Optimizing Surgical Planning for Epilepsy Patients With Multimodal Neuroimaging and Neurophysiology Integration: A Case Study.

SUMMARY: Current preoperative evaluation of epilepsy can be challenging because of the lack of a comprehensive view of the network's dysfunctions. To demonstrate the utility of our multimodal neurophysiology and neuroimaging integration approach in the presurgical evaluation, we present a proof-of-concept for using this approach in a patient with nonlesional frontal lobe epilepsy who underwent two resective surgeries to achieve seizure control. We conducted a post-hoc investigation using four neuroimaging and neurophysiology modalities: diffusion tensor imaging, resting-state functional MRI, and stereoelectroencephalography at rest and during seizures. We computed region-of-interest-based connectivity for each modality and applied betweenness centrality to identify key network hubs across modalities. Our results revealed that despite seizure semiology and stereoelectroencephalography indicating dysfunction in the right orbitofrontal region, the maximum overlap on the hubs across modalities extended to right temporal areas. Notably, the right middle temporal lobe region served as an overlap hub across diffusion tensor imaging, resting-state functional MRI, and rest stereoelectroencephalography networks and was only included in the resected area in the second surgery, which led to long-term seizure control of this patient. Our findings demonstrated that transmodal hubs could help identify key areas related to epileptogenic network. Therefore, this case presents a promising perspective of using a multimodal approach to improve the presurgical evaluation of patients with epilepsy.

EEG Abnormalities and Their Radiographic Correlates in a COVID-19 Inpatient Cohort.

Background and Objectives: To identify the prevalence of EEG abnormalities in patients with coronavirus disease 2019 (COVID-19) with neurologic changes, their associated neuroimaging abnormalities, and rates of mortality. Methods: A retrospective case series of 192 adult COVID-19-positive inpatients with EEG performed between March and June 2020 at 4 hospitals: 161 undergoing continuous, 24 routine, and 7 reduced montage EEG. Study indication, epilepsy history, intubation status, administration of sedatives or antiseizure medications (ASMs), metabolic abnormalities, neuroimaging pathology associated with epileptiform abnormalities, and in-hospital mortality were analyzed. Results: EEG indications included encephalopathy (54.7%), seizure (18.2%), coma (17.2%), focal deficit (5.2%), and abnormal movements (4.6%). Epileptiform abnormalities occurred in 39.6% of patients: focal intermittent epileptiform discharges in 25.0%, lateralized periodic discharges in 6.3%, and generalized periodic discharges in 19.3%. Seizures were recorded in 8 patients, 3 with status epilepticus. ASM administration, epilepsy history, and older age were associated with epileptiform abnormalities. Only 26.3% of patients presented with any epileptiform abnormality, 37.5% with electrographic seizures, and 25.7% patients with clinical seizures had known epilepsy. Background findings included generalized slowing (88.5%), focal slowing (15.6%), burst suppression (3.6%), attenuation (3.1%), and normal EEG (3.1%). Neuroimaging pathology was identified in 67.1% of patients with epileptiform abnormalities, over two-thirds acute. In-hospital mortality was 39.5% for patients with epileptiform abnormalities and 36.2% for those without. Risk factors for mortality were coma and ventilator support at time of EEG. Discussion: This article highlights the range of EEG abnormalities frequently associated with acute neuroimaging abnormalities in COVID-19. Mortality rates were high, particularly for patients in coma requiring mechanical ventilation. These findings may guide the prognosis and management of patients with COVID-19 and neurologic changes.

Intracranial EEG Validation of Single-Channel Subgaleal EEG for Seizure Identification.

PURPOSE: A device that provides continuous, long-term, accurate seizure detection information to providers and patients could fundamentally alter epilepsy care. Subgaleal (SG) EEG is a promising modality that offers a minimally invasive, safe, and accurate means of long-term seizure monitoring. METHODS: Subgaleal EEG electrodes were placed, at or near the cranial vertex, simultaneously with intracranial EEG electrodes in 21 epilepsy patients undergoing intracranial EEG studies for up to 13 days. A total of 219, 10-minute single-channel SGEEG samples, including 138 interictal awake or sleep segments and 81 seizures (36 temporal lobe, 32 extra-temporal, and 13 simultaneous temporal/extra-emporal onsets) were reviewed by 3 expert readers blinded to the intracranial EEG results, then analyzed for accuracy and interrater reliability. RESULTS: Using a single-channel of SGEEG, reviewers accurately identified 98% of temporal and extratemporal onset, intracranial, EEG-verified seizures with a sensitivity of 98% and specificity of 99%. All focal to bilateral tonic--clonic seizures were correctly identified. CONCLUSIONS: Single-channel SGEEG, placed at or near the vertex, reliably identifies focal and secondarily generalized seizures. These findings demonstrate that the SG space at the cranial vertex may be an appropriate site for long-term ambulatory seizure monitoring.

