Neurol Med Chir (Tokyo) 45, 221¿231, 2005 Hypothalamic Hamartoma Kazunori ARITA,KaoruKURISU, Yoshihiro KIURA,KojiIIDA*, and Hiroshi OTSUBO* Department of Neurosurgery, Graduate School of Biomedical Science, Hiroshima University, Hiroshima; *Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada Abstract The incidence of hypothalamic hamartomas (HHs) has increased since the introduction of magnetic resonance (MR) imaging. The etiology of this anomaly and the pathogenesis of its peculiar symptoms remain unclear, but recent electrophysiological, neuroimaging, and clinical studies have yielded important data. Categorizing HHs by the degree of hypothalamic involvement has contributed to the accurate prediction of their prognosis and to improved treatment strategies. Rather than undergoing corticectomy, HH patients with medically intractable seizures are now treated with surgery that targets the HH per se, e.g. HH removal, disconnection from the hypothalamus, stereotactic irradiation, and radiofrequency lesioning. Although surgical intervention carries risks, total eradication or disconnec- tion of the lesion leads to cessation or reduction of seizures and improves the cognitive and behavioral status of these patients. Precocious puberty in HH patients is safely controlled by long-acting gonadotropin-releasing hormone agonists. The accumulation of knowledge regarding the pathogenesis of symptoms and the development of safe, effective treatment modalities may lead to earlier interven- tion in young HH patients and prevent the decline in their cognitive abilities and quality of life. This review of hypothalamic hamartomas presents current classifications, pathophysiologies, and treatment modalities. Key words: hypothalamic hamartoma, epilepsy, gelastic seizure, precocious puberty, classification Introduction MR imaging. Hypothalamic hamartomas (HHs) are non-neoplas- Pathology tic, heterotopic nodules resembling the normal gray matter of the hypothalamus.15,46) Between 1934 and HHs occur as a round or ovoid mass between 5 and 1963, only around 30 cases have been described.74) 50 mm diameter, usually about 10–30 mm. The Despite their rarity, HHs have become well known tumors are either embedded in the hypothalamus or because of the characteristic symptoms of central- attached to it via a wide or narrow interface.15,46) type precocious puberty (CPP) and gelastic sei- Some are attached by a stalk, called a ``peduncle.'' zures.2,5,8,11,72,76) Due to advances in magnetic HHs are very rarely located in the interpeduncular resonance (MR) imaging, the number of cases of HH or prepontine cisterns without direct connection to has been on the rise.5,19,26,42,48) the hypothalamus.6,53,54) In the late 1990s we proposed a new classification HHs primarily consist of mature neurons inter- of HHs that takes into account the MR imaging mingledwithglialcells.3,46) The neurons resemble appearance and discussed treatment modalities those in the normal tuber cinereum,75) although large based on this classification.4,5) Recent reports includ- dysplastic neurons are occasionally found in HH ing our papers about the etiologies, symptoms, and patients with seizures.34) There may be moderate treatments of this disease have led to a better under- glial cellularity without neoplastic differentiation.46) standing of its nature and management. This review Myelinated and unmyelinated fibers have been provides an overview of these reports and adds a identified among the cellular components3,15,46) and summary of our 17 patients with HH identified by some of these nerve fiber bundles connect to hypothalamic nuclei.63,74) The lesion may contain Received April 15, 2004; Accepted December 6, ependymal cell lines, suggesting a primordial diver- 2004 ticulum from the third ventricle.2) Ultrastructural 221 222 K. Arita et al. Table 1 Symptoms associated with hypothalamic hamartoma Common Rare Endocrinological precocious puberty acromegaly65) obesity hypopituitarism45) diencephalic syndrome61) Neurological gelastic seizures ``pressure to laugh''70) focal seizures visual impairment72) secondary generalization developmental delay cognitive impairment behavioral disturbance Symptoms due to accompanying anomaly symptoms of other intracranial abnormality Pallister-Hall syndrome examination has identified neuroendocrine units seizure pattern is usually a gelastic seizure with with neurons containing neurosecretory granules, brief attacks of mechanical laughter starting during blood vessels with fenestrated endothelium, and early infancy.8–10,12,55) Ninety percent of patients double basement membranes.32) with HHs and seizures present with gelastic sei- zures.51) Gelastic seizure was not the initial seizure Etiology type in only a small group of patients