Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy that typically begins in early childhood, often between the ages of 1 and 7 years of age.1 It is characterized as a childhood epileptic encephalopathy with at least two seizure types, cognitive and behavioral impairments, and electroencephalogram (EEG) pattern of diffuse slow spike-and-wave discharges and generalized paroxysmal fast activity.2 In LGS, tonic seizures are the most common seizure type; however, patients frequently experience atypical absence, myoclonic, atonic, and other seizure types. The coexistence of multiple seizure types with varying semiologies substantially increases the risk of physical injuries.2

The syndrome can arise from many causes, including structural, genetic, infectious, metabolic, or immune factors, with an identifiable etiology in 65–75 % of patients.2,3 LGS accounts for approximately 1 %–2 % of all individuals with epilepsy and represents about 3.6 % of all childhood epilepsies.2

Management requires both pharmacologic and non-pharmacologic strategies, with attention not only to seizure control but also to comorbidity care. Among the classic anti-seizure medications, first-line for LGS includes valproate, lamotrigine, and topiramate. While valproate is widely preferred for initial therapy, it has not been specifically licensed for use in LGS, unlike lamotrigine and topiramate which are authorized in Europe and the USA for adjunct treatment.4 Due to its resistant nature and low response to monotherapy, recommended adjunctive therapies include rufinamide, clobazam, and felbamate.5 Epidiolex has also been approved for use in treatment-resistant epilepsies, like LGS, in the USA. Additionally, non-pharmacologic strategies have also been recommended in treatment resistant settings. Strategies include implementing the ketogenic diet, surgery, and neurostimulation.4 However, while necessary for attempting seizure control, these medications carry significant side effects such as cognitive and behavioral changes, aplastic anemia, and liver failure.5 The need for multiple treatments increases medical complexity and can be a source of significant burden to caregivers and disruptive to activities of daily living. A multidisciplinary, individualized approach is essential to optimize outcomes and improve quality of life (QoL).

Individuals with LGS face numerous comorbidities in addition to refractory seizures, including cognitive and intellectual disabilities, developmental delays, motor impairments, behavioral problems, psychiatric disorders, feeding difficulties, and sleep disturbances.6 LGS is also associated with increased mortality, often resulting from seizure-related injuries, status epilepticus, or sudden unexpected death in epilepsy (SUDEP). These comorbidities significantly impair QoL and long-term development. In this review, we examine neurodevelopmental, epilepsy-related, motor, and systemic comorbidities in LGS, emphasizing their contribution to disease burden, functional impairment, and quality of life.