Complete Seizure Suppression Research Articles

Perturbations both trigger and delay seizures due to generic properties of slow-fast relaxation oscillators.

The mechanisms underlying the emergence of seizures are one of the most important unresolved issues in epilepsy research. In this paper, we study how perturbations, exogenous or endogenous, may promote or delay seizure emergence. To this aim, due to the increasingly adopted view of epileptic dynamics in terms of slow-fast systems, we perform a theoretical analysis of the phase response of a generic relaxation oscillator. As relaxation oscillators are effectively bistable systems at the fast time scale, it is intuitive that perturbations of the non-seizing state with a suitable direction and amplitude may cause an immediate transition to seizure. By contrast, and perhaps less intuitively, smaller amplitude perturbations have been found to delay the spontaneous seizure initiation. By studying the isochrons of relaxation oscillators, we show that this is a generic phenomenon, with the size of such delay depending on the slow flow component. Therefore, depending on perturbation amplitudes, frequency and timing, a train of perturbations causes an occurrence increase, decrease or complete suppression of seizures. This dependence lends itself to analysis and mechanistic understanding through methods outlined in this paper. We illustrate this methodology by computing the isochrons, phase response curves and the response to perturbations in several epileptic models possessing different slow vector fields. While our theoretical results are applicable to any planar relaxation oscillator, in the motivating context of epilepsy they elucidate mechanisms of triggering and abating seizures, thus suggesting stimulation strategies with effects ranging from mere delaying to full suppression of seizures.

Intranasal delivery of phenytoin-loaded nanoparticles to the brain suppresses pentylenetetrazol-induced generalized tonic clonic seizures in an epilepsy mouse model.

In this work we describe the preparation and characterization of lecithin-chitosan nanoparticles (L10Ci+), and investigate their ability to deliver the anti-epileptic drug phenytoin (PHT) to mouse brain following intranasal (IN) administration. L10Ci+ were retained in the nasal cavity compared to PHT in PEG200 solution (PHT/PEG), which suffered immediate nasal drainage. PHT was detected in the brain after 5 min of IN administration reaching a maximum of 11.84 ± 2.31 %ID g-1 after 48 hours. L10Ci+ were associated with a higher brain/plasma ratio (Cb/p) compared to the experimental control comprising free PHT injected via the intraperitoneal route (PHT-IP) across all tested time points. Additionally, L10Ci+ led to lower PHT accumulation in the liver and spleen compared to PHT-IP, which is vital for lowering the systemic side effects of PHT. The relatively high drug targeting efficiency (DTE%) of 315.46% and the drug targeting percentage (DTP%) of 68.29%, combined with the increasing anterior-to-posterior gradient of PHT in the brain confirmed the direct nose-to-brain transport of PHT from L10Ci+. Electroencephalogram (EEG) analysis was used to monitor seizure progression. L10Ci+ resulted in a complete seizure suppression after 4 hours of administration, and this inhibition persisted even with an 8-fold reduction of the encapsulated dose compared to the required PHT-IP dose to achieve a similar inhibitory effect due to systemic loss. The presented findings confirm the possibility of using L10Ci+ as a non-invasive delivery system of PHT for the management of epilepsy using reduced doses of PHT.

Chronic DREADD Isn't As Bad As It Sounds.

Long-Term Chemogenetic Suppression of Spontaneous Seizures in a Mouse Model for Temporal Lobe Epilepsy Desloovere J, Boon P, Larsen LE, et al. Epilepsia. 2019;60(11):2314-2324. doi:10.1111/epi.16368.Objective:More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for TLE.Methods:Intrahippocampal IHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO; 1, 3, and 10 mg/kg) and clozapine (0.03 and 0.1 mg/kg), and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs), and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days, and the effect on seizures was monitored.Results:Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15 hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. Clozapine-N-oxide and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals.Significance:This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects.

