Extracerebral detection of seizures: a new era in epileptology?

The medical and psycho-socio-economic burden imposed on patients, caregivers, and health systems by pharmacoresistant epilepsies is enormous. Intracranial devices for automated detection, warning, and delivery of therapy, the presently preferred "line of attack" for an abundance of weighty reasons, would be insufficient to adequately address said burden on a global scale. Reliance on signals that, although extracerebral, are under cortical modulation or control and are altered by seizures, such as cardiac or motor signals, emerges as a viable research direction with potentially fruitful clinical applications. The greater ease of implementation and lower cost of automated real-time detection, warning, and therapy systems based on extracerebral signals, compared with those requiring intracranial placement, make them worthy of investigation. This article is part of a Supplemental Special Issue entitled The Future of Automated Seizure Detection and Prediction.

Huperzine A regulates amyloid precursor protein processing via protein kinase C and mitogen-activated protein kinase pathways in neuroblastoma SK-N-SH cells over-expressing wild type human amyloid precursor protein 695.

Alpha-secretase (alpha-secretase), cleaves the amyloid precursor protein (APP) within the amyloid-beta (Abeta) sequence, resulting in the release of a secreted fragment of APP (alphaAPPs) and precluding Abeta generation. We investigated the effects of the acetylcholinesterase inhibitor, huperzine A (Hup A), on APP processing and Abeta generation in human neuroblastoma SK-N-SH cells overexpressing wild-type human APP695. Hup A dose-dependently (0-10 microM) increased alphaAPPs release. Therefore, we evaluated two alpha-secretase candidates, a disintegrin and metalloprotease (ADAM) 10 and ADAM17 in Hup A-induced non-amyloidogenic APP metabolism. Hup A enhanced the level of ADAM10, and the inhibitor of tumor necrosis factor-alpha converting enzyme (TACE)/ADAM17 inhibited the Hup A-induced rise in alphaAPPs levels, further suggesting Hup A directed APP metabolism toward the non-amyloidogenic alpha-secretase pathway. Hup A had no effect on Abeta generation in this cell line. The steady-state levels of full-length APP and cell viability were unaffected by Hup A. Alpha-APPs release induced by Hup A treatment was significantly reduced by muscarinic acetylcholine receptor antagonists (particularly by an M1 antagonist), protein kinase C (PKC) inhibitors, GF109203X and calphostin C, and the mitogen-activated kinase kinase (MEK) inhibitors, U0126 and PD98059. Furthermore, Hup A markedly increased the phosphorylation of p44/p42 mitogen-activated protein (MAP) kinase, which was blocked by treatment with U0126 and PD98059. In addition, Hup A inhibited acetylcholinesterase activity by 20% in neuroblastoma cells. Our results indicate that the activation of muscarinic acetylcholine receptors, PKC and MAP kinase may be involved in Hup A-induced alphaAPPs secretion in neuroblastoma cells and suggest multiple pharmacological mechanisms of Hup A regarding the treatment of Alzheimer's disease (AD).

Huperzine A as a neuroprotective and antiepileptic drug: a review of preclinical research.

Huperzine A (HupA) is an acetylcholinesterase (AChE) inhibitor extracted from Huperzia Serrata, a firmoss, which has been used for various diseases in traditional Chinese medicine for fever and inflammation. More recently, it has been used in Alzheimer's disease and other forms of dementia with a presumed mechanism of action via central nicotinic and muscarinic receptors. HupA is marketed as a dietary supplement in the U.S. This article reviews newly proposed neuroprotective and anticonvulsant HupA properties based on animal studies. HupA exerts its effects mainly via α7nAChRs and α4ß2nAChRs, thereby producing a potent anti-inflammatory response by decreasing IL-1ß, TNF-α protein expression, and suppressing transcriptional activation of NF-κB signaling. Thus, it provides protection from excitotoxicity and neuronal death as well as increase in GABAergic transmission associated with anticonvulsant activity.

Huperzine A prophylaxis against pentylenetetrazole-induced seizures in rats is associated with increased cortical inhibition.

