Hypothalamic Hamartoma

Hypothalamic hamartoma is a rare, non-neoplastic congenital malformation of disorganised neuronal and glial tissue at the tuber cinereum and mammillary bodies. Incidence is about 1 in 50,000 to 1 in 200,000. It causes gelastic seizures, central precocious puberty, behavioural disturbance and cognitive decline. Most are sporadic, and some occur with Pallister-Hall syndrome (GLI3) as part of a multi-system disorder.

Pathophysiology. The hamartoma has intrinsic epileptogenic activity, and can contain gonadotrophin releasing hormone neurons that cause early puberty. Secondary epileptogenesis involves cortex.

Gelastic seizures from infancy, followed by multiple seizure types and epileptic encephalopathy, with cognitive regression, rage attacks and psychiatric disorder, and central precocious puberty (under 8 years in girls, under 9 in boys). Small lesions may cause isolated precocious puberty with no seizures. Visual loss and hypothalamic dysfunction occur with large lesions.

Red flags.

• Escalating seizures or developmental regression.
• Early puberty with gelastic seizures.

MRI with thin coronal and sagittal sections shows a hamartoma, isointense to grey matter on T1 and iso- to hyperintense on T2, without enhancement. Classification by size and attachment guides surgery. Video EEG, endocrine assessment (luteinising hormone, follicle stimulating hormone, sex steroids, bone age), neuropsychology and behavioural assessment. Genetic testing (GLI3) if syndromic features (polydactyly, imperforate anus).

Differential diagnosis.

• Craniopharyngioma, optic nerve, chiasm or hypothalamic glioma and germ cell tumour.
• Tuber cinereum cyst, Rathke cleft cyst and Langerhans cell histiocytosis.
• Other causes of precocious puberty and gelastic seizures.

Treat early to prevent the encephalopathy.

Seizures. Antiseizure drugs are usually ineffective. Use as needed, at usual doses.

Surgical and ablative treatment. Choice depends on size and attachment.

• Stereotactic radiofrequency thermocoagulation and laser interstitial thermal therapy (small to moderate lesions).
• Endoscopic disconnection, or microsurgical resection and disconnection by transcallosal or pterional approaches (larger lesions).
• Stereotactic radiosurgery (delayed effect over 1 to 2 years).

Seizure freedom in about 50 to 80% (best for gelastic seizures), with improvement in behaviour and cognition. Risks include memory disturbance, hypothalamic dysfunction (obesity, hypopituitarism, diabetes insipidus) and third nerve palsy.

Precocious puberty. Gonadotrophin releasing hormone analogue (for example leuprorelin 3.75 mg IM every 4 weeks, or the dose by weight), under paediatric endocrinology.

Behaviour and learning. Psychological and educational support, and treatment of aggression.

Monitoring. Seizure frequency, development, endocrine function, vision and MRI.

Referral and escalation. Refer early to a specialist paediatric epilepsy surgery centre.