Activation of small conductance calcium-activated potassium channels suppresses seizure susceptibility in the genetically epilepsy-prone rats

Small conductance calcium-activated potassium (SK) channels dampen neuronal excitability by contributing to slow afterhyperpolarization (AHP) that follows a series of action potentials, and therefore may represent an intrinsic inhibitory mechanism to prevent seizures. We have previously reported that susceptibility to acoustically evoked seizures was associated with downregulation of SK1 and SK3 subtypes of SK channels in the inferior colliculus of the moderated seizure severity strain of the genetically epilepsy-prone rats (GEPR-3s). Here, we evaluated the effects of 1-ethyl-2-benzimidazolinone (1-EBIO), a potent activator of SK channels, on acoustically evoked seizures in both male and female adult GEPR-3s at various time points post-treatment. Systemic administration of 1-EBIO at various tested doses suppressed seizure susceptibility in both male and female GEPR-3s; however, the complete seizure suppression was only observed following administration of relatively higher doses of 1-EBIO in females. These findings indicate that activation of SK channels results in anticonvulsive action against generalized tonic-clonic seizures in both male and female GEPR-3s, with males exhibiting higher sensitivity than females.

Long-term chemogenetic suppression of spontaneous seizures in a mouse model for temporal lobe epilepsy.

More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for temporal lobe epilepsy. IntrahippocampalIHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO) (1, 3, and 10mg/kg) and clozapine (0.03 and 0.1mg/kg) and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs) and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days and the effect on seizures was monitored. Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. CNO and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals. This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects.

Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein

Brivaracetam (BRV) and levetiracetam (LEV) are effective antiepileptic drugs that bind selectively to the synaptic vesicle 2A (SV2A) protein. However, BRV differs from LEV in that it exhibits more potent and complete seizure suppression in animal models including in amygdala-kindled mice, where BRV afforded nearly complete seizure suppression. This raises the possibility that aside from potency differences, BRV and LEV may interact differently with the SV2A protein, which is not apparent in radioligand-binding competition studies. In this study, we used a recently identified SV2A allosteric modulator, UCB1244283, that appears to induce conformational changes in SV2A, to probe the binding properties of labeled BRV and LEV. Radioligand binding studies were carried out using [3 H]BRV and [3 H]LEV. Studies were performed in membranes from both recombinant cells expressing human SV2A protein and human brain tissue. The modulator increased the binding of both radioligands but by different mechanisms. For [3 H]BRV, the increase was driven mainly by an increase in affinity, whereas for [3 H]LEV, the increase was due to an increase in the number of apparent binding sites. Kinetic studies confirmed this differential effect. These studies suggest that LEV and BRV may act at different binding sites or interact with different conformational states of the SV2A protein. It is possible that some of the pharmacologic differences between BRV and LEV could be due to different interactions with the SV2A protein.

Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment.

Despite availability of effective antiepileptic drugs (AEDs), many patients with epilepsy continue to experience refractory seizures and adverse events. Achievement of better seizure control and fewer side effects is key to improving quality of life. This review describes the rationale for the discovery and preclinical profile of brivaracetam (BRV), currently under regulatory review as adjunctive therapy for adults with partial-onset seizures. The discovery of BRV was triggered by the novel mechanism of action and atypical properties of levetiracetam (LEV) in preclinical seizure and epilepsy models. LEV is associated with several mechanisms that may contribute to its antiepileptic properties and adverse effect profile. Early findings observed a moderate affinity for a unique brain-specific LEV binding site (LBS) that correlated with anticonvulsant effects in animal models of epilepsy. This provided a promising molecular target and rationale for identifying selective, high-affinity ligands for LBS with potential for improved antiepileptic properties. The later discovery that synaptic vesicle protein 2A (SV2A) was the molecular correlate of LBS confirmed the novelty of the target. A drug discovery program resulted in the identification of anticonvulsants, comprising two distinct families of high-affinity SV2A ligands possessing different pharmacologic properties. Among these, BRV differed significantly from LEV by its selective, high affinity and differential interaction with SV2A as well as a higher lipophilicity, correlating with more potent and complete seizure suppression, as well as a more rapid brain penetration in preclinical models. Initial studies in animal models also revealed BRV had a greater antiepileptogenic potential than LEV. These properties of BRV highlight its promising potential as an AED that might provide broad-spectrum efficacy, associated with a promising tolerability profile and a fast onset of action. BRV represents the first selective SV2A ligand for epilepsy treatment and may add a significant contribution to the existing armamentarium of AEDs.

