J. C. Sackellares

In vivo cerebral metabolism and central benzodiazepine‐receptor binding in temporal lobe epilepsy

Positron emission tomography measured interictal cerebral glucose metabolism with [18F]fluorodeoxyglucose and central benzodiazepine-receptor binding with [11C]flumazenil in 10 mesial temporal lobe epilepsy (TLE) patients and in normal subjects. Eight TLE patients had mesial temporal, lateral temporal, and thalamic hypometabolism ipsilateral to EEG ictal onsets, with additional extratemporal hypometabolism in four. One had unilateral anterior mesial temporal hypometabolism only, and one had normal metabolism. Each patient had decreased benzodiazepine-receptor binding in the ipsilateral anterior mesial temporal region, without neocortical changes. Thus, interictal metabolic dysfunction is variable and usually extensive in TLE, whereas decreased central benzodiazepine-receptor density is more restricted to mesial temporal areas. Metabolic patterns in TLE may reflect diaschisis, while benzodiazepine-receptor changes may reflect localized neuronal and synaptic loss that is specific to the epileptogenic zone. [11C]Flumazenil imaging maybe useful in presurgical evaluation of refractory complex partial seizures.

Valproic acid versus ethosuximide in the treatment of absence seizures

Valproic acid (VPA) and ethosuximide (ESM) were compared in a double-blind, response- conditional crossover study of absence seizures in 16 naive (previously untreated for absence seizures) and 29 refractory patients (18 male and 27 female; 4 to 18 years of age). In the naive patients VPA was as effective as ESM in reducing generalized spike-wave discharges on the telemetered EEG. Adverse reactions to VPA or ESM were generally mild and responded to withdrawal or dosage reduction of the drug.

Felbamate A double‐blind controlled trial in patients undergoing presurgical evaluation of partial seizures

We studied the efficacy and safety of felbamate, an investigational antiepileptic drug, in a unique, double-blind, placebo-controlled trial. Sixty-four patients with refractory partial-onset seizures who completed a routine evaluation for epilepsy surgery met seizure frequency entry criteria. Each patient received felbamate or placebo in addition to the anticonvulsant regimen present at the conclusion of the presurgical evaluation. The treatment phase consisted of an 8-day inpatient period and a 21-day outpatient period. The efficacy variable was time to fourth seizure. The difference in time to fourth seizure was statistically significant (p = 0.028) in favor of felbamate. Eighty-eight percent of the patients in the placebo group had a fourth seizure during the treatment phase compared with 46% of the patients in the felbamate group (p = 0.001). Adverse experiences with felbamate were generally mild or moderate in severity. This trial demonstrated the ability of felbamate to quickly and safely reduce the occurrence of frequent partial-onset seizures and maintain effective seizure control following reductions in the dosages of standard antiepileptic drugs.

Efficacy and safety of zonisamide: results of a multicenter study

The safety and efficacy of zonisamide (ZNS), a new antiepileptic drug, was tested in 167 adult participants who entered a historical-controlled 16-week open label, multicenter study. The median percent reduction from baseline of partial seizures was 51.8% in the fourth month of the study (baseline median = 11.5 sz/month; treatment weeks 13-16 = 5.5 sz/month). Persons completing the efficacy study successfully were eligible for a long-term safety study; 113 entered this study. Adverse effects involved principally the CNS and were similar to those seen with other antiepileptic drugs. Four persons (3.7%) developed kidney stones and were withdrawn from the study 250-477 days after starting ZNS. Because of the high percentage of kidney stones, development of ZNS was stopped in the United States but was continued in Japan.

Differences between lateral and mesial temporal metabolism interictally in epilepsy of mesial temporal origin.

We performed interictal [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in 17 patients with well-defined unilateral anterior mesial temporal epileptogenic foci as determined by EEG procedures. Sixteen of these patients subsequently underwent surgical resection of the epileptogenic focus. We measured local cerebral metabolic rates for glucose in mesial and lateral temporal structures and compared them with metabolic rates for analogous regions in 16 healthy normal volunteers and the contralateral hemisphere of the epileptic patients. We found relative hypometabolism ipsilateral to the seizure focus more frequently and to a greater degree in the lateral than in the mesial temporal cortex. Since the physiologic abnormalities involved mesial temporal structures, this observation suggests that functional pathways exist between mesial and lateral temporal cortex normally and that these pathways are altered in epilepsy of mesial temporal origin. Hypometabolism did not correlate well with histologic abnormalities in the surgical specimens.

