Gelastic Research Articles

Clinical features and evolution of the gelastic seizures-hypothalamic hamartoma syndrome.

Gelastic seizures, usually with onset in early infancy, are the hallmark manifestation of hypothalamic hamartoma. This seizure type is directly generated by hamartoma itself, intrinsically epileptogenic because of its anatomofunctional organization. Other types of seizures, focal or generalized, may appear during the evolution, probably resulting from mechanisms of secondary epileptogenesis. Nevertheless, the clinical expression and the severity of the syndrome, ranging from a focal drug-resistant epilepsy to a catastrophic generalized encephalopathy with severe cognitive and behavioral impairments, depends on the size and the site of attachment of the hamartoma. Early suspicion, timely diagnosis, and appropriate treatment are mandatory to reverse a potential catastrophic evolution of this condition.

Medical management and antiepileptic drugs in hypothalamic hamartoma.

Hypothalamic hamartoma may present with epilepsy, specifically gelastic or dacrystic seizures, or endocrine dysfunction, commonly precocious puberty. The epilepsy in many patients is drug resistant, and has a high association with progressive cognitive, learning and behavioral difficulty. Medical treatment of seizures remains problematic, with many resistant to drug treatment. Surgical resection, or disconnection of the hamartoma provides the optimal chance of seizure control but with a relatively high risk of endocrine dysfunction, the result of interference with the hypothalamic-pituitary axis in many. Careful assessment and monitoring by specialist centers with discussion of optimal intervention is required for individual cases.

Hypothalamic hamartoma: Neuropathology and epileptogenesis.

Hypothalamic hamartomas (HHs) are congenital malformations of the ventral hypothalamus resulting in treatment-resistant epilepsy and are intrinsically epileptogenic for the gelastic seizures that are the hallmark symptom of this disorder. This paper reviews the neuropathologic features of HHs associated with epilepsy, with an emphasis on characterizing neuron phenotypes and an ultimate goal of understanding the cellular model of ictogenesis occurring locally within this tissue. We also present previously unpublished findings on Golgi staining of HH. The microarchitecture of HH is relatively simple, with nodular clusters of neurons that vary in size and abundance with poorly defined boundaries. Approximately 80-90% of HH neurons have an interneuron-like phenotype with small, round soma and short, unbranched processes that lack spines. These neurons express glutamic acid decarboxylase and likely utilize γ-aminobutyric acid (GABA) as their primary neurotransmitter. They have intrinsic membrane properties that lead to spontaneous pacemaker-like firing activity. The remaining HH neurons are large cells with pleomorphic, often pyramidal, soma and dendrites that are more likely to be branched and have spines. These neurons appear to be excitatory, projection-type neurons, and have the functionally immature behavior of depolarizing and firing in response to GABA ligands. We hypothesize that the irregular neuronal clusters are the functional unit for ictogenesis. Further research to define and characterize these local networks is required to fully understand the cellular mechanisms responsible for gelastic seizures.

Comparison of Perioperative Costs between Stereotactic Laser Ablation and Craniotomy for Hypothalamic Hamartoma

Hypothalamic hamartoma (HH) is a congenital intracranial lesion associated with precocious puberty and gelastic epilepsy in children. Surgical management of HH to treat refractory epilepsy is a mainstay of treatment. Our aim was to compare the demographic characteristics and perioperative costs associated with resection by craniotomy and stereotactic laser ablation (SLA) by reviewing our institutional experience with SLA and comparing these data to a national database for craniotomy and resection. Retrospective chart review was conducted for the Texas Children's Hospital cohort of patients who underwent SLA for HH between 2011 and 2013. Information about the craniotomy cohort representing historical cases of craniotomy was obtained from the Kids' Inpatient Database for years 2003, 2006, and 2009. The cohort definition for patients undergoing craniotomy for HH was modified from published adult literature to identify pediatric patients with refractory epilepsy secondary to HH. Our study has shown that children undergoing SLA for HH have a shorter length of stay and lower cost of hospitalization compared with those who underwent craniotomy and resection for the same diagnosis. Together with previous findings from our institution regarding the safety and efficacy of SLA, our findings suggest that SLA may represent an attractive alternative to craniotomy for the treatment of refractory epilepsy secondary to HH.

Ca2+ -permeable AMPA receptors associated with epileptogenesis of hypothalamic hamartoma.

