Abbreviated report of the NIH/NINDS workshop on sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy and is not rare. The NIH and National Institute of Neurological Disorders and Stroke sponsored a 3-day multidisciplinary workshop to advance research into SUDEP and its prevention. Parallel sessions were held: one with a focus on the science of SUDEP, and the other with a focus on issues related to the education of health care practitioners and people with epilepsy. This report summarizes the discussions and recommendations of the workshop, including lessons learned from investigations of sudden infant death syndrome (SIDS), sudden cardiac death, autonomic and respiratory physiology, medical devices, genetics, and animal models. Recommendations include educating all people with epilepsy about SUDEP as part of their general education on the potential harm of seizures, except in extenuating circumstances. Increasing awareness of SUDEP may facilitate improved seizure control, possibly decreasing SUDEP incidence. There have been significant advances in our understanding of the clinical and physiologic features of SIDS, sudden cardiac death, and SUDEP in both people and animals. Research should continue to focus on the cardiac, autonomic, respiratory, and genetic factors that likely contribute to the risk of SUDEP. Multicenter collaborative research should be encouraged, especially investigations with direct implications for the prevention of SUDEP. An ongoing SUDEP Coalition has been established to facilitate this effort. With the expansion of clinical, genetic, and basic science research, there is reasonable hope of advancing our understanding of SUDEP and ultimately our ability to prevent it.

Accuracy of family history information on epilepsy and other seizure disorders.

BACKGROUND: In epilepsy as in other disorders, family history information is often obtained by asking patients about the medical histories of their relatives rather than interviewing or examining the relatives directly. The accuracy of this type of information for epilepsy and other seizure disorders is unclear. METHODS: This study used data from the Genetic Epidemiology of Seizure Disorders in Rochester study, a population-based investigation including all Rochester, MN, residents born ≥1920 with incidence of unprovoked seizures from 1935 to 1994 (case probands) and control probands matched by age, gender, and prior Rochester residency period. Seizure disorders in the first-degree relatives of case and control probands were ascertained by reviewing the relatives' medical records. Case and control probands were interviewed about seizures in their first-degree relatives using a validated 9-question screening interview. Interviewers were blinded to case-control status. RESULTS: Sensitivity of the family history (i.e., proportion of relatives with medical record-documented seizures who screened positive in the proband interview) was 62% (32/52) for epilepsy, 50% (7/14) for isolated unprovoked seizures, and 56% (9/16) for febrile seizures. Sensitivity did not differ by case/control status of the proband. Sensitivity was much higher for probands reporting on their offspring or siblings than their parents. Among relatives with epilepsy, 90% of offspring and 80% of siblings but only 32% of parents screened positive. CONCLUSIONS: Family histories of epilepsy are reasonably accurate for siblings and offspring, but are underreported in parents. Family histories of other seizure disorders are underreported.

Peri-ictal SPECT and surgical treatment for intractable epilepsy related to schizencephaly.

The authors evaluated four patients with schizencephaly who underwent subtraction ictal SPECT coregistered to MRI (SISCOM) prior to epilepsy surgery. Three patients had a SISCOM alteration that was concordant with the epileptic brain tissue. Two of these patients were rendered seizure-free and one individual experienced a significant reduction in seizures. The patient with an indeterminate SISCOM had an unfavorable outcome. SISCOM is useful in evaluating patients with schizencephaly for epilepsy surgery.

Advances in computer-assisted single-photon emission computed tomography (SPECT) for epilepsy surgery in children.

Epilepsy surgery has emerged as an important option in the treatment of children with epilepsy that is refractory to antiepileptic drug management. The cornerstone of successful surgery is accurate localization of the brain region of seizure onset. Traditional techniques of seizure onset localization, e.g. surface electroencephalography (EEG) recording and magnetic resonance imaging (MRI), allow accurate localization in a significant number of patients. When the focus of seizure onset is not apparent from these non-invasive techniques, other methods of localization, e.g. intracranial EEG recording, may be needed before resection of the focus. Single-photon emission computed tomography (SPECT) is a nuclear medicine blood-flow technique that has been used to identify a region of epileptogenic brain associated with low blood flow in the resting state (interictal SPECT) or increased blood flow at the time of seizure activity (ictal SPECT). This report describes the validation and utility of a computer-assisted method of subtracting the interictal from the ictal SPECT scans and co-registering the difference image on the MRI. This method, called subtraction ictal SPECT co-registered on MRI (SISCOM), is used in guiding the location and the extent of intracranial electrode implantation, or in obviating the need for the implantation in some cases.

