2-Deoxy-d-glucose reduces epileptiform activity by presynaptic mechanisms.

2-Deoxy-d-glucose (2DG), a glucose analog that inhibits glycolysis, has acute and chronic antiepileptic effects. We evaluated 2DG's acute effects on synaptic and membrane properties of CA3 pyramidal neurons in vitro. 2DG (10 mM) had no effects on spontaneously occurring postsynaptic currents (PSCs) in 3.5 mM extracellular potassium concentration ([K+]o). In 7.5 mM [K+]o, 2DG significantly reduced the frequency of epileptiform bursting and the charge carried by postsynaptic currents (PSCs) with a greater effect on inward excitatory compared with outward inhibitory charge (71% vs. 40%). In 7.5 mM [K+]o and bicuculline, 2DG reduced significantly the excitatory charge by 67% and decreased the frequency but not amplitude of excitatory PSCs between bursts. In 7.5 mM [K+]o, 2DG reduced pharmacologically isolated inhibitory PSC frequency without a change in amplitude. The frequency but not amplitude of inward miniature PSCs was reduced when 2DG was applied in 7.5 mM [K+]o before bath application of TTX, but there was no effect when 2DG was applied after TTX, indicating a use-dependent uptake of 2DG was required for its actions at a presynaptic locus. 2DG did not alter membrane properties of CA3 neurons except for reducing the slow afterhyperpolarization in 3.5 but not 7.5 mM [K+]o. The reduction in frequency of spontaneous and inward miniature PSCs in elevated [K+]o indicates a presynaptic mechanism of action. 2DG effects required use-dependent uptake and suggest an important role for glycolysis in neuronal metabolism and energetics in states of high neural activity as occur during abnormal network synchronization and seizures. NEW & NOTEWORTHY 2-Deoxy-d-glucose (2DG) is a glycolytic inhibitor and suppresses epileptiform activity acutely and has chronic antiepileptic effects. The mechanisms of the acute effects are not well delineated. In this study, we show 2DG suppressed abnormal network epileptiform activity without effecting normal synaptic network activity or membrane properties. The effects appear to be use dependent and have a presynaptic locus of action. Inhibition of glycolysis is a novel presynaptic mechanism to limit abnormal neuronal network activity and seizures.

Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy.

OBJECTIVE: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin. METHODS: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. RESULTS: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices). SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography.

OBJECTIVE: Patients with suspected mesial temporal lobe (MTL) epilepsy typically undergo inpatient video-electroencephalography (EEG) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography (ECoG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory ECoG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions. METHODS: Ambulatory ECoG was reviewed in patients with suspected bilateral MTL epilepsy who were among a larger cohort with intractable epilepsy participating in a randomized controlled trial of responsive neurostimulation. Subjects were implanted with bilateral MTL leads and a cranially implanted neurostimulator programmed to detect abnormal interictal and ictal ECoG activity. ECoG data stored by the neurostimulator were reviewed to determine the lateralization of electrographic seizures and the interval of time until independent bilateral MTL electrographic seizures were recorded. RESULTS: Eighty-two subjects were implanted with bilateral MTL leads and followed for 4.7 years on average (median 4.9 years). Independent bilateral MTL electrographic seizures were recorded in 84%. The average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13 days, range 0-376 days). Sixteen percent had only unilateral electrographic seizures after an average of 4.6 years of recording. SIGNIFICANCE: About one third of the subjects implanted with bilateral MTL electrodes required >1 month of chronic ambulatory ECoG before the first contralateral MTL electrographic seizure was recorded. Some patients with suspected bilateral MTL seizures had only unilateral electrographic seizures. Chronic ambulatory ECoG in patients with suspected bilateral MTL seizures provides data in a naturalistic setting, may complement data from inpatient video-EEG monitoring, and can contribute to treatment decisions.

A Case of Celiac Disease, Epilepsy, and Cerebral Calcifications With Temporal Lobe Epilepsy.

