Richard W. Homan

A method of quantification for the evaluation of antiepileptic drug therapy

The design of clinical trials of antiepileptic drugs should include explicit methods for numeric quantification of seizures and side effects. Rating scales were developed to assess frequency and severity of seizures (partial and generalized tonic-clonic), systemic toxicity, and neurotoxicity. These scales are combined to form a single composite rating that reflects the overall effect of the drug on the patient. The rating system can be adapted to compare efficacy and toxicity of any antiepileptic drugs, for any types of seizures.

Assessment of a computer program to detect epileptiform spikes

This study compares an automated spike detection program to a group of 6 electroencephalographers. Since group members varied in experience, an expertise factor was devised to weight their scoring. EEGers underscored epileptiform events on 6 records in a manner analogous to the computers storage of EEG segments. A summation of expertise factors was determined for every event. This sum was normalized and interpreted as a probability the event would be called a spike by a given EEGer. The performance of each scorer and of the computer at different amplitude thresholds was analyzed based on this probability. Higher rated scorers identified more subtle events. Lowering the threshold of the computer program produced a comparable increase in sensitivity. The increase in total events detected by the computer was linear over the range studied. While the proportion of false positive detections increased with lowering threshold, our readers have not found a moderate number of these distracting. We conclude that the computer system, while not as specific as an EEGer, can be as sensitive and can be a reliable screening editor for large amounts of monitoring data. On balance it is more effective than an EEGer for this limited purpose.

Kindled seizures elevate blood pressure and induce cardiac arrhythmias

Summary: The effect of kindled seizures on the cardio‐ vascular system was examined in amygdaloid kindled rats. The most prominent cardiovascular response during a generalized kindled seizure was an abrupt 50% increase in mean arterial pressure (MAP) lasting 20–30 s after initiation of the seizure. Superimposed on this change in blood pressure (BP) was a profound bradycardia characterized by a rate about half that recorded before stimulation. Changes in heart rate (HR) and BP observed during amygdaloid kindled seizures were similar to those ob‐ served during secondary spontaneous seizures. These effects apparently are independent of the kindling stimulus because stimulus‐induced cardiovascular changes were not present at the beginning of the kindling process. These results suggest that the kindling seizure model is useful to study the underlying mechanisms of seizure‐ induced cardiac arrhythmias and possibly the clinical phenomenon of sudden unexplained death in epileptic patients.

A design for the prospective evaluation of the efficacy and toxicity of antiepileptic drugs in adults

The design for the comparative evaluation of the efficacy and toxicity of phenobarbital, phenytoin, primidone, and carbamazepine is outlined. A double-blind prospective study of a sufficient number of patients can determine the optimum drug to use initially for partial and generalized tonic-clonic seizures in adults. The rationale for methods defines the major parameters that should be addressed in order to determine optimum drug for longterm seizure therapy. Major problems in the function of such a project include aspects of sample size attainment, screeningh-ecruitment, non-drug-related losses, and adjustments to the ongoing protocol. The design, with modifications, can be used to study other antiepileptic drugs and other types of seizures.

Kindled seizures activate both branches of the autonomic nervous system

Amygdaloid kindled seizures in the rat induce an abrupt elevation of blood pressure accompanied by a significant decrease in heart rate. The autonomic pharmacology of this response was examined in unanesthetized kindled rats. Muscarinic receptor blockade with atropine (1 mg/kg, intravenous (i.v.)) abolished the seizure-induced bradycardia. The seizure-induced hypertension was unaffected by beta-adrenergic blockade with timolol (1 mg/kg, i.v.), but was reduced by phentolamine (5 mg/kg, subcutaneous (s.c.)), an alpha-adrenergic receptor antagonist. A chemical sympathectomy was induced with 6-hydroxydopamine (100 mg/kg, i.v.), an agent that does not cross the blood-brain barrier. This eliminated the pressor response but did not completely block the seizure-induced bradycardia. The effectiveness of 6-hydroxydopamine was tested with tyramine (0.5 mg/kg, i.v.) an agent that releases endogenous catecholamines. These results indicate amygdaloid kindled seizures activate both branches of the autonomic nervous system. The bradycardia was mediated by the parasympathetic system; the pressor response was caused by an increase in peripheral resistance due to alpha-adrenergic receptor activation. More important, these findings show that kindling is a useful seizure model for future studies on the effect of seizures on cardiovascular function and possible mechanisms of seizure-related sudden unexplained death.

Phenytoin plasma concentrations in paroxysmal kinesigenic choreoathetosis

We studied five patients with paroxysmal kinesigenic choreoathetosis (PKC) to evaluate the minimum effective plasma concentration of phenytoin. In two children, the minimum concentration necessary to control symptoms approximated the concentrations necessary to control epileptic seizures. In three adults, symptoms were controlled with concentrations of phenytoin well below the therapeutic range of phenytoin in epilepsy. These findings suggest an age-dependent change in the disease state, and support the concept that the clinical course of PKC may be explained by delayed maturation of extrapyramidal systems.

Causes of treatment failure with antiepileptic drugs vary over time

The V.A. Epilepsy Cooperative Study Group evaluated monotherapy with carbamazepine, phenobarbital, phenytoin, and primidone in a total of 622 patients with previously untreated partial seizures. In the 24 months following onset of treatment, 223 patients failed treatment. Analysis of these failures reveals that the majority occurred during the first 6 months with equal contributions to failure from systemic toxicity, neurotoxicity, and seizures. The contribution of systemic toxicity to failure was significantly less in the next 18 months. An increase in the contribution of seizures to failure was seen in this latter period.

Hemispheric contributions to manual communication (signing and finger‐spelling)

The neurology of manual communication was evaluated by intracarotid injection of amobarbital sodium in a patient who had learned speech and manual communication (signing) simultaneously. Hemispheric dominance for the prepositional components of manual communication and spoken language were the same, except that lateralization was less complete. The right hemisphere contributed to both prepositional and emotional components of manual communication.