Effectiveness of vagus nerve stimulation in epilepsy patients: a 12-year observation.

A retrospective review of the safety, tolerability, and efficacy of vagus nerve stimulation (VNS) in 48 patients with intractable partial epilepsy was performed. Side effects were few and mild to moderate. Mean seizure frequency decreased by 26% after 1 year, 30% after 5 years, and 52% after 12 years with VNS treatment.

MMPI-2 profiles of patients with intractable epilepsy.

MMPI-2 profiles of 93 presurgical intractable epilepsy patients were examined using Ward's method of cluster analysis. Three clusters were identified. The means of each cluster suggest that 45% of the sample had minimal psychological complaints, 30% presented with generalized clinical elevations, and 25% of the patients had profiles of intermediate elevations with a tendency to emphasize somatic complaints and/or depression. Gender, age of seizure onset, and seizure laterality were not found to be uniquely associated with the cluster profiles. Further examination of correlates of group membership is warranted to provide information for treatment planning.

An essential role for the H218/AGR16/Edg-5/LP(B2) sphingosine 1-phosphate receptor in neuronal excitability.

A wealth of indirect data suggest that the H218/AGR16/Edg-5/LP(B2) sphingosine 1-phosphate (S1P) receptor plays important roles in development. In vitro, it activates several forms of development-related signal transduction and regulates cellular proliferation, differentiation and survival. It is expressed during embryogenesis, and mutation of an H218-like gene in zebrafish leads to profound defects in embryonic development. Nevertheless, the in vivo functions served by H218 signalling have not been directly investigated. We report here that mice in which the H218 gene has been disrupted are unexpectedly born with no apparent anatomical or physiological defects. In addition, no abnormalities were observed in general neurological development, peripheral axon growth or brain structure. However, between 3 and 7 weeks of age, H218(-/-) mice have seizures which are spontaneous, sporadic and occasionally lethal. Electroencephalographic abnormalities were identified both during and between the seizures. At a cellular level, whole-cell patch-clamp recordings revealed that the loss of H218 leads to a large increase in the excitability of neocortical pyramidal neurons. Therefore, H218 plays an essential, unanticipated and functionally important role in the proper development and/or mediation of neuronal excitability.

Brain-derived neurotrophic factor enhances fast excitatory synaptic transmission in human epileptic dentate gyrus.

Brain-derived neurotrophic factor (BDNF) has trophic effects and modulates synaptic transmission in the hippocampal formation in animal studies. It is also upregulated in acute and chronic epilepsy models and in human temporal lobe epilepsy. This study was undertaken to examine the effects of BDNF on fast synaptic transmission in the human epileptic dentate gyrus. Hippocampal specimens were acquired from patients with temporal lobe epilepsy during surgical removal of the anterior temporal lobe intended to treat the epileptic condition. Whole-cell patch-clamp recordings were obtained from dentate granule cells in transverse hippocampal slices in vitro. Application of BDNF increased the amplitude and frequency of spontaneous excitatory postsynaptic currents and increased the amplitude of evoked excitatory postsynaptic currents. BDNF had no effect on spontaneous inhibitory postsynaptic currents but produced a decrease in amplitude of evoked inhibitory postsynaptic currents. BDNF's effects were abolished by coapplication of the tyrosine kinase inhibitor K252a. Therefore, BDNF enhances fast excitatory transmission in the epileptic human dentate gyrus and may play an important role in epileptogenesis in temporal lobe epilepsy. This raises the possibility of designing therapies for this disorder that may be both anticonvulsant and antiepileptogenic.

Lateralization of temporal lobe foci: depth versus subdural electrodes.

