Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase.

Succinate semialdehyde dehydrogenase (ALDH5A1, encoding SSADH deficiency is a defect of 4-aminobutyric acid (GABA) degradation that manifests in humans as 4-hydroxybutyric (gamma-hydroxybutyric, GHB) aciduria. It is characterized by a non-specific neurological disorder including psychomotor retardation, language delay, seizures, hypotonia and ataxia. The current therapy, vigabatrin (VGB), is not uniformly successful. Here we report the development of Aldh5a1-deficient mice. At postnatal day 16-22 Aldh5a1-/- mice display ataxia and develop generalized seizures leading to rapid death. We observed increased amounts of GHB and total GABA in urine, brain and liver homogenates and detected significant gliosis in the hippocampus of Aldh5a1-/- mice. We found therapeutic intervention with phenobarbital or phenytoin ineffective, whereas intervention with vigabatrin or the GABAB receptor antagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions and significantly enhanced survival of the mutant mice. Because neurologic deterioration coincided with weaning, we hypothesized the presence of a protective compound in breast milk. Indeed, treatment of mutant mice with the amino acid taurine rescued Aldh5a1-/- mice. These findings provide insight into pathomechanisms and may have therapeutic relevance for the human SSADH deficiency disease and GHB overdose and toxicity.

Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy.

Lafora's disease (LD; OMIM 254780) is an autosomal recessive form of progressive myoclonus epilepsy characterized by seizures and cumulative neurological deterioration. Onset occurs during late childhood and usually results in death within ten years of the first symptoms. With few exceptions, patients follow a homogeneous clinical course despite the existence of genetic heterogeneity. Biopsy of various tissues, including brain, revealed characteristic polyglucosan inclusions called Lafora bodies, which suggested LD might be a generalized storage disease. Using a positional cloning approach, we have identified at chromosome 6q24 a novel gene, EPM2A, that encodes a protein with consensus amino acid sequence indicative of a protein tyrosine phosphatase (PTP). mRNA transcripts representing alternatively spliced forms of EPM2A were found in every tissue examined, including brain. Six distinct DNA sequence variations in EPM2A in nine families, and one homozygous microdeletion in another family, have been found to cosegregate with LD. These mutations are predicted to cause deleterious effects in the putative protein product, named laforin, resulting in LD.

Neuromagnetic imaging of movement-related cortical oscillations in children and adults: age predicts post-movement beta rebound.

We measured visually-cued motor responses in two developmentally separate groups of children and compared these responses to a group of adults. We hypothesized that if post-movement beta rebound (PMBR) depends on developmentally sensitive processes, PMBR will be greatest in adults and progressively decrease in children performing a basic motor task as a function of age. Twenty children (10 young children 4-6 years; 10 adolescent children 11-13 years) and 10 adults all had MEG recorded during separate recordings of right and left index finger movements. Beta band (15-30 Hz) event-related desynchronization (ERD) of bi-lateral sensorimotor areas was observed to increase significantly from both contralateral and ipsilateral MI with age. Movement-related gamma synchrony (60-90 Hz) was also observed from contralateral MI for each age group. However, PMBR was significantly reduced in the 4-6 year group and, while more prominent, remained significantly diminished in the adolescent (11-13 year) age group as compared to adults. PMBR measures were weak or absent in the youngest children tested and appear maximally from bilateral MI in adults. Thus PMBR may reflect an age-dependent inhibitory process of the primary motor cortex which comes on-line with normal development. Previous studies have shown PMBR may be observed from MI following a variety of movement-related tasks in adult participants - however, the origin and purpose of the PMBR is unclear. The current study shows that the expected PMBR from MI observed from adults is increasingly diminished in adolescent and young children respectively. A reduction in PMBR from children may reflect reduced motor cortical inhibition. Relatively less motor inhibition may facilitate neuronal plasticity and promote motor learning in children.

Anticonvulsants specific for petit mal antagonize epileptogenic effect of leucine enkephalin.

