Hypothalamic Hamartoma

Etiology

Hypothalamic hamartomas represent random abnormalities usually not associated with congenital malformations and have no known family history. Nearly 95% of cases are sporadic, although 5% of cases are associated with Pallister-Hall syndrome, which presents with dysmorphology in the hands and feet in the form of polydactyly and syndactyly, as well as laryngeal abnormalities (such as a bifid epiglottis), imperforate anus, and a hypothalamic hamartoma. Other possible features associated with this syndrome include dysplastic or misplaced kidneys, facial and laryngeal abnormalities such as a cleft palate and small tongue, shortened arms and/or legs, and growth hormone deficiency. The syndrome is associated with a mutation in the GLI3 gene, which encodes a transcription factor in the Sonic Hedgehog intracellular pathway.[5][6] Patients with sporadic hamartomas can present with the somatic mutation of GLI3 in up to 25% of cases; somatic mutations are found in 40% of patients.

Epidemiology

A hypothalamic hamartoma is a rare condition that occurs in approximately 1 in 100,000 children, with a slight predominance in males of around 1.3 to 1.4 times the frequency in females.[2] No geographical preference or predisposition is associated with this disorder, and it is not linked to any specific ethnic group. No maternal risk factors or a known history of fetal exposure have been identified for the development of a hypothalamic hamartoma.[2][7]

Pathophysiology

Hypothalamic hamartomas cause gelastic seizures due to intrinsic epileptogenesis. The molecular etiology responsible for epileptogenesis is not well understood. However, some studies have concluded that the small neurons contained in these lesions possess the intrinsic membrane capability to cause depolarization.[7]

Histopathology

Hypothalamic hamartomas consist of clusters of small neurons intermixed with glia and large neurons. Neuronal clusters have been traditionally described histopathologically as having a configuration similar to that of grapes. These clusters can represent the functional unit responsible for the source of epileptogenesis in these lesions. These lesions have very low Ki-67 levels, indicating a low proliferative capacity.[8]

History and Physical

Two clinical presentations are usually encountered in hypothalamic hamartomas:

• Epilepsy and related neurobehavioral symptoms
• Central precocious puberty

Patients with hypothalamic hamartomas that have epilepsy present with gelastic seizures that are characterized by unprovoked laughing or crying as their most common symptom, which usually begins during infancy. Other associated findings are developmental delay, cognitive decline, difficulty with concentration and memory, behavioral problems such as uncontrolled rage, and psychiatric symptoms associated with lesions involving the posterior hypothalamus near the mamillary bodies.

Approximately 40% of patients who present with gelastic seizures also experience precocious puberty. When both conditions co-occur, the lesions tend to be more extensive, as demonstrated by magnetic resonance imaging, and often involve both the anterior and posterior hypothalamus. Gelastic seizures in patients with hypothalamic hamartomas usually represent the first type of seizure that is experienced. The diagnosis of this seizure type is generally made due to the uncommon occurrence of laughing spells, which typically begin by age 1 and usually cease by age 10.[9]

The average duration of these episodes is approximately 1 to 30 seconds and may occur multiple times per hour in the most severe cases.[9] These seizures may or may not be associated with an altered level of consciousness. In some cases, other seizure types may also be present.[10] In nearly 75% of cases, some seizure subtypes can be very disabling, such as tonic-clonic seizures, complex partial seizures, drop attacks, and atypical absence seizures.[2] Some patients can have episodes that mimic crying and are called dacrystic seizures. Very rarely, a patient can present with gelastic seizures, and they do not have a hypothalamic hamartoma; in such cases, a lesion in the frontal or temporal lobe has been the suspected cause of the epilepsy.[11] 

Cognitive deficits are prevalent in patients with hypothalamic hamartomas and epilepsy. Difficulty with short-term memory, a decrease in the speed of thought processing, and progressive decline in intellectual ability have been found on neuropsychological testing in nearly 50% of cases of hypothalamic hamartoma.[9] Factors that predispose to more significant cognitive impairment include increased usage of antiepileptic medications, a larger-sized hypothalamic hamartoma, younger age at seizure onset, and a higher frequency of seizure activity. Behavioral and psychiatric symptoms are relatively common and include oppositional defiant disorder, attention-deficit/hyperactivity disorder, conduct disorder, and mood disorder.[2] Most patients experience a progressive worsening of symptoms throughout their lives.