OBJECTIVES: Definitive localization of an epileptic focus correlates with a favorable outcome following epilepsy surgery. This study was undertaken to determine the incremental value of data yielded for surgical decision making when using subdural electrodes alone and in addition to depth electrodes for temporal lobe epilepsy. METHODS: Standardized placement for intracranial electrodes included: (1) longitudinal placement of bilateral temporal lobe depth electrodes; (2) bilateral subtemporal subdural strips; and (3) bilateral orbitofrontal subdural strips. Sixty-three events were randomly reviewed for: (1) subdural electrodes alone; and (2) depth electrodes in conjunction with subdural electrodes. RESULTS: Of the 63 seizures, 54 (85.7%) demonstrated congruent lateralization to ipsilateral subtemporal subdural strip electrodes (based on depth electrode localization) when subdural strip electrodes were utilized alone. In 3 of 22 patients, 7 seizures demonstrated 'false localization' on subdural electrode analysis alone when compared with depth recording and post-surgical outcome. For these 3 patients, retrospective review of neuroimaging demonstrated suboptimal ipsilateral placement of subtemporal subdural electrodes with the most mesial electrode lateral to the collateral sulcus. Four additional patients had suboptimal placement of subtemporal subdural electrodes. Two of these 4 patients had congruent localization with subdural electrodes to ipsilateral depth electrodes despite suboptimal placement. Subtemporal subdural electrodes accurately localized for all seizures from the mesial temporal lobe when the mesial electrodes of the subtemporal subdural strip recorded mesial to the collateral sulcus from the parahippocampal region. CONCLUSION: We conclude that although there are high concordance rates between subdural and depth electrodes, localization of seizure onset based on subdural strip electrodes alone may result in inaccurate focus identification with potential for possible suboptimal treatment of temporal lobe epilepsy. When subtemporal subdural electrodes provide recording from the parahippocampal region, there is accurate localization of the seizure focus. If suboptimal placement occurs lateral to the collateral sulcus, the electroencephalographer cannot make a definitive identification of the seizure focus.

Electroencephalographic, volumetric, and neuropsychological indicators of seizure focus lateralization in temporal lobe epilepsy.

CONTEXT: Anterior temporal lobectomy is an effective treatment for medically intractable temporal lobe seizures. Identification of seizure focus is essential to surgical success. OBJECTIVE: To examine the usefulness of presurgical electroencephalography (EEG), magnetic resonance imaging (MRI), and neuropsychological data in the lateralization of seizure focus. DESIGN: Presurgical EEG, MRI, and neuropsychological data were entered, independently and in combination, as indicators of seizure focus lateralization in discriminant function analyses, yielding correct seizure lateralization rates for each set of indicators. SETTING: Comprehensive Epilepsy Program, Shands Teaching Hospital, University of Florida, Gainesville. PATIENTS: Forty-four right-handed adult patients who ultimately underwent successful anterior temporal lobectomy. Left-handed patients, those with less-than-optimal surgical outcome, and any patients with a history of neurological insult unrelated to seizure disorder were excluded from this study. MAIN OUTCOME MEASURES: For each patient presurgical EEG was represented as a seizure lateralization index reflecting the numbers of seizures originating in the left hemisphere, right hemisphere, and those unable to be lateralized. Magnetic resonance imaging data were represented as left-right difference in hippocampal volume. Neuropsychological data consisted of mean scores in each of 5 cognitive domains. RESULTS: The EEG was a better indicator of lateralization (89% correct) than MRI (86%), although not significantly. The EEG and MRI were significantly superior to neuropsychological data (66%) (P=.02 and .04, respectively). Combining EEG and MRI yielded a significantly higher lateralization rate (93%) than EEG alone (P<.01). Adding neuropsychological data improved this slightly (95%). CONCLUSIONS: The EEG and MRI were of high lateralization value, while neuropsychological data were of limited use in this regard. Combining EEG, MRI, and neuropsychological improved focus lateralization relative to using these data independently.

Bcl-2 immunoreactive cells with immature neuronal phenotype exist in the nonepileptic adult human brain.

