Achieving a cure for hypothalamic hamartomas: aSisyphean quest?

A child with uncontrollable bursts of laughter

Clinical Neurophysiology: EEG–Video Monitoring

Hypothalamic hamartoma (HH) is a rare, congenital, and benign lesion of the tuber cinereum, typically presenting with central precocious puberty (CPP), gelastic seizure, and developmental delay. This study aimed to investigate CPP in HH patients and compare clinical features between before and after gonadotropin-releasing hormone (GnRH) agonist treatment. A total of 30 HH patients under 18 years of age who visited Severance Children’s Hospital between January 2005 and May 2020 were retrospectively reviewed. Fourteen patients were male (46.7%) and sixteen (53.3%) were female, with a mean age at diagnosis was4.2 ± 2.9 years. During follow-up, 24 patients (80.0%) were diagnosed with CPP, 15 patients (50.0%) had gelastic seizure, and 13 patients (43.3%) had developmental delay. The gelastic seizure was significantly associated with sessile type HH rather than pedunculated type HH (85.7% vs. 18.8%, p = 0.001). After GnRH agonist treatment, discrepancies between bone age and chronological age decreased (3.3 ± 1.3 years to 2.0 ± 1.7 years, p = 0.002). Additionally, height standard deviation score for bone age was increased, and predicted adult height increased significantly in females, while males showed an increasing trend. Clinical symptoms of HH were closely associated with the location of HH, and GnRH agonist treatment was safe and effective in the management of CPP caused by HH.

Various radiosurgery (RS) techniques are available for the therapy of epilepsy related to hypothalamic hamartomas (HH). As shown in previous reports, each RS method can reduce the frequency of seizures, as well as behavioral and cognitive alterations related to HH. This review summarizes the safety and efficacy of the most frequently used RS techniques for HH patients, with a particular focus on the Gamma Knife RS, interstitial brachytherapy, and linear accelerator (LINAC) RS. Literature compilation was achieved through use of a wide spectrum of information—namely, Cochrane Library, PubMed®, and the National Institute of Health (NIH) clinical trials register. All identified reports were peer-reviewed and less than 20 years old. Relevant patient information, including RS method, follow-up, seizure outcome, and side effects, were selected from the above databases. Thirty-four reports with a total number of 123 patients, including 48 patients from singular randomized trial, were included in the review. The most common clinical presentations were gelastic seizures and cognitive dysfunctions. All RS techniques demonstrate approximately the same seizure reduction outcomes achieving maximal values of 90%. The brachytherapy was reported to have a higher risk of brain edema or memory deterioration compared to the Gamma Knife or LINAC-based RS. Common limitations for the RS therapies included large sizes of hamartomas and their prolonged time latencies. RS is the least invasive curative therapy with a lower rate of complications compared to surgery. RS can be considered the therapy of choice especially for small or medium-sized HH.

Objective To study the clinical features of hypothalamic hamartoma (HH) in adults. Methods A retrospective review of 27 cases of hypothalamic hamartoma in adults was performed, which account for 12.62% in all 214 hypothalamic hamartoma patients diagnosed in Beijing Tiantan Hospital from 1994 to 2008. Results The mean age of the patients diagnosed as hypothalamic hamartoma was 29.22 years old ranged from 18 to 66 years old, the rate of male to female was 2∶1. Eight patients (29.63%) were asymptomatic and 19 patients (70.37%) were symptomatic. The onset of symptom developed before adult life were found in 14 patients (73.68%), the other 5 patients (26.32%) developed a milder epileptic seizures in adult life which ranged from 19 to 51 years old. Most patients presented grand mal epilepsy. Hypothalamic hamartoma was diagnosed by the combination of medical history with CT and MRI which presented space occupying lesion at interpeduncular cistern or in the third ventricle. The first symptom presented in 19 cases of symptomatic patients were as follow: precocious puberty in 3 cases (15.79% ), gelastic seizure in 9 patients (47.37%), absence seizure in 2 patients (10.52%) and generalized tonic⁃clonic seizure in 5 patients (26.32%). Two patients combined with mental retardation. Among the 9 patients with gelastic seizure, 2 patients had generalized tonic⁃clonic seizure at the time of onset of gelastic seizure, 6 patients presented with generalized tonic⁃clonic seizure at the mean time of 10.70 years (ranged from 6 months to 21 years) after the onset of gelastic seizure, one patient presented with gelastic seizure only. All the patients performed CT and MRI, and the time of follow⁃up was 14 months to 9 years and 10 months. Six patients underwent resection of hypothalamic hamartoma through pterional approach or callosal⁃septum pellucidum⁃interforniceal approach. Three cases were cured (Engel class Ⅰ). Seizures were almost free in 2 cases (Engel classⅡ). Seizures were not changed in one case (Engel class Ⅴ). Two patients underwent γ⁃knife surgery: one case showed no change at seizure onset and another one showed reduction of seizure frequency (Engel class Ⅳ). Antiepileptic drugs were used in 9 patients, but no effect was seen on gelastic seizure. Conclusion Adults with hypothalamic hamartoma usually present with mild epilepsy and seldom occur intellectual disturbance. Treatment should be given with caution. DOI：10.3969/j.issn.1672-6731.2010.03.019

