Hypothalamic hamartomas (HHs) are congenital mass lesions in the region of the third ventricle and tuber cinereum. Their true prevalence is unknown and is approximated to be 1 in 100,000. This estimated prevalence appears high but may actually be an underestimate as the diagnosis is often missed or at least significantly delayed.¹

Two “main” clinical syndromes are recognized: precocious puberty and intractable epilepsy, including gelastic (laughing) seizures. Gelastic seizures are usually followed by the development of other seizure types including tonic, tonic–clonic, and complex partial.² Predominantly gelastic seizures, but also all other seizure types are often extremely refractory to antiepileptic drugs (AEDs). Associated clinical problems with the intrahypothalamic (sessile) subtype include developmental retardation, cognitive decline, and psychiatric symptoms such as mood liability and rage behavior.³ Pedunculated lesions, which hang inferiorly from the tuber cinereum, are most likely to cause central precocious puberty, although many patients have both clinical syndromes.

There are several classifications of HHs. Arita et al classified lesions into two types on the basis of magnetic resonance imaging (MRI) characteristics. These include (1) a parahypothalamic type in which the HH is attached to the floor of the third ventricle or is pedunculated (and associated with precocious puberty) and (2) a intrahypothalamic type in which the HH is enveloped by the hypothalamus and distorts the third ventricle (more commonly associated with gelastic epilepsy, with or without precocious puberty, mental retardation, and behavioral problems).⁴ The sessile or intrahypothalamic types of HHs have a prominent intraventricular component and are strongly associated with gelastic epilepsy probably because of their juxtaposition to the body of the hypothalamus and central connections.

Various therapies to control seizures have met with only limited success. These include vagal nerve stimulation, gamma-knife therapy (probably most successful), stereotactic destruction of the lesion through radio frequency, and even GnRH analogue (standard treatment for precocious puberty).⁵ Initially, only single-case reports and small series reported favorable seizure control after surgical resection of the HH.⁶ Subsequently, two surgical techniques have proven to be beneficial, often leading to curative results in the treatment of HH patients. These include surgical resection via an anterior transcallosal interforniceal approach and an endoscopic transventricular approach.^7,8,9 Although complete resection of the HH is preferential, incomplete resection with presumed complete disconnection of the HH from its attachment to the hypothalamus can also achieve seizure freedom.

EPILEPSY

Gelastic seizures are the hallmark of HH. Gelastic seizures were first described by Daly and Mulder in 1957.¹⁰ They are usually quite brief, typically lasting less than 30 seconds, and more often lasting just a few seconds in duration. They may be associated with little or no change in consciousness, particularly early in the course. They are very frequent, up to multiple seizure events hourly in severely affected patients.

Gelastic seizures are characterized by bouts of laughter which may resemble but more commonly differ from the patients’ usual laughter that are associated with a slight sensation and appearance of discomfort. A related seizure type may involve crying and/or facial contraction with an exaggerated grimace; these are referred to as dacrystic seizures. Affected patients may manifest both forms of the seizures or seizures with mixed features of both types. Autonomic features such as flushing, tachycardia, and altered respiration are commonly associated. Most (but not all) seizures are simple partial with preserved awareness that are typically brief (less than 30 seconds) and lack a postictal phase. Status gelasticus is the most severe form, defined as a prolonged cluster of gelastic seizures lasting longer than 20–30 minutes although these clusters may actually last for several hours up to days.¹¹

At least 75% of patients with intrahypothalamic HH develop other types of seizures.¹ These include simple and complex partial seizures, atonic, tonic, atypical absence, and generalized tonic–clonic seizures. It is hypothesized that secondary epileptogenesis results from the constant electrical discharging from the HH activating distant epileptic foci and multiple seizure types. Hence many affected patients present with severe epileptic encephalopathy resembling the Lennox–Gastaut syndrome.² In many patients the encephalopathymay be more detrimental than the seizures themselves.