Cerebrovascular Complications of COVID-19.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) evolved quickly into a global pandemic with myriad systemic complications, including stroke. We report the largest case series to date of cerebrovascular complications of COVID-19 and compare with stroke patients without infection. METHODS: Retrospective case series of COVID-19 patients with imaging-confirmed stroke, treated at 11 hospitals in New York, between March 14 and April 26, 2020. Demographic, clinical, laboratory, imaging, and outcome data were collected, and cases were compared with date-matched controls without COVID-19 from 1 year prior. RESULTS: Eighty-six COVID-19-positive stroke cases were identified (mean age, 67.4 years; 44.2% women). Ischemic stroke (83.7%) and nonfocal neurological presentations (67.4%) predominated, commonly involving multivascular distributions (45.8%) with associated hemorrhage (20.8%). Compared with controls (n=499), COVID-19 was associated with in-hospital stroke onset (47.7% versus 5.0%; P<0.001), mortality (29.1% versus 9.0%; P<0.001), and Black/multiracial race (58.1% versus 36.9%; P=0.001). COVID-19 was the strongest independent risk factor for in-hospital stroke (odds ratio, 20.9 [95% CI, 10.4-42.2]; P<0.001), whereas COVID-19, older age, and intracranial hemorrhage independently predicted mortality. CONCLUSIONS: COVID-19 is an independent risk factor for stroke in hospitalized patients and mortality, and stroke presentations are frequently atypical.

Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports.

Coronavirus disease 2019 (COVID-19) is a highly infectious pandemic caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It frequently presents with unremitting fever, hypoxemic respiratory failure, and systemic complications (e.g., gastrointestinal, renal, cardiac, and hepatic involvement), encephalopathy, and thrombotic events. The respiratory symptoms are similar to those accompanying other genetically related beta-coronaviruses (CoVs) such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East Respiratory Syndrome CoV (MERS-CoV). Hypoxemic respiratory symptoms can rapidly progress to Acute Respiratory Distress Syndrome (ARDS) and secondary hemophagocytic lymphohistiocytosis, leading to multi-organ system dysfunction syndrome. Severe cases are typically associated with aberrant and excessive inflammatory responses. These include significant systemic upregulation of cytokines, chemokines, and pro-inflammatory mediators, associated with increased acute-phase proteins (APPs) production such as hyperferritinemia and elevated C-reactive protein (CRP), as well as lymphocytopenia. The neurological complications of SARS-CoV-2 infection are high among those with severe and critical illnesses. This review highlights the central nervous system (CNS) complications associated with COVID-19 attributed to primary CNS involvement due to rare direct neuroinvasion and more commonly secondary CNS sequelae due to exuberant systemic innate-mediated hyper-inflammation. It also provides a theoretical integration of clinical and experimental data to elucidate the pathogenesis of these disorders. Specifically, how systemic hyper-inflammation provoked by maladaptive innate immunity may impair neurovascular endothelial function, disrupt BBB, activate CNS innate immune signaling pathways, and induce para-infectious autoimmunity, potentially contributing to the CNS complications associated with SARS-CoV-2 infection. Direct viral infection of the brain parenchyma causing encephalitis, possibly with concurrent neurovascular endotheliitis and CNS renin angiotensin system (RAS) dysregulation, is also reviewed.

Mesial temporal resection following long-term ambulatory intracranial EEG monitoring with a direct brain-responsive neurostimulation system.