Patients can also present with isolated precocious puberty, characterized by lesions that primarily involve the anterior portion of the hypothalamus near the tuber cinereum, which appears pedunculated and extends below the third ventricle.[2][4] Symptoms of precocious puberty are relevant if they begin before the age of 8 in girls and 9 in boys. However, symptoms can present as early as age 1. These symptoms may include short stature, breast development, pubic hair growth, maturation of the sexual reproductive organs, a deep voice, and facial acne.[2]

Evaluation

Brain MRI with and without contrast is the gold standard for diagnosing a hypothalamic hamartoma. This study is essential in alerting radiologists to focus their imaging on the hypothalamic region to avoid misdiagnosis. Hypothalamic hamartomas appear different from the normal grey matter due to their decreased intensity on T1-weighted images and increased intensity on T2-weighted images.[12] A higher T2 signal is associated with a higher glial cell content and a peripheral subependymal band of myelinated fibers.[12] These lesions do not enhance after contrast administration.[2] Hypothalamic hamartomas can also be associated with the presence of arachnoid cysts. Currently, it is unclear whether the cysts are intrinsic or extrinsic to the lesion. Hypothalamic hamartomas do not usually enlarge. They expand in proportion to brain growth; therefore, their relative size compared to the brain will remain constant.[12]

Computed Tomography

Computed tomography (CT) of the brain will demonstrate a small, nonenhancing lesion near the interpeduncular and suprasellar cisterns that is usually isodense to the brain parenchyma. Computed tomography is now considered inadequate for detecting a HH and only adds unnecessary radiation exposure for the patients.[2]

Electroencephalography

Electroencephalography (EEG) typically appears normal during gelastic seizures, although its use may be beneficial when other seizure types are suspected. Continuous video 24-hour EEG will record the patient's laughing episodes, but does not demonstrate any electrical ictal activity during the gelastic seizure. Interictal and ictal EEG may show focal, multifocal, or general epileptic spikes in patients with other seizure types, and may be beneficial for an accurate diagnosis.[13] Depth electrode recordings have demonstrated that gelastic seizures originate from hypothalamic hamartomas.[14]

Single-photon emission CT will demonstrate hyperperfusion by the hypothalamic hamartoma after gelastic seizures and normal perfusion in the interictal phase.[15] Magnetic resonance spectroscopy reveals a decreased N-acetylaspartate-to-creatine ratio in patients with hypothalamic hamartoma compared to that of the hypothalamus in healthy individuals. Hypothalamic hamartomas have increased gliosis and decreased neuronal concentration compared to normal brain tissue.[2]

Treatment / Management

The symptoms, clinical course, and anatomy of the hypothalamic hamartoma for each patient need to be evaluated to determine the most appropriate treatment for that individual. For minor clinical manifestations such as inconsequential gelastic seizures, observation is generally recommended because brief and infrequent episodes are usually not disabling. However, on occasion, surgery is performed to prevent secondary epileptogenesis, where uncontrolled seizures can provoke epileptogenesis in distant cortical regions.

Antiepileptic Medications

Antiepileptic medications usually do not control or improve gelastic seizures. These medications are primarily administered to control associated tonic-clonic seizures, complex partial seizures, drop attacks, and atypical absence seizures. Anticonvulsants are often less successful in decreasing seizures associated with hypothalamic hamartomas; therefore, surgery is usually recommended.[16]

Gonadotropin-Releasing Hormone Agonists

Precocious puberty can usually be successfully treated with medication. Leuprolide acetate inhibits the release of gonadotropin-releasing hormone, which is required to trigger puberty. This medication is generally administered intramuscularly once a month for the duration that puberty needs to be suppressed.

Surgery

The standard treatment for a hypothalamic hamartoma is open surgical resection of the lesion. Surgery offers the best outcomes for seizure cessation and reduction of neurocognitive, behavioral, and psychiatric symptoms.[17] The neurosurgeon can select the ideal surgical approach for each case depending on the size of the hamartoma, its anatomical relationship to the hypothalamus, the proximity to adjacent neurovascular structures, patient age, and the patient's individual experience with a particular operative procedure.[17](B3)

The most common surgical procedure has been resection of the hypothalamic hamartoma by a craniotomy. Several technical approaches can be used to approach the lesion, including a transcallosal interforniceal resection, pterional resection, transtemporal transchoroidal resection, or a combined resection approach for extensive lesions. These approaches provide direct access to the hypothalamic region. However, there are limitations related to working through a narrow corridor in an area surrounded by the internal carotid artery, optic nerve, optic chiasm, fornices, internal cerebral veins, and the infundibulum of the pituitary gland that limit access to the third ventricle.

