Dezinamide for partial seizures: results of an n-of-1 design trial.

BACKGROUND: Dezinamide (DZM, ADD 94057) is a potential antiepileptic drug that binds to the voltage-sensitive sodium channel and showed preliminary evidence of efficacy and safety in an open-label study. METHODS: Our double-blind, placebo-controlled trial at two sites used an n-of-1 (single-patient) design. All 15 patients had medically intractable partial-onset seizures and were comedicated with phenytoin (PHT) only. Treatment was for six 5-week periods (three active paired with three placebo in random sequence). Assuming nonlinear kinetics, we used an initial pharmacokinetic profile to estimate dosages for reaching target plasma concentrations of DZM. RESULTS: Statistically significant seizure reduction was found by both a randomization test (p = 0.0025) and a signed rank test (p = 0.048). Median seizure frequency decreased 37.9%, and 40% of patients had > 50% seizure reduction, both compared with placebo. Pharmacokinetic predictions were not accurate; mean plasma concentrations fell well below target values. Plasma PHT concentrations increased (mean = 17.1%) during DZM treatment. The most common adverse experiences were fatigue, light-headedness, and abnormal gait; five patients required DZM dosage reductions. CONCLUSIONS: DZM showed minimal clinical toxicity and significant efficacy despite lower plasma concentrations than predicted by pharmacokinetics. This trial establishes the suitability of the n-of-1 design to investigational antiepileptic drug trials.

Self-abatement of simple partial epileptic seizures.

Two patients with simple partial epileptic seizures were able to abate their attacks by vigorous somatosensory stimulation of the body part initially involved by the seizure. In both patients, the seizure symptoms progressed in a marching fashion which suggests a gradual spread of the epileptic discharge from its initial locus to adjacent areas.

Barbiturate-related connective tissue disorders.

Development of Dupuytren's contractures, frozen shoulder, Ledderhose's syndrome, Peyronie's disease, fibromas, and general joint pain has been linked in retrospective studies and case reports to the use of antiepileptic drugs. We undertook a prospective survey of the incidence of connective tissue disorders in 622 patients newly treated with carbamazepine, phenobarbital, phenytoin sodium, or primidone. Ten of the 406 patients who were treated for 6 months or more developed connective tissue disorders. All affected patients were taking a barbiturate (primidone, 4 patients; phenobarbital, 6 patients). Seven of the 10 problems occurred during the first year of treatment. These data are prospective evidence of a statistically significant relationship between barbiturate use and the development of connective tissue disorders, and timing of appearance.

Treatment of amyotrophic lateral sclerosis with the TRH analog DN-1417.

Thyrotropin-releasing hormone has been reported to increase strength in patients with amyotrophic lateral sclerosis (ALS). DN-1417 is an analog of thyrotropin-releasing hormone, which has less endocrinologic activity, but more anterior horn cell stimulating effect (with no "autorefractory state"). However, 2 mg DN-1417, IM twice a day for 1 month in an open-label trial, produced no objective improvement of strength in nine patients with ALS. No patient entered the double-blind, placebo-controlled phase of the trial.

Periodic lateralized epileptiform discharges in asphyxiated neonates.

Electrographic seizures (EGS) were detected in 13 of 16 asphyxiated neonates who were undergoing continuous electroencephalographic monitoring for detection of evidence of central nervous system injury. Five of the 13 neonates with EGS also had periodic lateralized epileptiform discharges (PLEDs). The electrographic characteristics of PLEDs in these infants were similar to those reported in neonatal herpes simplex encephalitis and in older children and adults. Of the 5 neonates with PLEDs, 2 died, 2 are developmentally delayed and only 1 is normal at 12 months. This is in contrast to the normal outcome for 8 of the 11 infants who did not have PLEDs. One other was neurologically normal but died of pulmonary disease at 3 months and the other two were developmentally delayed. PLEDs in neonates, as in other age groups, lack diagnostic specificity, but when associated with neonatal asphyxia, may indicate a poor prognosis. Continuous EEG monitoring is helpful in identifying PLEDs in these cases.

Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures.