Gelastic seizures associated with hypothalamic hamartomas (HHs) are a clinicoradiologic syndrome presenting with a variety of symptoms, including pharmacoresistant epilepsy with multiple seizure types, electroencephalography (EEG) abnormalities, precocious puberty, behavioral disturbances, and progressive cognitive deterioration. Surgery in adults provides seizure freedom in only one third of patients. The poor results of epilepsy surgery could be explained by an extrahypothalamic epileptogenic zone. The existence of an independent, secondary epileptogenic area with persistent seizures after resection of the presumably primary lesion supports the concept of a "hypothalamic plus" epilepsy. "Hypothalamic plus" epilepsy could be related to either an extrahypothalamic structural lesion (visible on magnetic resonance imaging [MRI] or on neuropathology) or if the former is absent, to a functional alteration with enhanced epileptogenic properties due to a process termed secondary epileptogenesis. We report two patients with gelastic seizures with HH (gelastic seizures isolated or associated with dyscognitive seizures of temporal origin). Both patients underwent two-step surgery: first an endoscopic resection of the HH, followed at a later time by temporal lobectomy. Both patients became seizure-free only after the temporal lobectomy. In both cases, neuropathology failed to demonstrate a significant structural lesion in the temporal lobe. To our knowledge, for the first time, these two cases suggest the existence of independent secondary epileptogenesis in humans.

Epileptic network of hypothalamic hamartoma: An EEG-fMRI study

Management of Epilepsy Due to Hypothalamic Hamartomas

The LHRH-secreting hypothalamic hamartoma (HH), a congenital malformation consisting of a heterotopic mass of nervous tissue that contains LHRH neurosecretory neurons attached to the tuber cinereum or the floor of the third ventricle, can cause true or central precocious puberty (TPP). We have suggested that it functions as an ectopic LHRH pulse generator independent of the central nervous system inhibitory mechanism that normally restrains the hypothalamic LHRH pulse generator. TPP associated with a hamartoma has all of the hormonal hallmarks of puberty, including a pubertal pattern of pulsatile LH and a pubertal plasma LH response to LHRH administration. Little is known about the natural history of HH. We present long term data on 10 children (5 females and 5 males) with TPP due to HH. Physical signs of puberty were observed at a mean age of 2.2 +/- 1.6 yr (range, 0.5-5.1). Two of 10 had a pedunculated mass, and 8 of 10 had a sessile mass. The hamartoma varied in diameter from 4-25 mm and did not change with time (3.5-8.7 yr). Four patients have a seizure disorder, 3 with gelastic seizures (1 with mental retardation) and 1 with tonic-clonic seizures. The shape of the hamartoma, sessile or pedunculated, did not correlate with the occurrence of seizures. At presentation with sexual precocity, the mean height SD for chronological age was +3.5 +/- 0.4, the mean height SD for bone age was -1.9 +/- 0.4, and the mean bone age SD for chronological age was +6.8 +/- 0.7. Baseline data were comparable to those of 10 females with idiopathic TPP. Nine of 10 HH patients and all idiopathic TPP patients were treated with a LHRH agonist. The response to therapy was excellent in both groups and indistinguishable. Nine of 10 HH children attend school regularly and, aside from those with seizures, have no neurological handicap. While surgical resection of the hamartoma has been recommended, it carries an increased risk of morbidity and mortality and, if removal is incomplete, does not arrest the sexual precocity. In our experience, LHRH agonist therapy for TPP due to HH is the preferable approach.

