Landau-Kleffner syndrome. Treatment with subpial intracortical transection.

Landau-Kleffner syndrome (LKS) is an acquired epileptic aphasia occurring in childhood and associated with a generally poor prognosis for recovery of speech. It is thought to be the result of an epileptogenic lesion arising in speech cortex during a critical period of development. Utilizing a new surgical technique designed to eliminate the capacity of cortical tissue to generate seizures while preserving the normal cortical physiological function, we have treated 14 children with aphasia, seizures and a severely abnormal EEG by multiple subpial transection of the epileptogenic cortex. Seven of the 14 patients (50%) have recovered age-appropriate speech, are in regular classes in school and no longer require speech therapy. Four of the 14 (29%) have shown marked improvement, are speaking and understanding verbal instruction but are still receiving speech therapy. Thus, 11 of the 14 (79%), none of whom had used language to communicate for at least 2 years, are now speaking--a rate of sustained improvement considered unusual in this disorder. This study documents the value of a treatment modality not previously used in LKS. Success depends on selection of cases having severe epileptogenic abnormality that can be demonstrated to be unilateral in origin despite a bilateral electrographic manifestation.

Weight loss in patients taking felbamate.

Felbamate is a new antiepileptic drug (AED) with a good safety profile. Anorexia has been reported in patients taking felbamate, but the incidence and severity of this side effect have not been adequately investigated. We studied 65 patients with intractable seizures who received adjunctive felbamate therapy as part of clinical research trials or in a compassionate-use program. Mean treatment time on felbamate was 23 weeks (+/- SD 16; range, 6-116 weeks). Forty-nine patients (75%) lost weight during the trials. For subjects older than 15 years, there was a mean weight loss of 3.17 kg or 4.11% of body weight (T = 191.5, z = 4.18, p < 0.001). For subjects 15 years or younger there was a mean weight loss 0.20 kg or a loss of 1.77% of body weight (T = 52.5, NS). Twenty-two patients (34%) lost > 4 kg, and seven patients (11%) lost > 8 kg. Adjunctive treatment of adults with severe epilepsy with felbamate may be associated with clinically significant weight loss.

A 'stress' test for memory dysfunction. Electrophysiologic manifestations of early Alzheimer's disease.

Long-latency event-related potentials (P300) were assessed in patients with early probable Alzheimer's disease (AD), age-matched controls, and young adults during a task that imposed various degrees of demand on memory. Although patients with AD did not differ from age-matched controls when one item had to be remembered, their P300 potential was dramatically reduced in amplitude or absent with increasing memory load. Aged controls did not differ from young adults on this measure. P300 latency, however, did not differentiate patients with AD. Thus, electrophysiological abnormalities detected in the context of mnemonic demand may provide a sensitive marker of the early stages of probable AD.

The anticonvulsant valproic acid concentrates in the olfactory bulb: selective laminar localization.

Using autoradiography, we examined the distribution of radiolabel in the brain after intravenous administration of a tracer dose of [14C]valproic acid (VPA) into the anesthetized rat. The label was concentrated in the medial and dorsal portions of the olfactory bulb (highest levels in the glomerular layer) with almost no label elsewhere in the brain. The VPA seems to be a marker of a hitherto unrecognized spatial organization within the olfactory bulb. This unusual distribution of VPA may have a bearing on its anticonvulsant action.

Control of scar formation in experimentally induced epilepsy.

Penfield proposed that the meningocerebral scar that forms following trauma to the brain plays an important role in the development of posttraumatic epilepsy. Although the epileptogenic scar has come to be widely accepted as a cause of epilepsy, there is no direct evidence that scar formation contributes to epileptogenesis. This current study showed that procedures that control the development of collagen in a fibroblastic scar may modify the development of epilepsy. Epilepsy induced in the guinea pig by injection of metallic aluminum powder into the cerebral cortex was used as a model of posttraumatic epilepsy. Following application of aluminum and implantation of epidural electrodes, animals received either daily injections of prednisolone or an ascorbic acid-deficient diet to block scar formation. Control animals also had an injection of aluminum, but afterward received saline injections or a normal diet. Control animals developed epileptic spikes and often exhibited focal seizures. All manifestations of epileptogenesis were markedly reduced in animals treated with prednisolone or the ascorbic acid-deficient diet. The reduction in epileptiform activity corresponded to reduced collagenous scar formation in the treated animals. Although effective when given prophylactically, prednisolone did not inhibit the activity of an already established epileptic focus whether induced by aluminum or by amygdala kindling, nor did it block pentylenetetrazol-induced seizures. The finding that epileptogenesis is blocked by two procedures that inhibit scar formation but show no evidence of a direct anticonvulsant effect, suggests that scar formation is a significant factor in epileptogenesis induced by metallic aluminum. The collagenous component appears to be more significant than the glial component of the scar.

Hemispheric asymmetry of visual evoked potentials in patients with well-defined occipital lesions.

Visual evoked potentials were examined in 3 patients who had well defined unilateral occipital lobectomy. In an attempt to resolve discrepancies in the interpretation of hemispheric asymmetries in evoked potentials, recordings were obtained from a wide array of electrodes with multiple montages during full-field and hemi-field stimulation with checkerboard pattern reversal and during full-field flash stimulation. The discrepancies appear to be due primarily to differences in electrode montages used in recording. The use of a midfrontal reference electrode reliably produces a paradoxical EP lateralization: abnormal EPs are recorded over the intact occipital lobe and normal EPs are recorded over the ablated occipital lobe. These findings are fully consistent with the interpretation of Barrett et al. (1976) that the generator of the P100 has an equivalent dipole located in the calcarine cortex on the posteromedial surface of the contralateral hemisphere. Our findings support the use of the Queen Square montage (Halliday et al. 1977). The use of electrodes at O1 and O2 referred to the ipsilateral earlobe yields inconsistent lateralization and should be discouraged. The lateralization of EP abnormalities did not differ for flash and pattern reversal, although the asymmetries were sometimes more prominent with pattern reversal.

