Drug Treatment of Progressive Myoclonic Epilepsy

Abstract

The progressive myoclonic epilepsies (PMEs) represent a rare but devastating group of syndromes characterized by epileptic myoclonus, typically action-induced seizures, neurological regression, medically refractory epilepsy, and a variety of other signs and symptoms depending on the specific syndrome. Most of the PMEs begin in children who are developing as expected, with the onset of the disorder heralded by myoclonic and other seizure types. The conditions are considerably heterogenous, but medical intractability to epilepsy, particularly myoclonic seizures, is a core feature. With the increasing use of molecular genetic techniques, mutations and their abnormal protein products are being delineated, providing a basis for disease-based therapy. However, genetic and enzyme replacement or substrate removal are in the nascent stage, and the primary therapy is through antiepileptic drugs. Epilepsy in children with progressive myoclonic seizures is notoriously difficult to treat. The disorder is rare, so few double-blinded, placebo-controlled trials have been conducted in PME, and drugs are chosen based on small open-label trials or extrapolation of data from drug trials of other syndromes with myoclonic seizures. This review discusses the major PME syndromes and their neurogenetic basis, pathophysiological underpinning, electroencephalographic features, and currently available treatments.

Figure 1.

Schematic diagram of neuronal substrates involved in generalized seizures [22]. The key neuronal ensembles consist of the pyramidal cells (PC) and interneurons (IN) in the cortex and the thalamocortical relay cells (TC) and nucleus retularis thalami cells (NRT) in the thalamus. The model involves two dependent inhibitory neural populations IN1 and IN2 which are mediated by the fast and slow time scales of the inhibitory receptors GABA(A) and GABA(B), respectively. Excitatory synaptic connections are shown in red lines with arrows. Inhibitory synaptic connections are shown in green lines with arrows as well as closed circles, where solid and dashed ones represent the fast and slow synaptic function mediated by the GABA(A) and GABA(B), respectively.

Figure 2.

Examples of spike-and-wave discharges seen during myoclonic seizures in three children with PME. Note the generalized, irregular bursts of spike- and polyspikes and wave discharges during the myoclonus. Morphology, frequency and duration of the epileptiform discharges are not syndrome specific.

Fig. 3.

EEG from patient with Unverricht-Lundborg disease. EEG demonstrates mild slowing of the background with irregular spike-wave activity as designated by the (asterisk). Myoclonus occurred with and without spike-wave discharges.