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Objective: To establish reliable gross landmarks for resecting the amygdala intraoperatively, especially during anteromedial temporal lobectomy and amygdalohippocampectomy for epilepsy surgery. Reliable landmarks would allow its safe and complete resection as well as its potential en bloc removal for detailed electrophysiological and histopathological analyses., Methods: Ten adult cadavers (20 sides) were used. Two adjacent anatomic structures were identified: the bifurcation of the middle cerebral artery (MCA point) and the entry point of the anterior choroidal artery (AChoA) at the anterior origin of the choroid plexus into the temporal horn (inferior choroidal point referred to as the AChoA point). Following removal of the brain tissue inferior and anterior to the imaginary line connecting these 2 anatomic landmarks, cross sectional histopathological analysis of the remaining temporal and frontal lobes was performed to verify the presence or absence of any nervous tissue belonging to the amygdala complex., Results: In all 20 sides, the entire amygdala complex was found anterior and inferior to the transection made along the MCA-AChoA line. No apparent injury to the adjacent striatum was discovered., Conclusion: Two easily identifiable points, including the middle cerebral artery bifurcation and the inferior choroidal point, may define a line that reliably disconnects the amygdala complex from the remaining temporal and frontal lobes. These landmarks may assist in resection of the amygdale while preserving important adjacent structures, including the striatum.

Objective: Previous studies have revealed a surprising decrease in spike counts and Teager energy between on- and off-AEDs states during intracranial EEG (icEEG) monitoring. Here, we expand the measures evaluated to icEEG power and frequency band power., Methods: Two icEEG epochs, on- and off-AEDs, each 1h in duration, were studied for each of 21 unselected adult patients. Spike counts, Teager energy and total power were evaluated for each electrode contact. Power was also evaluated for delta (0-4Hz), theta (4-8Hz), alpha (8-13Hz), beta (13-25Hz), gamma (25-55Hz) and high (65-128Hz) frequency bands., Results: A decrease in power accompanies AED taper and the previously reported decrease in spike counts and Teager energy. The decrease in power was underpinned by a spatially widespread and broadband decrease in power in delta through gamma frequency bands with maximum decrease in the lowest frequency bands. An increase in high-frequency power was observed in some patients., Conclusions: There is a decrease in spike counts, Teager energy and power from on- to off-AEDs state during intracranial monitoring. The decrease in power is spatially widespread and broadband including power in the delta through gamma frequency bands., Significance: The decrease in cortical activity with AED taper suggests that seizure generation during intracranial monitoring may not be mediated solely by poorly regulated cortical excitation.

During neurosurgery, nonrigid brain deformation prevents preoperatively-acquired images from accurately depicting the intraoperative brain. Stereo vision systems can be used to track intraoperative cortical surface deformation and update preoperative brain images in conjunction with a biomechanical model. However, these stereo systems are often plagued with calibration error, which can corrupt the deformation estimation. In order to decouple the effects of camera calibration from the surface deformation estimation, a framework that can solve for disparate and often competing variables is needed. Game theory, which was developed to handle decision making in this type of competitive environment, has been applied to various fields from economics to biology. In this paper, game theory is applied to cortical surface tracking during neocortical epilepsy surgery and used to infer information about the physical processes of brain surface deformation and image acquisition. The method is successfully applied to eight in vivo cases, resulting in an 81% decrease in mean surface displacement error. This includes a case in which some of the initial camera calibration parameters had errors of 70%. Additionally, the advantages of using a game theoretic approach in neocortical epilepsy surgery are clearly demonstrated in its robustness to initial conditions.

Several large meta-analytic studies have failed to support a consistent relationship between visual or "nonverbal" memory deficits and right mesial temporal lobe changes. The Brown Location Test (BLT), a recently developed dot location learning and memory test, uses a nonsymmetrical array and provides control over many of the confounding variables (e.g., verbal influence and drawing requirements) inherent in other measures of visual memory. In the present investigation, we evaluated the clinical utility of the BLT in patients who had undergone left or right anterior mesial temporal lobectomy. We also provide normative data of 298 healthy adults for standardized scores. Results revealed significantly worse performance on the BLT in the right as compared to the left lobectomy group and the healthy adult normative sample. The present findings support a role for the right anterior mesial temporal lobe in dot location learning and memory., ((c) 2009 Elsevier Inc. All rights reserved.)

EEG power and high frequency activity in the seizure onset zone has been increasingly considered for its relationship with seizures in animal and human studies of epilepsy. We examine the relationship between quantitative EEG measures and metabolic imaging in epilepsy patients undergoing intracranial EEG (icEEG) analysis for seizure localization. Patients with mesial temporal lobe epilepsy (MTLE) and neocortical epilepsy (NE) were studied. Metabolic imaging was performed with MR spectroscopic imaging using N-acetyl aspartate (NAA) and creatine (Cr). All data were acquired from the mesial temporal lobe such that a direct comparison of the same anatomical regions between the two groups could be performed. While no difference was seen in the total power recorded from the mesial temporal lobe, the MTLE group had significantly greater power in the high frequency bands. There was a significant positive exponential relationship between total icEEG power with NAA/Cr in MTLE, R=+0.84 and p<0.001, which was not seen in NE. There was also a significant negative relationship between fractional gamma power with NAA/Cr in MTLE, R=-0.66 and p<0.02, also not seen in NE. These data argue that within the seizure onset zone, the tight correlation between total power and NAA/Cr suggests that total electrical output is powered by available mitochondrial function. These data are also consistent with the hypothesis that high frequency activity is an abnormal manifestation of tissue injury., (2009 Elsevier B.V. All rights reserved.)

Influenced by individuals such as his parents, Osler, and Halsted, and by his early medical student experience, Harvey Cushing developed a strong interest in collecting, especially antiquarian medical books. Even today, his collection housed at Yale University is one of the most prestigious in the world. Cushing's interest in archives is further manifested and reinforced by his establishment of the Cushing Brain Tumor Registry. The following is a review of Cushing's background not as an eminent clinician and surgeon but as an individual best described as a bibliophile, archivist, and ardent collector of medical paraphernalia.

Objective: During intracranial EEG (icEEG) monitoring the likelihood of observing a seizure is increased by tapering anti-epileptic drugs (AEDs). Presumably AED taper results in an increase in cortical excitation which in turn promotes seizure emergence. We measured change in signal energy of icEEGs in response to AED taper to quantify changes in excitation which accompany the increased propensity for seizures., Methods: Twelve consecutive adult patients who completed intracranial monitoring were studied. Two icEEG epochs from before and after AED taper, each 1h in duration, during wake, matched by time-of-day and removed from seizures were selected for each patient. Teager energy, a frequency weighted measure of signal energy, was estimated for both the seizure onset region as well as all other brain areas monitored., Results: Considerable changes in Teager energy, evaluated at a 1-h time-resolution, occur during intracranial monitoring. The most dominant trend is a decrease to lower values than those when the patient is on AEDs. A decrease of 35% was observed for both all the brain areas monitored and the seizure onset region., Conclusions: A decrease in signal energy occurs during intracranial EEG monitoring, possibly accompanying AED taper. If the decrease is due to AED taper this would suggest that AEDs prevent seizures in ways other than reduction of cortical excitation and seizure generation may be influenced by factors other than poorly regulated cortical excitation.