The anticonvulsants ethosuximide, sodium valproate, and trimethadione that are specific for petit mal epilepsy abolished in rats the electrical seizure activity and behavioral abnormalities produced by leucine enkephalin, whereas phenobarbital and phenytoin had no effect. The dose-response curve for naloxone against seizure activity induced by leucine enkephalin was the same as that in gamma-hydroxybutyrate-induced petit mal. These data indicate that the epileptic properties of leucine enkephalin are petit mal-like and raise the possibility of involvement of enkephalinergic systems in. The dose-response curve for naloxone against seizure activity induced by leucine enkephalin was the same as that in gamma-hydroxybutyrate-induced petit mal. These data indicate that the epileptic properties of leucine enkephalin are petit mal-like and raise the possibility of involvement of enkephalinergic systems in petit mal epilepsy.

Lipid abnormalities in succinate semialdehyde dehydrogenase (Aldh5a1-/-) deficient mouse brain provide additional evidence for myelin alterations.

Earlier work from our laboratory provided evidence for myelin abnormalities (decreased quantities of proteins associated with myelin compaction, decreased sheath thickness) in cortex and hippocampus of Aldh5a1(-/-) mice, which have a complete ablation of the succinate semialdehyde dehydrogenase protein [E.A. Donarum, D.A. Stephan, K. Larkin, E.J. Murphy, M. Gupta, H. Senephansiri, R.C. Switzer, P.L. Pearl, O.C. Snead, C. Jakobs, K.M. Gibson, Expression profiling reveals multiple myelin alterations in murine succinate semialdehyde dehydrogenase deficiency, J. Inher. Metab. Dis. 29 (2006) 143-156]. In the current report, we have extended these findings via comprehensive analysis of brain phospholipid fractions, including quantitation of fatty acids in individual phospholipid subclasses and estimation of hexose-ceramide in Aldh5a1(-/-) brain. In comparison to wild-type littermates (Aldh5a1(+/+)), we detected a 20% reduction in the ethanolamine glycerophospholipid content of Aldh5a1(-/-)mice, while other brain phospholipids (choline glycerophospholipid, phosphatidylserine and phosphatidylinositol) were within normal limits. Analysis of individual fatty acids in each of these fractions revealed consistent alterations in n-3 fatty acids, primarily increased 22:6n-3 levels (docosahexaenoic acid; DHA). In the phosphatidyl serine fraction there were marked increases in the proportions of polyunsaturated fatty acids with corresponding decreases of monounsaturated fatty acids. Interestingly, the levels of hexose-ceramide (glucosyl- and galactosylceramide, principal myelin cerebrosides) were decreased in Aldh5a1(-/-) brain tissue (one-tailed t test, p=0.0449). The current results suggest that lipid and myelin abnormalities in this animal may contribute to the pathophysiology.

Seizure response dogs: evaluation of a formal training program.

Evidence supporting seizure-related behaviors in dogs is emerging. The methods of seizure response dog (SRD) training programs are unstudied. A standardized survey was retrospectively applied to graduates of a large SRD program. Subjective changes in quality of life (QOL) parameters were explored. Data were captured on animal characteristics, training methods, response and alerting behaviors, effects on seizure frequency, and accuracy of epilepsy diagnosis. Twenty-two patients (88%) participated (median age=34, range=12-66, 73% female). Most had childhood-onset epilepsy (87%) that was refractory with averages of 36 seizures/month and 4.8 medications failed. All had neurologist-confirmed epilepsy, most being symptomatic partial (64%). SRD behaviors were reliable, including emergency response system activation in 27%. All reported SRD-related QOL improvements (major 82%, moderate 18%) across multiple parameters. Spontaneous alerting behavior developed in 59%. That SRD programs may select genuine epilepsy patients, instill valuable assistance skills, and generate meaningful QOL improvements supports further seizure dog research.

MRI, Magnetoencephalography, and Surgical Outcome of Oligodendrocytosis versus Focal Cortical Dysplasia Type I.

