Treatment options for gelastic epilepsy due to hypothalamic hamartoma: interstitial radiosurgery

Surgical treatment of hypothalamic hamartomas (HHs) as the underlying etiology of gelastic epilepsy is associated with a high risk of complications because of the close vicinity of adjacent structures such as the optic tracts and mammillary bodies. Treatment with interstitial radiosurgery uses stereotactically implanted (125)I seeds emitting gamma radiation from the center of the lesion, with a steep spatial gradient, over a period of about 3 weeks. This form of HH therapy offers particular advantages regarding the risk for major side effects. In a series of 15 children and adolescents treated in Freiburg, Germany, 53% of patients achieved significant improvement in seizure frequency (Engel class I or II outcome). Transient side effects were related to the development of local edema, resulting in headache and mental slowing. A persistent weight gain was noted in 3 patients, which was severe in 1 (20 kg). There were no other neurologic, neuropsychologic, or neuropsychiatric side effects, which compares favorably with most surgical series.     

The hypothalamic hamartoma: a model of subcortical epileptogenesis and encephalopathy

Although uncommon, the hypothalamic hamartoma (HH) is often associated with a devastating clinical syndrome, which may include refractory epilepsy, progressive cognitive decline, and deterioration in behavioral and psychiatric functioning. Contrary to conventional thinking which attributed seizure origin to cortical structures, the hamartoma itself has now been firmly established as the site of intrinsic epileptogenesis for the gelastic seizures (i.e., characterized by unusual mirth) peculiar to this disorder. It also appears that the HH contributes to a process of secondary epileptogenesis, with eventual cortical seizure onset of multiple types in some patients. Anticonvulsant medications are known to be poorly effective in this disorder. Treatment, including some innovative approaches to surgical resection, is now targeted directly at the HH itself, with impressive results. Younger patients, in particular, may avoid the deteriorating course described earlier. Access to tissue from larger numbers of patients at single or collaborating centers specializing in HH surgery will allow for research into the fundamental mechanisms producing this little understood disorder. Refractory epilepsy associated with HH is the premier human model for subcortical epilepsy and an excellent model for secondary epileptogenesis and epileptic encephalopathy.     

Unusual presentation of hypothalamic hamartoma with hypersomnia in an adult patient

We report a patient with polysomnography findings related to hypersomnia, as a primary presenting symptom, who was shown to have stereotypical gelastic seizures. Her cranial magnetic resonance imaging revealed a hypothalamic hamartoma in the posterior region of the hypothalamus. The patient had no previous history of gelastic seizures. We suggest that patients who present with hypersomnia should be investigated for gelastic seizures in order to avoid misdiagnosis and receive appropriate treatment.     

Hypothalamic hamartoma: basic mechanisms of intrinsic epileptogenesis

The hypothalamic hamartoma (HH) is a rare developmental malformation commonly associated with gelastic seizures that are notoriously refractory to medical therapy. Recent evidence supports the intrinsic seizure propensity of HH. Despite increasing clinical recognition of this condition, the mechanisms of seizure genesis in HH tissue remain unclear. This review summarizes the histochemical and electrophysiological properties of HH neurons, and relates these findings to those characteristics identified in other types of epileptic tissue. Initial studies have revealed two distinct populations of neurons in surgically resected HH tissue. One group consisted of small gamma-aminobutyric acid (GABA)-expressing neurons that occurred principally in clusters and displayed spontaneous rhythmic firing. The second group was composed of large, quiescent, pyramidal-like neurons with more extensive dendritic and axonal arborization. We propose that the small, spontaneously firing GABAergic neurons send inhibitory projections to and drive the synchrony of large output neurons. These observations constitute the basis for future investigations aimed at elucidating the mechanisms of subcortical epileptogenesis.     

Gelastic seizures associated with hypothalamic hamartomas. An update in the clinical presentation,diagnosis and treatment

Gelastic seizures are epileptic events characterized by bouts of laughter. Laughter-like vocalization is usually combined with facial contraction in the form of a smile. Autonomic features such as flushing, tachycardia, and altered respiration are widely recognized. Conscious state may not be impaired, although this is often difficult to asses particularly in young children. Gelastic seizures have been associated classically to hypothalamic hamartomas, although different extrahypothalamic localizations have been described. Hypothalamic hamartomas are rare congenital lesions presenting with the classic triad of gelastic epilepsy, precocious puberty and developmental delay. The clinical course of patients with gelastic seizures associated with hypothalamic hamartomas is progressive, commencing with gelastic seizures in infancy, deteriorating into more complex seizure disorder resulting in intractable epilepsy. Electrophysiological, radiological, and pathophysiological studies have confirmed the intrinsic epileptogenicity of the hypothalamic hamartoma. Currently the most effective surgical approach is the trancallosal anterior interforniceal approach, however newer approaches including the endoscopic and other treatment such as radiosurgery and gamma knife have been used with success. This review focuses on the syndrome of gelastic seizures associated with hypothalamic hamartomas, but it also reviews other concepts such as status gelasticus and some aspects of gelastic seizures in other locations.     