Long-term outcome of epilepsy surgery in patients with tuberous sclerosis.

Seizures associated with tuberous sclerosis (TS) can be difficult to control with medical therapy. The authors followed 22 patients with TS who underwent epilepsy surgery for 1 to 14 years to assess the value of epilepsy surgery and predictors of long-term postoperative outcome. Unifocal onset seizures and mild to no developmental delay at the time of surgery are predictive of excellent long-term outcome.

Long-term follow-up of temporal lobectomy in children.

Temporal lobectomy is an effective treatment for medically intractable seizures. The change in seizure status with prolonged postoperative follow-up is unclear. The authors followed 37 patients who underwent first time temporal lobectomy during childhood for at least 15 years. This study is the longest follow-up of children who have had a temporal lobectomy for intractable seizures. It demonstrates that seizure recurrence can increase with longer duration of follow-up.

Migraine-associated vomiting and asystole in a child.

A variety of symptoms that accompany migraine in the child and adult are mediated by the autonomic nervous system. Significant effects on cardiac rhythm are uncommon, but can be life threatening. We describe a 3-year-old girl in whom migraine-associated vomiting precipitated cardiac asystole which was effectively treated with a cardiac pacemaker.

Long-term seizure outcome in 74 patients with Lennox-Gastaut syndrome: effects of incorporating MRI head imaging in defining the cryptogenic subgroup.

PURPOSE: To determine if using more stringent criteria for cryptogenic Lennox-Gastaut syndrome (LGS) would result in an improved prognosis for that group. Cryptogenic, symptomatic, and non-cryptogenic LGS patients without etiology (indeterminate) were compared with respect to seizure and cognitive outcome. METHODS: Retrospective chart review was performed on 245 patients seen at the Mayo Clinic Rochester from 1976 to 1997, with a diagnosis of either LGS or slow spike wave on EEG. LGS was confirmed in 107 (64 male, 43 female) patients. This group was divided into cryptogenic, symptomatic, and indeterminate groups containing 23, 47, and 37 patients, respectively. In this study, cryptogenic patients all had normal development before onset of LGS, absence of dysmorphic features, normal neurologic examination, and normal magnetic resonance (MRI) brain imaging. Of the 107 patients, 74 had >/=3 years of follow-up. RESULTS: LGS onset in the 107 patients occurred at a median age of 4.0 years (range, 0.6-28.9 years). When last seen, 63% of those with symptomatic LGS had more than three seizures a day compared with 50% of cryptogenic and 34% of indeterminate patients. The most common seizure types were tonic (77%), atypical absence (61%), and generalized tonic-clonic (56%). Only three patients, all part of the indeterminate group, were seizure free at last follow-up. CONCLUSIONS: Using stringent criteria in defining the cryptogenic subgroup resulted in no significant difference in seizure outcome. Individuals with a normal cognitive outcome did not segregate into one etiologic subgroup, but did have LGS onset at an older age.

Cerebellar dysplasia and unilateral cataract in Marinesco-Sjögren syndrome.

The classic features of Marinesco-Sjögren syndrome include bilateral cataracts, cerebellar ataxia, and mental deficiency with an autosomal recessive inheritance pattern. Weakness and a variety of other characteristics are present inconsistently. A limited number of neuroimaging studies have indicated that cerebellar hypoplasia is the most common finding. We report a patient with near normal intelligence, unilateral cataract, and the previously unreported magnetic resonance imaging findings of cerebellar dysplasia, arachnoid cyst, and absent septum pellucidum. A review of the literature suggests significant heterogeneity in the Marinesco-Sjögren syndrome.

Inherited epilepsies of childhood.