OBJECTIVE: To describe seizure outcomes in patients with medically refractory epilepsy who had evidence of bilateral mesial temporal lobe (MTL) seizure onsets and underwent MTL resection based on chronic ambulatory intracranial EEG (ICEEG) data from a direct brain-responsive neurostimulator (RNS) system. METHODS: We retrospectively identified all patients at 17 epilepsy centers with MTL epilepsy who were treated with the RNS System using bilateral MTL leads, and in whom an MTL resection was subsequently performed. Presumed lateralization based on routine presurgical approaches was compared to lateralization determined by RNS System chronic ambulatory ICEEG recordings. The primary outcome was frequency of disabling seizures at last 3-month follow-up after MTL resection compared to seizure frequency 3 months before MTL resection. RESULTS: We identified 157 patients treated with the RNS System with bilateral MTL leads due to presumed bitemporal epilepsy. Twenty-five patients (16%) subsequently had an MTL resection informed by chronic ambulatory ICEEG (mean = 42 months ICEEG); follow-up was available for 24 patients. After MTL resection, the median reduction in disabling seizures at last follow-up was 100% (mean: 94%; range: 50%-100%). Nine patients (38%) had exclusively unilateral electrographic seizures recorded by chronic ambulatory ICEEG and all were seizure-free at last follow-up after MTL resection; eight of nine continued RNS System treatment. Fifteen patients (62%) had bilateral MTL electrographic seizures, had an MTL resection on the more active side, continued RNS System treatment, and achieved a median clinical seizure reduction of 100% (mean: 90%; range: 50%-100%) at last follow-up, with eight of fifteen seizure-free. For those with more than 1 year of follow-up (N = 21), 15 patients (71%) were seizure-free during the most recent year, including all eight patients with unilateral onsets and 7 of 13 patients (54%) with bilateral onsets. SIGNIFICANCE: Chronic ambulatory ICEEG data provide information about lateralization of MTL seizures and can identify additional patients who may benefit from MTL resection.

Racial differences in adult-onset MRI-negative temporal lobe epilepsy.

OBJECTIVE: We recently detected a significant racial difference in our population with temporal lobe epilepsy (TLE) at the University of Alabama at Birmingham (UAB) seizure monitoring unit. We found that Black patients were more likely than their White counterparts to carry a TLE diagnosis. Using this same patient population, we focus on the patients with TLE to better describe the relationship between race and epidemiology in this population. METHODS: We analyzed the data from patients diagnosed with TLE admitted to the UAB seizure monitoring unit between January 2000 and December 2011. For patients with a video electroencephalography (EEG) confirmed diagnosis of TLE (n = 385), basic demographic information including race and magnetic resonance imaging (MRI) findings were collected. Descriptive statistics and multivariate logistic regression were used to explore the relationship between MRI findings, demographic data, and race. RESULTS: For Black patients with TLE, we found that they were more likely to be female (odds ratio [OR] = 1.91, 95% confidence interval [CI]: 1.14-3.19), have seizure onset in adulthood (OR = 2.39, 95% CI: 1.43-3.19), and have normal MRIs (OR = 1.69, 95% CI: 1.04-2.77) compared to White counterparts with TLE after adjusting for covariates. CONCLUSIONS: These data suggest that Black race (compared to White) is associated with higher expression of adult-onset MRI-negative TLE, an important subtype of epilepsy with unique implications for evaluation, treatment, and prognosis. If validated in other cohorts, the findings may explain the lower reported rates of epilepsy surgery utilization among Blacks. The racial differences in surgical utilization could be due to a greater prevalence of an epilepsy that is less amenable to surgical resection rather than to cultural differences or access to care.

Hippocampal volumetric integrity in mesial temporal lobe epilepsy: A fast novel method for analysis of structural MRI.

OBJECTIVE: We investigate whether a rapid and novel automated MRI processing technique for assessing hippocampal volumetric integrity (HVI) can be used to identify hippocampal sclerosis (HS) in patients with mesial temporal lobe epilepsy (mTLE) and determine its performance relative to hippocampal volumetry (HV) and visual inspection. METHODS: We applied the HVI technique to T1-weighted brain images from healthy control (n = 35), mTLE (n = 29), non-HS temporal lobe epilepsy (TLE, n = 44), and extratemporal focal epilepsy (EXTLE, n = 25) subjects imaged using a standardized epilepsy research imaging protocol and on non-standardized clinically acquired images from mTLE subjects (n = 40) to investigate if the technique is translatable to clinical practice. Performance of HVI, HV, and visual inspection was assessed using receiver operating characteristic (ROC) analysis. RESULTS: mTLE patients from both research and clinical groups had significantly reduced ipsilateral HVI relative to controls (effect size: -0.053, 5.62%, p =  0.002 using a standardized research imaging protocol). For lateralizing mTLE, HVI had a sensitivity of 88% compared with a HV sensitivity of 92% when using specificity equal to 70%. CONCLUSIONS: The novel HVI approach can effectively detect HS in clinical populations, with an average image processing time of less than a minute. The fast processing speed suggests this technique could have utility as a quantitative tool to assist with imaging-based diagnosis and lateralization of HS in a clinical setting.