We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic-clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P less than 0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic-clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete control of partial seizures more often than primidone or phenobarbital (P less than 0.03). Overall, carbamazepine and phenytoin are recommended drugs of first choice for single-drug therapy of adults with partial or generalized tonic-clonic seizures or with both.

Verbal learning differences in epileptic patients with left and right temporal lobe foci.

A verbal learning test patterned after and using the same format as the Rey Auditory-Verbal Learning Test was administered to the following three groups: (1) patients with left temporal lobe epilepsy (L-TLE) as defined by EEG criteria (n = 11); (2) patients with right temporal lobe epilepsy (n = 10); and (3) normal controls (n = 11). Performance was highly similar for all three groups during the five immediate recall learning trials. The performance of the L-TLE group, averaged across three delayed recall trials (free recall, phonemic cued recall, semantic cued recall), was significantly poorer than that of the other two groups. The L-TLE group showed the worst performance on the phonemic cued recall trial, poor performance on the delayed free recall trial, and relatively intact performance on the semantic cued recall trial. Immediate and delayed free recall and phonemic and semantic cued recall for the distractor list did not discriminate groups. Word frequency, word presentation order, and concrete versus abstract words did not have different effects across groups.

EEG spectra following phenytoin infusion in seizure patients.

Diphenylhydantoin (DPH) kinetics were studied in five male patients with poorly controlled seizures. EEG recordings were taken on four of the patients immediately prior to and 30 minutes following a 60 minute i.v. infusion of phenytoin sodium. Mean phenytoin levels following post-infusion EEG recordings were 17.1 mg/L. Spectral analysis revealed that phenytoin produced a decrease in the variance of EEG spectral power as a function of time in frequencies between 8-18 Hz. This decrease in the variance of the time series of EEG spectra suggests increased EEG stability and may represent an electrographic marker of the anticonvulsant action of phenytoin.

Physiologic and prognostic significance of "alpha coma".

A patient with posthypoxic "alpha coma" is described whose EEGs were recorded before coma, within two hours following the onset of coma and after recovery. The differences observed between the alpha activity during coma and that seen before and after suggest that the alpha activity during coma and the physiologic alpha rhythm are different phenomena. This case, as well as others reported, also suggests that "alpha coma" resolving in the first 24 hours following hypoxia may have a better prognosis than "alpha coma" detected after the first day, and stresses the need for EEG monitoring begun in the immediate period following hypoxia in order to assess accurately the prognostic significance of this EEG pattern in the early stages of postanoxic encephalopathy. The aetiology of "alpha coma" also affects outcome. The survival rate appears higher in patients with respiratory arrest than in those with combined cardiopulmonary arrest.

Capsular ataxic hemiparesis.

Left hemiparesis and left-sided ataxia developed in a 67-year-old man. Computed tomography (CT) showed an area of decreased attenuation in the anterior part of the rostral posterior limb of the right internal capsule that enhanced with contrast. As the patient's condition improved, the contrast enhancement resolved. The clinical course combined with the changes in CT scans indicates that the responsible lesion was an infarct. This report suggests that ataxic hemiparesis can result from an infarct of the posterior limb of the internal capsule.

Grating contrast detection perimetry in a patient with occipital lobe epilepsy.

A new perimetry technique is based upon detection of faint gratings. This method permits assessment of visual field abnormalities that are not detectable by Goldmann perimetry or tangent screen examination. These abnormalities occurred in a 57-year-old man with a seizure disorder of left occipital origin. The technique may have advantages over conventional field study methods for the early detection of geniculocalcarine pathology.

Electrographic and clinical effects of intracarotid sodium amobarbital on bilateral myoclonic status epilepticus.

The effects of rapid intracarotid injection of 20 to 100 mg of sodium amobarbital were studied in three patients with bilateral myoclonic status epilepticus due to Jakob-Creutzfeldt disease, sequelae to anoxic encephalopathy, and hepatic coma, respectively. In each instance, the drug produced prompt abatement of clonic jerks contralaterally and attenuation of electroencephalographic epileptiform discharges ipsilaterally. These results suggest that the cerebral cortex actively participates in the elaboration of certain types of bilateral myoclonus in human beings.