Hypothalamic hamartomas (HH) are developmental malformations of the hypothalamus associated with a potentially treatable epileptic encephalopathy, characterized by early onset gelastic seizures, the later development of multiple seizure types and progressive cognitive and behavioral decline. Surgical treatment of HH can lead to seizure control and improvement in the cognitive-behavioral syndrome. Video-EEG telemetry (VET) is often necessary to characterize the semiology of the seizures, but there are no specific interictal or ictal EEG pattems that will confirm the diagnosis. Magnetic resonance imaging (MRI) can identify HH and define their anatomy, but the imaging findings may be subtle and susceptible to artifactual contamination. We present a patient with intractable gelastic epilepsy in whom the diagnosis of HH was initially missed due to failure to recognize the clinical syndrome and contamination of the MRI images with dental hardware artifact. VET confirmed the clinical diagnosis and the HH was identified on MRI after the dental hardware was removed. VET should be performed to confirm seizure semiology in patients with suspected gelastic epilepsy. Establishing this diagnosis can subsequently direct the appropriate neuroradiological evaluation for HH and surgical treatment of these lesions.

Hypothalamic hamartomas (HHs) are developmental malformations associated with focal epilepsy. We investigated the patterns of gray matter morphology and cerebral metabolism in individuals with HHs, with and without focal to bilateral tonic-clonic seizures (FBTCSs), aiming to clarify the accompanying network abnormalities. We analyzed magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (PET) data from 59 patients with HHs (28 with FBTCSs, 31 without), as well as MRI data from 30 healthy controls (HCs) and PET data from 45 HCs. We assessed gray matter voxel-based morphometry and quantitative analysis of cerebral glucose uptake in HH patients and controls, with age, sex, and total intracranial volume as covariates, and drew correlations with duration of epilepsy and seizure semiology and frequency. Compared to HCs, HH patients had significantly increased gray matter volume (GMV) in the ipsilateral amygdala, piriform cortex, hypothalamus, and bilateral temporal cortices; patients with FBTCSs primarily showed increased GMV in the HH stalk, whereas those without FBTCSs showed increased GMV prominently in the amygdala. GMVs of amygdala and piriform cortex were greater and the ipsilateral midtemporal cortex was more hypometabolic the longer the duration of epilepsy and the greater the seizure frequency. No significant GMV or cerebral glucose uptake differences were found between HH patients with and without FBTCSs. HH-related epilepsy is a network disorder characterized by widespread abnormalities beyond the lesion. This highlights the importance of considering the whole network when formulating diagnosis and treatment plans.

Objective To investigate the diagnosis and microsurgical treatment of hypothalamic hamartoma in children.Methods A retrospective analysis was conducted on five cases with hypothalamic hamartoma in children from January 1998 to December 2006.Five children(two boys and three girls)were treated for precocious puberty and gelastic seizures secondary to hypothalamic hamartoma.The age ranged from 20 months to 9 years with a mean of 44.4 months.Two cases mainly displayed precocious puberry,1 with gelastic seizures and the other 2 cases with both of precocious puberty and gelastic secures.The sex hormone level of four cases was about 5 to several dozen times more than nolTnal before operation.Magnetic resonance imaging clearly demonstrated an isointense mass in the interpeduncular cistern(5 cases)and suprasellar cistem(2 cases)ranged from 13.9 to 21.0mm in diameter without enhanced pictures after injected Gd-DTPA.The hamartomas were totally removed via a right frontotemporal approach under microscope.Results All hypothalamic hamartomas were completely resected under microscope and confirmed by pathological examination.The symptoms and signs of precocious puberty completely regressed postoperatively,and sex hormone level descended to prepubertal level in all patients.The symptoms of gelastic seizures completely disappeared in two patients and obviously reduced from ten times per day before operation to one time per fortnight in another one patient.There was no any complication during 1 year follow-up in all patients.Conclusions Microsurgery can be deserved the first choice of treatment for hypothalamic hamartoma in children. Key words: Hamartoma; Epilepsy; Microsurgery