Recent advances in neuroepidemiologic and molecular biological techniques have facilitated a growing understanding of the role that inherited factors play in epileptogenesis. During the last few years linkage analysis has mapped gene loci associated with the following epilepsy syndromes: benign familial neonatal convulsions, juvenile myoclonic epilepsy, Unverricht-Lundborg/Baltic/Mediterranean progressive myoclonic epilepsies, the juvenile form of ceroid lipofuscinosis, sialidosis I, and the myoclonus epilepsy with ragged red fibers (MERRF) syndrome. In addition, characterization of the inheritance patterns of other syndromes such as childhood epilepsy with occipital paroxysms and febrile convulsions has improved. It is apparent that a significant amount of clinical and genetic heterogeneity exists, which emphasizes the importance of accurate clinical classification. As genetic markers are found for well-defined groups of patients, traditional means of classification (seizure type, pathologic markers, progressive course, etc.) become less meaningful. It is proposed that the components of the phenotype of an epilepsy syndrome (eg, age of onset, seizure type, electroencephalographic pattern) may be controlled by multiple genes.

Inhibition of glutamate uptake with L-trans-pyrrolidine-2,4-dicarboxylate potentiates glutamate toxicity in primary hippocampal cultures.

Sodium-dependent, high-affinity glutamate transport is generally assumed to limit the toxicity of glutamate in vivo and in vitro, but there is very little direct evidence to support this hypothesis. In the present study, the effects of the specific uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate on the toxicity and clearance of glutamate were examined in hippocampal neuronal cultures. At a concentration that was not toxic by itself, L-trans-pyrrolidine-2,4-dicarboxylate increased the toxicity of glutamate approximately fivefold and slowed the clearance of glutamate from the extracellular space. This toxicity was almost completely blocked by the N-methyl-D-aspartate receptor antagonist, D-2-amino-5-phosphonopentanoate. These studies provide direct evidence that sodium-dependent, high-affinity glutamate transport limits glutamate toxicity in vitro.

Ictal SPECT in a 16-day-old infant.

Neonatal seizures can be difficult to classify according to partial versus generalized onset on the basis of clinical appearance or electroencephalography (EEG). Single-photon emission computed tomography has proven to be useful in adults when adjunctive tests are needed to identify the nature of seizure onset. Although its use has been extended recently to children, the lower age limit at which this technique is useful remains to be established. A case is reported in which ictal Tc-99m HMPAO SPECT of a 16-day-old infant revealed an area of focal hypermetabolism in the right temporal lobe corresponding to an area of focal atrophy revealed by MRI. The EEG of this infant demonstrated multifocal interictal epileptiform abnormalities and an ictal pattern with a generalized onset. This case indicates that ictal SPECT is a useful tool in the evaluation of even the youngest patients with seizures.

Animal models of inherited epilepsy.

A significant proportion of the childhood epilepsies have a genetic component. Therefore, animal models that can be bred for seizure expression may provide important information regarding the mechanisms by which molecular defects result in the neuronal hyperexcitability states collectively termed "epilepsy." Because of the rate and ease of breeding, rodent models are the most commonly used. The genetically epilepsy-prone rat has motor seizures in response to auditory stimuli. It is likely that the seizures are generated in the inferior colliculus because of an abnormality in the noradrenergic system. The seizure predisposition is inherited as an autosomal dominant trait. The genetic absence epilepsy rat has age-related spontaneous seizures characterized by motor arrest and head drops that are correlated with generalized spike-wave on the electroencephalogram (EEG). The seizure generating mechanism appears to be located in the lateral thalamic nuclei. The epileptic mongolian gerbil demonstrates behavioral arrest followed by myoclonic, tonic, and tonic-clonic seizures in response to unfamiliar environments. The underlying neuroanatomy involves hippocampal-cortical interactions indicative of a partial epilepsy. The tottering mouse has absence and myoclonic seizures, a 6- to 7-Hz ictal spike-wave EEG, and noradrenergic hyperinnervation that are linked to a mutation on chromosome 8. Hippocampal network hyperexcitability has been found with normal neuronal intrinsic properties. Stargazer is a mouse mutant with almost identical clinical and electrographic features as found in tottering. However, the genetic defect is located on chromosome 15 and no abnormalities of norepinephrine have been discovered. The El mouse demonstrates ictal automatisms in response to vestibular stimulation. Metabolic and structural abnormalities have been found in the hippocampus. Linkage to chromosomes 9 and 2 have been reported recently. The dilute brown agouiti mouse demonstrates motor seizures in response to auditory stimuli. Chromosomes 4 and 17 are linked to seizure expression. Thus, a variety of models exist to study the genetic, biochemical, structural and electrophysiological mechanisms that underlie the predisposition and expression of the inherited epilepsies.