BACKGROUND AND PURPOSE: Abnormalities of oligodendrocytes have been reported in surgical specimens of patients with medically intractable epilepsy. The aim of this study was to compare the MR imaging, magnetoencephalography, and surgical outcome of children with oligodendrocytosis relative to focal cortical dysplasia I. MATERIALS AND METHODS: Oligodendrocytosis included oligodendroglial hyperplasia, oligodendrogliosis, and oligodendroglial-like cells in the white matter, gray matter, or both from children with medically intractable epilepsy. Focal cortical dysplasia I included radial and tangential cortical dyslamination. The MR imaging, magnetoencephalography, type of operation, location, and seizure outcome of oligodendrocytosis, focal cortical dysplasia I, and oligodendrocytosis + focal cortical dysplasia I were compared. RESULTS: Eighteen subjects (39.1%) had oligodendrocytosis, 21 (45.7%) had focal cortical dysplasia I, and 7 (15.2%) had oligodendrocytosis + focal cortical dysplasia I. There were no significant differences in the type of seizures, focal or nonfocal epileptiform discharges, magnetoencephalography, and MR imaging features, including high T1 signal in the cortex, high T2/FLAIR signal in the cortex or subcortical white matter, increased cortical thickness, blurring of the gray-white junction, or abnormal sulcation and gyration among those with oligodendrocytosis, focal cortical dysplasia I, or oligodendrocytosis + focal cortical dysplasia I (P > .01). There were no significant differences in the extent of resection (unilobar versus multilobar versus hemispherectomy), location of the operation (temporal versus extratemporal versus both), or seizure-free outcome of oligodendrocytosis, focal cortical dysplasia I, and oligodendrocytosis + focal cortical dysplasia I (P > .05). CONCLUSIONS: Oligodendrocytosis shared MR imaging and magnetoencephalography features with focal cortical dysplasia I, and multilobar resection was frequently required to achieve seizure freedom. In 15% of cases, concurrent oligodendrocytosis and focal cortical dysplasia I were identified. The findings suggest that oligodendrocytosis may represent a mild spectrum of malformations of cortical development.

Magnetoencephalography for surgical treatment of refractory status epilepticus.

Magnetoencephalography (MEG) provides accurate localizing information of the epileptogenic zones in localization-related epilepsies. Refractory status epilepticus (RSE) is a life-threatening emergency that often requires prolonged high-dose suppressive therapy (HDST) to stop frequent and prolonged seizures. Surgical treatments for patients with RSE secondary to pre-existing epilepsy were reported. This article addresses the role of MEG in localizing the epileptogenic zone for the surgical treatment of patients with RSE. Five pediatric patients with RSE underwent epilepsy surgery using MEG, scalp video EEG and magnetic resonance imaging (MRI). Ictal MEG spike sources (MEGSSs) were localized in the clustered interictal MEGSSs in right Rolandic region (patient 3) and right temporal region (patient 5). Interictal MEG revealed unilateral clustered MEGSSs in four patients (patients 1, 2, 4, and 5) and bilateral (patient 3). Ictal-onset EEG findings were localized to one region in three patients (patients 1, 3, and 5) and two regions in the other two patients (patients 2 and 4). In all five patients, interictal discharges were widespread involving over two lobes (patients 2 and 4) or three lobes (patients 1, 3, and 5). Suppression burst pattern was obtained by HDST (patient 5). MRI showed cortical dysplasia in three patients (patients 1, 3, and 4). Patient 2 had a normal MRI. Patient 5 had normal MRI at the onset. Repeat MRI 5 days later showed diffusion restriction in the right hippocampus associated with increased signal intensity on T2 and FLAIR sequences. We performed cortical excision in two patients (patients 1 and 4), hemispherectotomy one (patient 3) and anterior temporal lobectomy two patients (patients 2 and 5). Two patients (patients 1 and 3) became seizure free, the other three patients experienced residual seizures. MEG showed clustered MEGSSs during the RSE in the pre-existing epilepsy patients and at an early time window in the acute symptomatic RSE patients. The complete resection of clustered MEGSSs can control RSE and possibly lead to a seizure free outcome.

Magnetoencephalography for surgical treatment of refractory status epilepticus.

