Hypothalamic hamartomas are nonneoplastic overgrowths of normal appearing tissue comprised of disorganized neurons and glia that are lacking the enlarged “balloon cells” characteristic of focal cortical dysplasia 1).
They are non-progressive lesions and do not expand, spread or metastasize to other locations.
Hypothalamic hamartomas are relatively rare. Population-based research has shown that HH with epilepsy occurs in 1 of 200,000 children and adolescents. The prevalence of HH with only precocious puberty is unknown. At least for HH with epilepsy, males appear to have a slightly higher risk than females (approximately 1.3 to 1 ratio). HH occurs worldwide, without any obvious geographical concentration of cases. It is currently felt that all ethnic groups are at equal risk. There are no identified maternal risk factors or fetal exposures that increase the risk of HH.
The underlying cause remains unknown. Over 95% of cases are sporadic (that is, there is no prior family history and the identified patient remains the only affected individual in the family). A defect in factors that regulate fetal development of the hypothalamus is most likely.
However, HH can also occur in patients with identified genetic disorders. Of these, Pallister Hall syndrome accounts for the vast majority.
Histologically, hypothalamic hamartomas resemble normal hypothalamic neurons, although some dysplastic neurons and glial cells have also been described
They are thought to arise from anomalous neural migration between 35 and 40 days in utero (time of hypothalamic formation).
There is tremendous diversity in the type and severity of symptoms from patient to patient. However, symptoms are apparent during childhood in the overwhelming majority of patients. Although significant overlap exists, two clinical phenotypes of HH are recognized:
Central precocious puberty
Hypothalamic hamartomas may be associated with gelastic seizures, focal seizures, and a generalized epileptic encephalopathy, with severe seizures and cognitive and behavior decline. Despite earlier views to the contrary, good evidence now exists that all these clinical features are caused, directly or indirectly, by the hamartoma.
MR imaging is sufficient to establish (or rule out) the diagnosis of HH. However, there are important considerations to imaging for HH. Imaging must be technically adequate to permit detailed visualization of the hypothalamus. Movement artifact resulting from restlessness of the patient within the scanner can obscure small HH lesions. Accordingly for children or other patients with limited cooperation, a sedated study is recommended. Additionally, the choice of specific imaging sequences is also important.
The study include a coronal T2 fast spin echo (FSE) sequence, with thin slices and no gap or space between slices. Lastly, the radiologist should be informed that HH is one of the clinical conditions under consideration, so as to include careful inspection of that region of the brain. Most patients (over 90%) have normal brain findings on MR imaging aside from the HH. A small number of patients may have additional abnormalities, such as malformations of cortical development.
T1: isointense to cerebral cortex
T1 C+ (Gd): no contrast enhancement
T2 iso- to hyperintense to cerebral cortex the higher the proportion of glial cells, the higher the T2 signal
reduced NAA/Cr increased myoinositol increased Cho/Cr compared to the amygdala has also been reported 2).
Computed tomography (CT) imaging is not adequate for detecting small HH lesions, and has the added disadvantage of radiation exposure.
Physical signs of precocious puberty require evaluation by an endocrinologist. The hypothalamus and pituitary together produce a number of different hormones, including the reproductive hormones responsible for puberty. Consequently, evaluation of patients with HH should include testing for other factors such as thyroid, adrenal, and growth-related hormones.
Electroencephalography (EEG) testing is routinely performed in patients with epileptic seizures or suspected epileptic seizures, and can be useful in evaluating patients with HH and epilepsy. However, it must be recognized that EEG results may be normal, particularly at younger ages when gelastic seizures are the only seizure type. This includes video-EEG monitoring that captures gelastic seizures. That is, the EEG may show no change even during the actual gelastic seizure event. This is due to the fact that gelastic seizures arise in the HH, and as a structure located deep at the base of the brain, it is distant from EEG electrodes on the scalp. This can lead to incorrect diagnoses.
EEG studies can show abnormal results, particularly in older patients who have developed other types of seizures. A wide variety of findings is possible, and can suggest either focal or generalized disturbances. Consultation with a neurologist experienced with evaluating patients with HH and epilepsy is recommended whenever possible. This expertise is usually available at regional epilepsy referral centers.
Neuropsychological testing can be an important tool for patient management, particularly those with HH and epilepsy. These patients are “at-risk” for developmental and cognitive deficits. For some patients, these difficulties may be progressive, with deterioration or worsening in their level of function. Neuropsychological testing can help define the pattern of functioning (i.e., strengths and weaknesses) in the various skills of higher brain functioning (such as memory, language, problem-solving, etc). This can help with adaptive therapies and provides a baseline for those patients who may be declining. Additionally, neuropsychological testing is very important for those undergoing surgical intervention in order to clarify changes (for either the better or worse) that may accompany surgical treatment.
The basic cellular mechanisms responsible for seizure onset within HH are unknown.
With intra-operative microwire recordings of single neuron activity to measure the spontaneous firing rate of neurons and the degree of functional connection between neurons within the tumor.
Resection of these lesions was long regarded as too hazardous and unlikely to benefit seizure control. It is now clear that hypothalamic hamartomas can be effectively treated with a variety of surgical approaches with sustained seizure control and often seizure freedom. Qualitative observations suggest that behavior and cognition also improve with treatment, but quantitative validation is required. The specific approach should be tailored according to the surgical anatomy of the lesion and the experience of the surgeon.