The transcallosal-interforniceal approach provides the ideal access for intraventricular hamartomas and is the favored approach by many neurosurgeons.[17][18] Transventricular endoscopic resection can also be performed successfully.[19][20][21][22] Defining and separating the borders of the hypothalamic hamartoma from the hypothalamus and mammillary bodies can be challenging. However, removal of the lesion typically results in a reduction of more than 90% in seizure frequency.[17][23][24](A1)

Stereotactic Radiosurgery

Stereotactic radiosurgery is a noninvasive radiosurgical technique that causes damage directly to the lesion.[25] The exact mechanism of seizure control has not been determined due to the absence of visible lesion necrosis on follow-up MRI scans. This finding suggests that a neuromodulatory process, characterized by a decrease in vascular supply and resultant gliosis, may be responsible for the outcome. Radiosurgery serves as an excellent tool to treat lesions that are difficult to resect without causing neuroendocrine deficits. The therapeutic effect typically requires 6 to 18 months to occur, but can sometimes take a total duration of up to 3 years. Radiosurgery achieves seizure freedom in approximately 40% of patients treated and offers a viable alternative for treating small to medium-sized lesions.[18][26]

Stereotactic Thermoablation

The hypothalamic hamartoma is heated to approximately 60 °C to damage the tissue and diminish its ability to generate seizures. Treatment usually provides immediate results. Larger lesions may require several passes to treat the entire lesion. Radiofrequency thermoablation results in seizure control in up to 71% of patients, with one-third requiring multiple treatments. This technique provides an excellent alternative to treat cases that do not respond to open surgical treatment.[17][27][28] Laser-mediated ablation will heat the lesion using real-time magnetic resonance thermography. This form of ablation can obtain seizure control in nearly 60% of cases.[17][29][30](B3)

Differential Diagnosis

Tumors that occur in the same region as a hypothalamic hamartoma represent the principal differential diagnosis for this mass and include craniopharyngioma, astrocytoma, optic glioma, pituitary adenoma, and meningioma. These lesions do not cause gelastic seizures, although they can be associated with neuroendocrine axis disruption that can produce precocious puberty.[12]

Prognosis

Surgical intervention can potentially reduce seizure frequency by up to 90%, making it the most effective treatment option. Stereotactic radiosurgery achieves seizure freedom in approximately 40% of patients, while radiofrequency thermoablation provides seizure control in up to 71% of cases, and laser-mediated thermoablation achieves control in approximately 67% of cases. In contrast, antiepileptic medications are generally ineffective in controlling or improving gelastic seizures, though they may be more successful for other seizure types. Medical therapy with leuprolide acetate is effective in inhibiting precocious puberty until an appropriate age is reached, at which point its use is discontinued. Cognitive impairment is more likely in patients with larger hamartomas, earlier seizure onset, higher seizure frequency, and increased antiepileptic medication usage.

Complications

Hypothalamic hamartomas may lead to systemic complications that include: 

• Multiple disabling seizure types, such as tonic-clonic seizures, complex partial seizures, drop attacks, and atypical absence seizures
• Cognitive decline
• Psychiatric symptoms that include oppositional defiant disorder, attention-deficit/hyperactivity disorder, conduct disorder, and mood disorder
• Developmental delay
• Short-term memory impairment
• Reduced thought processing speed
• Diminished intellectual ability
• Short stature
• Facial acne

The treatment modalities can also lead to complications, including:

• Surgical
  • Diabetes insipidus, meningitis, ischemic stroke, infection, hemorrhage, short-term memory deficit, death
• Stereotactic radiosurgery
  • Provides a slow treatment response
  • Patient remains exposed to the risks of persistent seizures for up to 3 years
• Thermoablation
  • Injury to neurovascular structures, temperature control problems, hyperphagia, hyponatremia, Horner syndrome, amnesia