Purpose: This work examines the efficacy of functional magnetic resonance imaging (fMRI) for language lateralization using a comprehensive three-task language-mapping approach. Two localization methods and four different metrics for quantifying activation within hemisphere are compared and validated with Wada testing. Sources of discordance between fMRI and Wada lateralization are discussed with respect to specific patient examples., Methods: fMRI language mapping was performed in patients with epilepsy (N = 40) using reading sentence comprehension, auditory sentence comprehension, and a verbal fluency task. This was compared with the Wada procedure using both whole-brain and midline exclusion-based analyses. Different laterality scores were examined as a function of statistical threshold to investigate the sensitivity to threshold effects., Results: For the lateralized patients categorized by Wada, fMRI laterality indices (LIs) were concordant with the Wada procedure results in 83.87% patients for the reading task, 83.33% patients for the auditory task, 76.92% patients for the verbal fluency task, and in 91.3% patients for the conjunction analysis. The patients categorized as bilateral via the Wada procedure showed some hemispheric dominance in fMRI, and discrepancies between the Wada test findings and the functional laterality scores arose for a range of reasons., Discussion: Discordance was dependent upon whether whole-brain or midline exclusion method-based lateralization was calculated, and in the former case the inclusion of the occipital and other midline regions often negatively influenced the lateralization scores. Overall fMRI was in agreement with the Wada test in 91.3% of patients, suggesting its utility for clinical use with the proper consideration given to the confounds discussed in this work.

Recent advances in magnet technology have enabled the construction of ultrahigh-field magnets (7T and higher) that can accommodate the human head and body. Despite the intrinsic advantages of performing spectroscopic imaging at 7T, increased signal-to-noise ratio (SNR), and spectral resolution, few studies have been reported to date. This limitation is largely due to increased power deposition and B(1) inhomogeneity. To overcome these limitations, we used an 8-channel transceiver array with a short TE (15 ms) spectroscopic imaging sequence. Utilizing phase and amplitude mapping and optimization schemes, the 8-element transceiver array provided both improved efficiency (17% less power for equivalent peak B(1)) and homogeneity (SD(B(1)) = +/-10% versus +/-22%) in comparison to a transverse electromagnetic (TEM) volume coil. To minimize the echo time to measure J-modulating compounds such as glutamate, we developed a short TE sequence utilizing a single-slice selective excitation pulse followed by a broadband semiselective refocusing pulse. Extracerebral lipid resonances were suppressed with an inversion recovery pulse and delay. The short TE sequence enabled visualization of a variety of resonances, including glutamate, in both a control subject and a patient with a Grade II oligodendroglioma., ((c) 2009 Wiley-Liss, Inc.)

In localization-related epilepsy, seizures are presumed to arise from a discrete cortical area. The control of seizures by epilepsy surgery can be poor, however, even when there has been complete resection of the area identified by standard clinical procedures to give rise to seizures. We used a coherence-based measure of functional connectivity to test for network effects within and outside the seizure-onset area. Connectivity was evaluated from the background intracranial electroencephalogram of six unselected patients. We show significant nonzero connectivity not only for the seizure-onset area but also several centimeters from it, for example, for the beta-frequency band (P<10(-5)), suggesting a nonlocal character to this disorder.

Background: This paper describes the development and application of a research interface to integrate research image analysis software with a commercial image-guided surgery navigation system. This interface enables bi-directional transfer of data such as images, visualizations and tool positions in real time., Methods: We describe both the design and the application programming interface of the research interface, as well as showing the function of an example client program. The resulting interface provides a practical and versatile link for bringing image analysis research techniques into the operating room (OR)., Results: We present examples from the successful use of this research interface in both phantom experiments and real neurosurgeries. In particular, we demonstrate that the integrated dual-computer system achieves tool-tracking performance that is comparable to the more typical single-computer scenario., Conclusions: Network interfaces for this type are viable solutions for the integration of commercial image-guided navigation systems and research software.

DCX-immunoreactive (DCX+) cells occur in the piriform cortex in adult mice and rats, but also in the neocortex in adult guinea pigs and rabbits. Here we describe these cells in adult domestic cats and primates. In cats and rhesus monkeys, DCX+ cells existed across the allo- and neocortex, with an overall ventrodorsal high to low gradient at a given frontal plane. Labeled cells formed a cellular band in layers II and upper III, exhibiting dramatic differences in somal size (5-20 microm), shape (unipolar, bipolar, multipolar and irregular), neuritic complexity and labeling intensity. Cell clusters were also seen in this band, and those in the entorhinal cortex extended into deeper layers as chain-like structures. Densitometry revealed a parallel decline of the cells across regions with age in cats. Besides the cellular band, medium-sized cells with weak DCX reactivity resided sparsely in other layers. Throughout the cortex, virtually all DCX+ cells co-expressed polysialylated neural cell adhesion molecule. Medium to large mature-looking DCX+ cells frequently colocalized with neuron-specific nuclear protein and gamma-aminobutyric acid (GABA), and those with a reduced DCX expression also partially co-labeled for glutamic acid decarboxylase, parvalbumin, calbindin, beta-nicotinamide adenine dinucleotide phosphate diaphorase and neuronal nitric oxide synthase. Similar to cats and monkeys, small and larger DCX+ cells were detected in surgically removed human frontal and temporal cortices. These data suggest that immature neurons persist into adulthood in many cortical areas in cats and primates, and that these cells appear to undergo development and differentiation to become functional subgroups of GABAergic interneurons.

During the past decade, substantial progress has been made in delineating clinical features of the epilepsies and the basic mechanisms responsible for these disorders. Eleven human epilepsy genes have been identified and many more are now known from animal models. Candidate targets for cures are now based upon newly identified cellular and molecular mechanisms that underlie epileptogenesis. However, epilepsy is increasingly recognized as a group of heterogeneous syndromes characterized by other conditions that co-exist with seizures. Cognitive, emotional and behavioral co-morbidities are common and offer fruitful areas for study. These advances in understanding mechanisms are being matched by the rapid development of new diagnostic methods and therapeutic approaches. This article reviews these areas of progress and suggests specific goals that once accomplished promise to lead to cures for epilepsy.

As the major inhibitory neurotransmitter in human brain, GABA is an important modulator of hyperexcitability in epilepsy patients. Given the high energetic cost of neurotransmission and synaptic activity, GABA concentrations may be hypothesized to correlate with metabolic function. We studied human epilepsy patients undergoing intracranial EEG monitoring for seizure localization to examine microdialysis measures of extracellular GABA (ecGABA), pre-operative MR spectroscopic measures of neuronal mitochondrial function (NAA/Cr), and wherever possible, neuropathology and hippocampal volumetry. Two groups undergoing intracranial monitoring for seizure localization were studied: surgically treated hippocampal epilepsy (MTLE) and neocortical (non-hippocampal seizure onset) epilepsy. All data are hippocampal and thus these groups allow comparisons between the epileptogenic and non-epileptogenic regions. ecGABA was measured using in vivo microdialysis performed during intracranial monitoring. Pre-operative in vivo MR spectroscopic imaging was performed to measure the ratio of N-acetyl aspartate (NAA) to creatine. Standard methods for neuropathology and hippocampal volumetry were used. In the neocortical group, increased ecGABA correlated with greater NAA/Cr (R = +0.70, p < 0.015, n = 12) while in the MTLE group, increased ecGABA linked with decreased NAA/Cr (R = -0.94, p < 0.001, n = 8). In MTLE, ecGABA (increased) and NAA/Cr (decreased) correlated with increased glial cell numbers (R = +0.71, p < 0.01, n = 12, R = -0.76 p < 0.03 respectively). No relationship was seen between ecGABA and hippocampal volumes in either group. In epilepsy, ecGABA increases occur across a range of metabolic function. Outside the seizure focus, ecGABA and NAA/Cr increase together; in contrast, within the seizure focus, ecGABA increases with declining mitochondrial function.

