Oral glutamine supplementation increases seizure severity in a rodent model of mesial temporal lobe epilepsy.

Background: Glutamine synthetase (GS) is the only enzyme known to synthesize significant amounts of glutamine in mammals, and loss of GS in the hippocampus has been implicated in the pathophysiology of medication refractory mesial temporal lobe epilepsy (MTLE). Moreover, loss-of-function mutations of the GS gene causes severe epileptic encephalopathy, and supplementation with glutamine has been shown to normalize EEG and possibly improve the outcome in these patients. Here we examined whether oral glutamine supplementation is an effective treatment for MTLE by assessing the frequency and severity of seizures after supplementation in a translationally relevant model of the disease.Methods: Male Sprague Dawley rats (380-400 g) were allowed to drink unlimited amounts of glutamine in water (3.6% w/v; n = 8) or pure water (n = 8) for several weeks. Ten days after the start of glutamine supplementation, GS was chronically inhibited in the hippocampus to induce MTLE. Continuous video-intracranial EEG was collected for 21 days to determine the frequency and severity of seizures.Results: While there was no change in seizure frequency between the groups, the proportion of convulsive seizures was significantly higher in glutamine treated animals during the first three days of GS inhibition.Conclusion: The results suggest that oral glutamine supplementation transiently increases seizure severity in the initial stages of an epilepsy model, indicating a potential role of the amino acid in seizure propagation and epileptogenesis.

Confounding effect of EEG implantation surgery: Inadequacy of surgical control in a two hit model of temporal lobe epilepsy.

In rodent models of epilepsy, EEG implantation surgery is an essential modality to evaluate electrographic seizures. The inflammatory consequences of EEG electrode-implantation and their resultant effects on seizure susceptibility are unclear. We evaluated electrode-implantation in a two-hit model of epileptogenesis in C57BL/6 mice that included brief, recurrent febrile seizures (FS) at P14 and kainic acid induced seizures (KA-SZ) at P28. During KA-SZ, latencies to first electrographic and behavioral seizures, seizure severity, and KA dose sensitivity were measured. Mice that received subdural screw electrode implants at P25 for EEG monitoring at P28 had significantly shorter latencies to seizures than sham mice, regardless of early life seizure experience. Electrode-implanted mice were sensitive to low dose KA as shown by high mortality rate at KA doses above 10mg/kg. We then directly compared electrode-implantation and KA-SZ in seizure naive CX3CR1(GFP/+) transgenic C57BL/6 mice, wherein microglia express green fluorescent protein (GFP), to determine if microglia activation related to surgery was associated with the increased seizure susceptibility in electrode-implanted mice from the two-hit model. Hippocampal microglia activation, as demonstrated by percent area GFP signal and GFP positive cell counts, prior to seizures was indistinguishable between electrode-implanted mice and controls, but was significantly greater in electrode-implanted mice following seizures. Electrode-implantation had a confounding priming effect on the inflammatory response to subsequent seizures.

Thalamic structural connectivity in medial temporal lobe epilepsy.

The thalamus has been implicated in various stages of medial temporal lobe epilepsy (MTLE) seizure evolution. The relative density and functional significance (in epileptogenesis) of thalamic projections to MTL subregions, however, remains to be determined. This study used structural and diffusion magnetic resonance imaging (MRI) to evaluate thalamic connection density with distinct MTL subregions in terms of location and volume. Nineteen MTLE patients with unilateral hippocampal sclerosis (HS; 12 right; 10 female) were compared to 19 age-matched controls. Five regions of interest (ROIs) per hemisphere were created in native space: thalamus, amygdala, entorhinal cortex, hippocampus, and parahippocampus. Separate probabilistic tractography analyses were performed between the thalamus and each ipsilateral MTL subregion (four per hemisphere). Individual connectivity profiles and regional volumes were assessed. The medial pulvinar consistently showed the highest connection density with the hippocampus in healthy controls and in MTLE patients. Decreased thalamic connected volume was observed for thalamohippocampal pathways in patients with MTLE, and indicates pathway-specific deafferentation. Regional hippocampal and thalamic atrophy was also observed, indicating gray and white matter loss in the thalamohippocampal pathway. Consistent localization of dense medial pulvinar (PuM) connectivity with the hippocampus suggests chronic PuM stimulation could modulate the MTLE seizure network. Decreased thalamic connected volume is a promising biomarker for epileptogenesis that merits longitudinal validation. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Distributed, limbic gray matter atrophy in patients after bacterial meningitis.