Huperzine A (HupA) is a naturally occurring compound found in the firmoss Huperzia serrata. While HupA is a potent acetylcholinesterase inhibitor, its full pharmacologic profile is incompletely described. Since previous works suggested a capacity for HupA to prophylax against seizures, we tested the HupA antiepileptic potential in pentylenetetrazole (PTZ) rat epilepsy model and explored its mechanism of action by spectral EEG analysis and by paired-pulse transcranial magnetic stimulation (ppTMS), a measure of GABA-mediated intracortical inhibition. We tested whether HupA suppresses seizures in the rat PTZ acute seizure model, and quantified latency to first myoclonus and to generalized tonic-clonic seizure, and spike frequency on EEG. Additionally, we measured power in the EEG gamma frequency band which is associated with GABAergic cortical interneuron activation. Then, as a step toward further examining the HupA antiepileptic mechanism of action, we tested long-interval intracortical inhibition (LICI) using ppTMS coupled with electromyography to assess whether HupA augments GABA-mediated paired-pulse inhibition of the motor evoked potential. We also tested whether the HupA effect on paired-pulse inhibition was central or peripheral by comparison of outcomes following administration of HupA or the peripheral acetylcholinesterase inhibitor pyridostigmine. We also tested whether the HupA effect was dependent on central muscarinic or GABAA receptors by co-administration of HupA and atropine or PTZ, respectively. In tests of antiepileptic potential, HupA suppressed seizures and epileptic spikes on EEG. Spectral EEG analysis also revealed enhanced gamma frequency band power with HupA treatment. By ppTMS we found that HupA increases intracortical inhibition and blocks PTZ-induced cortical excitation. Atropine co-administration with HupA did not alter HupA-induced intracortical inhibition suggesting independent of muscarinic acetylcholine receptors mechanism in this model. Last, pyridostigmine did not affect the ppTMS-measured cortical inhibition suggesting that HupA-induced effect is centrally-mediated. Our data support antiepileptic HupA applications, and suggest that such activity may be via enhancement of GABAergic intracortical inhibition.

Reduced stomach capacity in obese subjects after dieting.

The objective of the study was to assess the change in gastric capacity of obese subjects consuming a hypoenergetic diet. Otherwise healthy, obese subjects participated in a prospective controlled study as hospital outpatients. Fourteen (11 females, 3 males) subjects were assigned to the diet group and 9 (7 females, 2 males) were assigned to the control group. Subjects in the diet group were provided a 2508-kJ/d(600 kcal/d) formula diet for 4 wk. Subjects in the control group ate ad libitum for 4 wk. Gastric capacity was determined before the study and 4 wk later by oral insertion of a latex gastric balloon after an overnight fast. The balloon was infused with water at a rate of 100 mL/min, with pauses for measuring intragastric pressure, until no further distension was tolerated. Two indexes for estimating gastric capacity were used based on subjective and objective criteria: 1) the maximal volume that could be tolerated, and 2) the volume required to produce a rise in water pressure of 5 cm. Subjects in the diet group, who lost a mean of 9.1 kg, showed a 27% reduction in gastric capacity based on the first index (P = 0.004) and a 36% reduction based on the second index (P = 0.006). For the control subjects, gastric capacity did not change significantly with use of either index. The results demonstrate a reduction in gastric capacity in obese subjects after a restricted diet.

Hormonal considerations in women with seizures.

The relationships between seizures in epileptic women and the hormones estrogen and progesterone are under increasing study. Serum concentrations of estrogen and progesterone parallel cerebrospinal concentrations, and circulating sex hormones are concentrated in specific areas of the brain that regulate sexual behavior. These centers include two potentially epileptogenic regions--the amygdala and hippocampus. Many of these structures are physiologically affected in vitro by estrogen and progesterone. Exogenous sex hormones change the seizure threshold in animal models of epilepsy. Cyclical hormonal variations may influence electroencephalographic activity and affect seizure frequency in women with epilepsy. Hormonal therapy may be appropriate adjunctive anticonvulsant treatment, particularly for women with seizures that are catamenial or associated with a menstrual or reproductive endocrine disorder.

Medial thalamic hemorrhage with amnesia.

Three patients had amnesia and confusion as presenting features of thalamic hemorrhage. They had a relatively benign clinical appearance and lacked characteristics of the syndrome usually associated with thalamic hemorrhage. We reviewed hypotheses regarding a mechanism for the amnesic syndrome and concluded that lesions involving the medial thalamic nucleus were responsible for the amnesia observed.

Tiagabine for complex partial seizures: a randomized, add-on, dose-response trial.

