Evoked magnetic field recordings were used to localize multiple sources of the negative component of cortical responses to auditory stimuli. The negative cortical component of the auditory evoked response, often called the N100, has traditionally been of interest due to its sensitivity to both stimulation parameters and cognitive variables. Results indicate that this component appears to reflect spreading activation of adjacent cortical columns within the primary projection area of the temporal lobe, extending anteriorly for about 1 cm following the downward slope of the superior surface of the lobe.

• Magnetoencephalography offers the possibility of localizing accurately and noninvasively the source of intracranial currents associated with normal and abnormal brain activity. The purpose of this study was to assess the validity and across-subject reliability of localization of cortical sources responding to ipsilateral and contralateral auditory stimulation. Magnetic evoked fields to both stimulation conditions were measured in eight consecutive normal subjects, and the cortical sources of these fields were estimated on the basis of these measurements. Subsequent projection of the source location coordinates onto magnetic resonance images showed that in all subjects the sources were accurately estimated to fall in the vicinity of the auditory cortex and that two separate sources may account for the response to ipsilateral and contralateral stimulation.

We felt there was a need for a new device with "minimal invasive" tracking hardware, to be used in image-guided neurosurgery, and the system we designed to fill this need is now presented. It combines precision of movement, stability and self-positioning capabilities together with optically tracked registration and procedural control within the structure of a surgical microscope. The results are reduced setup time and minimal "distraction" from the procedure itself, factors of special relevance in child neurosurgery. The system is composed of a six-axis industrial robot suitable for use in the operating room, carrying a surgical microscope. Three progressive scan-synchronized infrared cameras mounted around the lenses of the scope are used to register the patient's position and track surgical instruments with reference to the registered space. Orientation of the microscope during surgery is obtained with a six-axis joystick used as a microscope handle. The system has been clinically used in 14 cases, and it has proven itself to be reliable, providing the expected performance advantages. The implementation of a tracked ultrasound or endoscope intraoperative imaging source is also described.

Objectives : The ability to analyze patterns of recorded seizure activity is important in the localization and classification of seizures. Ictal evolution is typically a dynamic process with signals composed of multiple frequencies; this can limit or complicate methods of analysis. The recently-developed matching pursuit algorithm permits continuous time–frequency analyses, making it particularly appealing for application to these signals. The studies here represent the initial applications of this method to intracranial ictal recordings. Methods : Mesial temporal onset partial seizures were recorded from 9 patients. The data were analyzed by the matching pursuit algorithm were continuous digitized single channel recordings from the depth electrode contact nearest the region of seizure onset. Time–frequency energy distributions were plotted for each seizure and correlated with the intracranial EEG recordings. Results : Periods of seizure initiation, transitional rhythmic bursting activity, organized rhythmic bursting activity and intermittent bursting activity were identified. During periods of organized rhythmic bursting activity, all mesial temporal onset seizures analyzed had a maximum predominant frequency of 5.3–8.4 Hz with a monotonic decline in frequency over a period of less than 60 s. The matching pursuit method allowed for time–frequency decomposition of entire seizures. Conclusions : The matching pursuit method is a valuable tool for time–frequency analyses of dynamic seizure activity. It is well suited for application to the non-stationary activity that typically characterizes seizure evolution. Time–frequency patterns of seizures originating from different brain regions can be compared using the matching pursuit method.