Neurosurgical planning and image guided neurosurgery require the visualization of multimodal data obtained from various functional and structural image modalities, such as Magnetic Resonance Imaging (MRI), Computed Tomography (CT), functional MRI, Single photon emission computed tomography (SPECT) and so on. In the case of epilepsy neurosurgery for example, these images are used to identify brain regions to guide intracranial electrode implantation and resection. Generally, such data is visualized using 2D slices and in some cases using a 3D volume rendering along with the functional imaging results. Visualizing the activation region effectively by still preserving sufficient surrounding brain regions for context is exceedingly important to neurologists and surgeons. We present novel interaction techniques for visualization of multimodal data to facilitate improved exploration and planning for neurosurgery. We extended the line widget from VTK to allow surgeons to control the shape of the region of the brain that they can visually crop away during exploration and surgery. We allow simple spherical, cubical, ellipsoidal and cylindrical (probe aligned cuts) for exploration purposes. In addition we integrate the cropping tool with the image-guided navigation system used for epilepsy neurosurgery. We are currently investigating the use of these new tools in surgical planning and based on further feedback from our neurosurgeons we will integrate them into the setup used for image-guided neurosurgery.

Purpose: Cortical stimulation to abort seizures is under human investigation. Ideal electrode placement and stimulating parameters are unknown with poor understanding of tissue volume affected by stimulation or duration and nature of its effect on cortical activity. To help characterize this effect, we analyzed electrocorticography (ECoG) recorded adjacent to stimulated contacts during and after bipolar stimulation in patients undergoing functional cortical mapping with subdural electrodes., Methods: We analyzed four functional mapping procedures in three patients. One row of contacts was chosen for bipolar stimulation at sequential distances. Stimulation parameters were those used for functional mapping. Pooled Teager energy (TE) and band power were calculated for: (1) baseline, (2) 5 s during stimulation, and (3) 5-15 s after the stimulus., Results: Average TE increased during stimulation, falling with distance from the stimulus. Average poststimulus TE increased (284-905%) compared to baseline. Increased TE was observed: (1) up to 10 s after stimulation, (2) stimulation amplitudes of 4 mA or greater, and (3) up to 2 cm from the stimulus. There was no difference in poststimulus TE between the stimulated pair of contacts and outside the pair. Greatest increase in poststimulus signal power occurred in beta and gamma bands., Conclusions: Human cortical stimulation of 50 Hz resulted in elevated ECoG energy measurements up to 10 s poststimulation. Contacts >2 cm from stimulated electrodes did not show significant response to stimulation. Separating contacts >2 cm on the cortical surface may not result in efficacious treatment of seizure activity using common stimulation amplitudes (2-10 mA).

Purpose: Temporal lobe epilepsy (TLE) is associated with smaller hippocampal volume and with elevated extracellular (EC) glutamate levels. We investigated the relationship between the hippocampal volume and glutamate in refractory TLE patients., Methods: We used quantitative MRI volumetrics to measure the hippocampal volume and zero-flow microdialysis to measure the interictal glutamate, glutamine, and GABA levels in the epileptogenic hippocampus of 17 patients with medication-resistant epilepsy undergoing intracranial EEG evaluation. The relationships between hippocampal volume, neurochemical levels, and relevant clinical factors were examined., Results: Increased EC glutamate in the epileptogenic hippocampus was significantly related to smaller ipsilateral (R(2)= 0.75, p < 0.0001), but not contralateral hippocampal volume when controlled for glutamine and GABA levels, and for clinical factors known to influence hippocampal volume. Glutamate in the atrophic hippocampus was significantly higher (p = 0.008, n = 9), with the threshold for hippocampal atrophy estimated as 5 microM. GABA and glutamine levels in the atrophic and nonatrophic hippocampus were comparable. Decreased hippocampal volume was related to higher seizure frequency (p = 0.008), but not to disease duration or febrile seizure history. None of these clinical factors were related to the neurochemical levels., Conclusions: We provide evidence for a significant association between increased EC glutamate and decreased ipsilateral epileptogenic hippocampal volume in TLE. Future work will be needed to determine whether the increase in glutamate has a causal relationship with hippocampal atrophy, or whether another, yet unknown factor results in both. This work has implications for the understanding and treatment of epilepsy as well as other neurodegenerative disorders associated with hippocampal atrophy.

Studies of working memory load effects on human EEG power have indicated divergent effects in different frequency bands. Although gamma power typically increases with load, the load dependency of the lower frequency theta and alpha bands is uncertain. We obtained intracranial electroencephalography measurements from 1453 electrode sites in 14 epilepsy patients performing a Sternberg task, in order to characterize the anatomical distribution of load-related changes across the frequency spectrum. Gamma power increases occurred throughout the brain, but were most common in the occipital lobe. In the theta and alpha bands, both increases and decreases were observed, but with different anatomical distributions. Increases in theta and alpha power were most prevalent in frontal midline cortex. Decreases were most commonly observed in occipital cortex, colocalized with increases in the gamma range, but were also detected in lateral frontal and parietal regions. Spatial overlap with group functional magnetic resonance imaging results was minimal except in the precentral gyrus. These findings suggest that power in any given frequency band is not a unitary phenomenon; rather, reactivity in the same frequency band varies in different brain regions, and may relate to the engagement or inhibition of a given area in a cognitive task.

Objective: The aim of this study was to determine whether seizure occurrence in partial epilepsy is under the influence of circadian rhythms and rhythmic exogenous factors, and how this influence varies according to cortical brain region. For these ends, we determined and analyzed detailed temporal distributions of seizures arising from the frontal, parietal, occipital, neocortical temporal, and mesial temporal lobes., Methods: We retrospectively analyzed intracranial EEG recordings from 131 consecutive adult subjects whose partial epilepsy was sufficiently localized for surgical resection. In all, 669 seizures were analyzed: 132 frontal, 77 parietal, 83 occipital, 217 mesial temporal, and 160 neocortical temporal., Results: Seizure distribution was dependent on brain region (p < 10(-9)). Nonuniform seizure distributions were observed in the parietal (p < 10(-4)), occipital (p < 10(-7)), mesial temporal (p < 0.02), and neocortical temporal lobes (p < 0.04). Occipital and parietal seizures occurred in strong gaussian-like distributions, 180 degrees out of phase relative to each other; occipital seizure occurrence peaked between 16:00 and 19:00, whereas parietal seizures peaked between 4:00 and 7:00. Frontal lobe seizures followed a unimodal distribution, peaking between 4:00 and 7:00. Seizures from the mesial temporal lobe were distributed bimodally, with the primary peak in the late afternoon between 16:00 and 19:00 and secondary peak in the morning between 7:00 and 10:00. Neocortical temporal seizures peaked slightly before the primary peak observed in the mesial temporal lobe; however, these distributions did not differ significantly., Conclusions: Seizure occurrence in partial epilepsy is not random. Endogenous circadian rhythms and rhythmic exogenous factors likely play substantial roles in seizure occurrence. These roles vary considerably according to brain region. Frontal and parietal lobe seizures seem most likely to occur nocturnally, whereas occipital and temporal lobe seizures seem to have strong afternoon preferences.

Two-photon fluorescence lifetime imaging (FLIM) of molecules can reveal important information on the local microenvironment. NADH, an intrinsic fluorescent molecule and ubiquitous metabolic co-enzyme, has a lifetime that depends strongly on enzymatic binding. We present a custom image-processing algorithm for raw fluorescence lifetime and amplitude data that produces an image showing spatially distinct NADH fluorescence lifetimes in slices of rat and human brain. NADH FLIM images were collected in control and epileptic rat tissue. Differences in spatial patterns of NADH lifetimes support the hypothesis that NADH binding, and thus metabolic capacity, is significantly different between groups. This type of analysis can provide information on metabolic states in pathological material.

