Developmental and/or Epileptic Encephalopathy with Spike-Wave Activation in Sleep: From Thalamocortical Mechanisms to Precision Therapy

Developmental and/or epileptic encephalopathy with spike-wave activation in sleep (D/EE-SWAS), previously described as continuous spike-wave during slow-wave sleep (CSWS) or electrical status epilepticus in sleep (ESES), is a childhood-onset disorder characterized by cognitive, language, behavioral, and/or motor regression or stagnation associated with marked activation of epileptiform discharges during non-rapid eye movement sleep. Three themes are central to the evolving understanding of D/EE-SWAS. First, it is a network disorder in which thalamocortical dysfunction, impaired sleep-dependent synaptic homeostasis, and potentially neuroinflammatory mechanisms contribute to neurodevelopmental deterioration. Second, increasing recognition of its genetic and structural heterogeneity is reshaping diagnostic evaluation. Monogenic etiologies are identified in up to one-third of cases, with a higher yield in the developmental and epileptic encephalopathy subtype, supporting early genomic testing alongside prolonged sleep EEG, MRI, and serial neuropsychological assessment. Third, treatment remains empiric and constrained by limited comparative evidence. Corticosteroids retain the strongest evidence base for cognitive improvement, although the overall certainty of this evidence remains low to moderate. Benzodiazepines are commonly used alternatives, and epilepsy surgery can provide substantial benefit in appropriately selected patients with focal structural abnormalities. Emerging etiology-directed therapies, including L-serine for selected GRIN loss-of-function variants and primidone for TRPM3-related disease, illustrate a broader transition from syndrome-based to precision management. However, no pharmacological therapy is specifically approved for D/EE-SWAS, long-term neurodevelopmental morbidity remains common, and adequately powered trials using standardized EEG and neurocognitive outcomes are urgently needed.