R. Eugene Ramsay

A comparison of four treatments for generalized convulsive status epilepticus

BACKGROUND AND METHODS Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled. RESULTS Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days. CONCLUSIONS As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.

Randomized, Controlled Clinical Trial of Zonisamide as Adjunctive Treatment for Refractory Partial Seizures

Summary:  Purpose: This study was designed to evaluate efficacy and safety of zonisamide (ZNS) as adjunctive treatment for patients with refractory partial seizures.

Gabapentin bioavailability: effect of dose and frequency of administration in adult patients with epilepsy

UNLABELLED Gabapentin (GBP) is a non-metabolized antiepileptic drug that is eliminated by renal excretion and displays saturable, dose dependent absorption. The recommended dosing schedule for GBP is t.i.d. At large daily doses, oral bioavailability (F) may be improved by giving the daily dose more frequently. OBJECTIVE To evaluate whether switching GBP dosage regimen from t.i.d. to q.i.d. results in increased oral bioavailability. METHODS This study consisted of two parts; a computer simulated pharmacokinetic model and a clinical pharmacokinetic study in nine adult epileptic patients receiving 3600 mg/day and 11 receiving 4800 mg/day. All patients were evaluated during both t.i.d. and q.i.d. regimens. F were determined by calculation of percent of dose excreted unchanged using steady-state 24-h urine collections and were compared using a paired t-test. RESULTS At 3600 mg/day, mean F following t.i.d. and q.i.d. dosing were 38.7+/-22.1% and 40.0+/-18.9%, respectively (P=0.738). At 4800 mg/day, mean F following t.i.d. and q.i.d. dosing were 29.2+/-16.2% and 35.6+/-17.6%, respectively (P=0.006). DISCUSSION Good agreement was observed between values from this study and predicted values based on the pharmacokinetic model. Improved GBP F at doses of 3600 mg/day was not achieved with more frequent drug administration, and thus is not warranted. At 4800 mg/day, a 22% increase in F was observed with more frequent drug dosing. CONCLUSION GBP F may be significantly increased by q.i.d. versus t.i.d. dosing, depending upon dose level. This increase in F however must be balanced against the inconvenience of more frequent dosing. Therapeutic drug level monitoring may aid in the evaluation of such pharmacokinetic maneuvers.

Treatment of Status Epilepticus

Summary: Status epilepticus, particularly the convulsive form, is a medical emergency, warranting prompt and aggressive treatment. To do this, one must have a thorough understanding of the pharmacology of the anticonvulsant agents. Therapy should be directed toward rapid termination of the status epilepticus, prevention of seizure recurrence, and treatment of any underlying cause. Most importantly, one should establish and adhere to a standard treatment protocol for best results.

Vagus Nerve Stimulation in Humans: Neurophysiological Studies and Electrophysiological Monitoring

Summary: Evidence from studies of experimental animals indicates that electrical stimulation of the vagus nerve alters behavioral and electrographic seizure activity. We report on effects of electrical stimulation of the vagus nerve in five patients with medically intractable seizures as part of a clinical trial of chronic vagal stimulation for control of epilepsy. The mechanism of action of the vagal antiepileptic effect is unknown, and it is hoped that analysis of electrophysiological effects of vagal nerve stimulation will help elucidate which brain areas are affected. Stimulation of the left vagus nerve in the neck was accomplished with a programmable implanted stimulator. Effects of stimulus amplitude, duration, and rate were studied. Noncephalic reference recording of the vagus‐nerve‐evoked potential showed some unusual properties: a scalp negative component occurred with latency of 12 ms, very high amplitude (up to 60 μV), and widespread scalp distribution. Field distribution studies indicate that this potential is generated in the neck, in the region of the stimulating electrodes. Muscle paralysis confirms this observation. Stimulation at various frequencies had no noticeable effect on electroencephalographic (EEG) activity regardless of whether the patient was under general anesthesia, awake, or asleep.