Purpose: Because of the large and continuous energetic requirements of brain function, neurometabolic dysfunction is a key pathophysiologic aspect of the epileptic brain. Additionally, neurometabolic dysfunction has many self-propagating features that are typical of epileptogenic processes, that is, where each occurrence makes the likelihood of further mitochondrial and energetic injury more probable. Thus abnormal neurometabolism may be not only a chronic accompaniment of the epileptic brain, but also a direct contributor to epileptogenesis., Methods: We examine the evidence for neurometabolic dysfunction in epilepsy, integrating human studies of metabolic imaging, electrophysiology, microdialysis, as well as intracranial EEG and neuropathology., Results: As an approach of noninvasive functional imaging, quantitative magnetic resonance spectroscopic imaging (MRSI) measured abnormalities of mitochondrial and energetic dysfunction (via 1H or 31P spectroscopy) are related to several pathophysiologic indices of epileptic dysfunction. With patients undergoing hippocampal resection, intraoperative 13C-glucose turnover studies show a profound decrease in neurotransmitter (glutamate-glutamine) cycling relative to oxidation in the sclerotic hippocampus. Increased extracellular glutamate (which has long been associated with increased seizure likelihood) is significantly linked with declining energetics as measured by 31P MR, as well as with increased EEG measures of Teager energy, further arguing for a direct role of glutamate with hyperexcitability., Discussion: Given the important contribution that metabolic performance makes toward excitability in brain, it is not surprising that numerous aspects of mitochondrial and energetic state link significantly with electrophysiologic and microdialysis measures in human epilepsy. This may be of particular relevance with the self-propagating nature of mitochondrial injury, but may also help define the conditions for which interventions may be developed.

Objective: The goal of this work was to evaluate the relationship between neuronal injury/loss in the hippocampus, thalamus, and putamen in temporal lobe epilepsy (TLE) patients using (1)H magnetic resonance spectroscopic imaging., Methods: (1)H spectroscopic images from the hippocampus and thalamus of controls and patients with TLE were acquired at 4 T. The spectroscopic imaging data were reconstructed using an automated voxel-shifting method based on anatomic landmarks providing four, six, and three loci for the hippocampus, thalamus, and putamen, respectively. For correlation analysis, the hippocampal and striatal loci were averaged to provide single estimates of the entire structure, whereas the thalamus was divided into two regions, an anterior and posterior measure, using the average of three loci each., Results: The ratio of N-acetyl aspartate to creatine (NAA/Cr), a measure of neuronal injury/loss, was significantly reduced in both the ipsilateral and contralateral hippocampi and thalami. NAA/Cr in the ipsilateral hippocampus was significantly correlated with the ipsilateral and contralateral anterior and posterior thalami, putamen, and contralateral hippocampus. In control subjects, the hippocampi were only correlated with each other., Conclusions: The data demonstrate that there is significant neuronal injury/loss in both the ipsilateral and contralateral thalami in temporal lobe epilepsy patients, with greater impairment in the anterior portions of the ipsilateral thalamus. The degree of injury/loss in the ipsilateral and contralateral thalamus and putamen is directly correlated with that of the ipsilateral hippocampus. This is consistent with the hypothesis that the impairment and damage associated with recurrent seizures as measured by N-acetyl aspartate originating in the hippocampus results in injury and impairment in other subcortical structures.

Temporal lobe epilepsy (TLE) with hippocampal sclerosis is associated with high extracellular glutamate levels, which could trigger seizures. Down-regulation of glial glutamate transporters GLAST (EAAT1) and GLT-1 (EAAT2) in sclerotic hippocampi may account for such increases. Their distribution was compared immunohistochemically in non-sclerotic and sclerotic hippocampi and localized only in astrocytes, with weaker immunoreactivity for both transporters in areas associated with pronounced neuronal loss, especially in CA1, but no decrease or even an increase in areas with less neuronal loss, like CA2 and the subiculum in the sclerotic group. Such compensatory changes in immunoreactivity may account for the lack of differences between the groups in immunoblot studies as blots show the average concentrations in the samples. These data suggest that differences in glial glutamate transporter distribution between the two groups of hippocampi may be an insufficient explanation for the high levels of extracellular glutamate in sclerotic seizure foci observed through in vivo dialysis studies.

Patients with mesial temporal lobe epilepsy (MTLE) have increased basal concentrations of extracellular glutamate in the epileptogenic versus the non-epileptogenic hippocampus. Such elevated glutamate levels have been proposed to underlie the initiation and maintenance of recurrent seizures, and a key question is what causes the elevation of glutamate in MTLE. Here, we explore the possibility that neurons in the hippocampal formation contain higher levels of the glutamate synthesizing enzyme phosphate-activated glutaminase (PAG) in patients with MTLE versus patients with other forms of temporal lobe epilepsy (non-MTLE). Increased PAG immunoreactivity was recorded in subpopulations of surviving neurons in the MTLE hippocampal formation, particularly in CA1 and CA3 and in the polymorphic layer of the dentate gyrus. Immunogold analysis revealed that PAG was concentrated in mitochondria. Double-labeling experiments indicated a positive correlation between the mitochondrial contents of PAG protein and glutamate, as well as between PAG enzyme activity and PAG protein as determined by Western blots. These data suggest that the antibodies recognize an enzymatically active pool of PAG. Western blots and enzyme activity assays of hippocampal homogenates revealed no change in PAG between MTLE and non-MTLE, despite a greatly (>50%) reduced number of neurons in the MTLE hippocampal formation compared to non-MTLE. Thus, the MTLE hippocampal formation contains an increased concentration and activity of PAG per neuron compared to non-MTLE. This increase suggests an enhanced capacity for glutamate synthesis-a finding that might contribute to the disrupted glutamate homeostasis in MTLE.

During neurosurgery, brain deformation renders preoperative images unreliable for localizing pathologic structures. In order to visualize the current brain anatomy, it is necessary to nonrigidly warp these preoperative images to reflect the intraoperative brain. This can be accomplished using a biomechanical model driven by sparse intraoperative information. In this paper, a linear elastic model of the brain is developed which can infer volumetric brain deformation given the cortical surface displacement. This model was tested on both a realistic brain phantom and in vivo, proving its ability to account for large brain deformations. Also, an efficient semiautomatic strategy for preoperative cortical feature detection is outlined, since accurate segmentation of cortical features can aid intraoperative cortical surface tracking.

Patients with temporal lobe epilepsy (TLE) often have a shrunken hippocampus that is known to be the location in which seizures originate. The role of the sclerotic hippocampus in the causation and maintenance of seizures in temporal lobe epilepsy (TLE) has remained incompletely understood despite extensive neuropathological investigations of this substrate. To gain new insights and develop new testable hypotheses on the role of sclerosis in the pathophysiology of TLE, the differential gene expression profile was studied. To this end, DNA microarray analysis was used to compare gene expression profiles in sclerotic and non-sclerotic hippocampi surgically removed from TLE patients. Sclerotic hippocampi had transcriptional signatures that were different from non-sclerotic hippocampi. The differentially expressed gene set in sclerotic hippocampi revealed changes in several molecular signaling pathways, which included the increased expression of genes associated with astrocyte structure (glial fibrillary acidic protein, ezrin-moesin-radixin, palladin), calcium regulation (S100 calcium binding protein beta, chemokine (C-X-C motif) receptor 4) and blood-brain barrier function (Aquaaporin 4, Chemokine (C-C- motif) ligand 2, Chemokine (C-C- motif) ligand 3, Plectin 1, intermediate filament binding protein 55kDa) and inflammatory responses. Immunohistochemical localization studies show that there is altered distribution of the gene-associated proteins in astrocytes from sclerotic foci compared with non-sclerotic foci. It is hypothesized that the astrocytes in sclerotic tissue have activated molecular pathways that could lead to enhanced release of glutamate by these cells. Such glutamate release may excite surrounding neurons and elicit seizure activity.

