Knowledge on rare diseases and orphan drugs

The actual prevalence is unknown because of previous heterogeneous definitions and late recognition. Developmental (D)EE-SWAS has been estimated to account for 1% of childhood-onset epilepsies; LKS accounts for a small subgroup.

LKS only affects children and adolescents. The age of onset ranges from 4 to 8 years, but can be as early as 2 and late as 12 years of age. The previous development of language is typically normal but language delay may be present. Acquired aphasia in childhood is the defining feature of this disorder and it usually presents as auditory verbal agnosia without any hearing impairment. Expressive aphasia follows the receptive aphasia and spontaneous speech becomes limited. Behavioral problems such as attention deficits, hyperactivity, impulsivity, and distractibility often accompany the language regression. Seizures occur in 2/3 of patients, are sporadic in most cases, often easy to control, and remit spontaneously before or during adolescence. Seizure types observed include focal motor (most common), generalized clonic and atypical absence. The disease course is initially progressive with spontaneous fluctuations in severity over time.

The etiology is heterogeneous, and remains often unknown. Structural brain lesions are infrequently seen in LKS patients, unlike (D)EE-SWAS. Genetic variants may be found; GRIN2A (16p13.2) variants appear to be causal in this phenotype. A variety of other genetic variants are reported, including ZEB2, CNKSR2 and chromosome 17q21.31 deletions, each of which demonstrated unique clinical characteristics, EEG patterns, and age of onset.

Diagnosis must be based on neuropsychological assessment, including language evaluation, and sleep electroencephalogram (EEG). The EEG pattern shows a (uni- or bilateral) spike wave activation during non-REM sleep that can occupy > 85% of the tracing but may be much lower. Usually, the localization of spike and waves focus is temporal and bilateral, observed during wakefulness and activated during sleep, with or without bilateral synchronization. Genetic testing is part of the diagnostic workup.

The differential diagnosis includes any epilepsy syndrome with sleep activation of epileptiform activity (e.g. SeLECT, SeLEAS, autism spectrum disorders and intellectual disability of different etiologies); caution is needed not to over-diagnose LKS in the absence of acquired clear and persisting aphasia. Patients bearing GRIN2A variants may present with LKS or other phenotypes with focal epilepsy and preexistent severe expressive language disorder (verbal dyspraxia), but without language regression.

Variants are found de novo in the majority of cases. Transmission and recurrence risk depend on the variant identified.

Seizures are usually well controlled by anti-seizure medications. Carbamazepine, oxcarbazepine, phenytoin and phenobarbital should be generally avoided due to a risk of exacerbation of the electro-clinical picture. Corticosteroids treatment may be required to improve or stabilize the language abilities. Epilepsy surgery with subpial transections is currently unavailable in most centers due to limited evidence of its efficacy. Intensive rehabilitation with a speech therapist is recommended, with the transient use of nonverbal communication. Special education adapted to children with language disorders or impaired hearing may be necessary. Periodic neuropsychological and sleep EEG assessments with an expert team are necessary to adapt the therapeutic management.

Both seizures and activation of the EEG abnormalities during sleep remit spontaneously around puberty. Language has variable improvement with treatment, but may not return to the pre-disease state. The final prognosis is influenced by type and timing of the treatment, pre-disease cognitive development, duration of the symptoms, and genetic etiology (if present).

Last update: October 2024 - Expert reviewer(s): Dr Anne DE SAINT-MARTIN | EpiCARE* - Dr F.E. [Floor] JANSEN | EpiCARE* - Pr Patrick VAN BOGAERT | EpiCARE*

* European Reference Network