Hypothalamic hamartoma: basic mechanisms of intrinsic epileptogenesis.

The hypothalamic hamartoma (HH) is a rare developmental malformation commonly associated with gelastic seizures that are notoriously refractory to medical therapy. Recent evidence supports the intrinsic seizure propensity of HH. Despite increasing clinical recognition of this condition, the mechanisms of seizure genesis in HH tissue remain unclear. This review summarizes the histochemical and electrophysiological properties of HH neurons, and relates these findings to those characteristics identified in other types of epileptic tissue. Initial studies have revealed two distinct populations of neurons in surgically resected HH tissue. One group consisted of small gamma-aminobutyric acid (GABA)-expressing neurons that occurred principally in clusters and displayed spontaneous rhythmic firing. The second group was composed of large, quiescent, pyramidal-like neurons with more extensive dendritic and axonal arborization. We propose that the small, spontaneously firing GABAergic neurons send inhibitory projections to and drive the synchrony of large output neurons. These observations constitute the basis for future investigations aimed at elucidating the mechanisms of subcortical epileptogenesis.

The histopathology of hypothalamic hamartomas: study of 57 cases.

Hypothalamic hamartomas (HHs) are rare developmental tumors that cause seizures or pituitary axis dysfunction, usually beginning in childhood. We analyzed HH tissue from 57 patients whose tumors were resected through recently developed transcallosal interforniceal and transventricular endoscopic surgical approaches. All cases were composed of abnormally distributed but cytologically normal neurons and glia, including fibrillary astrocytes and oligodendrocytes. Neuronal elements predominated in most cases, but a relative increase in astrocytic elements was seen with increasing age. All had various sized nodular foci of neurons as well as areas of diffusely distributed neurons with interspersed glial cells. Smaller neurons predominated, and most cases had only a few interspersed large ganglion cells. Immunohistochemistry demonstrated extensive production of synapse-associated proteins. Immunohistochemistry for phosphorylated and nonphosphorylated neurofilament and alpha-internexin demonstrated staining patterns consistent with mature neurons. In contrast to cortical dysplasia, atypical large ganglion-like balloon cells were almost never seen. In summary, although their number and distribution vary, mature smaller neurons were the most prominent and most consistent histologic feature of HH. Nodules of these small neurons were a universal feature of the microarchitecture of HH lesions associated with epilepsy. Characterization of these neurons may aid in understanding the mechanism of seizure development in HH.