Ficus religiosa L. figs — A potential herbal adjuvant to phenytoin for improved management of epilepsy and associated behavioral comorbidities

Oxidative stress, together with mitochondrial dysfunction, has been reported to be involved in the pathogenesis of epileptogenesis and its associated comorbidities. Phytoflavonoids have shown numerous beneficial ameliorative effects on different neurological disorders by virtue of their antioxidant effect. The present study investigated the effect of flavonoid-rich ethyl acetate fraction of the crude fig extract of Ficus religiosa in combination with phenytoin on seizure severity, depressive behavior, and cognitive deficit in pentylenetetrazol (PTZ)-kindled mice. The flavonoid-rich ethyl acetate fraction of the crude fig extract was found to show significant antioxidant potential in various in vitro free radical scavenging assays. Combined treatment of this fraction (2.5, 5, and 10mg/kg; i.p.) along with a subeffective dose of phenytoin (15mg/kg; i.p.) in postkindled animals once daily for fifteen days showed a dose-dependent decrease in the seizure severity score, a decreased number of mistakes, increased step-down latency in passive shock avoidance paradigm, and decreased immobility time in the tail suspension test in comparison with the phenytoin only-treated group. Biochemical investigations of the brain tissue showed amelioration of thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) levels, and reduced catalase and acetylcholinesterase (AChE) activities, thereby indicating suppression of oxidative stress. In conclusion, the results of the present study showed the protective effect of the flavonoid-rich fraction of F. religiosa along with a subeffective dose of phenytoin in PTZ-kindling-associated cognitive deficit and depressive behavior with complete suppression of seizures through reduction of oxidative stress, supporting the the need for clinical evaluation of the supplementation of phytoflavonoids along with antiepileptic drugs (AEDs) for management of epilepsy and its psychiatric and cognitive comorbidities.

Low doses of ethanol markedly potentiate the anti-seizure effect of diazepam in a mouse model of difficult-to-treat focal seizures

Ethanol is commonly used as a solvent in injectable formulations of poorly water-soluble drugs. The concentrations of ethanol in such formulations are generally considered reasonably safe. It is long known that ethanol can potentiate central effects of sedatives and tranquillizers, particularly the benzodiazepines, most likely as a result of a synergistic interaction at the GABAA receptor. However, whether this occurs at the low systemic doses of ethanol resulting from its use as solvent in parenteral formulations of benzodiazepines is not known. In the present study we evaluated whether a commercial ethanol-containing aqueous solution of diazepam exerts more potent anti-seizure effects than an aqueous solution of diazepam hydrochloride or an aqueous emulsion of this drug in the intrahippocampal kainate model of temporal lobe epilepsy in mice. Spontaneous epileptic seizures in this model are known to be resistant to major antiepileptic drugs. Administration of the ethanol-containing formulation of diazepam caused an almost complete suppression of seizures. This was not seen when the same dose (5 mg/kg) of diazepam was administered as aqueous solution or emulsion, although all three diazepam formulations resulted in similar drug and metabolite concentrations in plasma. Our data demonstrate that ethanol-containing solutions of diazepam are superior to block difficult-to-treat seizures to other formulations of diazepam. To our knowledge, this has not been demonstrated before and, if this finding can be translated to humans, may have important consequences for emergency treatment of acute seizures, series of seizures, and initial treatment of status epilepticus in patients.

American Clinical Neurophysiology Society's standardized critical care EEG terminology: Interrater reliability and 2012 version

American Clinical Neurophysiology Society's standardized critical care EEG terminology: Interrater reliability and 2012 version

Sturge-weber syndrome.