This is a case report of a 55-year-old man with medication refractory right temporal lobe epilepsy since adolescence. He was found to have bilateral posterior cerebral calcifications on routine head computed tomography with confirmation on magnetic resonance imaging. He also had elevated antibody markers for celiac disease. He was diagnosed with the rare, but well-described syndrome of celiac disease, epilepsy, and cerebral calcifications (CEC). He failed a brief trial of gluten-free diet and went on to have a right temporal lobectomy with sustained freedom from disabling seizures. This case is an example of the growing recognition of neurologic disorders associated with celiac disease. It also provides an example of the characteristic radiographic sign associated with CEC.

Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial.

OBJECTIVE: To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. METHODS: Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up. RESULTS: All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was -37.9% in the active and -17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. SIGNIFICANCE: Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.

CB1 receptor antagonism impairs the induction of epileptiform activity by group I metabotropic glutamate receptor activation.

Exposure to the group I metabotropic glutamate receptor (mGluR) agonist dihydroxy phenylglycine (DHPG) induces epileptiform activity in the CA3 region of the hippocampus that persists following washout of DHPG. DHPG also can cause long-term depression of synaptic transmission, and at some synapses this may be mediated by endocannabinoids. We evaluated whether the selective cannabinoid type 1 (CB1) receptor antagonists SR 141716 or AM 251 could modify induction of epileptiform activity produced by DHPG exposure. The induction of epileptiform activity by DHPG exposure was significantly reduced by CB1 receptor antagonists, SR 141716 or AM 251. Minimal effects on epileptiform activity were noted once the activity had been induced. In control slices, exposure to DHPG for 30 min produced long-term depression (LTD) of synaptic transmission, on average about a 70% reduction in slope of the field excitatory postsynaptic potential (EPSP). When slices were exposed to both DHPG and SR 141716 (3 microm), LTD did not occur and the population EPSP remained at control values or greater. These results suggest that CB1 receptors mediate some of DHPG effects that result in persistent epileptiform activity, and antagonism of CB1 receptors has antiepileptogenic properties. Paradoxically DHPG also caused LTD of excitatory synaptic transmission in the CA3 region and CB1 receptor antagonism prevents the depression. We hypothesize that the ictal activity induced by DHPG requires depression of synaptic strength and CB1 receptor antagonism prevents this depression and the induction of ictal activity.

Genetic Background Influences Acute Response to TBI in Kindling-Susceptible, Kindling-Resistant, and Outbred Rats.

We hypothesized that the acute response to traumatic brain injury (TBI) shares mechanisms with brain plasticity in the kindling model. Utilizing two unique, complementary strains of inbred rats, selected to be either susceptible or resistant to seizure-induced plasticity evoked by kindling of the perforant path, we examined acute electrophysiological alterations and differences in brain-derived neurotrophic factor (BDNF) protein concentrations after a moderate-to-severe brain injury. At baseline, limited strain-dependent differences in acute electrophysiological activity were found, and no differences in BDNF. Following injury, pronounced strain-dependent differences in electrophysiologic activity were noted at 0.5 min. However, the divergence is transient, with diminished differences at 5 min after injury and no differences at 10 and 15 min after injury. Strain-specific differences in BDNF protein concentration were noted 4 h after injury. A simple risk score model generated by machine learning and based solely on post-injury electrophysiologic activity at the 0.5-min timepoint distinguished perforant path kindling susceptible (PPKS) rats from non-plasticity-susceptible strains. The findings demonstrate that genetic background which affects brain circuit plasticity also affects acute response to TBI. An improved understanding of the effect of genetic background on the cellular, molecular, and circuit plasticity mechanisms activated in response to TBI and their timecourse is key in developing much-needed novel therapeutic approaches.

Treatment of drug-resistant epilepsy in patients with periventricular nodular heterotopia using RNS® System: Efficacy and description of chronic electrophysiological recordings.