Purpose: Pathophysiologic mechanisms underlying temporal lobe epilepsy (TLE) are still poorly understood. One major hypothesis links alterations in energy metabolism to glutamate excitotoxicity associated with seizures in TLE. The purpose of this study was to determine whether changes in the activities of enzymes critical in energy and neurotransmitter metabolism contributed to the alterations in metabolic status leading to the excitotoxic effects of glutamate., Methods: Activities of four key enzymes involved in energy metabolism and glutamate cycling in the brain [aspartate aminotransferase (AAT), citrate synthase (CS), glutamate dehydrogenase (GDH), and lactate dehydrogenase (LDH)] were measured in anterolateral temporal neocortical and hippocampal tissues obtained from three different groups of medically intractable epilepsy patients having either mesial, paradoxical, or mass lesion-associated temporal lobe epilepsy (MTLE, PTLE, MaTLE), respectively., Results: We found that GDH activity was significantly decreased in the temporal cortex mainly in the MTLE group. A similar trend was recognized in the hippocampus of the MTLE. In all three patient groups, GDH activity was considerably lower, and AAT and LDH activities were higher in cortex of MTLE as compared with the corresponding activities in hippocampus (p<0.05). In the MTLE cortex and hippocampus, GDH activities were negatively correlated with the duration since the first intractable seizure., Conclusions: Our results support the hypothesis suggesting major alteration in GDH activity mainly in the MTLE group. It is proposed that significant alterations in the enzyme activities may be contributing to decreased metabolism of glutamate, leading to its accumulation.

We have evaluated a three-dimensional localized spectroscopic imaging sequence that uses two pairs of adiabatic full-passage pulses, which optimizes the detection of glutamate resonances at moderate echo times. This sequence provides excellent volume localization while simultaneously reducing J-modulation losses of glutamate. We have simulated the performance of this sequence for glutamate and used it to quantitatively measure glutamate in the human hippocampus using a linear components model. Using tissue segmentation and regression analysis, we measured a glutamate concentration of 8.8 +/- 2.1 mM in hippocampal and temporal gray matter and 3.7 +/- 1.1 mM in temporal white matter (95% CI). We have used this approach in a small group of patients (n = 5) with unilateral hippocampal epilepsy.

The gamma amino butyric acid (GABA) transporters GAT-1 and GAT-3 were localized by immunohistochemistry in hippocampi removed for the control of medically intractable temporal lobe epilepsy (TLE). The study aimed to determine the relationship of GABA transporter expression to known patterns of hippocampal hyperexcitability and extracellular GABA levels. GAT-1 was localized in axon terminals and small neuronal cell bodies, and in non-sclerotic hippocampi was strongly expressed throughout all regions of the hippocampal formation. In the epileptogenic hippocampus exhibiting Ammon's horn sclerosis, immunoreactivity was reduced in the sclerotic regions CA3 and CA1, and around the cell bodies of dentate granule cells, but was increased along granule cell dendrites. GAT-3 was weakly expressed, if at all, in non-sclerotic hippocampi, but more prominently expressed in sclerotic hippocampi. GAT-3 expression was confined to cells resembling protoplasmic astrocytes, which were located in regions of relative neuronal sparing such as the dentate gyrus and hilus of the sclerotic hippocampus. The reduction in GAT-1 around granule cells in the sclerotic hippocampus could explain the prolonged GABA responses in this region. The loss of GAT-1 (a marker of GABAergic terminals) would also suggest a reduced GABAergic input to the granule cells, thus facilitating hyperexcitability. The increased GAT-3 expression in astrocytes in regions of relative neuronal sparing in the sclerotic hippocampus may be related to the overall low levels of extracellular GABA observed in the sclerotic hippocampus and their increased excitability.

The retrieval of temporal-order versus spatial-location information was investigated using fMRI. The primary finding in the hippocampus proper, seen in region of interest analyses, was an increase in BOLD signal intensity for temporal retrieval, and a decrease in signal intensity for spatial retrieval, relative to baseline. The negative BOLD signal change with spatial memory processing, while unexpected, is consistent with the recent fMRI literature indicating decreased BOLD can be associated with neuronal activation, and it is argued that the deactivation observed here may facilitate spatial performance. Spatial-location judgments also yielded a stronger (positive) response in the right midfrontal gyrus, while temporal-order judgments (autobiographic condition only) showed greater activity in the left superior temporal gyrus, suggesting greater working memory demands and greater semantization for each judgment type, respectively. Finally, all conditions activated the left midfrontal gyrus, although autobiographic memories showed additional activity in the medial frontal gyrus.

The evolution of transsphenoidal surgery represents a special chapter in the progress of neurosurgery. Although Cushing initially advocated a transsphenoidal approach to pituitary tumors, he became disenchanted with this approach, ultimately favoring the subfrontal or "transfrontal" route late in his career. Other neurosurgeons followed Cushing's example, and the fate of transsphenoidal surgery entered a dark era in 1929. A review of Cushing's patients' records reveals that his abandonment of the transsphenoidal route was primarily related to the limitations of this approach in providing effective resection of large pituitary lesions-the symptomatic tumor recurrence rate after this procedure was substantial. Furthermore, given the preoperative uncertainty about the suprasellar extension of pituitary tumors prior to modern neuroimaging, the transfrontal route assured Cushing an adequate decompression of the optic chiasm. By 1927, Cushing's mastery of intracranial surgery was accompanied by the use of electrosurgical methods that enabled him to remove sellar lesions through the transfrontal route safely and with timely and effective restoration of visual loss. Transsphenoidal surgery remained relatively dormant, awaiting the efforts and enthusiasm of Norman Dott who bridged the gap between Cushing and Gerard Guiot, the surgeon who revitalized transsphenoidal adenomectomy for future generations of pituitary surgeons.

Human temporal lobe epilepsy (TLE) is associated with bioenergetic abnormalities including decreased phosphocreatine (PCr) normalized to ATP. The physiological consequences of these metabolic alterations have not been established. We hypothesized that impaired bioenergetics would correlate with alterations in physiological functions under conditions that strongly activate neural metabolism. We correlated several physiological variables obtained from epileptic human dentate granule cells studied in slices with hippocampal PCr/ATP measured using in vivo magnetic resonance spectroscopy. The physiological variables included: the ability to fire multiple action potentials in response to single stimuli, the inhibitory postsynaptic potential (IPSP) conductance and the responses to a 10 Hz, 10 s stimulus train. We noted a significant negative correlation between the ability to fire multiple spikes in response to single synaptic stimulation and PCr/ATP (P < 0.03) and a positive correlation between the IPSP conductance and PCr/ATP (P < 0.05). Finally, there was a strong correlation between PCr/ATP and the recovery of the membrane potential following a stimulus train (P < 0.01), with low PCr/ATP being associated with prolonged recovery times. These data suggest that the bioenergetic impairment seen in this tissue is associated with specific changes in excitatory and inhibitory neuronal responses to synchronized synaptic inputs.