We try to see the babies prior to the onset of symptoms so that their parents can receive anticipatory guidance regarding seizures and how to recognize and respond to them and so that proper referrals to ophthalmology can be made. If there is any concern on history, exam, or EEG then we obtain a magnetic resonance imaging (MRI) with contrast. If presymptomatic diagnosis of brain involvement is made then treatment with low-dose aspirin is offered and if the brain involvement is extensively bilateral then an anticonvulsant such as levetiracetam is offered as well. Seizures are treated aggressively with a goal of obtaining and maintaining complete seizure suppression as much as possible often with a combination of low-dose aspirin and two anticonvulsants such as levetiracetam and oxcarbazepine. For many patients, this will provide adequate control of their seizures and stroke-like episodes. If the patient fails medical management and seizures are regular and accompanied by plateaued development, significant hemiparesis and visual field deficit and the patient is unilaterally involved and a surgical candidate then surgical management is urged. When the seizures are less regular, little or no hemiparesis or visual field deficit exist, and development is reasonable then this decision is more difficult. For bilaterally involved patients surgery is usually not a good option unless seizures are very severe and mostly coming from one side. Other therapeutic options include the ketogenic/Atkins diet and vagal nerve stimulator although in our experience these usually do not result in cessation of seizures. Endocrine problems occur with increased frequency and must be treated when they are present. The recent discovery of the somatic mutation causing Sturge-Weber syndrome holds promise for new treatment options in the future.

Efficacy and Tolerability of Lacosamide in the Concomitant Treatment of 130 Patients Under 16 Years of Age with Refractory Epilepsy

BackgroundThe safety and effectiveness of lacosamide, an antiepileptic drug (AED) that selectively enhances the slow inactivation of voltage-gated sodium channels without affecting rapid inactivation, has been demonstrated in randomized, double-blind, placebo-controlled trials in adults with focal epileptic seizures. Although lacosamide is approved for use in patients over 16 years of age, limited clinical experience exists for younger patients.ObjectiveTo assess the efficacy and tolerability of lacosamide in children with refractory epilepsy.Design/MethodsThe trial was a prospective, open-label, observational, multicenter study. A total of 130 patients aged less than 16 years (range 6 months to 16 years) with refractory epilepsy who had initiated treatment with lacosamide were enrolled at 18 neuropediatric units in hospitals across Spain. Patients with a variety of etiologies were enrolled, including those with partial epilepsies and symptomatic, generalized epilepsy syndromes. Lacosamide (VIMPAT®; UCB Pharma SA, Brussels, Belgium) was primarily administered once every 12 hours as an oral solution or as an oral tablet, with an initial dose of 1–2 mg/kg/day in the majority of cases. The majority of patients were also receiving stable concomitant therapy with ≥1 other AED. Treatment response to lacosamide was determined by assessing the change in seizure frequency after 3 months of lacosamide therapy. Responders were defined as patients who achieved a seizure frequency reduction of >50%. Tolerability was assessed by the reporting of adverse effects, laboratory testing, and electroencephalography recordings.ResultsLacosamide was dosed at a mean of 6.80 ± 2.39 mg/kg/day. After 3 months of lacosamide therapy, 62.3% of patients achieved a >50% reduction in seizure frequency, with complete seizure suppression being reported in 13.8% of patients. Adverse effects occurred in 39 patients (30%), but no dose-response relationship was observed in terms of these events. In ten patients, instability, difficulty walking, an inability to relate to subjective elements, and blurred vision or dizziness were reported. A total of 13 patients discontinued treatment — in five of these patients, symptom intensity remained unchanged despite dose reduction, which led to treatment discontinuation. The symptoms were markedly different in each patient, preventing determination of a causal factor(s).ConclusionsThe results of this study provide preliminary evidence for the efficacy of lacosamide in children with refractory epilepsy. Further evaluation in a randomized, controlled trial is needed to validate the efficacy in this population and to fully investigate the adverse effects described here. We recommend an initial dose of 1–2 mg/kg/day, uptitrated to 6–9 mg/kg/day over 4–6 weeks.

