Blockade of neuronal activity during hippocampal development produces a chronic focal epilepsy in the rat.

During brain development, neuronal activity can transform neurons characterized by widely ranging axonal projections to ones with more restricted patterns of synaptic connectivity. Previous studies have shown that an exuberant outgrowth of local recurrent excitatory axons occurs in hippocampal area CA3 during postnatal weeks 2 and 3. Axons are remodeled with maturation, and nearly half of the branches are eliminated. Postnatal weeks 2 and 3 also coincide with a "critical" period of development, when CA3 networks have a marked propensity to generate electrographic seizures. In an attempt to prevent axonal remodeling, local circuit activity was blocked unilaterally in dorsal hippocampus by continuous infusion of tetrodotoxin (TTX). Field potential recordings from behaving animals were dramatically altered when TTX infusion was initiated at the beginning of the critical period, week 2, but not later in life. Spontaneous, synchronized spikes and electrographic seizures with behavioral accompaniments were observed after 4 weeks of TTX infusion and persisted into adulthood. When recordings were made during TTX infusion, synchronized spiking was recorded in ventral hippocampus as early as 2 weeks after infusate introduction. At this same time, extracellular field recordings from in vitro slices demonstrated spontaneous network-driven "mini-bursts" arising from ventral hippocampal slices. These were abolished by glutamate receptor antagonists. Whole-cell recordings from CA3 neurons revealed bursts of excitatory synaptic potentials coincident with the network bursts recorded extracellularly. Thus, local assemblies of mutually excitatory CA3 pyramidal cells are hyperexcitable in these rats. Whether alterations in developmental axonal remodeling mediate these effects awaits further studies.

Sleep characteristics in infantile spasms.

Sleep staging was performed on 32 patients with infantile spasms. All patients demonstrated significantly less total sleep time and lower percentage of REM time than the expected normal values for age. Seventeen were treated with ACTH or prednisone. There was no increase in total sleep time in those who received hormone therapy, whether or not it was successful. However, the percentage of REM time increased significantly in patients who responded to therapy; this increase occurred concurrently with clinical and electroencephalographic improvement. There was no significant change in REM-sleep values in patients who did not respond.

A chronic focal epilepsy with mossy fiber sprouting follows recurrent seizures induced by intrahippocampal tetanus toxin injection in infant rats.

Studies were conducted to characterize a chronic epileptic condition that follows recurrent seizures induced by intrahippocampal tetanus toxin injection in infancy. Wistar rat pups received a single injection of tetanus toxin in the right CA3 region on postnatal day 10. Animals were monitored for epileptiform activity by video electroencephalographic or visual observation during the following three to five days. Repeat evaluation six months later demonstrated interictal discharges in 79% (11 of 14) and electrographic seizures in 42% (six of 14) of adult rats with tetanus toxin-induced seizures in infancy. Five of the animals had interictal activity which occurred focally in either the left (n = 2) or right (n = 3) hippocampus. One animal had focal interictal activity independently in these regions and in the left and right cortical regions. The remaining five animals had interictal activity in the hippocampus and synchronously in the ipsilateral cortex or the contralateral hippocampus. Electrographic seizures were focal (nine of 14) or bilateral (five of 14) in onset. The behaviors that accompanied these seizures were quite variable. Clonic face and forelimb movements were observed in some animals. However, a significant portion of rats had electrographic seizures with no associated behavioral change. Timm staining was performed on hippocampal sections from experimental and control animals. There was a significantly greater Timm score (aberrant Timm granules) in the inner molecular layer of the dentate gyrus in tetanus toxin-treated rats than in control rats. Our findings suggest that intrahippocampal tetanus toxin injection in infant rats results in a chronic focal epilepsy that persists for at least six months and is associated with aberrant mossy fiber sprouting in the dentate gyrus. The model described here contributes significantly to the evidence for chronic effects of recurrent seizures in early life, and provides a model for investigation of the molecular and cellular events that contribute to the development of chronic epilepsy.

Tetanus toxin-induced seizures in infant rats and their effects on hippocampal excitability in adulthood.