ENCEPHALOPATHY

Associated comorbidities include developmental delay, mental retardation, rage attacks, and psychiatric symptoms consistent with autism, attention deficit hyperactivity, and obsessive-compulsive disorders. Progression of epilepsy severity and interictal electroencephalographic (EEG) abnormalities may be accompanied by cognitive decline and worsening psychiatric impairment.¹ Conversely, psychiatric, behavioral, and cognitive improvement may occur after successful epilepsy surgery. There is a strong association between the comorbidities of refractory epilepsy, cognitive impairment, and behavioral disturbance.¹

PALLISTER–HALL SYNDROME

Most patients with HH have a sporadic form of the disease, without family history or risk of recurrence, and without associated congenital anomalies. However, roughly 5% of the subset of patients with the intrahypothalamic subtype of HH have Pallister–Hall syndrome which includes anomalies such as postradial polydactly, bifid epiglottis, and imperforate anus.^8,12 It is an autosomal dominant disease, fully penetrant but with variable expressivities, and a high new mutation rate. Specifically, Pallister–Hall syndrome is caused by genomic mutations in the Gli3 gene, a zinc-finger transcription factor in the intracellular signaling pathway for the sonic hedgehog protein.¹³ Sporadic HH cases with a somatic mutation in Gli3, demonstrated in HH tissue, but not in blood, has now been reported.¹⁴

PRECOCIOUS PUBERTY

Precocious puberty is predominantly associated with the pedunculated forms of the HH occurring either in isolation or with epilepsy and cognitive and behavioral impairment. As we continue to learn more about the HH, it is clear that there is overlap between the clinical presentations given the different neuroanatomical locations and forms of the HH. For example, the sessile form may be associated with isolated precocious puberty while the pedunculated form may present only with seizures. It has recently been suggested that the presence of precocious puberty (at least among the subgroup of HH patients with epilepsy) correlates with poorer intellectual functioning.¹⁵

NEUROIMAGING

Other than clinical presentation (where the diagnosis is often missed for months or even years), the definitive diagnosis is made by neuroimaging. MRI is typically required as computerized tomography may only diagnose larger HHs due to poorer resolution and reduced visualization toward the base of the brain. A dedicated imaging protocol consisting of fine cuts through the hypothalamus in both the sagittal and coronal planes is helpful for diagnosing smaller HHs.

HHs demonstrate various intensities on MRI, that is, various combinations of hyperintensity, isointensity, or hypointensity compared to normal gray matter on either T1- or T2-weighted images; they rarely enhance with gadolinium.

Analysis of MRI findings for 72 patients revealed that most HHs were hypointense on T1 (74%) and hyperintense on T2-weighted (93%) images.¹⁶ Intrahypothalamic extension was noted in nearly all cases (97%) with frequent displacement of the postcommisural fornix and hypothalamic gray matter anteriorly. The HH nestled was between the fornix, mamillary body, and mamillothalamic tract.

Another study of 14 HH cases showed correlation of MRI and MR spectroscopy with tumor glial content.¹⁷ Hyperintensity of the T2-weighted MRI lesions and higher myoinositol (mI)/creatine (Cr) ratios on MR spectroscopy positively correlated with higher glial content (glial/neuronal fraction as determined by histopathology).

ELECTROENCEPHALOGRAPHY

Routine scalp video-EEG monitoring in patients with HHs does not localize correctly. Although many patients with HHs evidence dramatic interictal multifocal and generalized epileptiform discharges, others do not exhibit interictal discharges. Gelastic seizures may or may be accompanied by ictal discharges and patterns. Thus, the scalp video-EEG monitoring is often misleading for localizing seizure onset. Not uncommonly seizures localize to temporal or nontemporal regions rather than the midline deep HH.

A case series of seven patients with HHs undergoing focal corticectomy following intracranial EEG recordings resulted in no improvement in their epilepsy.¹⁸ Figures 35–1 and 35–2 illustrate the scalp-EEG recordings of the onset of two different complex partial seizures with similar semiology. As can be clearly seen, the onset of one seizure appears to originate more often from the left temporal region (Fig. 35–1), while the other originated from the right temporal region (Fig. 35–2). In addition, frequent, bilateral independent temporal lobe epileptiform discharges were noted. A HH was noted on MRI (Fig. 35–3) and endoscopic resection produced seizure freedom (Fig. 35–4).