Conditioning of single units in visual association cortex: cell-specific behavior within a small population.

These experiments examine the interrelationships between the activity of adjacent neurons during learning. Does learning depend on coherent behavior in a population of neurons or does it depend on particular neurons engaging in a particular activity at specific times? A second purpose was to examine specificity in response modification as a function of reinforcement contingency. Cells from visual association cortex of locally anesthetized, paralyzed cats and rabbits were studied with extracellular microelectrodes capable of recording single and multiunit activity, as well as local field potentials. Multiunit records were fractionated by amplitude "windows" discrimination. Pavlovian discriminative conditioning procedures were used to evaluate selective plasticity. Cells that were activated by at least two different visual stimuli were selected. Only one of the effective stimuli was paired with foot-shock (reinforcement). Of the 180 cells or cell clusters studied, 27% exhibited conditioned modification to the reinforced stimulus (CS+) and 19% changed their response pattern to the unreinforced stimulus (CS-). None of the well isolated cells showed conditioning to both CS+ and CS-. Thus, cellular plasticity was specific to reinforcement contingency. These results provide a first demonstration of reinforcement-dependent functional distinctiveness at the neuronal level. Some cells showed no alteration of response pattern despite a most prolonged conditioning procedure. Neighboring cells, responsive to the same stimuli, revealed increases or decreases in firing rate, selective changes in the latency or amplitude of single response peaks, or the appearance of one or more new peaks as a function of conditioning. Rarely did adjacent cells show the same type of alteration when alteration occurred; there was no general tendency toward coherent firing patterns as conditioning proceeded.

Binocular interaction in the visual evoked response: temporal factors.

Binocular visual evoked responses (VERs) were examined in normal subjects and in patients with prolonged monocular latency. Visual evoked responses to binocular stimulation are normally similar to the response to monocular stimulation but are somewhat larger. When conduction from one eye is slowed relative to that from its fellow (as often occurs in demyelinating disease) binocular interaction varies widely. When the interocular difference in latency is substantially elevated the binocular response is often that of the fastest pathway with little or no contribution from the slower pathway. These findings suggest a delayed reciprocal inhibitin between the inputs from the two eyes which may suppress late arriving signals.

Influences of pituitary-adrenal hormones on kindling.

The kindling process represents a progressively augmenting electrical and behavioral response to brain stimulation, that has been proposed as a model for the development of epileptogenesis. The first experiment examined the effects of hypophysectomy on the kindling process. The effects of hypophysectomy were found to be dependent on the number of days between hypophysectomy and the beginning of kindling. The kindling rate was slowed, compared to intact controls, when hypophysectomy was performed less than 2 weeks prior to the first kindling stimulation. However, if more than 4 weeks and passed since hypophysectomy, the kindling rate was faster than that of intact controls. The second experiment tested the influence of systemic administration of cortisone (10 mg/animal), upon kindling of control and hypophysectomized animals. Cortisone was found to reverse the kindling deficit of hypophysectomized animals at less than 2 weeks and to slow kindling of intact controls, but to have no effect on hypophysectomized animals at more than 4 weeks (at this dose). These results are interpreted as indicating that pituitary-adrenal hormones have profound influences on the kindling process, but it is unclear whether the influence is upon brain excitability or more directly upon modification of synaptic function.

Conditioned inhibition: selective response of single units.

Single cell activity and local field potentials in parastriate cortex of cats and rabbits were studied during a Pavlovian discrimination procedure. Cell activity was selectively modified; conditioned changes occurred in response either to the reinforced stimulus or to the unreinforced one, but not to both. Cells exhibiting conditioned alteration in response to the unreinforced stimulus are thought to participate in specialized circuits mediating conditioned inhibition.

The BAER profile: a method for reporting electrophysiologic brainstem examinations in clinical practice.

We present a method for graphically reporting the results of brainstem auditory evoked response examinations on the basis of multiple parameters. The method is based on a transform that normalizes the many latency and amplitude measures obtained from the averaged evoked responses of normal subjects tested under standardized conditions. Among the advantages of the method are the simplicity of its use, the identification of disease profiles, and the isolation of relevant parameters for research and diagnosis.

Secondary epileptogenesis in frog forebrain: effect of inhibition of protein synthesis.

Secondary epileptogenesis was induced in the hippocampal cortex of the paralyzed bullfrog by means of localized, unilateral, intermittent electrical stimulation (kindling). Stimuli were designed to yield a brief but definite after-discharge. In control animals a progressive increase in after-discharge duration occurred at the 1 degree (stimulated) site and then at the 2 degrees site (contralateral hippocampus). Spontaneous epileptiform potentials (SEP's) occurred between stimuli, eventually independently on both sides. Cycloheximide (50 mg/kg) caused 88-99% reduction in protein synthesis, measured by 14C-leucine incorporation into brain protein. Cycloheximide-treated animals revealed no evidence of progressive prolongation of after-discharge duration when subjected to the kindling procedure (p = 0.1205 X 10(-7)). SEP's were reduced in the cycloheximide-treated animals, and confined to 1 degree hemisphere (p = 0.6 X 10(-10)). Since cycloheximide did not disturb normal electrogenesis or disrupt the after-discharges, this experiment distinguishes processes dependent upon electrical events from those requiring macromolecular synthesis. Protein synthesis seems critical to the emergence of spontaneous and autonomous epileptiform behavior of neural aggregates.