Clinical spectrum and difficulties in management of hypothalamic hamartoma in a developing country

Aim – We describe the clinical features, treatment and prognosis in a series of patients with epilepsy secondary to hypothalamic hamarthomas (HH) in a developing country. Materials and methods – Eight patients with epilepsy and HH were included between 1997 and 2006. We analyzed gender, age, age at seizure onset (ASO), seizure types (ST), mental retardation (MR), precocious puberty (PP), electroencephalogram (EEG)‐magnetic resonance imaging (MRI) features and response to treatment. Results – Mean age 25.1 years, 2/6 female/male, none had PP, ASO 4.5 years. Complex partial seizure were the most frequent (100%), mean similar to those seen in temporal (62.5%) or frontal lobe epilepsy (37.5%). Exactly 87.5% developed gelastic seizures (GS). Half of the patients showed MR. Mild‐to‐severe MR was associated with the presence of multiple ST including atonic and complex partial seizures with frontal semiology. Interictal EEG was abnormal in 87.5% patients. Video EEG was performed in three cases with unspecific findings. HH were small and sessile in seven patients whereas large and pedunculated in one. All patients were refractory to medical treatment. In five, an additional procedure was performed without any significant improvement. Conclusion – These series show the heterogeneous spectrum of this entity and the difficulties in its treatment in a developing country.     

Hypothalamic hamartoma treatment: surgical resection with the transcallosal approach

Multiple treatment options are available for patients with hypothalamic hamartoma (HH) including the frontotemporal approaches, the anterior transcallosal transseptal interforniceal approach, the transventricular endoscopic approach, and stereotactic radiosurgery. Relatively large patient series of the transcallosal resection/disconnection from Royal Children's Hospital in Melbourne and the Barrow Neurological Institute in Phoenix, AZ, show, respectively, that 52% to 54% are 100% seizure free, and 24% to 35% have >90% seizure reduction. However, there appears to be an 8% to 14% risk of persisting memory problems. The surgery should ideally be performed in the early years of childhood before secondary generalized epilepsy develops and developmental delay and behavioral problems are established. Radiosurgery may be a preferable option for higher-functioning adolescent or adult patients with HH. The choice of treatment must be individualized depending on the age and clinical circumstances of the patient and the size and anatomic relationships of the hamartoma. The transcallosal resection of HH is an effective and safe treatment, but there is a small risk of short-term memory impairment. The endoscopic approach is an alternative to the transcallosal approach for smaller HH.     

Cognitive and behavioral dysfunction in children with hypothalamic hamartoma and epilepsy

Hypothalamic hamartoma (HH) syndrome comprises the clinical triad of epilepsy, developmental retardation, and central precocious puberty. A predominant opinion has been that the acquired cognitive and behavioral disorders observed in children with this syndrome are a direct effect of their seizure activity. A review of the recent literature suggests that this opinion needs to be revised because it is only partially supported by the data. The size of the HH and its anatomic attachment/location, in addition to the seizure history, appear to contribute to the cognitive and behavioral disturbances in children with HH. Small sample sizes and the inability to use standard neuropsychological testing scales in more severely affected HH patients complicate the study of causality. The present literature, however, suggests that multiple factors contribute to the cognitive and behavioral problems of these children.     

Endoscopic resection of hypothalamic hamartoma for refractory epilepsy: preliminary report

The intrahypothalamic subtype of hypothalamic hamartoma (HH) is usually associated with refractory epilepsy, cognitive impairment, and organic behavioral disturbance. It is often a devastating disorder for both patient and family. The gelastic (laughing) seizure is the hallmark seizure type. However, multiple other seizure types can often develop during the course of the disease, and are typically refractory to antiepilepsy drugs (AEDs). Previously it was uncertain if HH tissue was responsible for seizure genesis or whether resection of the HH would result in improvement of the seizures. Recently both of these questions have been answered in the affirmative. Surgical resection using a transcallosal, interforniceal approach has recently been shown to be efficacious and generally safe for the treatment of the refractory seizures. However, even more recently, we have been performing the majority of HH surgical resection by using an endoscopic technique with a transventricular approach. This article presents the details of the operative technique and discusses preliminary outcome data, particularly with comparison to the transcallosal technique. Using an endoscope holder with micromanipulator facilitates endoscopic resection. Linking the endoscope to a system of frameless stereotaxis is essential for successful resection. Forty-four patients age 8 months to 44 years have undergone endoscopic resection. The ideal candidate for endoscopic removal has a hamartoma completely or nearly completely involving one wall of the third ventricle and is 1 cm or less in greatest diameter. Because it is essential to be able to visualize the lesion within the third ventricle for resection, there must be at least 6 mm of space between the top of the lesion and the roof of the third ventricle. Patients with intractable epilepsy caused by HH can be rendered seizure free or show marked improvement in seizure frequency by surgical removal, surgical disconnection, or radiosurgical ablation of the lesion. Which of these options should be recommended for an individual patient is not yet clear. One of the options involves resection or disconnection of the HH with a transventricular endoscopic approach. In selected patients, endoscopic resection of HH is effective in the treatment of intractable epilepsy, with lower complication rates and shorter hospital stays than transcallosal resection.     