Magnetoencephalography (MEG) provides accurate localizing information of the epileptogenic zones in localization-related epilepsies. Refractory status epilepticus (RSE) is a life-threatening emergency that often requires prolonged high-dose suppressive therapy (HDST) to stop frequent and prolonged seizures. Surgical treatments for patients with RSE secondary to pre-existing epilepsy were reported. This article addresses the role of MEG in localizing the epileptogenic zone for the surgical treatment of patients with RSE. Five pediatric patients with RSE underwent epilepsy surgery using MEG, scalp video EEG and magnetic resonance imaging (MRI). Ictal MEG spike sources (MEGSSs) were localized in the clustered interictal MEGSSs in right Rolandic region (patient 3) and right temporal region (patient 5). Interictal MEG revealed unilateral clustered MEGSSs in four patients (patients 1, 2, 4, and 5) and bilateral (patient 3). Ictal-onset EEG findings were localized to one region in three patients (patients 1, 3, and 5) and two regions in the other two patients (patients 2 and 4). In all five patients, interictal discharges were widespread involving over two lobes (patients 2 and 4) or three lobes (patients 1, 3, and 5). Suppression burst pattern was obtained by HDST (patient 5). MRI showed cortical dysplasia in three patients (patients 1, 3, and 4). Patient 2 had a normal MRI. Patient 5 had normal MRI at the onset. Repeat MRI 5 days later showed diffusion restriction in the right hippocampus associated with increased signal intensity on T2 and FLAIR sequences. We performed cortical excision in two patients (patients 1 and 4), hemispherectotomy one (patient 3) and anterior temporal lobectomy two patients (patients 2 and 5). Two patients (patients 1 and 3) became seizure free, the other three patients experienced residual seizures. MEG showed clustered MEGSSs during the RSE in the pre-existing epilepsy patients and at an early time window in the acute symptomatic RSE patients. The complete resection of clustered MEGSSs can control RSE and possibly lead to a seizure free outcome.

Magnetoencephalographic spike sources associated with auditory auras in paediatric localisation-related epilepsy.

OBJECTIVE: To characterise magnetoencephalographic spike sources in paediatric patients with auditory auras and recurrent localisation-related epilepsy. METHODS: Six patients (four boys and two girls (ages 7-14 years) were retrospectively studied. All patients had auditory auras as part of their initial seizure manifestation, including four patients who underwent previous brain surgery. Scalp video electroencephalography and magnetoencephalography (MEG) were carried out in six patients, intraoperative electrocorticography in three patients and extraoperative intracranial video electroencephalography in one patient. MEG auditory-evoked fields (AEFs) were studied in four patients. RESULTS: Three patients had elementary auditory auras, one had complex auditory aura and two had both complex and elementary auras. All six patients had clustered MEG spike sources with coexisting scattered spike sources. MEG clusters were localised in the superior temporal gyrus with surrounding scatters in four patients (two left and two right); two patients had scattered spikes in the superior temporal gyrus in addition to clustered MEG spike sources in the left inferior and middle frontal gyri or parieto-occipital region. AEFs were located within an MEG cluster in one patient and within 3 cm of a cluster in two patients. Surgical resection, including the regions of MEG clusters, was carried out in four patients. Three of four patients who had previous surgeries were seizure free at 2 years after excision of the MEG cluster region. CONCLUSIONS: MEG spike sources clustered in the superior temporal gyrus in six patients with auditory auras. These spike sources were in close proximity or seemed to engulf the magnetic AEF. Areas with MEG spike sources contained the residual or recurrent epileptogenic zone after incomplete cortical excision for lesional epilepsy.

Altered glutamate and GABA release within thalamocortical circuitry in metabotropic glutamate receptor 4 knockout mice.

The metabotropic glutamate receptor 4 is highly expressed presynaptically on thalamocortical neurons that are involved in the pathogenesis of generalized absence seizures. Mutant mice devoid of metabotropic glutamate receptor 4 are completely resistant to absence seizures induced by low doses of GABA type A receptor antagonists. The purpose of this study was to test the hypothesis that there is altered glutamate and GABA release within thalamocortical circuitry in mice devoid of metabotropic glutamate receptor 4. Extracellular GABA and glutamate release were determined in ventrobasal thalamus, the nucleus reticularis thalami and laminae I-III, and IV-VI of cerebral cortex (laminae I-III of cerebral cortex, and laminae IV-VI of cerebral cortex) using in vivo microdialysis techniques on awake, free moving mice. A significant increase of both basal and K(+)-evoked glutamate release was detected in the ventrobasal thalamus, the nucleus reticularis thalami and laminae IV-VI of cerebral cortex of mice devoid of metabotropic glutamate receptor 4 mice. There also was a significant increase in both basal and K(+)-evoked GABA release in the mice devoid of metabotropic glutamate receptor 4, but a significant decrease of GABA release in laminae IV-VI of cerebral cortex. However, there was no alteration of either GABA or glutamate release in laminae I-III of cerebral cortex, cortical laminae that are not involved in absence seizures. These data indicate that deletion of the metabotropic glutamate receptor 4 gene results in a selective perturbation of glutamate and GABA release within the thalamocortical circuitry involved in the pathogenesis of absence seizures.