BACKGROUND AND PURPOSE: The structural basis of cognitive sequelae after bacterial meningitis in humans is still poorly understood. In animal models and human autopsy cases, neuronal apoptosis of the hippocampal formation in particular seems to play an important role. Here, we aimed to analyze if BM entails MR imaging structural consequences in humans in vivo. MATERIALS AND METHODS: We applied voxel-based morphometry in a cohort of BM survivors with normal conventional MR imaging after resolution of the acute inflammation to assess morphologic differences. RESULTS: We found clear gray matter volume loss in the limbic system including the hippocampal formation, thalamus, and cingulate gyri bilaterally as well as in the temporal lobe. These results were corroborated by an alternative atlas-based method. CONCLUSIONS: Even in patients with normal routine MR imaging results, clear-cut gray matter atrophy with a mesial temporal/limbic pattern was evident. The anatomic distribution is compatible with the neuropsychological deficit commonly observed in patients after BM. The similarity of the observed atrophy may point to causal link between BM and mesial temporal epilepsy.

GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy.

Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ectopia that persists into adulthood. Febrile seizures induced an upregulation of GABA(A) receptors (GABA(A)-Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABA(A)-Rs caused a reversal in the direction of granule cell migration. This abnormal migration was prevented by RNAi-mediated knockdown of the Na(+)K(+)2Cl(-) co-transporter (NKCC1), which regulates the excitatory action of GABA. NKCC1 inhibition with bumetanide after febrile seizures rescued the granule cell ectopia, susceptibility to limbic seizures and development of epilepsy. Thus, this work identifies a previously unknown pathogenic role of excitatory GABA(A)-R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.

[Neuroprotection in epilepsy].

Brain damage and neuronal loss caused by traumatic brain injury, ischemic stroke, and symptomatic status epilepticus can lead to severe long-term consequences, such as impairment in learning and memory and cognitive functions, and development of chronic epilepsy. This can be the result of morphologic and functional changes underlying temporal lobe epilepsy. Epilepsy patients have increased risk of status epilepticus. It is a life-threatening condition when seizures last for more than 30 min and trigger processes leading to neuronal apoptosis and necrosis in various parts of brain. Administration of neuroprotective drugs preventing these pathologic processes could improve the prognosis for such patients. However despite of active research of neuroprotective drugs, the effective ways to prevent brain damage resulting from prolonged seizures are yet to be found. Studies of neuroprotective properties of classic and novel anticonvulsant drugs showed that most of them do not have the sufficient neuroprotective effect and are not able to prevent epileptogenesis. Thus the studies of other potential neuroprotective drugs seem to be promising.

Seizure precipitants and inhibiting factors in mesial temporal lobe epilepsy.

Epileptic seizures may be triggered by both nonspecific facilitating factors and specific reflex epileptic mechanisms. These consist of sensory or cognitive inputs activating neural networks that, due to some functional instability, may respond with an epileptic discharge. The aim of this study was to determine the prevalence and nature of self-perceived seizure-inducing and -inhibiting factors in patients with mesial temporal lobe epilepsy (MTLE) followed from March 3rd to December 8th, 2009 at the Centro de Epilepsia de Santa Catarina Outpatient Clinic of the Hospital Governador Celso Ramos in Florianópolis, Brazil and their relation to demographics, epilepsy-related variables and anxiety level. Of the 71 patients, 60 (84.5%) patients identified at least one seizure trigger, and 36 (50.7%) patients identified inhibiting factors. In order of frequency, the most freely recalled precipitants were nervousness (58.8%), worrying (21.6%) and menstruation (19.6%), while the precipitants that were most frequently identified from a list were worrying (73.2%), anxiety (66.2%) and anger (53.5%). Knowledge of precipitant factors may have implications on the treatment and seizure control of patients.

The omega-3 fatty acid-derived neuroprotectin D1 limits hippocampal hyperexcitability and seizure susceptibility in kindling epileptogenesis.