Bcl-2, a cell death suppressor protein, is expressed during brain development but is largely down-regulated in the adult central nervous system. We previously reported strong expression of bcl-2 in small, "oligodendrocyte-like" cells (OLC) found in glioneuronal hamartias. These hamartias are microscopic cell rests found in temporal lobe resections from patients with intractable epilepsy and are considered a form of cerebral microdysgenesis. However, a causative relationship between these rests and seizures is not clear. We now report the identification, lineage characterization, and postnatal ontogeny of hamartia-like cell rests in temporal lobes of nonepileptic humans. Postmortem temporal lobes from 28 patients without history of neurologic disease (mean age = 53 years; range = 20 to 83 years) were studied. Microscopic cellular aggregates containing immature-appearing, bcl-2-immunoreactive cells (BIC) (identical to OLC) were observed in 23 of 28 (82%) temporal lobes from nonepileptic individuals. BIC were strongly immunoreactive for neuronal-specific class III beta tubulin, neuronal nuclear antigen, and MAP-2, but were consistently negative for neurofilament proteins and Ki67. Such cells were localized to subventricular regions of the caudal amygdala and often extended into the adjacent subcortical white matter and periamygdaloid cortex. BIC became less abundant with advancing age. These findings suggest that hamartia-like rests containing immature postmitotic neurons are normally present in the human brain and that glioneuronal hamartias may not always represent a maldevelopmental lesion associated with epilepsy.

Altered mRNA expression for brain-derived neurotrophic factor and type II calcium/calmodulin-dependent protein kinase in the hippocampus of patients with intractable temporal lobe epilepsy.

The expression of brain-derived neurotrophic factor and the alpha subunit of calcium/calmodulin-dependent protein kinase II mRNA in hippocampi obtained during surgical resections for intractable temporal lobe epilepsy were examined. Both calcium/calmodulin-dependent protein kinase II and brain-derived neurotrophic factor are localized heavily within the hippocampus and have been implicated in regulating hippocampal activity (Kang and Schuman [1995] Science 267:1658-1662; Suzuki [1994] Intl J Biochem 26:735-744). Also, the autocrine and paracrine actions of brain-derived neurotrophic factor within the central nervous system make it a likely candidate for mediating morphologic changes typically seen in the epileptic hippocampus. Quantitative assessments of mRNA levels in epileptic hippocampi relative to autopsy controls were made by using normalized densitometric analysis of in situ hybridization. In addition, correlations between clinical data and mRNA levels were studied. Relative to autopsy control tissue, decreased hybridization to mRNA of the alpha subunit of calcium/calmodulin-dependent protein kinase II and increased hybridization to brain-derived neurotrophic factor mRNA were found throughout the granule cells of the epileptic hippocampus. There also was a significant negative correlation between the duration of epilepsy and the expression of mRNA for brain-derived neurotrophic factor. These results are similar qualitatively to those found in animal models of epilepsy and suggest that chronic seizure activity in humans leads to persistent alterations in gene expression. Furthermore, these alterations in gene expression may play a role in the etiology of the epileptic condition.

Reduced inhibition in an animal model of cortical dysplasia.

Cortical dysplasia has a strong association with epilepsy in humans, but the underlying mechanisms for this are poorly understood. In utero irradiation of rats produces diffuse cortical dysplasia and neuronal heterotopia in the neocortex and hippocampus. Using in vitro neocortical slices, whole-cell patch-clamp recordings were obtained from pyramidal neurons in dysplastic cortex and control neocortex. Spontaneous IPSCs were reduced in amplitude (35%) and frequency (70%) in pyramidal cells from dysplastic cortex. Miniature IPSCs were reduced in frequency (66%) in dysplastic cortex. Two additional measures of cortical inhibition, monosynaptic evoked IPSCs and paired pulse depression of evoked EPSCs, were also impaired in dysplastic cortex. Spontaneous EPSCs were increased in amplitude (42%) and frequency (77%) in dysplastic cortex, but miniature EPSCs were not different between the two groups. These data demonstrate significant physiological impairment in inhibitory synaptic transmission in experimental cortical dysplasia. This supports previous immunohistochemical findings in this model and observations in humans of a reduction in the density of inhibitory interneurons in dysplastic cortex.