Hypothalamic hamartoma (HH), composed of neurons and glia without apparent cytologic abnormalities, is a rare developmental malformation in humans. Patients with HH often have characteristic medically refractory gelastic seizures, and intrinsic epileptogenesis within the lesions has been speculated. Herein we provide evidence to suggest that in HH neurons, Ca2+ permeability through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors is aberrantly elevated. In needle biopsy specimens of HH tissue, field potential recordings demonstrated spontaneous epileptiform activities similar to those observed in other etiologically distinct epileptogenic tissues. In HH, however, these activities were clearly abolished by application of Joro Spider Toxin (JSTX), a specific inhibitor of the Ca2+ -permeable AMPA receptor. Consistent with these physiologic findings, the neuronal nuclei showed disappearance of adenosine deaminase acting on RNA 2 (ADAR2) immunoreactivity. Furthermore, examination of glutamate receptor 2 (GluA2) messenger RNA (mRNA) revealed that editing efficiency at the glutamine/arginine site was significantly low. These results suggest that neurons in HH may bear Ca2+ -permeable AMPA receptors due to dislocation of ADAR2.

Pure endoscopic management of epileptogenic hypothalamic hamartomas.

Hypothalamic hamartomas (HH) are rare congenital malformations located in the region of the tuber cinereum and third ventricle. Their usual clinical presentation is characterized by gelastic/dacrystic seizures which often become pharmaco-resistant and progress to secondary focal/generalized intractable epilepsy causing mostly in children cognitive and behavioral problems (particularly in cases of progressive epileptic encephalopathy) and precocious puberty. Whereas gelastic seizures can be surgically controlled either by resection of the lesion or disconnection (tissue-destructive) procedures, aimed at functionally prevent the spreading of the epileptic burst; generalized seizures tend to respond better to HH excision rather than isolated neocortical resections, which generally fail to control them. Prospective analysis of 14 consecutive patients harboring HH treated in an 8-year period; 12 patients had unilateral and two bilateral HH. All patients were managed by pure endoscopic excision of the HH. The mean operative time was 48min and mean hospital stay was 2days; perioperative blood loss was negligible in all cases. Two patients showed a transient diabetes insipidus (DI); no transient or permanent postoperative neurological deficit or memory impairment was recorded. Complete HH excision was achieved in 10/14 patients. At a mean follow-up of 48months, no wound infection, meningitis, postoperative hydrocephalus, and/or mortality were recorded in this series of patients. Eight patients became seizure free (Engel class I), 2 other experienced worthwhile improvement of disabling seizures (Engel class II); 2 patients were cured from gelastic attacks while still experiencing focal dyscognitive seizures; and 2, having bilateral HH (both undergoing unilateral HH excision), did not experience significant improvement and required later on a temporal lobectomy coupled to amygdalohyppocampectomy. Overall, the followings resulted to be predictive factors for better outcomes in terms of seizure control: (1) cases of unilateral, Delalande class B, HH, (2) shorter history of epilepsy. Endoscopic resection of HH proved, in our series, to be effective in achieving complete control or in reducing the frequency of seizures. Furthermore, this approach has confirmed its minimally invasive nature with a very low morbidity rate: of note, it allowed to better preserve short-term memory and hypothalamic function.

EPILEPSY WITH GELASTIC SEIZURES AND HYPOTHALAMIC HAMARTOMA: A RARE CLINICAL CASE

Among the various types of epileptic syndromes, gelastic seizures are considered the rarest one. The condition is characterized by forced laughter and the finding of hypothalamic hamartoma. Gelastic seizures may be associated with temporal or frontal foci of epilepsy, tumors, tuberous sclerosis, hemangiomas, and infectious lesions, including hypothalamic hamartoma. The tissue of a hypothalamic hamartoma is, by its nature, an epileptogenic zone. In the presence of a hypothalamic hamartoma, the expression of neuropeptides is often disturbed, which can contribute to the development of a seizure attack. Episodes of forced laughter in patients with hypothalamic hamartomas can be combined with various vegetative manifestations, motoric and mental symptoms. The report presents a clinical case of gelastic seizures in an adult male with hypothalamic hamartoma; the report includes the stepwise diagnosis and the treatment with transcranial magnetic stimulation (TMS). After a course of restorative therapy, control of epileptic seizures has been improved.

Epilepsy surgery in children.

Approximately 60% of all patients with epilepsy suffer from focal epilepsy syndromes. In approximately 15% of these patients, the seizures are not adequately controlled with anticonvulsive drugs, and such patients are potential candidates for surgical treatment and majority are children. Epilepsy surgery in children, who have been carefully chosen, can result in either seizure freedom or a marked (>90%) reduction in seizures in approximately two-third of children with intractable seizures. In the multimodality presurgical evaluation approach, sufficient concordance should be established among various independent investigations, thus identifying the location and extent of the epileptogenic zone with a high degree of confidence. Early surgery improves the quality of life and cognitive and developmental outcome of the child. Surgically remediable epilepsies in children should be identified early and include temporal lobe epilepsy with focal lesions, lesional extratemporal epilepsies, hemispherical epilepsies, and gelastic epilepsy with hypothalamic hamartoma, and can be treated by resective or disconnection surgery. Palliative procedures include corpus callosotomy and vagal nerve stimulation for children with diffuse and multifocal epilepsies, who are not candidates for resective surgery. Deep brain stimulation in patients with epilepsy is still under evaluation. For children with "surgically remedial epilepsy," surgery should be offered as a procedure of choice rather than as a treatment of last resort.