PURPOSE: Temporal lobe epilepsy, one of the most common epilepsy syndromes, is characterized by hippocampal hyperexcitability and progressive seizure susceptibility. Omega-3 fatty acids are involved in neuronal excitability and have anticonvulsant properties. We studied the effect of docosahexaenoic acid (DHA) or its derived lipid mediator, neuroprotectin D1 (NPD1, 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid), in evoked seizures using a rapid kindling model of temporal lobe epilepsy. METHODS: DHA or NPD1 was administered in rodents with or without kindling acquisition. Locomotor seizures and evoked epileptiform hippocampal activity immediately after hippocampal stimulations were analyzed. KEY FINDINGS: DHA or NPD1 limits hippocampal electrically induced hyperexcitability. Seizures induced by kindling triggered NPD1 synthesis in the hippocampus. Supplying its precursor, DHA, or direct injection of NPD1 into the third ventricle resulted in attenuation of kindling progression and hippocampal hyperexcitability. SIGNIFICANCE: The significance of NPD1 in temporal lobe epilepsy could open new pathways for understanding the initiation and propagation of seizures and the role this lipid mediator plays in the neuronal network.

Grafting of striatal precursor cells into hippocampus shortly after status epilepticus restrains chronic temporal lobe epilepsy.

Status epilepticus (SE) typically progresses into temporal lobe epilepsy (TLE) typified by complex partial seizures. Because sizable fraction of patients with TLE exhibit chronic seizures that are resistant to antiepileptic drugs, alternative therapies that are efficient for diminishing SE-induced chronic epilepsy have great significance. We hypothesize that bilateral grafting of appropriately treated striatal precursor cells into hippocampi shortly after SE is efficacious for diminishing SE-induced chronic epilepsy through long-term survival and differentiation into GABA-ergic neurons. We induced SE in adult rats via graded intraperitoneal injections of kainic acid, bilaterally placed grafts of striatal precursors (pre-treated with fibroblast growth factor-2 and caspase inhibitor) into hippocampi at 4 days post-SE, and examined long-term effects of grafting on spontaneous recurrent motor seizures (SRMS). Analyses at 9-12 months post-grafting revealed that, the overall frequency of SRMS was 67-89% less than that observed in SE-rats that underwent sham-grafting surgery and epilepsy-only controls. Graft cell survival was approximately 33% of injected cells and approximately 69% of surviving cells differentiated into GABA-ergic neurons, which comprised subclasses expressing calbindin, parvalbumin, calretinin and neuropeptide Y. Grafting considerably preserved hippocampal calbindin but had no effects on aberrant mossy fiber sprouting. The results provide novel evidence that bilateral grafting of appropriately treated striatal precursor cells into hippocampi shortly after SE is proficient for greatly reducing the frequency of SRMS on a long-term basis in the chronic epilepsy period. Presence of a large number of GABA-ergic neurons in grafts further suggests that strengthening of the inhibitory control in host hippocampi likely underlies the beneficial effects mediated by grafts.

Hypothermia in VGKC antibody-associated limbic encephalitis.

Voltage-gated potassium channel antibody (VGKC-Ab)-associated limbic encephalitis (LE) is a recently described syndrome that broadens the spectrum of immunotherapy-responsive central nervous system disorders. Limbic encephalitis is typically characterised by a sub-acute onset of disorientation, amnesia and seizures, but the clinical spectrum is not yet fully defined and the syndrome could be under-diagnosed. We here describe the clinical profile of four patients with VGKC-Ab-associated LE who had intermittent, episodic hypothermia. One of the patients also described a prodrome of severe neuropathic pain preceding the development of limbic symptoms. Both of these novel symptoms responded well to immunosuppressive therapy, with concurrent amelioration of amnesia/seizures.

Meditation and epilepsy: a still hung jury.

Meditation has been advocated as a treatment for several medical problems, including epilepsy. Conversely, concern has been raised that meditation may aggravate or even precipitate epilepsy. We present a case of new onset mesial temporal lobe epilepsy in a young woman meditator lacking other apparent risk factors for epilepsy as a springboard for a balanced discussion concerning the potential relationship between meditation and epilepsy, and a criticism of the current literature in this field. Prospective clinical studies of meditators with video-electroencephalography and clinical trials of meditation in refractory epilepsy patients are needed to resolve current controversies concerning meditation and epilepsy.

Evidence for augmented brainstem activated forebrain seizures in Wistar Audiogenic Rats subjected to transauricular electroshock.