A new experimental model of developmental epilepsy is reported. Behavioral and EEG features of seizures produced by unilateral intrahippocampal injection of tetanus toxin in postnatal day 9-11 rats, are described. Within 24-72 h of tetanus toxin injection, rat pups developed frequent and often prolonged seizures which included combinations of repetitive wet dog shakes, and wild running-jumping seizures. Intrahippocampal and cortical surface EEG recordings showed that coincident with these behaviors, electrographic seizures occurred not only in the injected hippocampus, but also in the contralateral hippocampus and bilaterally in the neocortex. Analysis of the interictal EEG revealed multiple independent spike foci. One week following tetanus toxin injection, the number of seizures markedly decreased; however, interictal spiking persisted. After injection rats were allowed to mature some were observed to have unprovoked behavioral seizures and/or epileptiform EEG activity. Mature animals were also studied using in vitro slice techniques. Recordings from hippocampal slices demonstrated spontaneous epileptiform burst discharges in the majority of rats which had tetanus toxin induced seizures as infants. These events occurred in area CA3 and consisted of interictal spikes and intracellularly recorded paroxysmal depolarization shifts (PDSs). On rarer occasions, electrographic seizures were recorded. The use of the tetanus toxin model in developing rats may facilitate a better understanding of the unique features of epileptogenesis in the developing brain and the consequences early-life seizures have on brain maturation and the genesis of epileptic conditions in later life.

Insights into the tetanus toxin model of early-onset epilepsy from long-term video monitoring during anticonvulsant therapy.

Video monitoring studies were undertaken to determine if the anticonvulsant, carbamazepine (CBZ), could prevent seizures in infant rats that had been intrahippocampally injected with tetanus toxin (TNTX). In control rats, seizure frequency peaked 5-6 days after injection and rapidly declined by postinjection day 9. Twice-daily CBZ treatments dramatically suppressed behavioral seizures for 7 days. However, despite increasing the dosage of CBZ, rats experienced more behavioral seizures during the second week after TNTX injection. Paradoxically, tetanus-toxin-injected control rats had very few seizures at this time. Results not only suggest that this TNTX model may be useful in screening drugs for treating intractable focal epilepsy of infancy but also provide some insight into the processes that may contribute to the rapid decline in behavioral seizure frequency that occurs during the acute phase of epileptogenesis in this model.

The significance of excessive rhythmic alpha and/or theta frequency activity in the EEG of the neonate.

OBJECTIVE: The goal of this study was to determine the significance of excessive rhythmic alpha and/or theta frequency activity in neonatal EEGs. METHODS: The EEGs of 963 neonates, 26-44 weeks conceptional age (CA), performed during the years 1992-1994 at the Texas Children's Hospital, Houston, Texas, were reviewed for the presence of excessive rhythmic alpha and/or theta frequency activity. Cases in which such activity was identified were further characterized by the presence or absence of other EEG abnormalities. The medical records of these patients and a group of control infants with normal EEGs were reviewed to identify associated pathological conditions. RESULTS: Forty patients were identified whose EEGs revealed such activity. The CA of these patients ranged from 37 to 44 weeks. A variety of pathological conditions were seen in these patients, most commonly congenital heart disease, congenital brain anomalies and hypoxia. These conditions were not seen in the control group of infants. Twenty patients had received CNS-active drugs. The EEGs of 32 patients revealed additional abnormalities, most commonly multifocal sharp waves and episodes of voltage attenuation during slow-wave sleep. CONCLUSIONS: The results indicate that excessive rhythmic alpha and/or theta frequency activity is an abnormal finding in the newborn's EEG.

Coupling of focal electrical seizure discharges with infantile spasms: incidence during long-term monitoring in newly diagnosed patients.

To investigate the coupling of focal electrical seizure discharges (FS) and infantile spasms, we analyzed the video/polygraphic monitoring studies performed on 96 consecutive patients newly diagnosed with infantile spasms and hypsarrhythmic EEGs. A FS was considered to be coupled with infantile spasms if it occurred during a cluster of spasms (a series of individual spasms separated by < 1 min) or within 10 s of spasm onset or cessation. Ten patients demonstrated FS. In five patients (5% of the entire population) an apparent coupling of some FS with infantile spasms was observed during the baseline monitoring study. However, in three patients (only 3% of the entire population) was the observed coupling of FS and infantile spasms significant (p < 0.05). These results indicate that coupling of FS and infantile spasms occurs rarely, and that, in some instances, apparent couplings of FS and infantile spasms are best explained by chance coincidence. These findings do not support the hypothesis that the generation of infantile spasms at a subcortical level is dependent on a focal cortical discharge.

Increased susceptibility to tetanus toxin-induced seizures in immature rats.

Studies were undertaken to compare tetanus toxin-induced electrographic and behavioral seizure activity in immature and adult rats. Multifocal epileptiform activity was induced by unilateral hippocampal injection of tetanus toxin in 10-day-old immature and in 90-120-day-old adult rats. Bilateral cortical surface electrodes and, in some animals, hippocampal depth electrodes were placed and serial video EEG was recorded for 2 h during the week following tetanus toxin injection. Tetanus toxin-induced interictal spike frequency was significantly higher and seizure duration was significantly longer in immature compared to adult rats. Immature rats tended to have more frequent seizures compared with adults, but the difference was not statistically significant. Ictal behaviors were different for the two groups with immature rats commonly demonstrating wild running seizures which were not seen in adult rats. These findings suggest that there are age-dependent differences in electrographic and behavioral seizure expression in the tetanus toxin seizure model and that the epileptic syndrome in immature rats is more severe.