Personality of patients with pseudoseizures

We studied personality features of 19 patients with pseudoseizures (PS) only. Scores on a personality inventory (MMPI) were compared with those of adults with generalized seizures and correlated to cognitive measures (Halstead-Reitan). Mean MMPI scores did not differ significantly, and no profile distinguished PS and epilepsy patients. MMPI abnormalities of PS patients were diverse and seldom characteristic of hysteria. Eight PS patients had cognitive impairment, two without MMPI evidence of personality disorder. These findings suggest that the etiology of pseudoseizures is multi factorial, involving different psychopathologies and sometimes cerebral dysfunction.

Temporal lobe central benzodiazepine binding in unilateral mesial temporal lobe epilepsy

Article abstract—PET-demonstrated decreases in [11C]flumazenil binding occur in anterior mesial temporal structures on the side of epileptogenesis in unilateral mesial temporal lobe epilepsy. We performed quantitative autoradiog-raphy on anterior mesial and lateral temporal specimens from 11 subjects with unilateral mesial temporal lobe epilepsy and six neurologically normal controls to identify the predominant in vitro correlates of the decreased [11C]flumazenil binding. In anterior mesial temporal regions exhibiting the greatest neuronal cell loss, decreases in agonist and antagonist binding to type 1 and 2 (central) benzodiazepine binding sites were highly correlated with neuronal cell counts. Cell loss and decreased binding were particularly prominent in the lateral portion of hippocampal region CA1, adjacent to CA2. Lateral temporal central benzodiazepine binding was diffusely increased, achieving statistical significance in cortical laminae V and VI. These findings suggest that the predominant source of PET-demonstrated decreases in [11C]flumazenil binding in mesial temporal epilepsy is hippocampal sclerosis, rather than down-regulation of central benzodiazepine binding sites on surviving hippocampal neurons.

Intensive monitoring in refractory epilepsy

Forty patients with intractable seizures were studied in an epilepsy unit for an average of 8 weeks with video-electroencephalographic telemetry and continuous observation by trained personnel. Drugs were administered on the basis of antiepileptic drug measurements and seizure classification determined by clinical observation and telemetry. Seizure frequency was reduced in 24 patients (60%). Unrecognized seizure types were identified in 8 patients (20%), and diagnostic classification was changed in 19 patients (47.5%). At least one antiepileptic drug was eliminated in 25 patients (6O%), and the average drug reduction per patientp0.60—was highly significant (p <0.01). In patients with seizures refractory to conventional out-patient and hospital management, improvement in diagnostic accuracy and refinement in observation techniques result in significant reduction of seizure frequency, elimination of drugs, and limitation of toxicity.

Patients with pseudoseizures Intellectual and cognitive performance

We compared cognitive and intellectual performance of patients with pseudoseizures (pseudoseizure-only group), pseudoseizures and epilepsy (mixed seizure group), and generalized epileptic seizures (generalized seizure group). The pseudoseizure-only group performed significantly better on all measures except those of simple motor function. There were no significant differences between those with mixed and generalized seizures. Therefore, cognitive and intellectual performances of patients with pseudoseizures are influenced by the presence or absence of concomitant epilepsy, and suggest that it is necessary to distinguish patients with and without epilepsy in studies of pseudoseizures.

Flunarizine for treatment of partial seizures Results of a concentration‐controlled trial

The National Institutes of Health sponsored a randomized, double-blind, multicenter, placebo-controlled trial of flunarizine (FNR) in epileptic patients receiving concomitant phenytoin (PHT) or carbamazepine (CBZ). Because of FNRs long half-life (up to 7 weeks), a parallel rather than crossover design was used. Each patient received an individualized loading dose and maintenance dosage targeted at a 60-ng/ml plasma FNR concentration. Of 93 patients randomized, 92 provided seizure data for the full 25-week treatment period; one placebo-treated patient dropped out for personal reasons. Fifty-four patients received CBZ only, nine received PHT only, and 30 received both CBZ and PHT. Eighty-seven patients had a history of complex partial seizures, and 60 had secondarily generalized seizures. Eight patients discontinued FNR prematurely, all because of adverse neurologic or psychiatric signs or symptoms; depression was the specific cause in three cases. Calculated maintenance dosages, based on single-dose pharmacokinetic profiles, ranged from 7 to 138 mg/day (mean, 40 mg/day). Plasma FNR concentrations generally exceeded the target, with the highest concentrations observed immediately after loading; excluding the first three treatment weeks and all concentrations after a FNR dosage change, the median plasma FNR concentration was 71.7 ng/ml. The percent reduction from baseline seizure rate was statistically greater (p = 0.002) in the FNR-treated group (mean, 24.4%) than in the placebo-treated group (mean, 5.7%).