Clinical features and postoperative seizure outcome in patients with drug-resistant gelastic seizures without hypothalamic hamartoma

The objective of this study was to describe the clinical characteristics and surgical outcome in patients with gelastic seizures without hypothalamic hamartoma. We retrospectively reviewed all the video-EEG reports over a 5-year period (2007-2011) for the occurrence of the terms "laugh" or "giggle" in the text body. All the patients with at least one documented gelastic seizure at the epilepsy monitoring unit were studied. In patients who underwent epilepsy surgery, seizure outcomes were analyzed. Sixteen patients (10 females and 6 males) with a mean age of 46.3years were studied. Seven patients had invasive intracranial EEG recordings. Seizure onset zone was in a temporal lobe in four patients and the frontal lobe in one patient. Two patients did not have gelastic seizures during their intracranial EEG monitoring. Nine patients underwent resective epilepsy surgery for their seizures. Six patients (67%) were seizure-free after surgery. In adult patients, gelastic seizures can be seen in patients with focal epilepsy without hypothalamic hamartoma. Nonhypothalamic hamartoma gelastic seizures originating from the temporal lobe can be amenable to surgery.

Magnetic resonance imaging-guided laser interstitial thermal therapy for previously treated hypothalamic hamartomas.

OBJECTIVE Hypothalamic hamartomas (HHs) are associated with gelastic seizures and the development of medically refractory epilepsy. Magnetic resonance imaging-guided laser interstitial thermal therapy (MRg-LITT) is a minimally invasive ablative treatment that may have applicability for these deep-seated lesions. Here, the authors describe 3 patients with refractory HHs who they treated with MRg-LITT. METHODS An institutional review board-approved prospective database of patients undergoing Visualase MRg-LITT was retrospectively reviewed. Demographic and historical medical data, including seizure and medication histories, previous surgeries, procedural details, and surgical complications, along with radiological interpretation of the HHs, were recorded. The primary outcome was seizure freedom, and secondary outcomes included medication reduction, seizure frequency, operative morbidity, and clinical outcome at the latest follow-up. RESULTS All 3 patients in the multi-institutional database had developed gelastic seizures related to HH at the ages of 7, 7, and 9 years. They presented for further treatment at 25, 28, and 48 years of age, after previous treatments with stereotactic radiosurgery in all cases and partial hamartoma resection in one case. One ablation was complicated by a small tract hemorrhage, which was stable on postoperative imaging. One patient developed hyponatremia and experienced weight gain, which were respectively managed with fluid restriction and counseling. At the most recent follow-up at a mean of 21 months (range 1-32 months), one patient was seizure free while another had meaningful seizure reduction. Medication was reduced in one case. CONCLUSIONS Adults with gelastic seizures despite previous treatments can undergo MRg-LITT with reasonable safety and efficacy. This novel therapy may provide a minimally invasive alternative for primary and recurrent HH as the technique is refined.

The diagnosis and management of hypothalamic hamartomas in children

Hypothalamic hamartoma (HH) is a rare developmental malformation often characterized by gelastic seizures. Recent advances in treating HH have led to dramatic improvements. However, clinical protocol of HH is poorly understood. Since 2002, department Pediatric Neurosurgery of Xinhua Hospital has maintained a multidisciplinary clinical program to evaluate and treat children with HH. This program has provided the opportunity to investigate the management of HH. In this review, we summarize the clinical progress and propose a clear management principle for different HH patients.

Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy

Hypothalamic hamartoma (HH) with gelastic epilepsy is a well-recognized drug-resistant epilepsy syndrome of early life.(1) Surgical resection allows limited access to the small deep-seated lesions that cause the disease. Here, we report the results of a search for somatic mutations in paired hamartoma- and leukocyte-derived DNA samples from 38 individuals which we conducted by using whole-exome sequencing (WES), chromosomal microarray (CMA), and targeted resequencing (TRS) of candidate genes. Somatic mutations were identified in genes involving regulation of the sonic hedgehog (Shh) pathway in 14/38 individuals (37%). Three individuals had somatic mutations in PRKACA, which encodes a cAMP-dependent protein kinase that acts as a repressor protein in the Shh pathway, and four subjects had somatic mutations in GLI3, an Shh pathway gene associated with HH. In seven other individuals, we identified two recurrent and three single brain-tissue-specific, large copy-number or loss-of-heterozygosity (LOH) variants involving multiple Shh genes, as well as other genes without an obvious biological link to the Shh pathway. The Shh pathway genes in these large somatic lesions include the ligand itself (SHH and IHH), the receptor SMO, and several other Shh downstream pathway members, including CREBBP and GLI2. Taken together, our data implicate perturbation of the Shh pathway in at least 37% of individuals with the HH epilepsy syndrome, consistent with the concept of a developmental pathway brain disease.