Utility of magnetic resonance spectroscopic imaging for human epilepsy.

This review discusses the potential utility of broad based use of magnetic resonance (MR) spectroscopic imaging for human epilepsy and seizure localization. The clinical challenges are well known to the epilepsy community, intrinsic in the variability of location, volumetric size and network extent of epileptogenic tissue in individual patients. The technical challenges are also evident, with high performance requirements in multiple steps, including magnet homogeneity, detector performance, sequence design, speed of acquisition in addition to large territory spectral processing. We consider how MR spectroscopy and spectroscopic imaging has been informative for epilepsy thus far, with specific attention to what is measured, the interpretation of such measurements and technical performance challenges. Examples are shown from medial temporal lobe and neocortical epilepsies are considered from 4T, 7T and most recently 3T.

The brain connectome as a personalized biomarker of seizure outcomes after temporal lobectomy.

OBJECTIVE: We examined whether individual neuronal architecture obtained from the brain connectome can be used to estimate the surgical success of anterior temporal lobectomy (ATL) in patients with temporal lobe epilepsy (TLE). METHODS: We retrospectively studied 35 consecutive patients with TLE who underwent ATL. The structural brain connectome was reconstructed from all patients using presurgical diffusion MRI. Network links in patients were standardized as Z scores based on connectomes reconstructed from healthy controls. The topography of abnormalities in linkwise elements of the connectome was assessed on subnetworks linking ipsilateral temporal with extratemporal regions. Predictive models were constructed based on the individual prevalence of linkwise Z scores >2 and based on presurgical clinical data. RESULTS: Patients were more likely to achieve postsurgical seizure freedom if they exhibited fewer abnormalities within a subnetwork composed of the ipsilateral hippocampus, amygdala, thalamus, superior frontal region, lateral temporal gyri, insula, orbitofrontal cortex, cingulate, and lateral occipital gyrus. Seizure-free surgical outcome was predicted by neural architecture alone with 90% specificity (83% accuracy), and by neural architecture combined with clinical data with 94% specificity (88% accuracy). CONCLUSIONS: Individual variations in connectome topography, combined with presurgical clinical data, may be used as biomarkers to better estimate surgical outcomes in patients with TLE.

Quantitative assessment of corpus callosum morphology in periventricular nodular heterotopia.

We investigated systematic differences in corpus callosum morphology in periventricular nodular heterotopia (PVNH). Differences in corpus callosum mid-sagittal area and subregional area changes were measured using an automated software-based method. Heterotopic gray matter deposits were automatically labeled and compared with corpus callosum changes. The spatial pattern of corpus callosum changes were interpreted in the context of the characteristic anterior-posterior development of the corpus callosum in healthy individuals. Individuals with periventricular nodular heterotopia were imaged at the Melbourne Brain Center or as part of the multi-site Epilepsy Phenome Genome project. Whole brain T1 weighted MRI was acquired in cases (n=48) and controls (n=663). The corpus callosum was segmented on the mid-sagittal plane using the software "yuki". Heterotopic gray matter and intracranial brain volume was measured using Freesurfer. Differences in corpus callosum area and subregional areas were assessed, as well as the relationship between corpus callosum area and heterotopic GM volume. The anterior-posterior distribution of corpus callosum changes and heterotopic GM nodules were quantified using a novel metric and compared with each other. Corpus callosum area was reduced by 14% in PVNH (p=1.59×10(-9)). The magnitude of the effect was least in the genu (7% reduction) and greatest in the isthmus and splenium (26% reduction). Individuals with higher heterotopic GM volume had a smaller corpus callosum. Heterotopic GM volume was highest in posterior brain regions, however there was no linear relationship between the anterior-posterior position of corpus callosum changes and PVNH nodules. Reduced corpus callosum area is strongly associated with PVNH, and is probably associated with abnormal brain development in this neurological disorder. The primarily posterior corpus callosum changes may inform our understanding of the etiology of PVNH. Our results suggest that interhemispheric pathways are affected in PVNH.

Neuroimaging the epileptogenic process.