Disrupted Global and Regional Structural Networks and Subnetworks in Children with Localization-Related Epilepsy.

BACKGROUND AND PURPOSE: Structural connectivity has been thought to be a less sensitive measure of network changes relative to functional connectivity in children with localization-related epilepsy. The aims of this study were to investigate the structural networks in children with localization-related epilepsy and to assess the relation among structural connectivity, intelligence quotient, and clinical parameters. MATERIALS AND METHODS: Forty-five children with nonlesional localization-related epilepsy and 28 healthy controls underwent DTI. Global network (network strength, clustering coefficient, characteristic path length, global efficiency, and small-world parameters), regional network (nodal efficiency), and the network-based statistic were compared between patients and controls and correlated with intelligence quotient and clinical parameters. RESULTS: Patients showed disrupted global network connectivity relative to controls, including reduced network strength, increased characteristic path length and reduced global efficiency, and reduced nodal efficiency in the frontal, temporal, and occipital lobes. Connectivity in multiple subnetworks was reduced in patients, including the frontal-temporal, insula-temporal, temporal-temporal, frontal-occipital, and temporal-occipital lobes. The frontal lobe epilepsy subgroup demonstrated more areas with reduced nodal efficiency and more impaired subnetworks than the temporal lobe epilepsy subgroup. Network parameters were not significantly associated with intelligence quotient, age at seizure onset, or duration of epilepsy. CONCLUSIONS: We found disruption in global and regional networks and subnetworks in children with localization-related epilepsy. Regional efficiency and subnetworks were more impaired in frontal lobe epilepsy than in temporal lobe epilepsy. Future studies are needed to evaluate the implications of disrupted networks for surgical resection and outcomes for specific epileptogenic zones and the relation of disrupted networks to more complex cognitive function.

Gamma hydroxybutyrate in the monkey. I. Electroencephalographic, behavioral, and pharmacokinetic studies.

Gamma hydroxybutyrate (GHB) was administered to adult and prepubescent rhesus monkeys intravenously in varying dosages while an electroencephalogram (EEG) was recorded from scalp electrodes and the body core temperature was monitored. Blood and cerebrospinal fluid samples were assayed for gamma hydroxybutyrate. GHB produced a trancelike stupor in all the monkeys, associated with marked EEG changes and hypothermia. There was a striking age specificity in that prepubescent rhesus monkeys responded to a lower threshold dosage, had a higher incidence of myoclonic jerking, and showed characteristic EEG changes not seen in the adult animals. The EEG-behavioral changes paralleled the hypothermia. There was good correlation between the serum levels of GHB and the EEG-behavioral effects. These studies suggest that the GHB-treated monkey may have utility as a petit mal seizure model.

Gamma hydroxybutyrate in the monkey. II. Effect of chronic oral anticonvulsant drugs.

Gamma hydroxybutyrate (GHB) was administered intravenously to monkeys that had been pretreated orally for 2 weeks with various anticonvulsant drugs or with L-DOPA at different dosage levels. Continuous electroencephalographic (EEG) monitoring was performed during and after GHB administration. Bloood was assayed for GHB and for the anticonvulsant drug the animal was receiving. The EEG and behavioral changes produced by GHB were improved by ethosuximide and phenobarbital, made worse by phenytoin, and unchanged by L-DOPA.

Gamma hydroxybutyrate in the monkey. III. Effect of intravenous anticonvulsant drugs.

Monkeys were treated intravenously with various anticonvulsant drugs before and after the intravenous administration of gamma hydroxybutyrate (GHB). Continuous electroencephalographic (EEG) and temperature monitoring was performed throughout all experiments. The GHB-induced EEG changes were abolished by ethosuximide and clonazepam, marginally improved by diazepam, and unaffected by phenobarbital. The GHB-induced myoclonic jerks were abolished by ethosuximide, significantly improved by diazepam, and worsened by clonazepam. Phenobarbital was effective in diminishing the frequency of GHB-induced myoclonic jerks only when given prior to administration of GHB. The GHB-induced stupor was improved only by ethosuximide. The GHB model of petit mal seizures is quite specific for drugs used in this disorder. GHB may play a role in the pathogenesis of absence seizures in children.

Gamma hydroxybutyrate in the monkey. IV. Dopaminergic mechanisms.