Object: The syndrome of medial temporal lobe epilepsy (MTLE) may occur in patients in whom magnetic resonance (MR) images demonstrate normal findings. In these patients, there is no evidence of hippocampal sclerosis on neuroimaging, and histopathological examination of the resected hippocampus does not reveal significant neuron loss. In this paper the authors describe the distinct clinical features of this MTLE subtype, referred to as paradoxical temporal lobe epilepsy (PTLE)., Methods: The authors selected 12 consecutive patients with preoperative findings consistent with MTLE in whom MR imaging did not demonstrate any hippocampal abnormality. Onset of hippocampal seizure was confirmed by long-term intracranial monitoring. There were six female and six male patients with a mean age of 32 +/- 11 years, (mean +/- standard deviation [SD]) at presentation. These patients' seizure histories, available hippocampal volumetric measurements, and hippocampal cell densities in different subfields were reviewed. Sharp electrode recordings from dentate granule cells that had been maintained in hippocampal slices provided a measure of excitation and inhibition in the tissue. We compared these data with those of a cohort of 50 randomly selected patients who underwent anteromedial temporal resection for medial temporal sclerosis (MTS) during the same time period (1987-1999). The durations of follow up (means +/- SDs) for the PTLE and MTS groups were 51 +/- 59 months and 88 +/- 44 months, respectively. A history of febrile seizure was present less frequently in the PTLE group (8%) than in the MTS group (34%). Other risk factors for epilepsy such as trauma, meningoencephalitis, or perinatal injuries were present more frequently in the PTLE group (50%) than in the MTS cohort (36%). In patients in the PTLE group the first seizure occurred later in life (mean age at seizure onset 14 years in the PTLE group compared with 9 years in the MTS group, p = 0.09). Ten patients (83%) in the PTLE cohort and 23 patients (46%) in the MTLE cohort had secondary generalization of their seizures. Among patients with PTLE, volumetric measurements (five patients) and randomized blinded visual inspection (seven patients) of the bilateral hippocampi revealed no atrophy and no increased T2 signal change on preoperative MR images. All patients with PTLE underwent anteromedial temporal resection (amygdalohippocampectomy, in five patients on the left side and in seven on the right side). Electrophysiological studies of hippocampal slices demonstrated that dentate granule cells from patients with PTLE were significantly less excitable than those from patients with MTS. The mean pyramidal cell loss in the CAI subfield in patients in the PTLE group was 20% (range 0-59%) and that in patients in the MTS group was 75% (range 41-90%) (p < 0.001). Maximal neuron loss (mean loss 38%) occurred in the CA4 region in six patients with PTLE (end folium sclerosis). At the last follow-up examination, six patients (50%) in the PTLE group were seizure free compared with 38 patients (76%) in the MTS group., Conclusions: Clinical PTLE is a distinct syndrome with clinical features and surgical outcomes different from-those of MTS.

Although Harvey Cushing is best known for his role in developing surgical treatments for tumors of the central nervous system, he performed diverse neurosurgical procedures throughout his career, both at The Johns Hopkins Hospital (1886--1912) and at the Peter Bent Brigham Hospital (1912--1932). His unique and innovative approach to the treatment of myelomeningoceles associated with hydrocephalus, displayed early in his career, is characteristic of his attempts to circumvent the technical limitations of his time in the management of neurosurgical problems. In this report, the authors discuss the evolution of Cushing's technique in the treatment of myelomeningoceles through two illustrative patient records.

At the end of the 19th century, the early evolution of the specialty of neurological surgery was restricted by complications related to infection, increased intracranial pressure, and excessive intraoperative blood loss. These complications often caused mortality rates of 30 to 50%. An improved understanding of pathophysiological factors involved in increased intracranial pressure, along with meticulous surgical techniques learned from William Halsted, allowed Harvey Cushing to increase the safety of neurosurgical procedures that were then in their infancy. Cushing's later development of the "silver clip" and incorporation of electrosurgical techniques facilitated safe resection of brain tumors previously assumed to be inoperable. These pivotal accomplishments paved the way for the establishment of our specialty.

For his pioneering spirit, definitive work, and unparalleled devotion to conquering neurosurgery's toughest obstacles, Harvey Williams Cushing inarguably has earned the title, "The Father of Neurosurgery." His revolutionary incorporation of electrosurgical techniques in neurosurgery was not exceptional, but part of a pattern of recognizing, embracing, and establishing the use of medical technologies with great potential. Until 1910, Cushing had systematically reduced neurosurgery's primary complications--infection and the effects of intracranial pressure--to decrease mortality rates. Hemostasis had always been a concern of William Halsted's surgical protégé, but only after 1910 could Cushing primarily focus on it. In fact, Cushing's crucial collaboration with William T. Bovie and his electrosurgical apparatus conquered this major obstacle in 1926. The nature of their collaboration--two experts in their respective fields who were passionate about their work, working side by side in the operating room--resulted in progress that surpassed all predecessors in the field. Cushing never did learn the physics behind one of the most important advances of his career. Nonetheless, he did know that by greatly reducing blood loss, electrosurgery allowed him to operate in patients whose tumors had been previously deemed inoperable and on the entire spectrum of neurosurgical patients more safely.

Objectives: There is increasing evidence for a dysfunctional metabolic network in human mesial temporal lobe epilepsy (MTLE). To further describe this, we evaluated the bioenergetic status in unilateral MTLE inter-regionally and in relation to neuropathology., Materials and Methods: We used whole brain high field (4 T) 31P MR spectroscopic imaging to determine in vivo PCr and ATP, studying n=22 patients (all candidates for hippocampal resection) and n=14 control volunteers. The degree of bioenergetic impairment was assessed by calculating the ratio of PCr to ATP., Results: Compared to controls, patients demonstrated significant decreases in PCr/ATP from the ipsilateral amygdala and pes (0.84 +/- 0.14, 0.87 +/- 0.10, respectively, patients vs 0.97 +/- 0.15, 0.98 +/- 0.16, controls). In patients, the ipsilateral thalamic energetics positively correlated with contralateral hippocampal energetics. In addition, the ipsilateral thalamic and striatal energetics negatively correlated with hippocampal total glial counts., Conclusions: These data are consistent with a view that in MTLE, the bilateral hippocampi, ipsilateral thalamus and striatum are linked in their energetic depression, possibly reflecting the propagation of seizures throughout the brain.

An abnormal accumulation of extracellular K+ in the brain has been implicated in the generation of seizures in patients with mesial temporal lobe epilepsy (MTLE) and hippocampal sclerosis. Experimental studies have shown that clearance of extracellular K+ is compromised by removal of the perivascular pool of the water channel aquaporin 4 (AQP4), suggesting that an efficient clearance of K+ depends on a concomitant water flux through astrocyte membranes. Therefore, we hypothesized that loss of perivascular AQP4 might be involved in the pathogenesis of MTLE. Whereas Western blot analysis showed an overall increase in AQP4 levels in MTLE compared with non-MTLE hippocampi, quantitative ImmunoGold electron microscopy revealed that the density of AQP4 along the perivascular membrane domain of astrocytes was reduced by 44% in area CA1 of MTLE vs. non-MTLE hippocampi. There was no difference in the density of AQP4 on the astrocyte membrane facing the neuropil. Because anchoring of AQP4 to the perivascular astrocyte endfoot membrane depends on the dystrophin complex, the localization of the 71-kDa brain-specific isoform of dystrophin was assessed by immunohistochemistry. In non-MTLE hippocampus, dystrophin was preferentially localized near blood vessels. However, in the MTLE hippocampus, the perivascular dystrophin was absent in sclerotic areas, suggesting that the loss of perivascular AQP4 is secondary to a disruption of the dystrophin complex. We postulate that the loss of perivascular AQP4 in MTLE is likely to result in a perturbed flux of water through astrocytes leading to an impaired buffering of extracellular K+ and an increased propensity for seizures.

Harvey Cushing's refinement of Halsted's meticulous surgical techniques facilitated safe resection of intradural spinal tumors. Although Cushing focused his attention on brain tumors at the Peter Bent Brigham Hospital, his numerous contributions to the treatment of intradural spinal tumors include the description of these tumors' natural histories and their histological classifications. The application of his experienced intracranial techniques to the resection of spinal tumors improved outcomes. The authors review selected operative notes and sketches to demonstrate his technique in the excision of the spinal cord tumors.