Epilepsy is one of the most common chronic neurological conditions worldwide. Anti-epileptic drugs (AEDs) can suppress seizures, but do not affect the underlying epileptic state, and many epilepsy patients are unable to attain seizure control with AEDs. To cure or prevent epilepsy, disease-modifying interventions that inhibit or reverse the disease process of epileptogenesis must be developed. A major limitation in the development and implementation of such an intervention is the current poor understanding, and the lack of reliable biomarkers, of the epileptogenic process. Neuroimaging represents a non-invasive medical and research tool with the ability to identify early pathophysiological changes involved in epileptogenesis, monitor disease progression, and assess the effectiveness of possible therapies. Here we will provide an overview of studies conducted in animal models and in patients with epilepsy that have utilized various neuroimaging modalities to investigate epileptogenesis.

Long-term behavioral, electrophysiological, and neurochemical monitoring of the safety of an experimental antiepileptic implant, the muscimol-delivering Subdural Pharmacotherapy Device in monkeys.

OBJECT: The authors evaluated the extent to which the Subdural Pharmacotherapy Device (SPD), chronically implanted over the frontal cortex to perform periodic, localized muscimol-delivery/CSF removal cycles, affects overall behavior, motor performance, electroencephalography (EEG) activity, and blood and CSF neurochemistry in macaque monkeys. METHODS: Two monkeys were used to adjust methodology and 4 monkeys were subjected to comprehensive testing. Prior to surgery, the animals' behavior in a large test chamber was monitored, and the motor skills required to remove food pellets from food ports located on the walls of the chamber were determined. The monkeys underwent implantation of the subdural and extracranial SPD units. The subdural unit, a silicone strip integrating EEG electrodes and fluid-exchange ports, was positioned over the right frontal cortex. The control unit included a battery-powered, microprocessor-regulated dual minipump and radiofrequency module secured to the cranium. After implantation, the SPD automatically performed periodic saline or muscimol (1.0 mM) deliveries at 12-hour intervals, alternating with local CSF removals at 6-hour intervals. The antiepileptic efficacy of this muscimol concentration was verified by demonstrating its ability to prevent focal acetylcholine-induced seizures. During SPD treatment, the monkeys' behavior and motor performance were again monitored, and the power spectrum of their radiofrequency-transmitted EEG recordings was analyzed. Serum and CSF muscimol levels were measured with high-performance liquid chromatography electrochemical detection, and CSF protein levels were measured with turbidimetry. RESULTS: The SPD was well tolerated in all monkeys for up to 11 months. The behavioral study revealed that during both saline and muscimol SPD treatment, the monkeys could achieve the maximum motor performance of 40 food-pellet removals per session, as before surgery. The EEG study showed that local EEG power spectra were not affected by muscimol treatment with SPD. The neurochemical study demonstrated that the administration of 1.0 mM muscimol into the neocortical subarachnoid space led to no detectable levels of this compound in the blood and cisternal CSF, as measured 1-125 minutes after delivery. Total protein levels were within the normal range in the cisternal CSF, but protein levels in the cortical-site CSF were significantly higher than normal: 361 ± 81.6 mg/dl. Abrupt discontinuation of 3-month, periodic, subdural muscimol treatments induced withdrawal seizures, which could be completely prevented by gradually tapering off the subdural muscimol concentration from 1.0 mM to 0.12-0.03 mM over a period of 2 weeks. The monkeys' general health and weight were maintained. Infection occurred only in one monkey 9 months after surgery. CONCLUSIONS: Long-term, periodic, transmeningeal muscimol delivery with the SPD is essentially a safe procedure. If further improved and successfully adapted for use in humans, the SPD can be used for the treatment of intractable focal neocortical epilepsy affecting approximately 150,000 patients in the US.

A developmental and genetic classification for malformations of cortical development: update 2012.

Malformations of cerebral cortical development include a wide range of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. In addition, study of these disorders contributes greatly to the understanding of normal brain development and its perturbations. The rapid recent evolution of molecular biology, genetics and imaging has resulted in an explosive increase in our knowledge of cerebral cortex development and in the number and types of malformations of cortical development that have been reported. These advances continue to modify our perception of these malformations. This review addresses recent changes in our perception of these disorders and proposes a modified classification based upon updates in our knowledge of cerebral cortical development.

Autoradiographic evidence for the transmeningeal diffusion of muscimol into the neocortex in rats.