OBJECTIVES: Describe changes in clinical seizure frequency and electrophysiological data recorded in patients with medically-intractable seizures and periventricular nodular heterotopias (PVNH) treated with the RNS® System (NeuroPace, Inc., Mountain View, CA). METHODS: Clinical seizures from eight patients (mean follow-up of 10.1 years) were analyzed pre- and post-treatment. Chronic ambulatory electrocorticograms (ECoGs) recorded from PVNHs, hippocampus and neocortex were evaluated to identify the earliest electrographic seizure onset type, pattern of spread, and interictal characteristics. RESULTS: Mean reduction in disabling seizures was 85.7 % (n = 8); seven patients had >50% seizure reduction and two were seizure-free in the final year of analysis. Seizure rate showed a progressive reduction over the course of the study with the highest rate of improvement in the first two to three years after implantation. Four of seven patients with one PVNH lead and a second lead in the hippocampus or neocortex had some electrographic seizures first recorded at either lead location, suggesting two foci or seizure propagation patterns. Low voltage fast type activity was the prominent seizure onset pattern. Interictal ECoG power was lower in PVNH than hippocampus. CONCLUSIONS: RNS® System treatment substantially reduced clinical seizure frequency in patients with PVNH. Analysis of ictal ECoG records suggests PVNH may be involved in seizure generation. SIGNIFICANCE: Chronic ECoG recordings suggest PVNH tissue can actively participate in epileptogenic networks. Direct brain-responsive neurostimulation is a safe and effective treatment option in such patients, progressively reducing seizure rate over a period of years.

Activity-dependent induction and maintenance of epileptiform activity produced by group I metabotropic glutamate receptors in the rat hippocampal slice.

Activation of group I metabotropic glutamate receptors (mGluRs) produces a long-lasting change in hippocampal excitability that persists in the absence of an agonist. Exposure to the group I mGluR agonist dihydroxyphenylglycine (DHPG) results in the induction of spontaneously occurring epileptiform activity in the CA3 region of rat hippocampal slices that includes both brief interictal discharges and longer synchronous activity that resembles seizure or ictal activity (>2s duration oscillating at a frequency greater than 2 Hz). We evaluated activity-dependent mechanisms for the induction and maintenance of epileptiform activity. Both the induction and maintenance of epileptiform activity was blocked by inhibiting action potential generation with tetrodotoxin or substitution of sodium with choline or by blocking AMPA/KA ionotropic glutamate receptors. The ictal epileptiform activity induced by DHPG was composed of synchronous synaptic activity. Antagonists of group I mGluRs, either mGluR1 or mGluR5, suppressed the induction of ictal activity but had minimal effects on the maintenance of epileptiform activity. Group I mGluRs activate phospholipase C and inhibition of phospholipase C suppressed the induction but not the maintenance of epileptiform activity. Taken together, these results point to a use dependent change in CA3 neuronal network function produced by group I mGluR activation. Furthermore, activation of both mGluR1 and 5 is required to induce ictal discharges. The induction of epileptiform activity by DHPG is an in vitro model of epileptogenesis, and the development of epileptiform activity in this model depends on neuronal activity and synaptic transmission.

Group I metabotropic glutamate receptor activation produces prolonged epileptiform neuronal synchronization and alters evoked population responses in the hippocampus.

Glutamate activates a class of receptors coupled to G-proteins that initiate second messenger cascades, change ion channel function, cause release of calcium from intracellular stores, and produce long-term changes in synaptic strength. We used the CA3 region of the adult rat hippocampal slice to evaluate group I metabotropic glutamate receptor (mGluR) activation on epileptiform activity and the population response recorded extracellularly evoked by stratum radiatum stimulation. The selective group I mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) accelerated the rate of bicuculline-induced interictal discharges at concentrations of 10 and 30 microM. At a concentration of 100 microM, DHPG produced prolonged recurrent discharges that last more than 2s and consisted of an oscillation of the field potential at 2-20 Hz that resembled electrographic seizure activity (ictal). DHPG (100 microM) when bath-applied alone for 30-120 min produced both ictal and interictal discharges that persisted following removal of DHPG from the bathing solution. DHPG (100 microM) reduced the amplitude of the first population spike evoked by stratum radiatum stimulation and changed the relationship of paired evoked population spikes from suppression of the second response relative to the first to facilitation of the second response at interpulse intervals of 15 and 25 ms. To test the possibility that a reduction of the first evoked population spike and loss of inhibition of a second evoked population spike generated prolonged ictal discharges, we used 4-aminopyridine (4-AP 50 microM) to enhance synaptic transmission. 4-AP converted ictal discharges produced by DHPG to an interictal pattern of synchronous activity, reversed the DHPG-induced reduction in the first evoked population spike, and changed paired-pulse facilitation to inhibition. Reversing the changes of evoked population neuronal activity produced by group I mGluR activation favored interictal patterns of epileptiform activity. These results confirm that group I mGluR activation promotes epileptiform activity in the hippocampus and support the hypothesis that a lower efficacy of synaptic transmission favors the generation of prolonged synchronization of neurons that underlies seizures.