The electrical seizure activity and trancelike state induced in the rhesus monkey by gamma-hydroxybutyrate (GHB) were abolished by dextroamphetamine. Dextroamphetamine blockade of this neurophysiologic effect was overcome with chlorpromazine, a dopamine receptor blocker. These results suggest that the electroencephalographic (EEG) and behavioral effects of GHB are related to effects on dopaminergic systems. Such a relationship, if substantiated by further studies, might indicate that anticonvulsant drugs used to treat petit mal epilepsy have a dopaminergic mode of action.

Naloxone overcomes the dopaminergic, EEG, and behavioral effects of gamma-hydroxybutyrate.

The specific opiate antagonists--naloxone and naltrexone--attenuated or abolished the electrical seizure activity, behavioral abnormalities, and increased striatal dopamine content produced by gamma-butyrolactone, the prodrug of gamma-hydroxybutyrate. The effects of naloxone and naltrexone were dose-dependent. These data suggest that gamma-hydroxybutyric acid exerts its effects by action either at the opiate receptor or on enkephalinergic systems, which may be involved in petit mal epilepsy.

A model of atypical absence seizures: EEG, pharmacology, and developmental characterization.

OBJECTIVE AND BACKGROUND: Atypical absence seizures differ markedly from typical absence seizures in EEG findings, ictal behavior, and neurodevelopmental outcome. The object of these experiments was to provide electrical, behavioral, pharmacologic, and developmental characterization of a putative animal model of atypical absence seizures. METHODS: Atypical absence seizures were induced in Long Evans hooded rats by treatment with a cholesterol biosynthesis inhibitor, AY-9944 (AY), during development. Prolonged video EEG recordings were made from chronically implanted depth electrodes in the waking and sleep states in adult and developing animals during and after AY treatment. Also, the response of AY-induced atypical absence seizures to drugs known to exacerbate and block typical absence seizures was ascertained. RESULTS: AY treatment resulted in spontaneous, bilaterally synchronous, slow spike-and-wave discharges (SWD), which were frequent, recurrent, prolonged, and lifelong. SWD began as early as postnatal day 21, occurred throughout all stages of sleep, and were associated with myoclonic jerks during sleep. The SWD were significantly prolonged by carbamazepine, gamma-hydroxybutyrate, and the gamma-aminobutyrate type B (GABA(B)) receptor (GABA(B)R) agonist baclofen. AY-induced seizures were abolished by diazepam, ethosuximide, and the GABA(B)R antagonist CGP 35348 but returned as the drugs were eliminated. Atypical features of absence seizures in this model are slow spike-wave, emanation of SWD from hippocampus, gradual onset and offset of ictal behavior, and the ability of the animals to move during the spike-and-wave bursts. CONCLUSION: The AY-treated rat represents a predictable, reproducible, and clinically relevant animal model of atypical absence seizures that may be used to investigate the pathogenesis and treatment of this malignant disorder.

Gamma hydroxybutyrate. Correlation of serum and cerebrospinal fluid levels with electroencephalographic and behavioral effects.

Gamma hydroxybutyrate was administered to adult cats by intravenous infusion at varying dosages while an electroencephalogram (EEG) was recorded from electrodes placed stereotactically in the right and left hippocampus and thalamic intralaminar nucleus and from cortical electrodes. Blood cerebrospinal fluid samples were assayed for gamma hydroxybutyrate. The first EEG change, slowing was occasional spikes, was seen at serum levels of 75 mug per milliliter. Changes in the recordings progressed through a number of stages, culminating in bursts of poly spiking interspersed among periods of electrical silence first seen at 350 mug per milliliter. Behavior was characterized by a progressively deepening trancelike state punctuated at higher serum levels by spontaneous and stimulus-induced myoclonic jerks. These changes were correlated with serum levels and are more similar to petit mal stupor than any kind of natural sleep-like state previously used to describe them.

ACTH and prednisone in childhood seizure disorders.

We treated 116 children with ACTH or prednisone. Fifty-two had infantile spasms with hypsarhythmia, and 64 had other types of intractable seizures. ACTH completely controlled seizures in all patients with infantile spasms and hypsarhythmia and 74% of those with other types of seizures. Prednisone controlled 51% of patients with infantile spasms and none with other seizures. Serious side effects were minimal for both drugs, and recurrent seizures occurred in 40 to 50% of patients within 4 to 14 months after completion of therapy.