Sodium valproate enteric-coated tablets were administered as monotherapy to 118 patients (median age, 19 years) with primary generalized epilepsies. More than half (56%) of these patients were transferred from prior drug therapy, most of them because of inadequate seizure control, and some because of adverse effects. Seventy-one percent of the patients experienced tonic-clonic seizures, either alone or in combination with other types of seizures, principally absences. Mean duration of follow-up was 18 months (median, 17 months; range, 1-68 months). At a mean daily dosage of less than 20 mg/kg, 83% of the patients became seizure-free. Therapy was equally effective against tonic-clonic seizures, absences, and myoclonic seizures. Tonic-clonic seizures were suppressed in 85% of cases (89% when patient had only one seizure type), absences in 82% (95% when patient had only one seizure type), and myoclonic seizures in 82%. Paroxysmal activity was present in 88% of the electroencephalogram (EEG) records before valproate monotherapy, and in 32.4% at the study's end. These results were achieved with generally mild and mostly transient side effects; side effects were reported by 16% of patients during the first month, and 2% at the last follow-up. No hematologic or hepatic toxicity was observed. The lag time between attaining steady-state serum concentrations and achieving maximal clinical improvement suggests that sodium valproate monotherapy should be given an adequate trial to ensure that patients derive the greatest possible benefit before adding or switching to another drug.
Summary: In 45 patients suffering from secondary generalized epilepsy, we have recorded 239 drop seizures both by radio‐telemetered EEG/split‐screen video taping and poly‐graphically. Twenty of these patients had pure tonic drop seizures. Nine patients each had myoclonic‐atonic or pure atonic seizures, whereas seven had slow falls that occurred during gradually developing tonic or akinetic seizures. We term the pure tonic drop seizure “axial spasm.” It consists of a uniform pattern of movement lasting from 0.5 to 0.8 s and leading to a specific bearing characterized by a moderate flexion of the hips, the upper trunk, and the head. The arms are almost always involved being abducted, elevated and in a semiflexed position. A fall is provoked by the rapidity and violence of the flexion in the hips. The spasms can occur independently (pure axial spasm) or in connection with other seizure manifestations (combined axial spasm). In pure spasms, no disturbance of consciousness and no significant EEG changes—apart from a slight attentuation—are seen. In the combined axial spasms, distinct epileptic phenomena, in close connection with the axial spasms, can be observed, appearing either in the postspasm phase or in both the pre‐ and the afterphases. The prephase consists always of an absence and spike‐and‐wave activity. The onset of the spasm coincides with the last generalized spike, which is followed by a biphasic high‐voltage slow wave. In the afterphases, various seizure patterns can be seen; quite characteristic are arrest states during which the patients are completely immobile and take up a postural‐like or athetoid position. Almost as frequent are absences or absence‐like states and tonic seizures. The afterphase can be compounded by two or three of these seizure patterns, the most common sequence of events in these cases being tonic—arrest state—absence. From the clinical and neurophysiological points of view, axial spasms can be regarded as a more mature form of infantile spasms. Clinical and experimental findings suppose a brainstem origin. ZUSAMMENFASSUNG Bei 45 Patienten mit sekundärer generalisierter Epilepsie haben wir in den letzten Jahren 239 Sturzanfälle abgeleitet, 174 radio‐telemetrisch mit Video im Doppelbild‐Verfahren, 65 polygraphisch. Bei 20 Patienten waren die Sturzanfälle rein tonisch, bei je 9 Patienten myoklonisch‐atonisch oder rein atonisch. 7 Patienten hatten langsame Stürze, welche im Verlauf allmählich sich entwickelnder tonischer oder bei akine‐tischen Anfällen auftraten. Die tonischen Sturzanfälle, die wir als axiale Spasmen bezeichnen, beruhen auf einem gleichförmigen Bew‐egungsmuster von 0.5–0.8 Sekunden Dauer. Der axiale Spasmus führt zu einer charakteristischen Haltung mit mässiger Flexion der Hüftge‐lenke, des oberen Rumpfs und des Kopfes. Die Arme sind fast immer beteiligt. Sie werden in Semiflexions‐Stellung abduziert und bis auf Schulterhöhe eleviert. Die rasante Flexion in den Hüftgelenken ist für den Sturz verantwortlich. Zwei Formen axialer Spasmen können unterschieden werden: 1....
A patient with advanced progressive myoclonic epilepsy (Unverricht type) with Lafora bodies is presented. Although the clinical history and symptoms were classical, the regional distribution of the cerebral involvement differed from the classical picture: the corpora mamillaria, the nucleus subthalamicus, and the nucleus ruber, which are normally reported to be spared, contained multiple Lafora bodies, whereas the lateral geniculate body, which is usually involved, was intact. The number of inclusions per cell, up to 25, was extremely high and correlated with the marked cortical atrophy and the prolonged clinical course. Using electron microscopy, type I and type II Lafora bodies were found, but the latter lacked the typical filamentous ultrastructure in the peripheral zone. The lack of visceral Lafora bodies in this case suggests that liver, muscle, and skin biopsies, which are widely used for the diagnosis, may lead to false negative results and cannot always replace a stereotactic brain biopsy. The differential diagnosis on polyglucosan bodies is emphasized.
Stereoselective metabolism has been demonstrated for mephenytoin (MHT), R-MHT being demethylated to the pharmacologically active metabolite 5-phenyl-5-ethylhydantoin (PEH; nirvanol), and S-MHT undergoing aromatic hydroxylation to 4-OH-MHT, with formation of an intermediate arene oxide metabolite. PEH is responsible for the therapeutic effect, whereas 4-OH-MHT is rapidly eliminated by the kidneys. The arene oxide metabolite may have implications in MHT toxicity. The metabolism of PEH is also stereospecific. In the present study, the R-enantiomer of PEH (R-PEH; R-normephenytoin) was administered chronically during 8 weeks to four epileptic patients, as a single dose every 3 days. The half-lives of R-PEH ranged from 77.7 to 175.8 h, and correlated closely with the creatinine clearance. Mean urinary recovery of R-PEH was 86.6% of the dose at steady state, with 4-OH-PEH accounting for only 5%. This indicates that, unlike Nirvanol (a racemic mixture of R- and S-PEH), R-PEH is only minimally metabolized, even after several weeks of treatment and despite potential enzymatic autoinduction and heteroinduction by other antiepileptic drugs. Complete blood counts and liver function tests revealed no alteration, and no other adverse effects were noted. If arene oxide intermediate metabolites are indeed involved in the toxicity of MHT and nirvanol, R-PEH may represent a safer alternative.
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