Electrophysiological responses in vivo of hippocampal CA1 pyramidal neurons in an animal model of neuronal migration disorders.

Cortical dysgenesis arising from neuronal migration disorders is closely associated with intractable epilepsy in humans. We used extracellular field potential and conventional intracellular recordings from the dorsal hippocampus of intact adult rats to determine if the excitability of CA1 pyramidal cells was enhanced in rats with experimentally induced hippocampal dysplasia. Electrical stimulation of afferent fibers resulted in more robust population responses in the CA1 region of irradiated rats versus controls. Synaptic inhibition of pyramidal cells was also reduced in these animals. These results suggest that the excitability of the CA1 region in rats with hippocampal dysplasia is greater than in control animals.

Synaptic responses of neurons in heterotopic gray matter in an animal model of cortical dysgenesis.

Neuronal heterotopia is a malformation of cortical development that is closely associated with epilepsy in humans. Despite emerging interest in the structure and function of the heterotopic cortex, little is known about the membrane properties and synaptic connections of these displaced neurons. We used whole-cell patch-clamp and extracellular field potential recordings from heterotopic neurons in slices from young adult rats with experimentally induced cortical dysgenesis to determine if local synaptic connections were present in nodular heterotopia. Complex synaptic responses were observed after electrical stimulation of adjacent white matter. The results suggest that neurons in nodular heterotopic gray matter can form local excitatory and inhibitory synaptic connections and may participate in epileptiform events.

Reduced density of parvalbumin- and calbindin D28-immunoreactive neurons in experimental cortical dysplasia.

Cortical dysplasia (CD) is a congenital brain malformation in humans that is closely associated with intractable epilepsy. This study utilized an animal model of CD, in utero irradiation in rats, to determine if experimental dysplastic cortex demonstrates a reduction in the density of inhibitory interneurons. Fetal rats were exposed to external irradiation on gestational day 17 to produce diffuse CD and heterotopic grey matter. As adults, these rats were processed for immunohistochemistry using primary antibodies for parvalbumin (PA), calbindin D28k (CA), the 67 kD subunit of glutamic acid decarboxylase (GAD67), and cresyl violet staining. Quantitative methods were used to determine the density of immunoreactive neurons and cresyl violet-stained neurons in the neocortex at the rostro-caudal level of the anterior commissure. Compared to control values, the density of PA- and CA-immunoreactive neurons was reduced in dysplastic cortex. Density of glutamic acic decarboxylase-immunoreactive neurons was not different between control and dysplastic cortex. Overall neuronal density, measured in cresyl violet-stained sections, was not significantly different between control and dysplastic cortex. These data suggest a selective reduction in inhibitory interneurons in experimental CD cortex or an impaired ability for these neurons to produce PA and CA.

Tuberous sclerosis-related gene expression in normal and dysplastic brain.

Cortical dysplasia (CD) broadly defines a complex cerebral malformative lesion associated clinically with intractable, pharmacoresistant epilepsy (including infantile spasms), especially in infants and children. In CD, the spectrum of structural brain abnormalities includes (at a minimum) neuronal dyslamination and (in severe cases) neuronal cytomegaly with cytoskeletal alterations and the presence of gemistocyte-like 'balloon cells'. In some CD variants, the neuropathological features are essentially indistinguishable from those of a tuber of tuberous sclerosis (TSC). Two genes associated with the autosomal dominant, multi-system disorder TSC have recently been cloned: TSC2 (on chromosome 16p13.3) encodes the protein tuberin and TSC1 (on 9q34) encodes hamartin. Tuberin has been immunolocalized to neurons and possibly astrocytes in normal brain and CD/TSC tubers, and is widely expressed in normal viscera; loss of heterozygosity and tissue culture studies suggest it functions as a growth suppressor. The TSC1 gene has been cloned within the last year and hamartin as yet has no well-defined cellular function, though its protein product may also function as a growth suppressor. This article focuses on the cellular pathogenesis of CD and TSC brain lesions and how the two may be biologically related. Studies of how TSC1 and TSC2 function in normal and dysplastic cerebral neocortex may provide a paradigm for understanding the neurobiology of other genes that determine epilepsy-associated cerebral malformations (e.g. lissencephaly, double cortex).