This issue of Neurosurgical Focus is devoted to epilepsy surgery and includes a variety of topics ranging from technical nuances to edge-of-the-envelope interventions that are just beginning to find their place in surgical management. Eleven papers are included. Some of the new findings and methods that we think will interest readers involve magnetoencephalography (MEG), stereoelectroencephalography (SEEG), and a-methyl-l-tryptophan (AMT)–PET, as well as novel ways of coregistering preand postoperative MR images. We also include a review of optogenetics as it could apply to excitation or inhibition of neural circuits still being studied in animal models. Other reports consider more standard, but no less relevant, issues: complications and specific etiologies such as new-onset refractory status epilepticus and hypothalamic hamartoma. In the report, “Tissue localization during resective epilepsy surgery,” the authors describe methods they use for localization of specific brain regions and implantable electrodes as well as tissue removed by coregistering preand postoperative information from MRI, including functional MRI (fMRI), allowing for the correlation of anatomy, pathology (even at a molecular level), and outcome. Similarly, new methodology for localization is considered in “Correlation between magnetoencephalography-based ‘clusterectomy’ and postoperative seizure freedom,” in which the authors describe using clustering of MEG-derived information from interictal spikes to guide resections, particularly for extratemporal foci. Another report, “Complications after mesial temporal lobe epilepsy surgery via inferior temporal gyrus approach,” considers related complications, which in the authors’ hands showed very acceptable risks. The report, “Seizure control after subtotal lesional resection,” includes the description of a single case as well as a comprehensive literature review of tailored subtotal resection for lesional epilepsy. Also included in this issue is a valuable review of hemispherectomy, “Hemispherectomy: historical review and recent technical advances.” As the title indicates, this paper expands the discussion to more novel imaging and surgical strategies. Another report continues the discussion of hemispherectomy and hemispherotomy—“Disconnective surgery in posterior quadrantic epilepsy: experience in a consecutive series of 10 patients”—but restricts considerations to temporal parietooccipital resections and disconnections accordingly. Stereoelectroencephalography is discussed in the report, “Stereoelectroencephalography for continuous twodimensional cursor control in a brain-machine interface,” in which the methodology of analyzing information from specially designed depth electrodes, each with multiple contacts, is presented. The relevance to localization for epilepsy as well as to brain-machine interfaces is considered. “Optogenetics in epilepsy” presents an overview of futuristic methodology, induction of ion channels using viral vectors, and the use of light to stimulate or inhibit neural circuits. The authors review the work done in animal models and their relevance to human seizures. Several reports consider specific etiologies: inflammation and hypothalamic hamartomas (the latter discussed in 2 parts). “Successful surgical treatment of an inflammatory lesion associated with new-onset refractory status epilepticus” presents a single case and reviews the topic, including a discussion of more standard methods for localization coregistered with molecular information from AMT-PET. The paired reports on hypothalamic hamartomas review this entity in detail as well as management strategies. Epilepsy surgery sits at the juncture of classic anatomical neurosurgery and functional neurosurgery. Surgery to treat epilepsy also provides us with an opportunity to understand neuronal networks. The papers in this issue illustrate some of the issues, challenges, and exciting developments in the field. (http://thejns.org/doi/abs/10.3171/2013.4.FOCUS13138)

Summary: We report the case of a 44-year-old woman with complex partial seizures (CPS) of right frontotemporal origin who developed generalized amnesia after undergoing intracranial electrode implantation complicated by left hippocampal hemorrhage. Serial memory testing disclosed recovery from the amnesic disorder, while repeated magnetic resonance imaging (MRI) showed resolution of her left hippocampal hemorrhage in a 2-month period. A second intracarotid amytal procedure confirmed the capability of her left temporal region to support memory. Consequently, aright orbitofrontotemporal lobectomy was performed without complication.

This study investigated the usefulness of a delayed alternation task in characterizing the cognitive sequelae of closed head injury in children and adolescents. Verbal learning and memory (California Verbal Learning Test) were also studied for comparison. Sixty-two closed head injury patients (mean age, 9.6 years), who were studied after an average postinjury interval of 20 months, were divided according to both their lowest postresuscitation Glasgow Coma Scale score (3 to 8 versus 9 to 15) and age range (5 to 7 years versus 8 to 16 years) at the time of testing. Magnetic resonance imaging was performed to evaluate the relationship of focal brain lesions to cognitive and memory performance. Fifty-six neurologically normal children (mean age, 9.9 years) were tested on the same measures. The results disclosed no relationship between delayed alternation performance and severity of injury. In contrast, verbal memory was impaired in the severely-injured patients, relative to both controls and less severely-injured patients. Frontal lobe (but not extrafrontal) lesion size incremented the Glasgow Coma Scale score in predicting verbal memory, but there was no relationship between focal brain lesions and delayed alternation performance. In contrast to the tendency for more efficient delayed alternation performance in the 5- to 7-year-old subjects than in the 8- to 16-year-old subjects, verbal memory significantly improved with age in the closed head injury and control groups. Notwithstanding our essentially negative findings for delayed alternation, it is possible that this task may be useful for assessing frontal lobe injury in younger children or infants. Our results indicate limitations in extrapolating from nonhuman primate studies of delayed alternation to frontal lobe function in children and adolescents. (J Child Neurol 1994;9:81-89).

