Knowledge on rare diseases and orphan drugs

The incidence of Lennox-Gastaut syndrome (LGS) is estimated at 0.1 to 0.28 per 100,000 people per year, the lifetime prevalence at the age of ten years amounts to 0.26 per 1000 children. Although rare, it represents 1-10% of childhood epilepsies, and 1-2% of all epilepsy patients. Males are slightly more affected.

Characteristic seizure types include atypical absences and tonic seizures during sleep, but atonic seizures during wakefulness, myoclonic, tonic-clonic, and focal seizures as well as non-convulsive status epilepticus commonly occur. Tonic, myoclonic, or atonic seizures can lead to sudden falls (drop attacks). The interictal EEG typically shows slow spike-wave complexes (< 3/s), paroxysmal fast rhythms (10-20/s) during non-REM (rapid eye movement) sleep, and a slowing of the background activity. The disease begins mostly between 3 and 5 years of age and the full triad develops over time. In more than half of the patients, intellectual impairment is present at disease-onset and worsens over time. Behavioral problems are commonly observed and may complicate the treatment.

The etiology is heterogeneous including prenatal or perinatal infarctions, central nervous system infections, metabolic disorders, traumatic lesions, and cortical malformations. Genetic de-novo mutations are increasingly identified, such as in GABRB3 (15q12), CHD2 (15q26.1) DNM1 (9q34.11), SCN1A (2q24.3), MAPK10 (4q21.3), CUX2 (12q24.11-q24.12), and CACNA1A (19p13.13). LGS can evolve from early epileptic encephalopathies like West syndrome. In about one fourth of cases, the etiology remains unclear.

The presence of typical clinical features and EEG abnormalities confirms the diagnosis. Magnetic resonance imaging identifies structural abnormalities in more than two thirds of the patients. Genetic testing helps to distinguish between LGS and other disease entities and should be performed in selected cases (e.g. suspected tuberous sclerosis complex, late infantile neuronal ceroid lipofuscinosis, ring chromosome 20 syndrome).

In principle, all epilepsies with frequent and brief motor seizures occurring in childhood may be considered; the most relevant differential diagnoses include myoclonic atonic epilepsy, Dravet syndrome, and focal epilepsies with secondary bilateral synchrony.

If a monogenetic etiology is suspected, genetic counseling is recommended.

Seizures in LGS are difficult to treat and the treatment should aim to improve the quality of life and reduce the burden of seizures with falls. Sodium valproate is recommended as a first line anti-seizure medicine. Randomized controlled trials with lamotrigine, felbamate, clobazam have demonstrated efficacy in all seizure types. The use of felbamate is limited by adverse side effects. Topiramate, rufinamide, and cannabidiol proved effective in reducing drop attacks. Other anti-seizures medicines levetiracetam, zonisamide, perampanel as well as a ketogenic diet, vagus nerve stimulation, corpus callosotomy, and resective brain surgery in candidate cases, should be considered. In some cases, seizure worsening was reported with carbamazepine, lacosamide, oxcarbazepine, phenytoin, and vigabatrin.

The prognosis of children with LGS is poor. 80-90% of the patients have recurrent seizures and the mortality rate is 14 times higher than in the general population, mainly due to epilepsy-related events (e.g. status epilepticus, sudden unexpected death in epilepsy). Cognitive and behavioral problems are present in nearly all affected individuals. The severity of the disease has a significant impact on family members.

Last update: April 2021 - Expert reviewer(s): Pr Alexis ARZIMANOGLOU | EpiCARE* - Pr Rima NABBOUT | EpiCARE* - Pr Rainer SURGES | EpiCARE*

* European Reference Network