In utero irradiation of rats as a model of human cerebrocortical dysgenesis: a review.

Certain developmental abnormalities of the cerebral cortex are closely associated with epilepsy in humans. Exposure of fetal rats to external gamma-irradiation produces diffuse cortical dysplasia and neuronal heterotopia. These abnormalities are the result of radiation-induced cell death coupled with continued cortical development in an altered cellular environment. In vivo electroencephalography studies in these animals have revealed an increased propensity for electrographic seizures in the presence of the sedating agents, acepromazine and xylazine. In vitro neocortical slices containing dysplastic cortex demonstrate enhanced excitability, as compared to control neocortex, when inhibition that is mediated by the A-type gamma-amino butyric acid receptor is blocked with bicuculline methiodide. In utero irradiation of rats produces structural changes that mimic some aspects of cerebral dysgenesis in humans and results in physiologic changes that increase the animals' propensity for seizures. Similarities and differences between the animal model and the human syndromes are discussed.

In vivo detection of experimentally induced cortical dysgenesis in the adult rat neocortex using optical coherence tomography.

Imaging cerebral structure in vivo can be accomplished by many methods, including MRI, ultrasound, and computed tomography. Each offers advantages and disadvantages with respect to the others, but all are limited in spatial resolution to millimeter-scale features when used in routine applications. Optical coherence tomography (OCT) is a new, high resolution imaging technique which uses light to directly image living tissue. Here, we investigate the potential use of OCT for structural imaging of the fully developed mammalian cerebral cortex. In particular, we show that OCT can perform in vivo detection of neocortex and differentiate normal and abnormal cortical anatomy. We present the results of detailed optical coherence tomographic (OCT) observations of both normal and abnormal rat neocortex obtained in vivo. Comparative histologic analysis shows excellent correlation with the OCT tomograms.

White matter neuronal heterotopia in temporal lobe epilepsy: a morphometric and immunohistochemical study.

A frequent abnormality in temporal lobes (TL) resected for pharmacoresistant epilepsy is the presence of heterotopic neurons within white matter (WM). We compared heterotopic neuron density in 22 TLs surgically resected from epilepsy patients with TLs from 22 non-neurologic cases obtained at autopsies. Neuronal density was assessed on LFB-PAS-stained and parallel sections immunoreacted for microtubule-associated-protein-2 (MAP-2). The white matter area was outlined by an image analysis system. Neurons, identified by morphologic features, were counted within the marked area. Results are expressed as mean +/- SD neurons/mm2. LFB/PAS sections: Epilepsy cases 4.11 +/- 1.86 Autopsy (normal) 2.35 +/- 0.96; MAP-2 sections: Epilepsy cases 4.08 +/- 1.22, autopsy (normal) 1.68 +/-0.92 (significant at 0.05 level by Wilcoxon's Rank Sums test). The lower number of MAP-2-immunopositive neurons in the control group as compared with the histologically identified group is most likely the result of antigen degradation resulting from an increased postmortem interval. These results indicate that normal TLWM contains a heterotopic population of neurons, and that this neuronal density is significantly higher in epilepsy patients. It is felt that this increased neuronal density is an epiphenomenon rather than the cause of seizures, and may be the result of decreased white matter either secondary to disruption of myelination, or loss of neurons as part of mesial temporal sclerosis.

Invasive monitoring of limbic epilepsy using stereotactic depth and subdural strip electrodes: surgical technique.