OBJECTIVE: To determine the efficacy and tolerability of tiagabine, a new antiepileptic drug (AED) that inhibits gamma-aminobutyric acid (GABA) uptake, at 3 dose levels vs placebo as adjunctive therapy in patients with intractable complex partial seizures (CPS). DESIGN: Randomized, double-blind, placebo-controlled study with a parallel-group, add-on design, starting with a 12-week unblinded baseline phase followed by a 20-week double-blind treatment phase. SETTING: Twenty-one US medical centers. PATIENTS: Patients (N = 297) aged 12 to 77 years, previously diagnosed as having CPS and receiving stable regimens of 1 to 3 hepatic enzyme-inducing AEDs; divalproex sodium or valproic acid was allowed in combination with any of these drugs. INTERVENTIONS: Placebo or tiagabine 4 times a day at 16, 32, or 56 mg daily. MAIN OUTCOME MEASURES: Median change in 4-week CPS frequency and adverse events. RESULTS: Median decreases in 4-week CPS frequency for the 32-mg (-2.2) and 56-mg (-2.8) tiagabine groups were significantly greater than for the placebo (-0.7) group (P = .03 and P < .03, respectively); 20% and 29% of patients in the 32- and 56-mg groups had a 50% or greater reduction in the frequency of CPS vs 4% in the placebo group (P = .002 and P < .001, respectively). Adverse effects were similar for placebo and tiagabine except for a significantly greater incidence of dizziness in the 32-mg tiagabine group, tremor in the 32- and 56-mg groups, abnormal thinking (usually mental lethargy or difficulty concentrating) in the 56-mg group, and depressed mood in the 16- and 56-mg groups. CONCLUSIONS: Tiagabine is efficacious and well tolerated as adjunctive therapy for CPS; there is a clear dose-response relationship.

Oxcarbazepine (Trileptal) as monotherapy in patients with partial seizures.

OBJECTIVE: To evaluate the efficacy and safety of oxcarbazepine (OXC) as monotherapy for patients with uncontrolled partial seizures. METHODS: A multicenter, double-blind, randomized, parallel-group, dose-controlled monotherapy trial compared OXC at 2400 mg/day with OXC at 300 mg/day in patients with uncontrolled partial-onset seizures previously receiving carbamazepine (CBZ) monotherapy. During a 28-day open-label conversion phase, patients were tapered off CBZ and titrated to OXC 2400 mg/day. After a 56-day open-label baseline phase on OXC 2400 mg/day, patients entered a 126-day double-blind treatment phase in which they were randomized to continue OXC at 2400 mg/day or were down titrated over 6 weeks to OXC at 300 mg/day. Patients met the efficacy endpoint by completing the double-blind treatment phase or by meeting one of four predefined exit criteria. The primary efficacy variable was time to meeting one of the exit criteria. The secondary efficacy variable was the percentage of patients meeting one of the exit criteria in each of the two treatment groups. RESULTS: Of the 143 patients enrolled, 96 were randomized in the double-blind treatment phase. Time to meeting an exit criterion was significantly in favor of the OXC 2400 mg/day group (p = 0.0001). The median time to meeting an exit criterion was 68 days for the OXC 2400 mg/day Group and 28 days for the OXC 300 mg/day Group. In addition, the percentage of patients meeting one of the exit criteria was significantly lower for the OXC 2400 mg/day Group (p = 0.0001). Overall, OXC was well tolerated with the most common adverse events consisting of fatigue, nausea, ataxia, and headache. CONCLUSION: This trial demonstrated that OXC at 2400 mg/day is well tolerated and efficacious when administered as monotherapy in patients with uncontrolled partial onset seizures.

Oxcarbazepine: double-blind, randomized, placebo-control, monotherapy trial for partial seizures.

OBJECTIVE: To evaluate the efficacy and safety of oxcarbazepine in a placebo-control trial. METHODS: A multicenter, double-blind, randomized, placebo-control, two-arm parallel group, monotherapy design was used to compare oxcarbazepine administered 1,200 mg twice daily to placebo in hospitalized patients with refractory partial seizures, including simple and complex partial seizures and partial seizures evolving to secondarily generalized seizures. Patients exited the trial after completing the 10-day double-blind treatment phase or after experiencing four partial seizures, two new-onset secondarily generalized seizures, serial seizures, or status epilepticus, whichever came first. RESULTS: Analysis of the primary efficacy variable--time to meeting one of the exit criteria--showed a statistically significant effect in favor of oxcarbazepine (p = 0.0001). The secondary efficacy variables--percentage of patients who met one of the exit criteria (p = 0.0001) and total partial seizure frequency per 9 days during the double-blind treatment (p = 0.0001)--were also statistically significant in favor of oxcarbazepine. CONCLUSION: These results demonstrate that oxcarbazepine given as monotherapy is effective and safe for the treatment of partial seizures in this paradigm.

Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial.

OBJECTIVE: The purpose of this multicenter, add-on, double-blind, randomized, active-control study was to compare the efficacy and safety of presumably therapeutic (high) vagus nerve stimulation with less (low) stimulation. BACKGROUND: Chronic intermittent left vagus nerve stimulation has been shown in animal models and in preliminary clinical trials to suppress the occurrence of seizures. METHODS: Patients had at least six partial-onset seizures over 30 days involving complex partial or secondarily generalized seizures. Concurrent antiepileptic drugs were unaltered. After a 3-month baseline, patients were surgically implanted with stimulating leads coiled around the left vagus nerve and connected to an infraclavicular subcutaneous programmable pacemaker-like generator. After randomization, device initiation, and a 2-week ramp-up period, patients were assessed for seizure counts and safety over 3 months. The primary efficacy variable was the percentage change in total seizure frequency compared with baseline. RESULTS: Patients receiving high stimulation (94 patients, ages 13 to 54 years) had an average 28% reduction in total seizure frequency compared with a 15% reduction in the low stimulation group (102 patients, ages 15 to 60 year; p = 0.04). The high-stimulation group also had greater improvements on global evaluation scores, as rated by a blinded interviewer and the patient. High stimulation was associated with more voice alteration and dyspnea. No changes in physiologic indicators of gastric, cardiac, or pulmonary functions occurred. CONCLUSIONS: Vagus nerve stimulation is an effective and safe adjunctive treatment for patients with refractory partial-onset seizures. It represents the advent of a new, nonpharmacologic treatment for epilepsy.

Vagus nerve stimulation therapy for epilepsy in older adults.

The authors assessed the efficacy, safety, and tolerability of vagus nerve stimulation (VNS) for refractory epilepsy in 45 adults 50 years of age and older. They determined seizure frequency, adverse effects, and quality of life. At 3 months, 12 patients had a >50% decrease in seizure frequency; at 1 year, 21 of 31 studied individuals had a >50% seizure decrease. Side effects were mild and transient. Quality of life scores improved significantly with time.

Handedness in women with intrauterine exposure to diethylstilbestrol.

Completed forms containing the Edinburgh handedness inventory were received from 77 women exposed to diethylstilbestrol (DES) in utero. Laterality scores (LSs; range: -100 to +100) were calculated for each respondent based on the handedness inventory and were compared with LSs from 514 female controls. The handedness distribution in the DES daughters was significantly shifted away from strong righthandedness compared with the handedness distribution in the controls (chi-square = 22.0, P < 0.0001). Possible explanations for the association between handedness and DES exposure are presented, and aspects of handedness measurement are discussed.

Associations of handedness with hair color and learning disabilities.

Forms containing the Edinburgh handedness inventory and questions about learning disabilities, hair color, self-described handedness, age, gender, parental handedness and twinning were received from 1117 randomly selected professionals. Laterality scores (LS, range -100 to +100) were calculated for each respondent based on the handedness inventory and were correlated with the above variables. Among blonds, the frequency of non right-handedness (NRH, LS less than or equal to 70) was 44% compared to 24% of non-blonds (chi 2 = 23.5, P less than 0.0001). Learning disabilities (LD) were present in 9% of NRH (LS less than or equal to 70) as against 3% of those with LS greater than 70 (chi 2 = 22.1, P less than 0.0001). Associations between LS and self-described handedness, parental handedness, gender, and age are also presented. Possible explanations for the association of hair color and handedness are discussed in light of recent data on altered visual system pathways in albinos. Problems in the measurement of handedness are discussed.

Remacemide: current status and clinical applications.

Remacemide (RMC) is a non-competitive, low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist that does not cause the behavioural and neuropathological side effects seen with other NMDA receptor antagonists. RMC and its active metabolite, AR-R 12495 AR, which has moderate affinity for the NMDA receptor, also interact with voltage-dependent neuronal sodium channels. Both agents show efficacy in a variety of animal models of epilepsy, parkinsonism and cerebral ischaemia. There is no evidence for teratogenicity or genotoxicity. RMC delays the absorption of L-dopa and elevates the concentrations of drugs metabolised by the hepatic cytochrome P450 3A4 isoform. RMC and AR-R 12495 AR have moderate protein binding and linear pharmacokinetics. Controlled studies show evidence of efficacy in treating epilepsy and Parkinson's disease. Post-surgical outcomes in RMC-treated patients at risk for intra-operative cerebral ischaemia are also encouraging. Adverse effects are related to the gastrointestinal and central nervous systems. RMC is a promising drug with numerous potential applications for both acute or chronic conditions associated with glutamate-mediated neurotoxicity.