Alpha rhythm slowing during initiation of carbamazepine therapy: implications for future cognitive performance.

A prospective study comparing the immediate changes in occipital electroencephalographic (EEG) frequency following institution of carbamazepine therapy to long-term alterations of neuropsychological performance is reported. The patient group consisted of 16 previously untreated children in the 5-14-year age range who had recent onset partial seizures and were managed for at least 1 year with carbamazepine monotherapy. EEG changes following initiation of carbamazepine therapy, as compared to baseline, were determined by a computer-based quantitative method. Neuropsychological factors were assessed at baseline and after 1 year of therapy. While the alpha frequency decreased following institution of carbamazepine in most subjects, a greater decline (typically > 0.5 Hz) was observed in the subset who subsequently demonstrated decreased neuropsychological performance at 1 year. The major effects could be attributed to the Arithmetic and Picture Completion subtests of the Wechsler Intelligence Scale for Children-Revised (WISC-R). The findings suggest that quantitative EEG analysis may be useful for identifying individuals at increased risk for developing anticonvulsant-related long-term cognitive changes.

Computed tomography in infantile spasms: effects of hormonal therapy.

During a prospective double-blind, crossover study of ACTH versus prednisone therapy, serial computed tomography (CT) scans were performed on 16 children with infantile spasms. Pre-treatment scans revealed four findings: normal (6 patients), generalized atrophy (bilaterally enlarged ventricles and/or subarachnoid space) (2 patients), predominantly focal atrophy (3 patients), and congenital anomalies (5 patients). Within 2 weeks of initiating relatively low therapeutic dosages of ACTH or prednisone, a significant number of the infants (63%) had CT findings consistent with decreased cortical volume; in many cases (44%), these findings had not reversed 4 to 6 weeks after discontinuing therapy. Duration of therapy did not correlate significantly with the persistence of CT changes.

Infantile spasms.

Infantile spasms constitute a relatively rare disorder of infancy and early childhood; their onset is usually within the first 6 to 8 months of life. A large percentage of patients with this disorder (85-90 per cent) show various degrees of retardation. Infantile spasms typically occur in clusters immediately on arousal, or soon thereafter, but rarely occur while the infant is actually asleep. The usual interictal EEG pattern associated with infantile spasms is hypsarrhythmia, but infantile spasms may occur in the absence of this EEG pattern. The pathophysiology of infantile spasms is not known, but recent evidence suggests that certain regions in the brain stem that are associated with sleep cycling may be responsible for the clinical and EEG manifestations of this disorder. At present, the only known effective treatment for infantile spasms is ACTH or corticosteroids. The therapeutic efficacy of these two agents is relatively equal, and one drug may be effective if the other drug fails. The effectiveness of certain traditional anticonvulsants (valproic acid and the benzodiazepines) and pyridoxine in the treatment of infantile spasms has not been adequately assessed. The long-term mental and developmental outcome of patients with infantile spasms is poor. The only factor that appears to be important in terms of long-term outcome is whether the patient is initially classified as cryptogenic or symptomatic, with the cryptogenic patients having the better outcomes. Approximately half of the infantile spasm patients will continue to have other types of seizures after their spasms stop.

Recurrent fluent aphasia associated with a seizure focus.

The relationship between dominant hemisphere seizure activity and aphasia is unclear. Although speech arrest, expressive speech problems, and comprehension difficulties have often been associated with temporal lobe seizure activity, neologistic, paraphasic speech is rare. We report a patient with seizures following encephalitis who had recurrent episodes of fluent, severely aphasic speech with impaired comprehension which correlated with continuous, high voltage spike and slow wave activity in the left temporal region. During a several-day period of intermittent electrographic seizure activity, he had fluctuating receptive aphasia, and he developed transient paranoid psychosis following treatment. We discuss the behavioral manifestations of his left temporal seizures and correlate the changing nature of his behavior with therapeutic interventions. This case, as well as a review of others, suggests that paroxysmal fluent aphasia results from a partially treated electrographic seizure focus in the dominant temporal lobe.

Hypsarrhythmia: variations on the theme.

