Myoclonic-astatic epilepsy (ORPHA:1942)
A rare, childhood onset epilepsy syndrome characterized by multiple seizure types including myoclonic-atonic (MA) seizures that occur usually in previously healthy children.
Epidemiology
The prevalence is estimated at 1-2% of all childhood epilepsies with a sex ratio of 2.7-3.1:1 males to females.
Clinical description
Onset is between 2-5 years (peak 3-4 years), occurring typically in normally developing children. In 20 % of patients, simple febrile seizures have occurred before onset. Generalized tonic-clonic seizure (GTCS) is usually the first seizure type. After days to months, additional myoclonic, atonic and/or myoclonic-atonic seizures and atypical absences occur with increasing frequency until a ''stormy phase''. MA seizure consists of proximal muscle myoclonic jerks followed by an atonic phase. Brief tonic seizures may be seen in some patients. Children often display a non-convulsive status epilepticus (NCSE) with episodes of drowsiness, gait impairment and erratic myoclonus, which may last hours to days.
Etiology
Etiology is unknown in the majority of cases and a polygenic inheritance is suspected. The most common monogenic causes include SLC6A1 (3p25.3), CHD2 (15q26.1), AP2M1 (10q23.2). Other causal variants reported include SLC2A1 (1p34.2), SCN1A (2q24.3), SYNGAP1 (6p21.32), KCNA2, and NEXMIF (Xq13.3).
Diagnostic methods
Diagnosis is based on history, seizure semiology, neurologic examination and electroencephalogram (EEG) findings. EEG may be normal at onset or display a slowing of the background activity and generalized 2-3 Hz spike-wave discharges. Myoclonic, atonic and MA seizures can cause drops, and video-EEG with electromyogram (EMG) of deltoids and neck is essential to differentiate them from other seizures types (tonic, epileptic spasms). Neuroimaging is normal. Genetic and metabolic testing should be performed if differential diagnosis is suspected, and when clinical features are suspicious for a specific genetic mutation. Intermittent photic stimulation at low frequencies should be systematically performed during EEG to exclude neuronal ceroid lipofuscinosis type 2 (CLN2 disease).
Differential diagnosis
Dravet disease differs by earlier onset and prolonged febrile seizures. Myoclonic epilepsy of infancy also occurs earlier and displays brief myoclonic seizures as the single seizure type; Lennox-Gastaut syndrome is frequently associated with structural/metabolic etiology and tonic seizures in sleep and atypical absences as the main seizure types. CLN2 disease, with onset in the same age range, is the other important differential diagnosis.
Genetic counseling
Patients with an identified de novo variant and families with a known genetic mutation can benefit from genetic counseling.
Management and treatment
Even in children with a favorable clinical course, seizures can be initially resistant to anti-seizure medicines (ASMs). Broad spectrum ASMs are recommended, often a bi or tri-therapy is needed: sodium valproate, combination of sodium valproate with lamotrigine (synergistic effect), levetiracetam, ethosuximide (especially if myoclonic seizures are prominent). Other alternatives are zonisamide, topiramate, clobazam or clonazepam. Ketogenic diet is the most effective therapy in myoclonic-astastic epilepsy (> 50% seizure reduction in 50-90% of cases) and is recommended as soon as the first line ASMs fail. Vigabatrin and sodium channel blockers like carbamazepine or phenytoin are contraindicated as they worsen seizures. Benzodiazepines or steroids are suggested for treating NCSE. Few cases have undergone epilepsy surgery (corpus callosotomy, vagal nerve stimulator).
Prognosis
Outcome is variable. 60% of patients evolve with normal cognition or a mild cognitive delay. Cognition and behavior are impaired in unfavorable cases where seizures persist after 3 years of evolution. NCSE, tonic seizures, atypical absence seizures and epileptic encephalopathy are risk factors of unfavorable outcome.

                            Last update: 
                            April 2021


                            - Expert reviewer(s): 
                            Dr Nicolas JANNONE-PEDRO | EpiCARE* - Dr Anna KAMINSKA | EpiCARE* - Dr Vicente VILLANUEVA | EpiCARE*


                                * European Reference Network