The effects of transcallosal surgery on interhemispheric transfer of information were investigated in five patients who underwent partial section of the corpus callosum for evacuation of a brain tumor. In comparison with normal controls, postoperative findings indicated subtle motor and/or sensory manifestations of hemispheric disconnection which tended to resolve overtime. However, in no case were the disconnection effects disabling in the performance of daily activities.

To characterize the brain pathology in relation to long-term outcome after pediatric head injury, 55 children were studied by magnetic resonance imaging (MRI) at least 3 months after sustaining moderate to severe closed head injury (CHI). Thirty-nine of the patients had abnormal signal intensity consistent with residual brain lesions, including 28 children with lesions involving the frontal lobes. The clinical features of children with frontal lesions, extrafrontal lesions, and diffuse injury were compared. The analysis disclosed that children with frontal lobe lesions were more frequently disabled than children who sustained diffuse injury. Our MRI findings indicate that residual brain lesions are more common after moderate to severe CHI in children than previously thought and that the frontal lobes are most frequently involved. Further investigation is indicated to elucidate whether distinctive cognitive and behavioral sequelae are associated with frontal lobe lesions in children.

Randomized and infrequent omissions during presentation of a steady train of visual stimulation produced distinctive wave forms of both the magnetic fields and electrical potentials. Electrical potentials at Pz showed a positive peak in response to the omitted stimuli which occurred on the average 445 msec after the time when a stimulus was anticipated. Analyses of the magnetic wave forms indicated that at least two separate sources appear to be active coincident with the electrical positive peak. One source localized in the occipital lobes in the vicinity of the visual cortex while the other source was located in the medial aspects of the temporal lobe or even deeper in the lateral thalamus. Judging from the calculated direction of current flow it appeared that the deep source would contribute greater potentials in the frontal areas of the scalp while the source in the occipital area would contribute to more posterior placement of electrodes, especially at Pz.

In this study, two related issues were addressed: first, whether the P3 component of auditory evoked responses, obtained in the context of an oddball paradigm, and its magnetoencephalographically recorded counterpart (P3m) are generated by the same intracranial sources; and, second, whether these sources, modeled as equivalent current dipoles, can be localized in particular brain structures using magnetic resonance imaging. The study involving 8 normal adult subjects resulted in the following findings. (1) Both the similarities and differences in wave form characteristics of the simultaneously recorded P3 and P3m can be best accounted for by common intracranial sources. (2) Several successively activated single-dipolar sources, rather than a single source, account for the entire evolution of the P3m component. (3) Most of these sources were localized in the vicinity of the auditory cortex in all subjects, although some sources appeared to be in deeper structures, possibly the lateral thalamus. (4) The succesive activation of sources followed an orderly medial-to-lateral course. These results suggest that activity responsible for the surface-recorded P3 (and P3m) component may be initiated in deep structures, but it quickly spreads over and is sustained in areas near the auditory cortex.

The relationship between intracranial hypertension and residual memory deficit after closed head injury was evaluated using the 6-month and 1-year neurobehavioral outcome data obtained by the Traumatic Coma Data Bank. Intracranial pressure was analyzed using the percentage of time that it exceeded 20 mm Hg and the maximum value recorded during the first 72 hours after injury. Memory measures included recall of word lists, prose recall, and visual memory for designs that were obtained 6 months (n = 149) and 1 year (n = 132) after injury. Intracranial hypertension occurred in more than half of the Traumatic Coma Data Bank cohort who met the criteria for the neurobehavioral follow-up study. Linear regression analysis disclosed an effect of elevated intracranial pressure on some, but not all, measures of memory at 6 months, whereas the results were negative for the 1-year follow-up examination. We conclude that the elevation of intracranial pressure exerts little if any effect on later memory functioning, and that any effect it does have diminishes over 1 year in survivors of severe head injury.

