Gelastic seizures and the hypothalamic hamartoma syndrome: Epileptogenesis beyond the lesion?

Abstract The clinicoradiologic syndrome of hypothalamic hamartoma (HH) manifests with a variety of symptoms, including pharmacoresistant epilepsy with multiple seizure types, precocious puberty, behavioral disturbances, and cognitive impairment. Gelastic seizures are an early marker of epilepsy with HH in most of the cases. Despite a high variability, two major epilepsy phenotypes can be distinguished, based on electroclinical features: (i) focal seizures with epigastric or deja-vu aura, loss of consciousness, and oroalimentary or gestural automatisms suggestive of temporal lobe involvement; and (ii) motor seizures with tonic, atonic, myoclonic, or versive phenomena, suggesting frontoparietal network involvement, with possible evolution toward an epileptic encephalopathy. The underlying physiopathologic mechanisms are not completely elucidated. The well-known intrinsic epileptogenicity of the HH represents the rationale for direct HH-aiming surgical procedures, with variable success in achieving seizure freedom. The concept of kindling-like secondary epileptogenesis has been suggested as a possible putative mechanism since the very beginnings of the hamartocentric era. Accordingly, a cortical area with enhanced epileptogenic properties due to an independent stage of secondary epileptogenesis would be responsible for seizures persisting after hamartoma ablation. However, recent intracerebral stereotactic EEG (SEEG) explorations demonstrated more complex, both reciprocal and hierarchical, relationships within the hypothalamo-cortical epileptogenic networks. Network formation may be due to either secondary epileptogenesis or widespread epileptogenicity present at the outset. A short time window from epilepsy onset to surgery seems to be crucial to cure epilepsy by direct surgery addressing a hamartoma. SEEG exploration may be reasonably proposed in cases where clinical data suggest an extension of the epileptogenic zone outside the limits of the HH, especially in focal seizures with impaired awareness and absence of gelastic seizures, or after a failure of the direct HH-aiming procedure.