Induction of Pseudoseizures with Intravenous Saline Placebo

Summary: For a 2‐year period, all patients admitted to the inpatient adult EEG videotelemetry unit of the University of Miami School of Medicine underwent attempted event induction with intravenous normal saline placebo. Of 175 patients monitored during that period, 101 underwent attempted placebo saline induction, whereas 58 patients were either in the pediatric age group, were undergoing a repeat hospitalization (i.e., depth electrode monitoring), or refused induction. The final diagnosis in each patient was established after re‐view of the history; physical, interictal, and ictal EEG findings; brain imaging studies; interictal and postictal brain single photon emission computed tomography (SPECT) and serum prolactin levels; psychiatric and psychological evaluations; and detailed neuropsychological testing. Final diagnoses were separated into epilepsy alone, pseudoseizures, epilepsy and pseudoseizures, and other (neither epilepsy nor pseudoseizures). No patient with an eventual diagnosis of epilepsy alone was inducible. Forty‐one patients with a diagnosis of epilepsy were not inducible. Of 32 patients with an eventual diagnosis of pseudoseizures, 29 were inducible. One of these 29 was also diagnosed with epilepsy. Three patients with aneventual diagnosis of pseudoseizures were not inducible; 90.6% of patients with an eventual diagnosis of pseudoseizures were inducible, i.e., had events identical to those reported by history, after injection of saline placebo. Placebo saline injection is a safe and effective means of distinguishing epilepsy from pseudoseizures.

Characteristics of patients with nonepileptic seizures

Abstract The personality features, neuropsychological data, and ictal characteristics of 23 patients with nonepileptic seizures (NES) were compared to 25 patients with EEG-confirmed epileptic seizure (ES) disorders. A distinctive pattern of seizure, behavior, and personality features was evident in NES patients. NES was characterized by later disease onset and shorter disease duration. NES tends to last significantly longer than ES and rarely results in tongue-biting or self-injury. Patients who develop NES frequently have witnessed seizures prior to developing the disorder and have greater somatic concerns than patients with ES. Neuropsychological group data failed to differentiate NES from ES. However, the absence of group differences may reflect heterogeneity within the NES population. Although many NES patients performed well within normal limits on all neuropsychological measures, most were mildly to severely impaired. Qualitative analysis of neuropsychological data also revealed inconsistencies within the NES group. These findings suggest that a more global neurobehavioral profile may be useful in the diagnosis of NES. Future studies of NES must also recognize that important individual differences may be masked within group data.

Topiramate in older patients with partial-onset seizures: A pilot double-blind, dose-comparison study

Purpose: Pharmacokinetics of antiepileptic drugs (AEDs) can be altered by age‐related changes in physiology, thereby altering clinical effects, especially tolerability, in older adults. We compared two dosages of topiramate (TPM) in a pilot study of patients ≥60 years of age with partial‐onset seizures.

Corpus Callosotomy for Seizures Associated with Band Heterotopia

Summary: Band heterotopia is a severe form of neuronal migration disorder associated with intractable epilepsy and neurologic impairment. Surgical treatment of seizures associated with this malformation has not been reported previously. We report a patient with band heterotopia and poorly controlled atonic seizures causing falls and injury. The patient was treated with anterior corpus callosotomy, with significant postoperative decrease in seizure frequency. Corpus callosotomy is a reasonable alternative to consider in management of patients with cortical heterotopia and intractable seizures.

Effects of Antiepileptic Drugs on Hormones

Summary: : A hormone is an intrinsic substance carried via the blood to a target organ which is then functionally stimulated. Similar to extrinsically administered medications, the metabolism and function of the hormones may be altered by antiepileptic drugs (AEDs). The proposed mechanisms are (a) enhanced metabolism (natural steroids, synthetic steroids, e.g., decadron and birth control pills, thyroxine, and vitamin D3), (b) altered protein bonding (thyroxine, sex hormones), (c) impaired release into the systemic circulation (calcitonin, insulin, vitamin K clotting factors) and (d) altered end‐organ effect. The AEDs most likely to interact with hormones are barbiturates, carbamazepine, and phenytoin.