Auditory evoked magnetic fields were recorded in response to contralateral stimulation over the right hemisphere in 6 adult males and 6 adult females. The data were fit to a model of a current-dipole source in a homogeneous sphere and 5 parameters of the dipole were computed — 3 spatial coordinates, orientation, and strength. When average values for the dipole parameters were compared between sexes, it was found that the current source for the N100 m is located more than 1 cm posterior in females and is oriented pointing more downward. These findings were replicated in separate measurements sessions. Viewing of individual magnetic resonance images did not reveal a corresponding anatomical disparity in the location of the primary auditory cortex which is assumed to produce the N100 m . Therefore, functional organization of the auditory cortex may be different for the sexes.

We are fortunate to be physicians at a time when the molecular pathogenesis of disease is being unraveled. Beginning with the discovery of the structure of DNA to the Human Genome Project, molecular biology over the past 45 years has revolutionized medicine. Neurosurgery has a strong scientific tradition, but to remain active participants in this new era of medicine, we must understand the science of pathology at the molecular level, applying our unique perspective to its advancement. We will review most of the current techniques used today by cell and molecular biologists. Interwoven with these descriptions will be a brief discussion of pertinent molecular and cell biology concepts, a full review being beyond the scope of this article.

To elucidate the clinical course of the vegetative state after severe closed-head injury, the Traumatic Coma Data Bank was analyzed for outcome at the time of discharge from the hospital and after follow-up intervals ranging up to 3 years after injury. Of 650 patients with closed-head injury available for analysis, 93 (14%) were discharged in a vegetative state. In comparison with conscious survivors, patients in a vegetative state sustained more severe closed-head injury as reflected by the Glasgow Coma Scale scores and pupillary findings and more frequently had diffuse injury complicated by swelling or shift in midline structures. Of 84 patients in a vegetative state who provided follow-up data, 41% became conscious by 6 months, 52% regained consciousness by 1 year, and 58% recovered consciousness within the 3-year follow-up interval. A logistic regression failed to identify predictors of recovery from the vegetative state.

Inconsistencies across studies concerning outcome after mild head injury may reflect differences in the diagnostic criteria used for selection of patients. Consequently, we compared the neurobehavioral outcome in three groups of consecutively hospitalized patients (aged 16 to 50 years) who sustained a closed head injury (CHI) and had a Glasgow Coma Scale (GCS) score in the 9 to 15 range. These groups included patients with uncomplicated CHI with mild impairment of consciousness as reflected by a GCS score in the 13 to 15 range (n = 78), patients with initially mild impairment of consciousness complicated by brain lesion or depressed skull fracture (n = 77), and patients with moderate CHI (n = 60). Tests of memory, information processing, and verbal fluency were administered within 1 to 3 months after injury, and the Glasgow Outcome Scale was completed at 6 months. Neurobehavioral functioning was impaired in the groups with complicated mild CHI and moderate CHI as compared to the group with uncomplicated mild CHI. Although moderate CHI produced longer durations of impaired consciousness and posttraumatic amnesia than complicated mild head injury, patients in these groups did not differ in neurobehavioral performance. Global outcome at 6 months was better in the patients with mild CHI than in patients with complicated mild and moderate injuries. Analysis of the various complications of mild CHI revealed that the presence of an intracranial lesion was related to more severe neurobehavioral sequelae than injuries complicated by a depressed fracture.

A male infant with communicating hydrocephalus and a position dependent obstruction in the posterior third ventricle is described. The apparent mass in the posterior third ventricle was seen only when the child was inverted. Possible factors relating to hydrocephalus which can cause the walls of the posterior third ventricle to come together and explain this unusual finding are discussed. These include dilated ambient cisterns and dilated posteriormedial aspects of the temporal horns.