Gelastic seizures comprise a very rare form of epilepsy. They present with recurrent bursts of laughter voices without mirth and are most commonly associated with the evolution of a hypothalamic hamartoma. The purpose of this article is to describe the second reported ictal fluorodeoxyglucose-positron emission tomography study in a unique case of an infant with intractable gelastic seizures since the neonatal period associated with a hypothalamic hamartoma. The patient presented at 4 months old with recurrent, almost persistent, gelastic seizures consisting of laughter bouts without mirth. The seizures were noticeable at the first week of life and increased in frequency to last up to 12 hours, namely status gelasticus. These gelastic fits were accompanied with focal motor seizures, including unilateral right-eye blinking and mouth twitching. Developmental mile-stones were intact for age. Magnetic resonance imaging of the cortex demonstrated a large hypothalamic hamartoma within the third ventricle, hampering cerebrovascular fluid drainage of the lateral ventricles. An electroencephalography was nondiagnostic. Ictal fluorodeoxyglucose-positron emission tomography demonstrated a large circumscribed hypermetabolic region within the location of the hypothalamic hamartoma, representing localized intense epileptiform activity. The infant became instantly free of all seizure types given minute doses of oral benzodiazepine (clonazepam) and remains completely controlled after 12 months. Her overall development remains intact. This ictal fluorodeoxyglucose-positron emission tomography is the second reported study verifying that the main source of the epileptic activity inducing gelastic seizures originates from the hypothalamic hamartoma itself; therefore, a complementary fluorodeoxyglucose-positron emission tomography study should be considered in any patient presenting with intractable gelastic seizures, especially in those associated with hypothalamic hamartoma, in order to localize the region of epileptiform activity amenable to surgical resection if intensive drug therapy fails.

Background: Hypothalamic hamartomas (HHs) are congenital lesions composed of neurons and astroglia. Frequently, HHs cause central precocious puberty (CPP) and/or gelastic seizures. Because HHs might express genes similar to those required for the initiation of normal puberty, we used cDNA arrays to compare the gene expression profile of an HH associated with CPP with three HHs not accompanied by sexual precocity. Methods: Global changes in gene expression were detected using Affymetrix arrays. The results were confirmed by semiquantitative PCR, which also served to examine the expression of selected genes in the hypothalamus of female monkeys undergoing puberty. Results: All HHs were associated with seizures. Ten genes whose expression was increased in the HH with CPP were identified. They encode proteins involved in three key cellular processes: transcriptional regulation, cell-cell signaling, and cell adhesiveness. They include IA-1 and MEF2A, two transcription factors required for neuronal development; mGluR1 and VILIP-1, which encode proteins involved in neuronal communication, and TSG-6 that encodes a protein involved in cell adhesiveness. Of these, expression of mGluR1 also increases in the female monkey hypothalamus at puberty. Conclusions: Increased expression of these genes in HHs may be relevant to the ability of some HHs to induce sexual precocity.

Achieving favorable seizure outcomes is challenging in patients with seizures resulting from hypothalamic hamartoma. Although minimally invasive and non-invasive surgical procedures are used to treat this population, these procedures have limitations. Therefore, we analyzed the outcomes of patients with hypothalamic hamartoma following direct resection. We included 159 patients with hypothalamic hamartoma who underwent direct resection using the transcallosal interforniceal approach between 2011 and 2018. The relationships between clinical parameters and seizure outcomes were analyzed. In total, 55.3% achieved gross total resection and 25.2% underwent near-total resection. Of all patients, 79.2% were overall seizure-free at one year, but this number dropped to 77.0% at more than five years. Moreover, 88.4% (129/146) reached gelastic seizure (GS)-free status at one year and this number increased to 89.0% (97/109) at more than five years. Seventy-one patients took antiseizure medication (ASM) long-term, 68 took it for one year, and 11 took it for one-half year. The duration of ASM consumption (p < 0.001) and extent of hypothalamic hamartoma resection (p = 0.016) were significant independent predictors of long-term overall seizure-free survival, while the duration of ASM consumption (p = 0.011) and extent of hypothalamic hamartoma resection (p = 0.026) were significant independent predictors of long-term GS-free survival. Most patients' behavior, school performance, and intelligence were not affected after surgery. Direct resection is effective and safe strategy for patients with hypothalamic hamartomas. Hypothalamic hamartomas should be removed as completely as possible, and patients should take ASM long-term following surgery to reach long-term overall seizure-free or GS-free status.