Early Clinical and EEG Features of Infantile Spasms in Down Syndrome

Summary: The combination of West syndrome (WS) and Down syndrome appears not to be coincidental. Fourteen patients free of cardiac malformation or history of perinatal hypoxia were referred and investigated before they had received any treatment and were followed to the mean age of 4.5 years (range 19 months to 14 years). Spasms had onset at the mean age of 8 months (range 4–18 months) in cluster and were symmetrical. Hypsarrhythmia was symmetrical and, after intravenous diazepam (4 patients, 0.5 mg/kg) it disappeared, without any remaining focus. Recorded spasms during a cluster were "independent," with recurrence of hypsarrhythmia between successive spasms, and thus had the ictal and interictal EEG characteristics of idiopathic WS. Seven patients exhibited other types of seizures after WS, consisting of myoclonic jerks, atonic, tonic-clonic or absence seizures, which proved quite easy to control with valproate and/or ethosuximide.     

Clinical characteristics and long-term outcome of surgery for hypothalamic hamartoma in children with refractory epilepsy

Context:

Hypothalamic hamartomas (HH) are ectopic masses of neuronal and glial tissue most commonly presenting with medically refractory gelastic seizures with evolution to other seizure types. They are also associated with cognitive and behavioral problems to varying extent. Surgery has been found to improve quality of life in more than 50% of patients.

Aim:

To evaluate the clinical characteristics and long-term outcome of surgery in children with HH and refractory epilepsy.

Materials and Methods:

A retrospective analysis of presurgical, surgical, and postsurgical data of six children who underwent surgery for HH and had at least 3 years follow-up was performed.

Results:

Six children (male: female = 5:1) aged 3-16 years (at the time of surgery) underwent surgical resection of HH for refractory epilepsy. At last follow-up (range 3-9 years), three children were in Engel''s class I, two in Class II, and one in class III outcome. Significant improvement in behavior, quality of life was noted in four children; while the change in intelligence quotient (IQ) was marginal.

Conclusions:

Medically refractory epilepsy associated with behavioral and cognitive dysfunction is the most common presentation of HH. Open surgical resection is safe with favorable outcome of epilepsy in 50% with significant improvement in behavior and marginal change in cognitive functions.     

Ictal bradycardia in a patient with a hypothalamic hamartoma: a stereo-EEG study

Little is known about bradycardia and cardiac asystole which occur during partial epileptic seizures, especially whether they relate to ictal involvement of well-defined cortical areas. Several reports based on simultaneous electrocardiographic and intracranial depth electroencephalographic monitoring have shown that either the fronto-orbital cortex or the amygdalohippocampal complex could be responsible for such cardiac variations. We performed stereo-EEG recordings in a patient with refractory localization-related epilepsy associated with a hypothalamic hamartoma. We found that other cortical areas, such as the frontocentral region and the temporal neocortex, can contribute to the genesis of ictal bradyarrhythmia. Second, the lesion per se, although located within the hypothalamus, is not involved with this phenomenon.     

Diagnosis of Infantile Spasms, Lennox-Gastaut Syndrome, and Progressive Myoclonic Epilepsy

Summary:  The epilepsies of childhood are distinguished by an interesting dichotomy between the benign and catastrophic disorders. Approximately 50% of children outgrow childhood epilepsy as they mature; although the disorder is disruptive for children and families alike, it is not considered a medical disaster. The catastrophic epilepsies of childhood, in contrast, are associated with significant morbidity and mortality. Infantile spasms, Lennox-Gastaut syndrome, and the progressive myoclonic epilepsies are correlated with significant disability and a multiplicity of underlying etiologies. Accurate diagnosis of both the syndrome and the etiology is very important for treatment purposes, as well as for family education, since many of the disorders have a significant genetic component.     

Non-convulsive status epilepticus and audiogenic seizures complicating a patient with asymmetrical epileptic spasms

A female infant suffered from epilepsy since the neonatal period, which evolved into West syndrome at the age of 2 months. Spasms in series and hypsarrhythmia disappeared after treatment with high-dose phenobarbital; however, single spasms persisted with right-sided predominance, and polyspike activity in the left parieto-temporal areas preceded or coincided with these spasms. Magnetic resonance imaging revealed a small calcification in the right occipital area, and positron emission tomography showed hypometabolism over the right hemisphere. Widespread epileptic discharges gradually increased on electroencephalography (EEG) during sleep thereafter. The patient presented with daytime unresponsiveness at 1 year and 6 months, when diffuse, irregular spike and wave activity characterized the waking EEG. Spasms or brief tonic seizures with right-sided predominance were provoked by auditory stimuli during this period, particularly by her mother’s voice, with ictal EEG of right posterior predominant fast activity and subsequent desynchronization. The administration of clobazam resulted in the marked improvement of EEG findings and transient disappearance of spasms. Presumably, certain patients with asymmetrical epileptic spasms may be regarded as a unique type of localization-related epilepsy, and can show an unusual course of evolution in comparison to other cases of epilepsy that evolve after West syndrome.