Antonio V. Escueta

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.

Lapse of consciousness and automatisms in temporal lobe epilepsy: A videotape analysis

Videotape analysis of 76 attacks in 14 epileptics showed two electro-clinical types of psychomotor attacks. The first and most common type had three clinical phases, consisting of an initial motionless stare, stereotyped movements, and reactive automatisms during impaired consciousness. The second and less common type started with stereotyped and reactive automatisms. In the first type, focal temporal or lateralizing features were common. In the second type, there were only diffuse changes in the electroencephalogram. The value of recording attacks with nasopharyngeal electrodes was emphasized by a high yield for focal-lateralizing electroencephalographic features.

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.

Prolonged twilight state and automatisms A case report

A prolonged state of mental confusion was associated with a unilateral seizure focus in the left medial anterior temporal lobe in a 39 year old patient with psychomotor status. Two electroclinical phases are differentiated: (1) a continuous twilight state with reactive automatisms interrupted every 10 minutes by (2) staring, total loss of responsiveness, and stereotyped gutomatisms. During the first clinical phase the electroencephalogram showed continuous, focal sharply contoured slow waves in the left anterior temporal areas preponderant medially. During the second clinical phase, 6 to 10 Hz rhythms engaged both medial temporal lobes and then progressively increased in amplitude and decreased in frequency to 3 to 5 Hz waves. A subcortical mechanism is suggested for both reactive and stereotyped automatisms.

Historical perspective on the choice of antiepileptic drugs for the treatment of seizures in adults.

Although numerous reports have appeared in the literature over the past 100 years describing various antiepileptic drugs, it is not possible to justify preference for a particular drug to treat specific types of adult seizures. Since the introduction of bromides a century ago, numerous antiepileptic drugs have been developed. Four such drugs, carbamazepine, phenobarbital, phenytoin, and primidone, have been found to be effective and acceptably safe for management of partial and secondarily generalized seizures. However, no studies have demonstrated the superior efficacy of any one drug. Clinical selection of therapy often is based on expected or assumed risk or absence of specific side effects. This review of classic papers demonstrates inconclusive and conflicting information. A new approach to the comparative evaluation of the efficacy and toxicity of major antiepileptic drugs is needed.

The freezing lesion. II. Potassium transport within nerve terminals isolated from epileptogenic foci

Abstract The generation of electrocorticographic seizures in freezing lesions was correlated with the ability of isolated synaptic terminals to actively transport potassiumin vitro. Potassium content of synaptosomes from epileptogenic lesions was not significantly different from controls. However, when synaptosomes were incubated in Tris media, total K uptake decreased 59% while ouabain inhibition dropped 48% in the primary foci. In the mirror foci total K accumulation and ouabain inhibition both decreased 39%. Synaptosome K transport decreased more in the primary foci and in 6 of 13 experiments K appeared to be leaking out rather than going into synaptosomes. In order to rule out the effects of neuronal injury, studies were performed of non-epileptogenic lesions. Ouabain inhibition was not significantly changed while total K accumulation decreased 28%. These results show that an impairment in the synaptosome (Na+K) pump is intimately associated with the generation of seizures in primary and mirror foci. In addition, they suggest that synaptosome K leakage may be enhanced in lesion sites because: (1) in synaptosomes from inactive lesions total K uptake dropped without changes in ouabain inhibition and (2) in epileptogenic primary sites total K uptake decreased more than ouabain inhibition.

Principles in designing clinical trials for antiepileptic drugs

The failure of previous studies to indicate clear differences in the relative seizure control and side effects of the major antiepileptic drugs has resulted from insufficient clinical trials or limitations in earlier studies. The principles for designing studies of the efficacy and toxicity of major antiepileptic drugs are outlined. These standards apply to the evaluation of new and old antiepileptic drugs used for all types of seizures in diverse populations.

The freezing lesion. III. The effects of diphenylhydantoin on potassium transport within nerve terminals from the primary foci

Possible mechanisms by which dephenylhydantoin (DPH) controls seizures were examined. The effects of intraperitoneal DPH on seizure discharges within epileptogenic freeze lesions were correlated with DPH action on in vitro potassium uptake within synaptosomes isolated from the same freeze foci. When in vivo DPH suppressed seizure discharges, it stimulated in vitro potassium uptake within synaptosomes incubated in a high-Kplus (10 mM) media. With 2-5 mM Naplus and 10mM Kplus, DPH stimulation of synaptosome potassium uptake was reversed by ouabain. With 50 mM Naplus and 10 mM Kplus, DPH stimulation of potassium uptake was not reversed by ouabain. In low-Kplus (0.2-5 mM) media, DPH did not affect potassium uptake even when sodium concentrations were varied at 10-100 mM. In sham-operated controls and in non-epileptogenic lesions, the effects of DPH on synaptosome potassium uptake were identical to those previously reported in normal brains. These results strongly suggest that DPH controls the epileptogenic state by stimulating potassium uptake within synaptic terminals. DPH controls the epileptogenic state by stimulating potassium uptake within synaptic terminals. DPH enhances synaptic potassium uptake by stimulating the (Naplus-Kplus) pump and a second potassium uptake process which is insensitive to ouabain.

The effects of electroshock seizures on potassium transport within synaptosomes from rat brain.

—Potassium transport was assessed within synaptic terminals isolated from cerebral cortices of rats which experienced one or two maximal electroshock (ES) convulsions daily. No significant change in endogenous K content was present after 2 consecutive days of ES‐seizures. However, K decreased 22 % and 41 % after 4 and 6 days of convulsions respectively. After 6 days, synaptosomes from ES rats were able to accumulate K to the same extent as controls and were inhibited by ouabain to an equivalent extent (50%). When these synaptosomes from ES rats were preloaded with high concentrations of K, K leaked out at an increased rate. When diphenylhydantoin (DPH) was administered intraperitoneally from the second to the sixth day of ES‐convulsions, the decrease in endogenous K induced by chronic convulsions was corrected. In ion‐free media or with 50 mM Na, DPH had no effects on the enhanced efflux of K observed in vitro after ES‐seizures. However, with high Na (50–100 mm) and low K (0.2–1 mm) DPH stimulated K uptake but did not affect the ouabain inhibition. Under conditions optimal for K uptake (50 mm Na and 10 mm K), DPH did not affect K accumulation but it prevented in vitro ouabain inhibition. Our results indicate that repeated ES‐convulsions decreased K content within isolated nerve terminals by enhancing its passive leakage. In vivo DPH prevented the effects of ES‐seizures by stimulating the Na‐K pump and not by directly blocking the K leak.

Cerebral Gigantism with Intermittent Fractional Hypopituitarism and Normal Sella Turcica

Excerpt A syndrome of cerebral gigantism with normal sella turcica occurring in childhood has recently been described by Sotos and co-workers (1). In all of their patients the growth spurt leading ...