Electrophysiological and behavioral studies have demonstrated that muscimol administered through the cranial meninges can prevent focal neocortical seizures. It was proposed that transmeningeal muscimol delivery can be used for the treatment of intractable focal neocortical epilepsy. However, it has not been proved that muscimol administered via the transmeningeal route can penetrate into the neocortex. The purpose of the present study was to solve this problem by using combined autoradiography-histology methods. Four rats were implanted with epidural cups over the parietal cortices. A 50 µL mixture of [³H] muscimol and unlabeled muscimol with a final concentration of 1.0mM was delivered through each cup on the dura mater. After a 1-hour exposure, the muscimol solution was removed and replaced with formalin to trap the transmeningeally diffused molecules. Then the whole brain was fixed transcardially, sectioned, with the sections subjected to autoradiography and thionine counterstaining. Results showed that (1) [³H] muscimol diffused through the meninges into the cortical tissue underlying the epidural cup in all rats. (2) [³H] muscimol-related autoradiography grains were distributed in all six neocortical layers. (3) [³H] muscimol-related autoradiography grains were localized to the cortical area underneath the epidural delivery site and were absent in the cerebral cortical white matter and other brain structures. This study provided evidence that muscimol can be delivered via the transmeningeal route into the neocortical tissue in a spatially controlled manner. The finding further supports the rationale of using transmeningeal muscimol for the treatment of intractable focal neocortical epilepsy.

An implantable triple-function device for local drug delivery, cerebrospinal fluid removal and EEG recording in the cranial subdural/subarachnoid space of primates.

Transmeningeal pharmacotherapy for cerebral cortical disorders requires drug delivery through the subdural/subarachnoid space, ideally with a feedback controlled mechanism. We have developed a device suitable for this function. The first novel component of the apparatus is a silicone rubber strip equipped with (a) fluid-exchange ports for both drug delivery and local cerebrospinal fluid (CSF) removal, and (b) EEG recording electrode contacts. This strip can be positioned between the dura and pia maters. The second novel component is an implantable dual minipump that directs fluid movement to and from the silicone strip and is accessible for refilling and emptying the drug and CSF reservoirs, respectively. This minipump is regulated by a battery-powered microcontroller integrating a bi-directional radiofrequency (RF) communication module. The entire apparatus was implanted in 5 macaque monkeys, with the subdural strip positioned over the frontal cortex and the minipump assembly secured to the cranium under a protective cap. The system was successfully tested for up to 8 months for (1) transmeningeal drug delivery using acetylcholine (ACh) and muscimol as test compounds, (2) RF-transmission of neocortical EEG data to assess the efficacy of drug delivery, and (3) local CSF removal for subsequent diagnostic analyses. The device can be used for (a) monitoring neocortical electrophysiology and neurochemistry in freely behaving nonhuman primates for more than 6 months, (b) determining the neurobiological impact of subdural/subarachnoid drug delivery interfaces, (c) obtaining novel neuropharmacological data on the effects of central nervous system (CNS) drugs, and (d) performing translational studies to develop subdural pharmacotherapy devices.

Periodic transmeningeal muscimol maintains its antiepileptic efficacy over three weeks without inducing tolerance, in rats.

Periodic transmeningeal administration of muscimol into the neocortical epileptogenic zone via a subdurally implanted device has been proposed for the treatment of intractable focal neocortical epilepsy. It is unknown whether such muscimol applications induce tolerance. The purpose of this study was to determine whether daily transmeningeal (epidural) muscimol applications into the rat parietal cortex induce tolerance to the antiepileptic effect of this drug. Rats were chronically implanted with an epidural cup and adjacent epidural EEG electrodes over the right parietal cortex. After recovery 1.0 mM muscimol was delivered into the implanted cortical area through the cup while the animal behaved freely, once per day for 4 consecutive days in each week, with each delivery followed within 3 min by the delivery of a seizure-inducing concentration of acetylcholine (Ach) into the same area. The study lasted for 3 weeks. In each week, one day was used to test the epileptogenicity of the examined cortical site by replacing muscimol with saline prior to Ach delivery. The duration of Ach-induced EEG seizures was measured in each experimental session to assess the antiepileptic efficacy of muscimol, while the rat's behavior was also monitored. The daily epidural muscimol pretreatments prevented Ach-induced EEG and behavioral seizures in all rats. This antiepileptic action did not diminish over time and was maintained throughout the 3-week test period. When muscimol was replaced with saline, the subsequent Ach administrations induced EEG and behavioral seizures. These results suggest that periodic transmeningeal administrations of a relatively low concentration of muscimol into the neocortex over three weeks do not induce tolerance to the localized antiepileptic effects of this drug.