Efficacy and Tolerability of Lacosamide in the Concomitant Treatment of 130 Patients Under 16 Years of Age with Refractory Epilepsy

The safety and effectiveness of lacosamide, an antiepileptic drug (AED) that selectively enhances the slow inactivation of voltage-gated sodium channels without affecting rapid inactivation, has been demonstrated in randomized, double-blind, placebo-controlled trials in adults with focal epileptic seizures. Although lacosamide is approved for use in patients over 16 years of age, limited clinical experience exists for younger patients. To assess the efficacy and tolerability of lacosamide in children with refractory epilepsy. The trial was a prospective, open-label, observational, multicenter study. A total of 130 patients aged less than 16 years (range 6 months to 16 years) with refractory epilepsy who had initiated treatment with lacosamide were enrolled at 18 neuropediatric units in hospitals across Spain. Patients with a variety of etiologies were enrolled, including those with partial epilepsies and symptomatic, generalized epilepsy syndromes. Lacosamide (VIMPAT®; UCB Pharma SA, Brussels, Belgium) was primarily administered once every 12 hours as an oral solution or as an oral tablet, with an initial dose of 1–2 mg/kg/day in the majority of cases. The majority of patients were also receiving stable concomitant therapy with ≥1 other AED. Treatment response to lacosamide was determined by assessing the change in seizure frequency after 3 months of lacosamide therapy. Responders were defined as patients who achieved a seizure frequency reduction of >50%. Tolerability was assessed by the reporting of adverse effects, laboratory testing, and electroencephalography recordings. Lacosamide was dosed at a mean of 6.80 ± 2.39 mg/kg/day. After 3 months of lacosamide therapy, 62.3% of patients achieved a >50% reduction in seizure frequency, with complete seizure suppression being reported in 13.8% of patients. Adverse effects occurred in 39 patients (30%), but no dose-response relationship was observed in terms of these events. In ten patients, instability, difficulty walking, an inability to relate to subjective elements, and blurred vision or dizziness were reported. A total of 13 patients discontinued treatment — in five of these patients, symptom intensity remained unchanged despite dose reduction, which led to treatment discontinuation. The symptoms were markedly different in each patient, preventing determination of a causal factor(s). The results of this study provide preliminary evidence for the efficacy of lacosamide in children with refractory epilepsy. Further evaluation in a randomized, controlled trial is needed to validate the efficacy in this population and to fully investigate the adverse effects described here. We recommend an initial dose of 1–2 mg/kg/day, uptitrated to 6–9 mg/kg/day over 4–6 weeks.

Management of epilepsy patients in Batamariba district, Togo

To describe the feasibility of managing epilepsy in a rural setting in a developing country. The project comprised four phases. After a study of the perception of epilepsy, we conducted a sensitization campaign in November 2001. The third phase was a survey, to detect epilepsy patients, in which 6249 persons were asked to complete a questionnaire. Persons with epilepsy were then examined, treated, mainly with phenobarbital, and followed up. The prevalence of epilepsy was estimated to be 15.7 per thousand. Ninety-two patients took antiepileptic drugs from 1 February 2002. By November 2005, 92.7% of all treated patients had achieved complete suppression of seizures, and 7.3% had reduced seizure frequency. Despite the stigma attached to epilepsy in many developing countries, it can be controlled by relatively simple measures. At present, 601 epilepsy patients are being followed up at the Nadoba health centre, where epilepsy is now the second commonest disease.

Dose–, Time–, Age–, and Sex–Response Profiles for the Anticonvulsant Effects of Deoxycorticosterone in 15-Day-Old Rats