EEG abnormalities in patients with atypical panic attacks.

BACKGROUND: Panic attacks and certain partial seizures have phenomenologic similarities which suggest that they may somehow be related. No evidence of such a relationship, however, was found when the routine EEGs of patients with panic attacks were examined. METHOD: Fifteen subjects with atypical panic attacks who met DSM-III-R criteria for panic disorder agreed to have routine followed by prolonged ambulatory EEG monitoring with sphenoidal electrodes. Fourteen subjects actually underwent monitoring; 1 had a panic attack during premonitoring routine EEG. RESULTS: Focal paroxysmal EEG changes consistent with partial seizure activity occurred during panic attacks in 33% (N = 5) of the 15 subjects; 2 (40%) of the 5 subjects with panic-related EEG changes had normal routine EEGs. Multiple attacks were recorded before panic-related EEG changes were demonstrated in several subjects. CONCLUSION: It may be necessary to monitor the EEG during multiple panic attacks to reveal an association between atypical panic attacks and epileptiform EEG changes.

An evaluation of antiepileptic drug therapy in nursing facilities.

OBJECTIVES: To describe the prescribing and use of antiepileptic drug (AED) therapy in nursing facility residents. DESIGN: A retrospective, multicenter drug use evaluation. SETTING: A total of 85 nursing facilities (average size, 119 beds) in five states. PARTICIPANTS: 1132 residents of the total 10,168 residents screened were prescribed at least one AED. MEASURES: Demographic information, primary indication for AED, comorbid conditions, prescribing physician's specialty, concomitant medications, and AED dosage regimen information were collected. Laboratory tests obtained in the most recent 6 months and seizure occurrence and seizure-related diagnostic assessments made in the most recent 3 months were also recorded. RESULTS: Of 1132 residents receiving AED therapy, 892 (78.8%) were prescribed AED therapy for a seizure-related diagnosis although 86% of seizure types were unspecified. Another 215 residents (19.0%) were prescribed AEDs for nonseizure diagnoses, and 25 (2.2%) had no indication for AED therapy. AEDs most frequently prescribed were phenytoin (56.8%), carbamazepine (23.0%), phenobarbital (15.6%), and valproic acid (13.1%). For residents with a seizure diagnosis, the most frequently prescribed monotherapy agents were phenytoin (52.0%), carbamazepine (12.2%), and phenobarbitol (7.1%). Almost 25% of residents with a seizure diagnosis took a combination of AEDs; more than 50% of all combinations included phenobarbital. About 9% of residents with a seizure diagnosis had one or more documented seizures during a 3-month review period. CONCLUSION: Among the substantial percentage of residents treated with AEDs, the lack of diagnosis of seizure type has serious implications for the choice of AED therapy. Opportunities exist for prescribing physicians, consultant pharmacists, and nursing staff to improve the medical management of nursing facility residents with seizures and of others receiving AEDs.

Cocaine decreases self-control in rats: a preliminary report.

Cocaine abuse is often associated with behavior that takes into account short-term, but not long-term consequences. However, there has been no empirical research concerning the effects of cocaine on self-control (choice of a larger, more delayed reinforcer over a smaller, less delayed reinforcer). In the present research, when food-deprived rats repeatedly chose between a larger, more delayed food reinforcer and a smaller, less delayed food reinforcer, chronic intraperitoneal injections of 15 mg/kg cocaine (but not 10 mg/kg fluoxetine) decreased the rats' choices of the larger, more delayed reinforcer. Cocaine can decrease rats' self-control.

Seizures in rats treated with kainic acid induce Fos-like immunoreactivity in locus coeruleus.

Kainic acid-triggered seizures (KATS) induce Fos-like immunoreactivity (FLI) in limbic structures, which send efferents to the locus coeruleus (LC). Following KATS, brain stem sections were stained for Fos immunocytochemistry and double immunostained for Fos and dopamine beta-hydroxylase (DBH). KA-treated animals showed significantly greater numbers of FLI neurons in the LC than control animals (p < 0.05). Co-localization of DBH/Fos was observed in 89.7% of the LC neurons in KA-treated animals and in 1.4% of LC neurons in control animals. Thus, KATS heavily induce Fos in DBH-containing neurons in the LC, which are known to project to the hippocampus. However, the role of activation of the LC noradrenergic neurons during KATS is not well understood at this present time.