Suppression of pilocarpine-induced ictal oscillations in the hippocampal slice.

Activation of muscarinic cholinergic receptors produces oscillations in the hippocampal slice that resemble the theta rhythm, but also may produce abnormal synchronous activity that is more characteristic of epileptiform activity. We used pilocarpine, a muscarinic agonist and convulsant, and an elevation in extracellular potassium (5-7.5 mM) to produce synchronous neuronal activity that was prolonged (>2 s) and mimicked synchronization noted during seizures in vivo (ictal activity). In the CA3 region of adult rat hippocampal slices, prolonged ictal oscillations consisted of rhythmic field potentials occurring at 4-10 Hz for up to 30 s (ictal duration) that occurred in a regular periodic pattern every 12-166 s (ictal interval). The duration and interval between ictal oscillations were measured before and after application of drugs to define determinants of ictal occurrence. High threshold calcium channel antagonists (nifedipine and verapamil) blocked ictal activity. Release of calcium from intracellular stores also appeared to be important for ictal synchronization because ictal activity was blocked by dantrolene, an inhibitor of calcium release from intracellular stores, and by thapsigargin which blocks the ATPase that maintains intracellular calcium stores. These suppressive effects appeared to be postsynaptic because nifedipine, dantrolene, and thapsigargin had no effect on evoked fEPSPs. Enhancement of presynaptic inhibition by activation of GABA(B) or adenosine A(1) receptors suppressed ictal activity and depressed the amplitude of evoked population synaptic potentials. The results point to an important role for high threshold calcium channels and release of calcium from intracellular stores in addition to strength of synaptic connections in generation of prolonged oscillations that underlie seizure activity.

Antiepileptic drug treatment in the developmentally disabled: treatment considerations with the newer antiepileptic drugs.

Epilepsy is a common comorbidity among developmentally disabled (DD) patients, and special considerations apply to its treatment. In particular, clinicians should try to avoid antiepileptic drugs (AEDs) with sedating properties or adverse cognitive effects that might further diminish quality of life for DD patients. Behavioral changes due to medication and significant pharmacokinetic interactions with other medications are also concerns. The newer AEDs, approved in the 1990s, offer new options for the treatment of individuals with developmental disability and epilepsy. Gabapentin does not interact with the hepatic metabolism of other AEDs or psychotropic agents, results in a statistically significant reduction in seizure frequency in mentally retarded children, and is generally well tolerated. Felbamate is an effective broad-spectrum AED, but has serious toxicity issues limiting its use. Lamotrigine has been extensively studied in the DD population, achieving seizure reduction rates of up to 50% in some trials. Although it is usually well tolerated in this population, its pharmacokinetic profile is influenced by concomitant medications. Levetiracetam has been found to be effective against kindled seizures and has been approved as adjunctive therapy for partial epilepsies. It does not cause any pharmacokinetic interactions, but may have behavioral side effects. Oxcarbazepine is a homologue of carbamazepine that has fewer drug interactions. It is approved for mono- or adjunctive therapy in patients with partial seizures, and its use in DD individuals appears to be worthwhile. Tiagabine is extensively bound to plasma proteins and is therefore subject to protein-binding displacement interactions by other highly protein-bound drugs, such as sodium valproate. While there are trial data showing its efficacy as adjunctive therapy in partial epilepsy in adults and children, there is a paucity of data specific to the DD population. Common side effects include sedation. Topiramate is a broad-spectrum AED approved as adjunctive therapy for partial and primary generalized tonic-clonic seizures. It appears to be particularly effective in patients with Lennox-Gastaut syndrome and those with cognitive disabilities. It appears to be better tolerated in the DD population than in the general population. Zonisamide has been effective in the DD population, yielding a seizure reduction of 50% in 41% of children in 1 trial. It has been associated with renal stone formation, sedation, and cognitive effects, however. The new AEDs have a role in treating seizures in the DD. Side effects that limit their use include anorexia, behavioral changes, and sedation. Seizure exacerbation can occur with the new AEDs and success is defined empirically and by improvements in quality of life.