Bottom-of-sulcus dysplasia: imaging features.

OBJECTIVE: Dysplasia at the bottom of a sulcus is a subtle but distinct malformation of cortical development relevant to epilepsy. The purpose of this study was to review the imaging features important to the clinical diagnosis of this lesion. MATERIALS AND METHODS: All cases recognized as typical bottom-of-sulcus dysplasia in our comprehensive epilepsy program over the period 2002-2007 were included in the study. RESULTS: In the 20 cases recognized, three major features were identified: cortical thickening at the bottom of a sulcus; a funnel-shaped extension of the lesion toward the ventricular surface, commonly with abnormal signal intensity; and an abnormal gyral pattern related to the bottom-of-sulcus dysplasia, sometimes with a puckered appearance. The pathologic features of the resected lesions were typical of focal cortical dysplasia. CONCLUSION: Bottom-of-sulcus dysplasia is a distinctive malformation of cortical development that can be diagnosed on the basis of imaging characteristics. Reliable identification of this type of malformation of cortical development is difficult but clinically important because the lesion appears to be highly epileptogenic and because the prognosis for seizure control is excellent after focal resection.

Transmeningeal muscimol can prevent focal EEG seizures in the rat neocortex without stopping multineuronal activity in the treated area.

Muscimol has potent antiepileptic efficacy after transmeningeal administration in animals. However, it is unknown whether this compound stops local neuronal firing at concentrations that prevent seizures. The purpose of this study was to test the hypothesis that epidurally administered muscimol can prevent acetylcholine (Ach)-induced focal seizures in the rat neocortex without causing cessation of multineuronal activity. Rats were chronically implanted with a modified epidural cup over the right frontal cortex, with microelectrodes positioned underneath the cup. In each postsurgical experimental day, either saline or 0.005-, 0.05-, 0.5- or 5.0-mM muscimol was delivered through the cup, followed by a 20-min monitoring of the multineuronal activity and the subsequent delivery of Ach in the same way. Saline and muscimol pretreatment in the concentration range of 0.005-0.05 mM did not prevent EEG seizures. In contrast, 0.5-mM muscimol reduced the average EEG Seizure Duration Ratio value from 0.30±0.04 to 0. At this muscimol concentration, the average baseline multineuronal firing rate of 10.9±4.4 spikes/s did not change significantly throughout the 20-min pretreatment. Muscimol at 5.0mM also prevented seizures, but decreased significantly the baseline multineuronal firing rate of 7.0±1.8 to 3.7±0.9 spikes/s in the last 10 min of pretreatment. These data indicate that transmeningeal muscimol in a submillimolar concentration range can prevent focal neocortical seizures without stopping multineuronal activity in the treated area, and thus this treatment is unlikely to interrupt local physiological functions.

Evolution and prospects for intracranial pharmacotherapy for refractory epilepsies: the subdural hybrid neuroprosthesis.

Intracranial pharmacotherapy is a novel strategy to treat drug refractory, localization-related epilepsies not amenable to resective surgery. The common feature of the method is the use of some type of antiepileptic drug (AED) delivery device placed inside the cranium to prevent or stop focal seizures. This distinguishes it from other nonconventional methods, such as intrathecal pharmacotherapy, electrical neurostimulation, gene therapy, cell transplantation, and local cooling. AED-delivery systems comprise drug releasing polymers and neuroprosthetic devices that can deliver AEDs into the brain via intraparenchymal, ventricular, or transmeningeal routes. One such device is the subdural Hybrid Neuroprosthesis (HNP), designed to deliver AEDs, such as muscimol, into the subdural/subarachnoid space overlaying neocortical epileptogenic zones, with electrophysiological feedback from the treated tissue. The idea of intracranial pharmacotherapy and HNP treatment for epilepsy originated from multiple sources, including the advent of implanted medical devices, safety data for intracranial electrodes and catheters, evidence for the seizure-controlling efficacy of intracerebral AEDs, and further understanding of the pathophysiology of focal epilepsy. Successful introduction of intracranial pharmacotherapy into clinical practice depends on how the intertwined scientific, engineering, clinical, neurosurgical and regulatory challenges will be met to produce an effective and commercially viable device.