Recently, we have shown that a single high dose of the adrenal steroid precursor hormone deoxycorticosterone (DOC) has potent anticonvulsant effects in 15-day-old rats. To better define the actions of DOC, the present study established dose–, time–, age–, and sex–response curves for the anticonvulsant actions of DOC. Methods. Dose– and time–response studies were done using two different seizure models: (1) maximal pentylenetetrazol seizures (MMT) and (2) maximal electroconvulsive shock (MES) seizures. Subsequently, age– and sex–response studies were done using MMT seizures and two different DOC doses, one low (nonsedating) and one high (sedating). Results. In dose–response studies, DOC suppressed MMT seizures with an ED50 of about 5 mg/kg (sc). Higher doses were necessary to suppress MES seizures, where the ED50 was about 20 mg/kg. In time–response studies, DOC's effects were rapid in onset. Complete suppression of seizures was seen by 5 min in the MES model and by 15 min in the MMT model. In developmental studies, both a low nonsedating and a high sedating dose of DOC suppressed MMT seizures in neonatal, infant, weanling, and juvenile rats of either sex. The suppressive effects of low-dose DOC were lost after puberty, however. The suppressive effects of high-dose DOC also declined after puberty, especially in males. Conclusion. DOC has significant anticonvulsant actions that occur in prepubertal, but not postpubertal subjects. DOC might have clinical importance in the future treatment of childhood seizure disorders.

Prognosis of childhood epilepsy in newly referred patients.

The aim of this study was to investigate the prognosis of childhood epilepsy and to analyze prognostic factors in addition to remission rate in a follow-up of newly referred patients. Two hundred eighty-one patients were followed for a mean period of 5.3 years. Overall, 253 patients (90%) achieved 1-year remission. The beginning of a 1-year seizure-free period was achieved in 77.9% by 1 year, in 84% by 2 years and in 88.6% by 3 years after onset of treatment. Early onset of seizures, symptomatic etiology, and neurologic handicap predicted a worse prognosis. In 44 of 253 children with complete suppression of seizures for 1 year, relapses occurred within the follow-up period. In one child with a relapse, remission could not be achieved in the 2nd year thereafter. In conclusion, our study shows a good prognosis for most children with epilepsy, especially in patients with idiopathic epilepsy and late onset of seizures and without neurologic dysfunction. Moreover, our data strongly suggest that the long-term pattern of seizure control is largely established during the first 2 years of treatment.

The effect of thyrotropin-releasing hormone (TRH) on limbic status epilepticus in rats

We produced limbic status epilepticus in rats by injecting a combination of dibutyryl-cAMP (db-cAMP) and ethylenediaminetetraacetic acid (EDTA) into the amygdala (AM). Thirty minutes after intra-AM db-cAMP/EDTA injection, thyrotropin-releasing hormone (TRH) was administered intravenously or intracerebroventricularly. Intravenous TRH (3, 25, 50 mg/kg) produced immediate activation of electroclinical seizures, lasting for 25–45 min. In some animals which showed this seizure activation, complete seizure suppression occurred 55–70 min after the TRH treatment. Similar activation of ictal seizures with delayed seizure suppression was obtained after intracerebroventricular TRH (25, 50 μg). The findings suggest that the effects of intravenous TRH are due to its central action and that the use of intravenous TRH is not a promising approach for the treatment of status epilepticus.

Prognosis of epilepsy in a rural African community: a 30-year follow-up of 164 patients in an outpatient clinic in rural Tanzania.

While working as a physician in Tanzania in the early 1960s, Dr. Louise Jilek-Aall founded an outpatient clinic for epilepsy among the Pogoro people of Mahenge mountains where epilepsy (locally termed Kifafa) had brought misery and death to an unusually high percentage of the population. With local assistance and overseas donations of phenobarbital (PB), this clinic treated approximately 200 patients for less than or equal to 10 years. The area was revisited 30 years later to trace these patients. Of the 164 patients who had started treatment, 86 (52.4%) achieved complete seizure suppression, 59 (36.0%) experienced reduction in seizure frequency, 13 (7.9%) experienced no change, and in 1 (0.6%) seizures were worse. The effect of treatment could not be assessed in 5 (3.0%) patients. After 30 years, only 36 (21.9%) of the 164 patients were known to be alive. Of the patients, 110 (67.1%) had died, and the whereabouts of 18 (11%) could not be traced. The causes of death were epilepsy related (status epilepticus, drowning, burns, dying in or after a seizure) in greater than 50% of the patients. Epilepsy-related deaths were proportionately higher after drug supply was stopped and among patients who were receiving drugs irregularly or who had only partial seizure control. Patients with epilepsy showed an increased mortality rate, which was twice that of the general rural Tanzanian population of similar age. Management of epilepsy in rural Africans should also emphasize methods to prevent epilepsy-related causes of death among patients with epilepsy.