who were adults at the onset of epilepsy.48) During the 5th or 6th week of gestation, the ventral Gelastic seizures are initially accompanied by aspect of the neuraxis approaches the anterior tip of little or no impairment of consciousness and no the end of the notochord. HHs may be due to tissue significant abnormalities are detected by scalp displacement during that period.7) HHs are associ- electroencephalography (EEG).8,12) After several ated with neither sexual preponderance nor familial years, gelastic attacks frequently become associated or racial predilection.51) No shared genetic anomaly with consciousness alterations. Seizure semiology has been identified in patients with HH, except for usually evolves into focal motor features, autonomic the group with Pallister-Hall syndrome. A pathologi- phenomena, and/or secondary generalization.8,41,55) cal study found very small hamartomatous nodules Some seizure types and EEG abnormalities are (1.0–1.5 mm in diameter) in the hypothalamus of suggestive of epileptogenic foci in the temporal or 21% of 239 consecutive autopsied cases,66) suggest- frontal lobe.12,40,41) ing that symptomatic HH may be an extreme of a Later on, seizures may become generalized and of normal variation. multiple types, e.g. absence, drop attacks, and tonic, atonic, and tonic-clonic seizures. EEGs typically Symptomatology show slow spike-and-wave patterns.8,55,58,70) Cogni- tive deterioration and behavioral disturbance are Table 1 lists the reported symptoms of patients with frequently seen at this stage. This malignant type of HHs. The two main manifestations are seizures and epilepsy occurs in about half of epileptic HH CPP. Among 277 HH patients, 174 (63%) manifested patients.51) Some concomitantly develop precocious CPP, 170 (61%) had experienced seizures, and 75 puberty.4) (27%) presented with both CPP and seizures.51) A benign form of later-age onset gelastic seizures Asymptomatic cases have also been reported.4,20,51,66) without deterioration has been reported in patients with small, 5–6 mm, hamartomas.70) These individ- I. Seizures uals may report only a strange feeling of ``pressure The age at onset of epilepsy ranged from the 1st to laugh'' and manifest little or no cognitive disor- postnatal day to 27 years (mean 2.5 years, median ders. Their interictal and ictal EEG findings may be 1.0 year).51) Among19HHpatientswithseizures,48) normal. 16 had gelastic seizures, nine had atypical absence, five had drop attacks, four had partial motor sei- II. Cognitive dysfunction and behavioral zures, seven had brief tonic seizures, 11 had com- problems plex partial seizures of the temporal lobe type, In patients with seizure onset during early child- and eight had generalized convulsions. The initial hood, cognitive dysfunction and behavioral Neurol Med Chir (Tokyo) 45, May, 2005 Hypothalamic Hamartoma 223 problems are commonly progressive.4,51,55) Develop- of Pallister-Hall syndrome is HH,29) but other mental delays correlate with the severity, frequency, manifestations include holoprosencephaly, deficient and variety of the seizure patterns.8,25,55) Of all olfactory bulbs and tracts, hypopituitarism, bifida reported patients with HH, 49% manifested cogni- epiglottis, craniofacial anomalies, polydactyly, tive disturbance and 31% had behavioral problems; imperforate anus, and renal anomalies.31) The all of them had seizures.51) The behavioral problems craniofacial anomalies are attributed to the disrup- have been described as restlessness, violence tion by the HH of midline development. The first including severe rage attacks, emotional instability, six reported patients were in serious condition at obsession, autism, and anti-social behavior.30,72) In birth and died within 10 days, and subsequent the majority of these patients, medical and psycho- reports have stressed the ominous nature of this syn- logical treatment frequently failed, so institutionali- drome.31) However, some patients have prolonged zation was often considered.55) survival and Pallister-Hall syndrome is not invaria- bly lethal.73) Fewer than 15% of patients with this III. CPP syndrome experience seizures, which are milder HHs are recognized as a major etiological factor than in patients with HHs.9) in CPP, and were present in 14–36% of patients with TheearlytermforwhatisnowknownasHHwas organic CPP.14,57) Conversely, more than half of hamartoblastoma, derived from the presence of patients with HHs manifested CPP.4,51) Pubertal primitive germ cells, which seemed to indicate manifestations include deepening of the voice and neoplastic potential, in the hypothalamic mass of enlarged testes and penis in males, breast develop- dead neonates.17) Subsequent pathological examina- ment and menses in females, and excessive