Prolonged monitoring studies of patients with infantile spasms have shown that hypsarrhythmia is a highly variable and dynamic electroencephalographic pattern. Variations of the prototypic pattern (modified hypsarrhythmia) include hypsarrhythmia with increased interhemispheric synchronization, asymmetrical hypsarrhythmia, hypsarrhythmia with a consistent focus of abnormal discharge, hypsarrhythmia with episodes of attenuation, and hypsarrhythmia comprising primarily high-voltage slow activity with little sharp-wave or spike activity. Marked changes in the hypsarrhythmic pattern usually occur during sleep, chiefly during rapid eye movement sleep, when there is a marked reduction in, or total disappearance of, the hypsarrhythmic pattern. Relative normalization of the hypsarrhythmic pattern can also be seen immediately on arousal and during clusters of infantile spasms. Thus, the specific EEG features seen in a given patient depend on multiple factors, including the duration of the EEG recording, the clinical state of the patient, and the presence of various structural abnormalities of the brain.

High-dose, long-duration versus low-dose, short-duration corticotropin therapy for infantile spasms.

Fifty patients in whom the diagnosis of infantile spasms had recently been made and who had hypsarrhythmic electroencephalographic findings were randomly assigned to receive either high- or low-dose therapy with corticotropin (adrenocorticotropic hormone; ACTH). Twenty-six patients receiving the high-dose therapy were treated as follows: 150 U/m2 per day for 3 weeks, 80 U/m2 per day for 2 weeks, 80 U/m2 every other day for 3 weeks, and 50 U/m2 per day every other day for 1 week, with the dosage then tapered to zero during a 3-week period. The 24 patients assigned to the low-dose therapy group received 20 to 30 U/day for 2 to 6 weeks; the dosage was then tapered to zero during a 1-week period. Population characteristics (cryptogenic vs symptomatic, treatment lag, and age at start of treatment) of the two groups were similar. Response, defined as cessation of spasms and disappearance of hypsarrhythmia, was determined objectively by serial prolonged video and polygraphic monitoring studies. Of the 26 patients treated with the high-dose therapy, 13 (50%) responded; of the 24 patients treated with the low-dose therapy, 14 (58%) responded (p value not significant). No significant difference in the relapse rate between the two groups was observed. The side effects seen in both treatment groups were similar, except that hypertension occurred more frequently in the high-dose group. These results indicate that there is no major difference in the effectiveness of these two regimens in the treatment of infantile spasms with respect to spasm cessation and improvement in the patients' electroencephalographic findings.

Treatment of infantile spasms with tetrabenazine.

Twelve patients with infantile spasms and hypsarrhythmic EEGs were treated with tetrabenazine, a drug with antiserotonergic and antiadrenergic activity. Before treatment, and after 3 weeks of therapy, 24-h polygraphic/video monitoring studies were performed to determine response objectively. None of the patients showed cessation of spasms, EEG improvement, or improvement in development and social skills during treatment with tetrabenazine.

A retrospective study of spontaneous remission and long-term outcome in patients with infantile spasms.

The spontaneous remission rate and long-term outcome in 44 patients with infantile spasms not treated with hormonal drugs were studied. The cumulative spontaneous remission rate during the first 12 months after onset of infantile spasms, as determined by retrospective analysis, was as follows: 1 month, 2%; 2 months, 2%; 3 months, 5%; 4 months, 7%; 5 months, 9%; 6 months, 11%; 7 months, 11%; 8 months, 14%; 9 months, 16%; 10 months, 18%; 11 months, 25%; 12 months, 25%. The average age at follow-up was 80 months. Nine percent of patients had normal development or only mild impairment. The remainder showed various degrees of retardation. These data should be useful in the design and interpretation of therapeutic drug trials in patients with infantile spasms.

Spike morphology in childhood focal epilepsy: relationship to syndromic classification.

The waveform morphology of interictal spike activity associated with uncontrolled childhood focal epilepsy was quantified in 40 patients by a computer-based technique. The findings were then analyzed with respect to epileptic syndromes. Samples of spike activity from each patient were characterized by determination of average amplitude (A), duration (D), and sharpness (S). A single morphologic index, the composite spike parameter (CSP), was also derived from the basic spike parameters (CSP = A x D/S). The spikes of patients in the benign focal epilepsy category differed from those of patients in other syndromic categories (symptomatic, cryptogenic, and Landau-Kleffner). Specifically, they were higher in amplitude, longer in duration, less sharp, and had a higher CSP value. The pretreatment spike parameters did not differ significantly in patients who responded favorably to initial antiepileptic drug (AED) therapy as compared with those whose seizures were harder to control. The findings suggest that quantitative assessment of interictal spike morphology may help develop a more objective basis for classifying patients according to epileptic syndrome.