Object: Intracarotid Amytal testing (the Wada test) has been used to lateralize language and identify patients who may be at risk for memory impairment after temporal lobectomy. The goal of this study was to determine the validity of the Wada test in the assessment of pathological conditions of the hippocampus among candidates for epilepsy surgery. The authors examined the correlation between the functional integrity of the hippocampus, measured using the Wada test, and quantitative measures of hippocampal pathology, determined by obtaining volumetric measurements of the hippocampus with the aid of magnetic resonance (MR) imaging., Methods: The authors reviewed the relationship between memory scores on the Wada test and hippocampal volumes measured on preoperative MR images in 76 patients who underwent anteromedial temporal lobectomy and amygdalohippocampectomy for the treatment of medically refractory temporal lobe epilepsy. The data were analyzed with respect to their usefulness in lateralizing the seizure focus and predicting the long-term postoperative memory outcome. Right and left hippocampal volume measurements did not correlate with one another (p > 0.1). Similarly, following a left carotid artery injection of Amytal the patients' right hemisphere memory was not significantly related to their left hemisphere memory on the Wada test (p'> 0.1). On the other hand, the patients' right hemisphere memory significantly correlated with their right hippocampal volume (r = 0.51; p < 0.001) and their left hemisphere memory significantly correlated with their left hippocampal volume (r = 0.51; p < 0.001). Both right and left hemisphere memory scores correlated with the hippocampal volumetry ratio (r = 0.47 and r = 0.45, respectively; both p < 0.001). Lateralization of a seizure focus based on hippocampal volumetry results was significantly related to lateralization based on the results of the Wada test (r = 0.49; p < 0.01). The disparity between the Wada memory scores on ipsilateral and contralateral sides was significantly and inversely related to the change in verbal memory following temporal lobectomy (r = -0.28; p < 0.02). The preoperative hippocampal volumetry ratio also significantly and inversely correlated with the change in verbal memory after surgery (r = -0.31; p < 0.01)., Conclusions: The Wada memory test may be a valuable method of measuring the functional integrity of the hippocampus. The systematic study of MR imaging-acquired morphological data and Wada-acquired neuropsychological data may increase our understanding of the location of material-specific memory and the selection of eligible candidates for epilepsy surgery.

Purpose: Approved neural-stimulation therapies for epilepsy use prolonged intermittent stimulation paradigms with no ability to respond automatically to seizures., Methods: A responsive neurostimulator that can automatically analyze electrocortical potentials, detect electrographic seizures, and rapidly deliver targeted electrical stimuli to suppress them was evaluated in an open multicenter trial in 50 patients, 40 of whom received responsive cortical stimulation via subdural electrodes implanted for epilepsy surgery evaluations., Results: Four patients, ages 15 to 28 years, monitored at three institutions, with clinical and electrographic response to neurostimulation, are described. Electrographic seizures were altered and suppressed in these patients during trials of neurostimulation lasting < or =68 h, with no major side effects. In one patient, stimulation appeared also to improve the baseline EEG., Conclusions: Responsive cortical neurostimulation may be a safe and effective treatment for partial epilepsy. This information was derived from a small group of patients in an observation study. A double-blind, controlled Food and Drug Administration (FDA)-approved study of a permanently implanted responsive neurostimulation system to treat medically refractory partial seizures is under way.

The hippocampus of patients with mesial temporal lobe epilepsy is often hardened and shrunken, a condition known as sclerosis. Magnetic resonance imaging reveals an increase in the T2-weighted signal, while diffusion weighted imaging shows a higher apparent diffusion coefficient in sclerotic hippocampi, indicating increased water content. As water transport appears to be coupled to K+ clearance and neuronal excitability [4], the molecular basis of the perturbed water homeostasis in the sclerotic hippocampus was explored. The expression of aquaporin-4 (AQP-4), the predominant water channel in the brain, was studied with quantitative real time PCR analysis, light microscopic immunohistochemistry and high-resolution immunogold labeling. A significant increase in AQP-4 was observed in sclerotic, but not in non-sclerotic, hippocampi obtained from patients with medically intractable temporal lobe epilepsy. This increase was positively correlated with an increase in the astrocyte marker glial fibrillary acidic protein. AQP-4 was localized to the plasma membranes of astrocytes including the perivascular end-feet. Gene expression associated with increased AQP-4 was evaluated by high throughput gene expression analysis using Affymetrix GeneChip U133A and related gene networks were investigated with Ingenuity Pathways Analysis. AQP-4 expression was associated with a decrease in expression of the dystrophin gene, a protein implicated in the anchoring of AQP-4 in perivascular endfeet. The decreased expression of dystrophin may indicate a loss of polarity in the distribution of AQP-4 in astrocytes. We conclude that the perturbed expression of AQP-4 and dystrophin may be one factor underlying the loss of ion and water homeostasis in the sclerotic hippocampus and hypothesize that the reported changes may contribute to the epileptogenic properties of the sclerotic tissue.

Malignant gliomas arise from two distinct pathways, as de novo lesions or from secondary transformation from low-grade lesions. Herein, we describe the cases of two patients to illustrate the proposition that de novo malignant gliomas can originate as non-enhancing tumors and rapidly progress to a pattern of ring enhancement characteristic of a glioblastoma. Both patients presented with new-onset seizures (simple partial and generalized). Their neurological examinations were unremarkable. Initial MRI evaluations revealed a right precentral gyrus and right medial temporal lobe lesions in each case, respectively. These lesions demonstrated increased T2 signal changes without contrast enhancement. The biopsy of the right frontal lesion in the first patient was consistent with an anaplastic astrocytoma; the second patient was followed expectantly. Repeat MRI for both patients within 17 weeks disclosed ring-enhancing lesions, consistent with an unusually rapid evolution to glioblastoma multiforme (GBM). Subsequent resection of the right medial temporal lesion in the second patient revealed a GBM. Neither tumor displayed abnormal overexpression of P53 by immunohistochemistry. Early MRI of de novo glioblastomas may demonstrate a non-enhancing tumor suggestive of a low-grade lesion. These tumors can rapidly evolve into ring-enhancing lesions more consistent with the traditional imaging findings., (Copyright 2004 Springer-Verlag)

Object: Proton magnetic resonance (MR) spectroscopy imaging of the ratio of N-acetylaspartate (NAA) to creatine (Cr) has proved efficacious as a localizing tool in demonstrating the metabolic changes associated with temporal lobe epilepsy. To analyze the significance of these MR spectroscopy findings further, the authors explored the relationship between regional alterations in the NAA/Cr ratio in hippocampi measured preoperatively and histopathological findings in hippocampi resected in patients with intractable mesial temporal lobe epilepsy (MTLE)., Methods: Twelve patients in whom the diagnosis of MTLE had been made and 12 healthy volunteers with no known history of neurological disease underwent high-resolution 1H MR spectroscopy imaging of NAA and Cr (0.64 cm3 nominal voxel resolution) in five voxels spanning the anteroposterior length of the hippocampus. The authors correlated the NAA/Cr ratio with neuropathological findings in resected hippocampi, specifically glial fibrillary acidic protein (GFAP) immunoreactivity and pyramidal neuronal loss. A linear regression analysis of the ipsilateral NAA/Cr ratio revealed a statistically significant relation to the extent of hippocampal neuronal loss in only the CA2 sector (correlation coefficient [r] = -0.66, p < 0.03). The ipsilateral NAA/Cr ratio displayed significant regressions with GFAP immunoreactivity from all the CA sectors (r values ranged from -0.69 and p < 0.01 for the CA4 sector to -0.88 and p < 0.001 for the CA2 sector) except for the CA1. The extent of neuronal cell loss in every hippocampal subfield (r = 0.71-0.74, p < 0.007), except the CA2 (p = 0.08), correlated to the extent of neuronal cell loss in the dentate gyrus. There was no significant relationship between the duration or frequency of seizures and the mean ipsilateral NAA/Cr ratio; however, the mean density of GFAP-immunopositive cells correlated with seizure frequency (p < 0.03)., Conclusions: The NAA/Cr ratio may not measure the full extent of hippocampal neuronal cell loss. The significant association of the NAA/Cr ratio with the GFAP immunoreactivity of most CA sectors indicates that the NAA/Cr ratio may provide a more accurate measurement of recent neuronal injury caused by epileptic activity. The coupling between neuronal impairment and astroglial GFAP expression may indicate the close association between neuronal and glial dysfunction in patients with epilepsy.