Electrophysiological comparison of pyramidal and stellate nonpyramidal neurons in dissociated cell culture of rat hippocampus.

Differences in electrophysiological properties between pyramidal and nonpyramidal neurons have been previously demonstrated in the hippocampal slice preparation. However, it has also been shown that nonpyramidal neurons from several hippocampal regions have different morphologies as well as different active membrane characteristics. In this study, active and passive electrophysiological characteristics of pyramidal and a single morphological type of nonpyramidal neuron in rat dissociated hippocampal culture were examined with intracellular recording at room temperature and at 33-35 degrees C. No significant differences were noted between the two groups of neurons, at either temperature, with regard to action potential amplitude, rate of rise and fall, duration at half maximal amplitude, adaptation to steady state depolarization or resting membrane potential and input resistance. We conclude that these electrophysiological properties cannot be used to distinguish these two neuron types in dissociated hippocampal cell culture.

The inherited epilepsies.

Our knowledge regarding the genetic bases of the human epilepsies is in a state of rapid flux. For some forms of epilepsy, epidemiologists are still trying to determine whether there is any familial (hereditary) predisposition. Other forms of epilepsy are known to run in families, but the mode of inheritance and degree of penetrance of the trait are still in doubt. Three forms of epilepsy have been tentatively localized to specific chromosomes, and several others are being analyzed with linkage analyses. In no case, has the gene responsible for any human epilepsy been isolated or characterized and we are not yet close to understanding how any specific genetically controlled biochemical or physiological parameter is responsible for the development of an epilepsy syndrome or of any specific epileptogenic increase in brain excitability. However, an extensive animal literature indicates that the mechanisms will be complex as a common phenotype can be the expression of multiple genes, and a single gene can be associated with several phenotypes (Buchhalter, 1993).

Hippocampal commissural connections in the neonatal rat.

The presence and specific connections of the hippocampal commissure were investigated in neonatal Sprague-Dawley rats. Unilateral hippocampal injections into specific subfields with rhodamine-labelled microspheres (RLM) were performed between 3 and 5 days of postnatal life. Retrograde transport of the RLM was allowed to proceed for 48 h following the injection, at which time brains were removed and prepared for histology. Frozen sections were cut at 30-microns intervals in the coronal plane and examined with fluorescence microscopy. All 5 brains which had an injection restricted to CA1 demonstrated contralateral retrograde transport to the homotopic CA1 subfield only, and all 5 brains with focal CA3 injections had contralateral homotopic CA3 labelling. Eight brains had injections involving more than one subfield; in 5 of these brains, the results were consistent with the CA3 to CA3 commissural projection demonstrated by the more restricted injections. However, 3 brains in which the injection involved CA1 as well as CA3, contralateral CA1 labelling was not found, most likely due to 'missing' the projection site in CA1. We conclude: (1) the hippocampal commissural projection exists in the early postnatal rat, (2) a CA3 to CA3 homotopic commissural projection exists, as it does in the adult, and (3) a CA1 to CA1 projection is present in the neonatal rat.

Effects of valproic acid in cultured mammalian neurons.

Valproic acid (VPA) has been postulated to exert its anticonvulsant effects by interaction with the postsynaptic GABA receptor. To test that hypothesis, we applied VPA in clinically appropriate concentrations to cortical neurons in dissociated cell culture. VPA did not enhance the postsynaptic effect of GABA, but did decrease the generation of sodium-dependent action potentials. VPA may exert anticonvulsant effects by inhibiting spike generation, independent of the GABAergic system.