Fisher statistics for analysis of diffusion tensor directional information.

A statistical approach is presented for the quantitative analysis of diffusion tensor imaging (DTI) directional information using Fisher statistics, which were originally developed for the analysis of vectors in the field of paleomagnetism. In this framework, descriptive and inferential statistics have been formulated based on the Fisher probability density function, a spherical analogue of the normal distribution. The Fisher approach was evaluated for investigation of rat brain DTI maps to characterize tissue orientation in the corpus callosum, fornix, and hilus of the dorsal hippocampal dentate gyrus, and to compare directional properties in these regions following status epilepticus (SE) or traumatic brain injury (TBI) with values in healthy brains. Direction vectors were determined for each region of interest (ROI) for each brain sample and Fisher statistics were applied to calculate the mean direction vector and variance parameters in the corpus callosum, fornix, and dentate gyrus of normal rats and rats that experienced TBI or SE. Hypothesis testing was performed by calculation of Watson's F-statistic and associated p-value giving the likelihood that grouped observations were from the same directional distribution. In the fornix and midline corpus callosum, no directional differences were detected between groups, however in the hilus, significant (p<0.0005) differences were found that robustly confirmed observations that were suggested by visual inspection of directionally encoded color DTI maps. The Fisher approach is a potentially useful analysis tool that may extend the current capabilities of DTI investigation by providing a means of statistical comparison of tissue structural orientation.

Determinants of ictal epileptiform patterns in the hippocampal slice.

PURPOSE: The transition from an interictal to an ictal pattern of epileptiform activity is a strategic target for antiepileptic drug (AED) action. Both the muscarinic agonist pilocarpine and the selective group I metabotropic glutamate receptor (mGluR) agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) produce prolonged synchronous activity in the hippocampal slice that resembles ictal discharges. We evaluated the role of synaptic mechanisms and release of calcium from intracellular stores in the generation of prolonged ictal oscillations. METHODS: Pilocarpine (10 microM) in 7.5 mM[K+]o or DHPG (100 microM) in 5 mM[K+]o artificial cerebrospinal fluid (ACSF) were bath applied to hippocampal slices, and extracellular recordings were made from the CA3 region. The pattern of activity was characterized as ictal if prolonged oscillations of discharges occurred at >2 Hz lasting for >3 s. The pattern of epileptiform activity was characterized and compared with the pattern observed after bath application of pharmacologic agents. RESULTS: The AMPA/kainic acid (KA) glutamate receptor blocker DNQX (20 microM) dampened and stopped ictal oscillations; however, antagonism of N-methyl-d-aspartate (NMDA) or gamma-aminobutyric acid (GABAA) receptors had minimal effects on ictal patterns. Ictal discharges were suppressed by dantrolene (30-100 microM), which blocks release of calcium from intracellular stores, or thapsigargin (1-5 microM), which inhibits the adenosine triphosphatase (ATPase) that maintains intracellular calcium stores. The L-type calcium channel antagonist nifedipine (1 microM) blocked ictal activity produced by pilocarpine or DHPG. CONCLUSIONS: Ictal discharges produced by pilocarpine or DHPG depended on intact synaptic transmission mediated by AMPA/KA receptors, release of calcium from intracellular stores, and L-type calcium channel activation. The results suggest that muscarinic and group I mGluRs activate a positive-feedback system that creates calcium oscillations and prolonged neuronal synchronization mediated by recurrent excitatory synaptic connections in the CA3 region of the hippocampus.