Choices include a transcallosal approach (good for intraventricular lesions), a pterional approach (useful for interpeduncular lesions), a transventricular endoscopic approach, or destruction of the lesion with radiofrequency probes or gamma knife radiosurgery. The previously dismal outlook for children with severe seizures associated with this lesion has now dramatically changed. These insights may have implications for other epileptic encephalopathies of childhood 3).
Magnetic resonance imaging (MRI)-guided stereotactic laser ablation (SLA) offers a potentially safer, minimally invasive method with high efficacy for the HH treatment 4).
They grow in proportion to normal brain growth, and consequently their relative size to the rest of the brain is the same for the lifetime of the patient when viewed with serial imaging.
Ten patients have undergone surgery for HH under the dual care of Alder Hey tumour and epilepsy neurosurgeons during this period. Eight cases had a midline transcallosal, interforniceal approach with the remaining 2 having a transcallosal, transforaminal approach. All patients had an IOMRI scan, with 40% needing further tumour resection post-IOMRI. Forty percent had a total resection, 3 patients had near-total resection and 3 patients had subtotal resection (~ 30% tumour residual on post-operative MRI). No new neurological complications developed post-operatively. Hypothalamic axis derangements were seen in 3 cases, including 1 diabetes insipidus with hypocortisolaemia, 1 hypodipsia and 1 transient hyperphagia. Eighty percent are seizure free; the remaining two patients have had significant improvements in seizure frequency.
IOMR was used to tailor the ideal tumour resection volume safely based on anatomy of the lesion, which combined with the open transcallosal, interforniceal route performed by surgeons experienced in the approach resulted in excellent, safe and effective seizure control 5)
14 patients with medically refractory gelastic epilepsy who underwent stereotactic frame-based placement of an MR-compatible laser catheter (1.6 mm diameter) through a 3.2-mm twist drill hole. A U.S. Food and Drug Administration (FDA)-cleared laser surgery system (Visualase, Inc.) was utilized to ablate the HH, using real-time MRI thermometry. Seizure freedom was obtained in 12 (86%) of 14 cases, with mean follow-up of 9 months. There were no permanent surgical complications, neurologic deficits, or neuroendocrine disturbances. One patient had a minor subarachnoid hemorrhage that was asymptomatic. Most patients were discharged home within 1 day. SLA was demonstrated to be a safe and effective minimally invasive tool in the ablation of epileptogenic HH. Because use of SLA for HH is being adopted by other medical centers, further data will be acquired to help treat this difficult disorder 6).
Fourteen patients underwent transventricular endoscopic resection of HH for treatment-resistant epilepsy. Prior to surgical resection, single neuron recordings from bundled microwires (total of nine contacts) were obtained from HH tissue. Spontaneous activity was recorded for two or three 5-min epochs under steady-state general anesthesia. Off-line analysis included cluster analysis of single unit activity and probability analysis of firing relationships between pairs of neurons. Results: Altogether, 222 neurons were identified (mean 6 neurons per recording epoch). Cluster analysis of single neuron firing utilizing a mixture of Gaussians model identified two distinct populations on the basis of firing rate (median firing frequency 0.6 versus 15.0 spikes per second; p < 10(-5)). Cluster analysis identified three populations determined by levels of burst firing (median burst indices of 0.015, 0.18, and 0.39; p < 10(-15)). Unbiased analysis of spontaneous single unit behavior showed that 51% of all possible neuron pairs within each recording epoch had a significant level of firing synchrony (p < 10(-15)). The subgroup of neurons with higher median firing frequencies was more likely to demonstrate synchronous firing (p < 10(-7)).
Hypothalamic hamartoma tissue in vivo contains neurons which fire spontaneously. The activity of single neurons is diverse but distributes into at least two electrophysiological phenoytpes. Functional linkage between single neurons suggests that HH neurons exist within local networks that may contribute to ictogenesis 7).
A 8-year-old boy who suffered from severe refractory seizures. After radiosurgery, the patient experienced a notable improvement in his symptoms, achieving seizure cessation within 3 months. However, 4 months after the procedure he presented drowsiness, fever and decreased level of consciousness due to a direct effect on the hypothalamus with local and regional edema secondary to the radiosurgery that was performed. He was successfully treated with corticosteroids (with a total duration of 11 months), and twelve months after the surgery, complete disappearance of both the nodular lesion and the secondary edema was observed. The patient remains seizure-free in the last 16 months, with remarkable changes in his behavior.
The present case shows that complete radiological resolution of a hypothalamic hamartoma after Gamma-knife technique is unusual but possible, without long-term neurological consequences. Nevertheless, despite its low incidence, if a patient presents neurological symptoms, primarily during the first year after intervention, possible complications of this type of surgery must be taken into account 8).
A 19-year-old man with cortical dysplasia and intractable focal seizures underwent a right temporal lobectomy. A hypothalamic hamartoma was subsequently recognized, and he then underwent MRI-guided stereotactic laser ablation. Unfortunately, he sustained damage to the bilateral medial mammillary bodies and suffered significant memory loss.
They postulate that his persistent memory disorder resulted from a combination of the right temporal lobectomy and injury to the bilateral medial mammillary bodies 9).