The surgical treatment of cerebrovascular malformations intrigued early neurosurgeons. Cushing defined vascular malformations as tumors arising from cerebral blood vessels. He successfully resected the first arteriovenous malformation 3 years after it had been irradiated. In the absence of angiography, the pathoanatomy of these lesions remained elusive and early techniques such as cortical vein ligation proved catastrophic. Cushing demonstrated the favorable results of radiation treatments on vascular malformations and advocated decompressive craniectomy followed by radiotherapy. He ligated cortical feeding vessels and external carotid arteries with an improved understanding of the angioarchitecture of vascular malformations. He stressed the importance of preoperative diagnosis because the radical resection of nonirradiated vascular malformations challenged the limitations of the available neurosurgical armamentarium.

The development of surgical techniques for the treatment of intracranial aneurysms has paralleled the evolution of the specialty of neurological surgery. During the Cushing era, intracranial aneurysms were considered inoperable and only ligation of the carotid artery was performed. Cushing understood the limitations of this approach and advised the need for a more thorough understanding of aneurysm pathology before further consideration could be given to the surgical treatment of cerebral aneurysms. Despite his focus on brain tumors, Cushing's contributions to the discipline of neurovascular surgery are of great importance. With the assistance of Sir Charles Symonds, Cushing described the syndrome of subarachnoid hemorrhage. He considered inserting muscle strips into cerebral aneurysms to promote aneurysm sac thrombosis and designed the "silver clip," which was modified by McKenzie and later used by Dandy to clip the first intracranial aneurysm. Cushing was the first surgeon to wrap aneurysms in muscle fragments to prevent recurrent hemorrhage. He established the foundation on which pioneers such as Norman Dott and Walter Dandy launched the modern era of neurovascular surgery.

Object: Reports of outcomes for surgical treatment of cortical dysplasia associated with epilepsy are conflicting due to the inclusion of patients with a wide range of malformations of cortical development. The authors report their experience and the long-term outcome for a subgroup of patients with the histopathological diagnosis of focal cortical dysplasia of Taylor., Methods: The records of 22 patients with focal cortical dysplasia of Taylor (15 with the balloon-cell type and seven with the nonballoon-cell type) were reviewed. There were 11 female and 11 male patients whose mean age was 26 +/- 17.6 years (mean +/- standard deviation [SD]) at surgery. The details of their epilepsy evaluation and resection were analyzed. Extent of resection was preoperatively planned using information obtained from long-term intracranial monitoring (15 patients) and/or more definitively determined by histopathologically proven clear margins during resection when feasible (12 patients). The mean duration of follow up was 6.3 +/- 5.1 years (mean +/- SD, range 0.5-15.6 years). Risk factors for epilepsy were trauma (seven patients) or meningoencephalitis (one patient); 14 patients (64%) had no obvious risk factors. The mean age at seizure onset was 9.2 years and the mean duration of their epilepsy was 16.1 +/- 9 years. In two patients there were no adverse findings on magnetic resonance (MR) imaging. In 15 patients (68%), the epileptogenic zone identified on long-term intracranial monitoring extended beyond the abnormality observed on MR images. Focal resection (lesion plus margins) was performed in 14 patients (64%), whereas eight (36%) underwent partial/tailored lobectomy. Two patients underwent multiple subpial transections in addition to partial lesionectomy because their lesions involved the sensorimotor cortex. In these two, functional MR imaging confirmed a normal functional anatomy despite the presence of the cortical dysplasia. Eleven (92%) of 12 patients who underwent resection guided by histopathologically proven clear margins and three (43%) of seven patients who underwent histopathologically proven subtotal resection have remained seizure free. Evidence of clear margins was significantly associated with an improved seizure outcome (p = 0.003). Postoperatively, expected deficits included nondisabling visual field defects, which occurred in three patients (14%), and transient sensorimotor deficits, which appeared in five (23%). Two patients had meningitis, which was successfully treated with antibiotics. Overall, 16 patients (73%) are either seizure free (13 patients), have rare nondisabling partial seizures (one patient), or had one seizure after their medication was changed (two patients). Thirteen patients (59%) have discontinued anticonvulsant medications or are being maintained on monotherapy. Of five patients (23%), two have had rare disabling seizures or significant reduction in their seizure frequency (three patients). One patient's seizures have remained the same., Conclusions: Focal cortical dysplasias are a distinct subgroup of malformations of cortical development and have a favorable outcome after resection. The epileptogenic zone often extends beyond the abnormality found on neuroimaging. Resection of the epileptogenic zone guided by histopathologically proven clear margins is associated with an improved seizure outcome.

We used intrinsic signal optical imaging to obtain maps of human somatosensory cortex during electrocutaneous stimulation of the face during a neurosurgical procedure for epilepsy. We found that human face somatotopy is organized like the macaque or cebus monkey, with peri-orbital skin located medial to peri-buccal skin, and that cortical magnification in the human is comparable to that in non-human primates. This study demonstrates that intrinsic signal imaging can be performed on humans during operative procedures with sufficient spatial resolution to reveal high-resolution topographic maps.

Previous studies have characterized the electrophysiological properties of astrocytes in the CA1 region of hippocampi resected from patients with intractable temporal lobe epilepsy (TLE). However, the properties of hilar astrocytes from such patients have not been studied although astrocytes display regional heterogeneity and a non-uniform response to injury. Thus, we performed patch-clamp recordings of putative astrocytes in hilar and CA1 regions of surgically removed epileptic hippocampi with and without sclerosis (mesial TLE, MTLE patients, and paradoxical TLE, PTLE patients, respectively), and non-epileptic, non-sclerotic hippocampi (tumor patients). Our data show that the current profile of hilar astrocytes undergoes significant changes in MTLE but not in PTLE or tumor hippocampi. In particular, inwardly rectifying K(+) (K(IR)) and outwardly rectifying K(+) currents were reduced, inward Na(+) currents and membrane resistances were increased in putative astrocytes from MLTE cases compared to PTLE and tumor cases. Because the conductance of K(IR) channels in cell-attached patches (approximately 34pS) from MTLE tissue was not altered, a reduction in the number of K(IR) channels likely accounts for the decrease in whole-cell K(IR) conductance. Presumed astrocytes in the CA1 region from each patient group displayed intercellular coupling and a passive current profile; these characteristics were never observed in hilar glial cells. No apparent changes in the current profile of coupled CA1 glial cells could be detected between MTLE, PTLE and tumor tissues. Additionally, CA1 glial cells expressed a high density of 34pS K(IR) channels. These data suggest that K(+) buffering via K(IR) channels may be functionally compromised in hilar astrocytes of epileptic and sclerotic (MTLE) human hippocampi. By contrast, CA1 astrocytes retained their intercellular coupling and K(IR) channel expression necessary for K(+) buffering.

The authors describe a patient who experienced stereotypical episodes of dyspnea and presyncopal sensation without loss of consciousness during a 4-month period. Further evaluation established intermittent arterial O2 desaturations associated with this dyspnea. After an extensive cardiopulmonary workup was performed for presumptive diagnosis of pulmonary embolism, a brain magnetic resonance image revealed a right medial temporal lobe lesion. The patient's dyspnea was then suspected to be a symptom of a seizure. His shortness of breath and O2 desaturation resolved with administration of phenytoin. This case, to the authors' knowledge, is the first documented example of simple partial seizures presenting with episodic autonomic cardiopulmonary symptoms in the absence of other ictal behavior. This case may also illustrate one specific limbic autonomic network.