Previous work from our laboratory has shown that naïve Wistar Audiogenic Rats (WARs), a genetic model of reflex epilepsy in which seizures are induced by high-intensity sound stimulation (120 dB SPL), are seizure-prone to a variety of pro-convulsive stimuli (e.g., transauricular electroshock, pentylenetetrazole and pilocarpine). On the other hand, repetitive acoustic stimulation of WARs causes a slow recruitment of limbic structures, known as audiogenic kindling, changing seizure expression to include behavior characteristic of temporal-lobe epilepsy. Thus, our hypothesis is that WARs have facilitated acoustic-limbic projections when compared to Wistar controls. Wistar controls (n = 9) and WARs (n = 9) underwent EEG electrode implants in the cortex-Cx, amygdaloid complex-AMY and inferior colliculus-IC and received one low current transauricular electrical stimulus (ES) daily, for three consecutive days, with intensities of 10, 20 and 30 mA, respectively. The video-electroencephalographic activity was recorded 1 min before and 4 min after ES. Our results confirm previously described data indicating a greater susceptibility of WARs to seizure. However, low current ES (e.g., 20 mA) triggered epileptiform activity in the AMY only after epileptiform EEG was visible in the Cx and IC electrode leads. The AMY after-discharge continued even though no evident epileptiform activity was present in the Cx. In conclusion, our results add electrophysiological data to previously published behavioral evidence of WAR enhanced susceptibility to ES seizures and, also, support the hypothesis that the acoustic-limbic circuitry is facilitated even in unkindled WARs.

Disconnecting surgical treatment of hypothalamic hamartoma in children and adults with refractory epilepsy and proposal of a new classification.

A series of 17 patients aged from 9 months to 32 years with refractory epilepsy due to hypothalamic hamartoma were treated by total removal (one case) and disconnection (16 cases) between 1997 and 2002. The mean age at seizure onset was 16 months. Sixteen patients had gelastic seizures, 14 had partial seizures and three had generalized tonic-clonic seizures. The mean seizure frequency was 21 per day. Four patients had borderline intelligence quotient and the others were mentally retarded. Five patients presented with precocious puberty, one with acromegaly, and four suffered from obesity. Brain magnetic resonance imaging, performed at least twice in each patient, showed the hamartoma as a stable homogeneous interpeduncular mass implanted either on the mammilary tubercle or on the wall of the third ventricle with variable extension to the bottom. Ictal single photon emission computed tomography, performed in four patients, showed hyperperfusion within the hamartoma in two patients. Twenty-five operations were performed in the 17 patients. The first patient underwent total removal of the hamartoma, whereas the following 16 patients underwent disconnection through open surgery (14 procedures) and/or endoscopy (9 procedures). Eight patients became seizure-free, one patient had only brief gelastic seizures, and eight patients were dramatically improved with a mean follow up of 18.6 months (8 days to 43 months). Surgery was safe in all but two patients: the first patient had transient hemiplegia and the third cranial nerve paresis, and the other developed hemiplegia due to ischemia of the middle cerebral artery territory. The quality of life, and behavior and school performance were greatly improved in most patients. Our series illustrates the feasibility and relative safety of disconnection surgery for hypothalamic hamartomas with seizure relief in 53% of patients and dramatic improvement in the others. Surgical observations led us to propose a new anatomical classification according to the anatomical relationship between the hamartoma and the adjacent hypothalamus and third ventricle. Endoscopic disconnection seems to be a very safe way to treat hamartomas in intraventricular locations.

Do recurrent febrile convulsions decrease the threshold for pilocarpine-induced seizures? Effects of nitric oxide.

The aim of the study was to determine whether (1) number of febrile convulsions is a predictor of development of temporal lobe epilepsy, (2) the susceptibility of rats to pilocarpine-induced seizures is increased due to febrile convulsions and (3) nitric oxide is a mediator in the pathogenesis of febrile convulsions. Rat pups were exposed to single or multiple hyperthermic seizures. Subconvulsant doses of pilocarpine (100 mg/kg and 150 mg/kg) were injected intraperitoneally to these rats at 60--70 days of age. Also L-arginine was applied to some rats before a single hyperthermic seizure. We found that risk of future epilepsy increases parallel to the number of febrile convulsions and nitric oxide does not have a pathogenetic role at given doses.