Anticonvulsant Activity of Two Orally Active Competitive N‐Methyl‐D‐Aspartate Antagonists, CGP 37849 and CGP 39551, Against Sound‐Induced Seizures in DBA/2 Mice and Photically Induced Myoclonus in Papio papio

Two novel N-methyl-D-aspartate (NMDA) antagonists, DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid CPG 37849 and the corresponding 1-ethyl ester CGP 39551, were tested as anticonvulsants in DBA/2 mice and photosensitive Senegalese baboons, Papio papio. In DBA/2 mice, CGP 37849 is more potent than CGP 39551 when administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) (ED50 for suppression of clonic seizures at 60 min: i.c.v. 0.038 and 0.21 nmol; i.p. 3.40 and 19.1 mumol/kg, respectively). When administered orally in mice, the two compounds are approximately equipotent (ED50 CGP 37849, 35.2 mumol/kg; ED50 CGP 39551, 28.1 mumol/kg). The time course of action of CGP 39551 is exceptionally prolonged: 42 mumol/kg i.p. protects against clonic seizures for 48 h. Protection provided by other NMDA antagonists in mice is of much shorter duration: 2-amino-5-phosphono-pentanoic acid (AP5) 1 h, 2-amino-7-phosphono-heptanoic acid (AP7) 4 h, 2-amino-7-phosphono-heptanoic acid 1-ethyl ester 3 h, 4-(3-phosphonopropyl)-2-piperazine carboxylic acid (CPP) 2 h, cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS 19755) 4 h, and CGP 37849 4 h. After oral administration of the drugs, the therapeutic index (TI = ratio of the ED50 values for rotorod performance and anticonvulsant protection) remains relatively constant at 5.9-7.2 for 3 h (CGP 37849) and 4.0-6.1 for 24 h (CGP 39551). After i.p. administration, the TI values are CGP 37849 at 1 h 2.4, and at 3 h 20.0, CGP 39551 at 1 h 2.3, at 3 h 7.1, and at 24 h 3.6. In baboons, acute administration of CGP 37849 at doses of 48-191 mumol/kg intravenously (i.v.) suppresses photically induced myoclonus for at least 285 min, with severe side effects at the highest dose tested. CGP 39551 at doses of 169-675 mumol/kg i.v. shows weak anticonvulsant activity only at the highest dose tested (accompanied by severe side effects). CGP 37849 at 48-96 mumol/kg orally (p.o.) fails to protect against photically induced myoclonus up to 4 h after administration, but 191 mumol/kg (40 mg/kg) p.o. produces complete suppression of seizures after 24 h. On the other hand, CGP 39551 at 169 mumol/kg (40 mg/kg) p.o. produces total suppression of seizure activity at 4 h with a longer duration of anticonvulsant action (2-3 days).(ABSTRACT TRUNCATED AT 400 WORDS)

Suppression of motor seizures after specific thalamotomy in chronic epileptic monkeys

In the monkey with a chronic motor epileptogenic focus, thalamic lesions restricted to the anterior part of the ventro-postero-lateral nucleus produced a long-lasting improvement, leading in most cases to almost complete seizure suppression. This improvement was attributed to the interruption of a long-loop recurrent excitatory mechanism, involving muscular afferents which are known to relay in the thalamic region where lesions were produced. The specific nature of this effect was suggested by the preliminary results of lesions performed in thalamic regions with non-specific cortical projections. Compared with the pre-lesional situation in which focal activity resulted in permanent motor troubles, the post-lesional state did not show any additional motor deficit. It is concluded that such lesions could be a new approach to controlling intractable motor epilepsies in man.