The syndrome of hypothalamic hamartoma (HH) with gelastic (laughing) seizures (GSs) is a rare but important epileptic syndrome (HHGS), being one of the most refractory, disabling, and poorly understood seizure disorders affecting children and adults. Over the last decade, much has been learned about the nature of HH and its often progressive neurologic and behavioral manifestations, and effective surgical treatments have also been developed.

Le Marquand and Russell⁴⁴ first used the term hamartoma in 1934 to describe a tumor-like lesion of the hypothalamus found at postmortem in a boy with precocious puberty. Chronic epilepsy associated with a hypothalamic lesion, designated an astrocytoma but likely an HH, was first reported 2 years earlier⁸⁶ in a boy with precocious puberty and mental retardation who died from status epilepticus. The first report of GS in a patient with HH was in 1938,¹⁸ the patient also having precocious puberty and pervasive developmental delay. Isolated reports of probable or proven HH with gelastic seizures followed.^{27,45,50,59,60,66,78} In 1988, the association was better characterized by Berkovic et al. as a recognizable and possibly progressive epileptic syndrome, their series incorporating neuroimaging diagnosis.⁴ The first report of a patient surviving surgical resection of an HH was in 1967,⁵⁹ but it was not until the mid-1990s that GSs were shown conclusively to arise in the HH^39,41,54 and surgical treatment for refractory seizures flourished. Over the last 10 years, there has been great interest in the nature of HH and its association with GSs, and great efforts in developing minimally invasive surgical techniques for treatment of the refractory seizure disorder. For further details concerning GSs, see Chapter 53.

A hamartoma is a focal malformation that resembles a neoplasm, composed of an abnormal mixture or proportion of tissue elements normally present in that site, which develop and grow at virtually the same rate as normal tissue.⁷¹ HHs are usually spherical in shape with a diameter between 0.5 and 4 cm, in most cases <1.5 cm. HHs arise from the tuber cinereum or from one or both mammillary bodies, and if large, may bulge into the third ventricle and compress (but not disrupt) the hypothalamic nuclei and fiber tracts.⁴⁵ Asymmetric location and attachment are seen in about two thirds of patients.²¹

Several anatomic classifications of HH based on magnetic resonance imaging (MRI) features have been proposed, distinguishing different sizes and patterns of hamartoma attachment to the hypothalamus.^1,8,15,85 The most important separation from clinical, pathophysiologic, and surgical perspectives seems to be the distinction between HHs sitting within the third ventricle that are attached to the mammillary bodies and/or the hypothalamic walls (sessile, intraventricular, intrahypothalamic) from those HHs beneath the third ventricle with attachment to the tuber cinereum (pedunculated, extraventricular, parahypothalamic). HHs associated with epilepsy are almost always intraventricular, at least in part, with a significant mammillary body attachment.

Histologically, HHs resemble normal gray matter,⁵⁷ though some neurons may show variation in size and shape^{8,14,37,59,62,75} and may appear in discrete nests or nodules of cells.^8,29,59 Fibrillary gliosis is also found,⁸ and cystic changes have been observed in large lesions.⁷⁰ Dysplastic neurons and balloon cells are not seen in HHs.

HHGS is an uncommon epileptic syndrome, with a prevalence in childhood of about 0.5 in 100,000.⁹ Most early reports of HHs were in patients with central precocious puberty,⁹¹ but most recent reports concern HHs and GSs. The current literature is biased toward surgical patients with severe seizure and other neurologic manifestations, making it hard to determine the proportion of patients with different clinical features. Also, it is likely that there are patients with HHs who are asymptomatic or have only mild or undiagnosed seizure manifestations,⁸¹ leading to underreporting of HH. A greater number of males with HHs and epilepsy is reported.⁸²

HHs are a nonfamilial, congenital malformation usually occurring in isolation. They are rarely associated with other intracranial malformations such as callosal dysgenesis, heterotopias, arachnoid cysts, and microgyria.^8,21,30 Rarely, HHs may occur as part of a multiple congenital malformation syndrome, most notably the autosomal dominant Pallister-Hall syndrome, which includes HH, polydactyly, hypopituitarism, imperforate anus, and dysplastic nails.⁷ Seizures occur in about 15% of patients with Pallister-Hall syndrome and are often mild, despite HHs often being very large. Patients with Pallister-Hall syndrome have mutations of the zinc-finger transcription factor gene GLI3 on chromosome 7p13,^35,40 but the role of GLI3 mutation in patients with sporadic HHs²⁴ is unconfirmed and so the etiology of sporadic HHs remains uncertain.

The genesis of seizures associated with HH is also incompletely understood. Mechanical irritation or distortion of the adjacent hypothalamus or midbrain by the HH was initially believed to be the cause of seizures.⁴⁵ The severity and
generalized nature of seizures and associated neurologic and behavioral problems in many patients with HHs, and the early poor results of HH surgery,^10,49,69,75 led to speculation that patients with HHs had widespread occult cerebral dysgenesis.^4,79 GSs were eventually shown to arise from the HH by stereotactic depth electroencephalographic (EEG) recording of seizures from the HH, by reproduction of symptoms with electrical stimulation of the HH, and by demonstration of HH hyperperfusion with ictal single photon emission computed tomography (SPECT).^{34,36,37,38,39,41,54} This led to a change in view from the HH simply being an epiphenomenon to the HH being intrinsically epileptogenic.⁶ Such intrinsic hyperexcitability has been documented with single cell studies of small neurons within cell clusters in resected HHs exhibiting pacemaker-like spontaneous repetitive firing,⁹⁰ similar to that seen in focal cortical dysplasia.^48,63

The reasons for marked variability of the neurologic manifestations of HHs, and the relationship between the size and attachment of the HH, and the neurologic manifestations remain uncertain. Some reports suggest that seizures are more frequent or severe in patients with larger HHs.^47,81 A connection of the HH with the mammillary bodies seems to be integral to epileptogenesis.^1,21,85 Tonic seizures that develop in a proportion of children do not seem to arise from the HH,³⁷ but rather occur as a related but independent neocortical phenomenon. The whole electroclinical picture of symptomatic generalized epilepsy, with slow spike-wave on EEG and generalized tonic seizures, may develop in patients with HHGS as a consequence of secondary epileptogenesis in the neocortex.²²

GSs are the characteristic epileptic manifestation of HH, occurring in nearly all patients (see Chapter 53). Early onset of GSs is characteristic^9,82 and onset from the day of life is well known.^{4,16,17,41,62,78} The sound produced during GSs associated with HH is described variously as laughter, chuckling, or giggling, often qualified by words such as unnatural, mechanical, mirthless, and inappropriate. Dacrystic (crying) seizures are noted in many patients,^{10,28,37,45,65,78,80,87,89} invariably accompanied by GSs. Very frequent, brief GSs occurring during wakefulness and sleep are common in infancy. A mild form of GSs is described in adults with small HHs, the patients sometimes describing only a “pressure to laugh”⁸¹ or an “urge to giggle.”⁵² Consciousness is said to be preserved during brief gelastic seizures.^4,12,78 Often accompanying laughter in gelastic seizures are autonomic features such as facial flushing and pupillary dilation, hypermotor automatisms, oro-alimentary automatisms, head and eye deviation, and tonic or clonic facial contraction.^4,78