BACKGROUND: In spite of advances in noninvasive localization of seizure foci, some cases of intractable limbic epilepsy still require invasive recordings in order to identify the site of seizure onset. This necessitates a safe and reliable method for placing depth and subdural electrodes in the mesial temporal and orbitofrontal regions. The University of Florida has devised a system that utilizes CRW-based stereotactic placement of bitemporal depth electrodes in conjunction with placement of subdural strips over the inferolateral temporal lobe and orbitofrontal cortex. This report describes the surgical technique and initial clinical experience using this method. METHODS: Depth electrodes are placed along the long axis of the hippocampi via an occipital approach. A CRW-based stereotactic system was developed that incorporates both computed tomography (CT) and magnetic resonance imaging (MRI) for selection of target and entry sites and displaying the electrode trajectory. Subdural strip electrodes are placed over the inferolateral temporal and orbitofrontal regions through burr holes. RESULTS: This method has been used in 18 patients (depth electrodes only in three patients and depth electrodes with subdural strips in 15 patients). This information lead to surgical resections in 15 patients. No resection was recommended in three patients (two with bitemporal onset and one with no seizures after 6 weeks). Complications were limited to an unplanned removal of one electrode and an asymptomatic lateral temporal lobe contusion in one patient. CONCLUSIONS: This method provides a safe and effective way to sample bilateral mesial temporal and orbitofrontal regions in cases of intractable limbic epilepsy.

Disinhibited in vitro neocortical slices containing experimentally induced cortical dysplasia demonstrate hyperexcitability.

Cortical dysplasia, a disorder of neuronal migration, has a strong association with intractable epilepsy in humans but little is known about the physiologic abnormalities that are present in this condition. Fetal rats were exposed to external irradiation to experimentally produce diffuse cortical dysplasia. In vitro neocortical slices from adult irradiated and control animals were examined in physiologic solution and in the presence of the A-type gamma-amino butyric acid (GABAA) receptor antagonist, bicuculline methiodide. Epileptiform bursts were quantified by counting the number of negative field potentials per epileptiform event. In the presence of bicuculline, neocortical slices with cortical dysplasia demonstrated more robust epileptiform activity in the form of an increased number of negative field potentials per epileptiform event. This demonstrates that areas of experimentally induced cortical dysplasia possess an inherent hyperexcitability when GABAA-mediated inhibition is effectively blocked.

Non-linearity in invasive EEG recordings from patients with temporal lobe epilepsy.

Electrographic recordings from depth and subdural electrodes, performed in two patients with seizures of mesial temporal origin, were analyzed for the presence of non-linearities in the signal. The correlation integral, a measure sensitive to a wide variety of non-linearities, was used for detection. Statistical significance was determined by comparison of the original signal to surrogate datasets. Statistically significant non-linearities were present in signals generated by the epileptogenic hippocampus and interictal spike foci in the temporal neocortex. Less prominent non-linearities were found in EEG signals generated by more normal areas of the brain. These results indicate that techniques developed for the study of non-linear systems can be used to characterize the epileptogenic regions of the brain during the interictal period and can elucidate the dynamical mechanisms of the epileptic transition.

Exposure to in utero irradiation produces disruption of radial glia in rats.

In utero exposure of fetal rats to gamma-irradiation produces diffuse cortical dysplasia and neuronal heterotopia. This study examined the effects of in utero irradiation on radial glia and astrocytes in the perinatal period in order to better understand the specific mechanisms which produce cortical dysgenesis in this model. Fetal rats were exposed to 225 cGy of gamma-irradiation on embryonic day 17. Vibratome sections were processed for cresyl violet staining and immunohistochemistry with Rat-401 and an antibody for glial fibrillary acidic protein (GFAP) on E20, P0, P2, and P4. In utero irradiation produced a profound disruption of the radial glia which lasted throughout the perinatal period. This injury coincided with the location of the most severe cortical dysplasia in this model. In addition, there was increased GFAP immunoreactivity in the cortex and the striatum when compared to nonirradiated controls on P0, P2, and P4. Our results demonstrate that in utero irradiation has a lasting, injurious effect on radial glia and also incites a reactive astrocytic response. This suggests that disruption of radial glial fibers by gamma-irradiation is a major factor in the pathogenesis of cortical dysgenesis in this model.