Relationship between EEG and positron emission tomography abnormalities in clinical epilepsy.

Positron emission tomography (PET) is a relatively noninvasive neuroimaging method by means of which a large variety of human brain functions can be assessed. Localized neurochemical abnormalities detected by PET were found in patients with partial epilepsy and suggested the use of this modality for localizing epileptogenic regions of the brain. The clinical usefulness of PET is determined by its sensitivity and specificity for identifying epileptogenic areas as defined by ictal surface and intracranial EEG recordings. The findings obtained from comparative EEG and glucose PET data are reviewed with special emphasis on patients undergoing presurgical evaluation because of medically intractable temporal and extratemporal lobe epilepsy. The utility of glucose PET studies for identifying regions of seizure onset is presented, and the limited specificity of glucose metabolic abnormalities for the detection of various EEG patterns in clinical epilepsy is discussed. The authors review the available intracranial EEG and PET comparisons using [11C]flumazenil (FMZ) PET, a tracer for the assessment of tau-amino-butyric acid/benzodiazepine receptor function. They also summarize their experience with [11C]flumazenil PET in identifying cortical regions that show various ictal and interictal cortical EEG abnormalities in patients with extratemporal seizure origin. Finally, the authors demonstrate that further development of new PET tracers, such as alpha-[11C]methyl-L-tryptophan, is feasible and clinically useful and may increase the number of patients in whom PET studies can replace invasive EEG monitoring.

Hypothalamic neuronal loss and altered circadian rhythm of temperature in a rat model of mesial temporal lobe epilepsy.

PURPOSE: Numerous dysfunctions in endogenous hypothalamic function have been associated with mesial temporal lobe epilepsy (MTLE). One endogenous activity is the circadian rhythm of temperature (CRT). In this study we examined whether hypothalamically mediated function is altered in the electrically induced, self-sustained, limbic status epilepticus model of MTLE. We then wished to determine whether there was a structural basis for regulatory alterations. METHODS: We measured CRT with peritoneal temperature telemetry obtained in light-entrained (LD) and in free-running, constant-dark (DD) conditions. CRT from epileptic and controls of normal animals and kindled animals were quantized by fast Fourier transform-nonlinear least squares analysis to determine rhythmic complexity. RESULTS: The circadian component of CRT was preserved in all animals. In DD, CRTs of epileptic animals were more complex than those of normal animals. CRT of kindled animals showed no increased complexity after electrically induced seizures. Neuronal density was decreased in regions of the anterior and posterior hypothalamus but not in the suprachiasmatic nuclei from the epileptic rats. CONCLUSIONS: Alterations in CRT due to the epileptic state were independent of isolated seizures. Altered circadian thermoregulation in epileptic rats corresponded to regional hypothalamic neuronal loss. Structural changes of the hypothalamus may explain alterations in endogenous rhythms in MTLE.

[Agenesis of the corpus callosum: modes of manifestation in adults]. / Agénésie du corps calleux: les modes de révélation chez l'adulte.

Agenesis of corpus callosum is an uncommon brain malformation that is usually detected in childhood. In adult, focal epileptic seizure is the most frequent manifestation. Otherwise, asymptomatic patients can be detected by cerebral imagery with specific criteria. Neither developmental disability nor interhemispheric transfer dysfunction are observed in those patients. Minor facial abnormalities can be found. Agenesis of corpus callosum in adult is usually paucisymptomatic. The prognosis depends on cerebral associated malformations which are involved in epilepsy and cognitive disturbances.

Lateralized effects of migraine and ANS seizures after closed head injury.

Theoretical issues associated with memory, neurocognitive and noradrenergic mechanisms in posttraumatic migraine and dysautonomic complex-partial seizure disorders are reviewed, compared and discussed. Additionally, pretreatment Contingent Negative Variation (CNV) was recorded in a No-GO/GO reaction-time paradigm for 15 normal, and 18 posttraumatic migraine and seizure patients tested not more than three months postinjury. Normals demonstrated that CNV GO and NO-GO responses significantly differed. In both migraine and seizure patients GO and NO-GO trials did not differ significantly. In uncontrolled trials, it was noted that B-Blocker administration increased the difference between GO and NO-GO trials for both migraine and seizure patients over midline leads.