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Hypothalamic hamartomas (HH) are an uncommon human pathology resulting in a distinctive and often severe epilepsy syndrome, usually including gelastic (laughing) seizures. This chapter focus on HH associated with epilepsy. The gross anatomy of HH lesions determines the nature of their clinical symptoms. Epilepsy associated with HH is a progressive disease for the majority of patients, with development of multiple seizure types, and coincident deterioration in cognition and behavior. Antiepilepsy drugs (AEDs) are unsuccessful in managing seizures associated with HH, and eradication or complete disconnection of the HH is successful for controlling seizures, and may help ameliorate the comorbid problems with cognition and behavior. Treatment choice is guided by the individual circumstances of the case, including the clinical course of the disease and an assessment of the size and attachment of the HH.