A rare central nervous system anomaly in a tuberous sclerosis case with gelastic seizures: Corpus callosum agenesis

Gelastic seizures are associated with hypothalamic hamartomas in general. Herein, we report a patient with gelastic seizures who was diagnosed with tuberous sclerosis complex and corpus callosum agenesis in the absence of hypothalamic hamartomas. As all these rare conditions were together in this patient, tuberosclerosis presented with gelastic seizures in the presence of corpus callosum agenesis without hypothalamic hamartomas, this case was regarded as valuable to be reported in the light of recent literature.

Epileptic network of hypothalamic hamartoma: An EEG-fMRI study

ObjectiveTo investigate the brain networks involved in epileptogenesis/encephalopathy associated with hypothalamic hamartoma (HH) by EEG with functional MRI (EEG-fMRI), and evaluate its efficacy in locating the HH interface in comparison with subtraction ictal SPECT coregistered to MRI (SISCOM). MethodsEight HH patients underwent EEG-fMRI. All had gelastic seizures (GS) and 7 developed other seizure types. Using a general linear model, spike-related activation/deactivation was analyzed individually by applying a hemodynamic response function before, at, and after spike onset (time-shift model=−8–+4s). Group analysis was also performed. The sensitivity of EEG-fMRI in identifying the HH interface was compared with SISCOM in HH patients having unilateral hypothalamic attachment. ResultsEEG-fMRI revealed activation and/or deactivation in subcortical structures and neocortices in all patients. 6/8 patients showed activation in or around the hypothalamus with the HH interface with time-shift model before spike onset. Group analysis showed common activation in the ipsilateral hypothalamus, brainstem tegmentum, and contralateral cerebellum. Deactivation occurred in the default mode network (DMN) and bilateral hippocampi. Among 5 patients with unilateral hypothalamic attachment, activation in or around the ipsilateral hypothalamus was seen in 3 using EEG-fMRI, whereas hyperperfusion was seen in 1 by SISCOM. SignificanceGroup analysis of this preliminary study may suggest that the commonly activated subcortical network is related to generation of GS and that frequent spikes lead to deactivation of the DMN and hippocampi, and eventually to a form of epileptic encephalopathy. Inter-individual variance in neocortex activation explains various seizure types among patients. EEG-fMRI enhances sensitivity in detecting the HH interface compared with SISCOM.

Gap Junctions and Epileptogenesis: No Laughing Matter

Gap Junctions and Epileptogenesis: No Laughing Matter

Robot Assisted Stereotactic Laser Ablation for a Radiosurgery Resistant Hypothalamic Hamartoma.

Hypothalamic hamartomas (HH) are benign tumors that can cause significant morbidity in adults as a cause of epilepsy, particularly gelastic seizures. Open and endoscopic resections of HH offer good seizure control but have high rates of morbidity and are technically challenging. Stereotactic radiosurgery has been an alternative treatment; however, it results in comparably poor seizure control. Recently, in children, stereotactic laser ablation has shown promise as a surgical technique that can combine the best features of both of these approaches for the treatment of HH. Here we present the first reported use of a frameless robot-assisted stereotactic system to treat an HH. The patient had failed two previous Gamma Knife radiosurgery treatments. Post-procedure he had a stable, but unintentional weight loss of 20 kg and a transient episode of hemiparesis the night of the operation. At six months postoperatively the patient remained seizure free. Stereotactic laser ablation may represent a new standard in the treatment of HH in adults, especially in those who have failed radiosurgery. Further study is warranted in this population to determine efficacy and safety profiles.

Adult-onset refractory epilepsy with hypothalamic hamartoma and no gelastic seizures successfully treated by stereotactic thermocoagulation: A case report

Adult-onset refractory epilepsy with hypothalamic hamartoma and no gelastic seizures successfully treated by stereotactic thermocoagulation: A case report

Ictal electrographic pattern of focal subcortical seizures induced by sound in rats

It is now recognized that both generalized and focal seizures may originate in subcortical structures. The well-known types of focal subcortically-driven seizures are gelastic seizures in patients with the hypothalamic hamartoma and sound-induced seizures in rodents with audiogenic epilepsy. The seizures are generated by subcortical intrinsically epileptogenic focus, the hamartoma in humans and the inferior colliculus (IC) in rodents. In patients with gelastic epilepsy additional seizure types may develop with time that are supposed to result from secondary epileptogenesis and spreading of epileptic discharges to the cortex. Repeated audiogenic seizures can also lead to development of additional seizure behavior and secondary epileptic activation of the cortex. This process, named audiogenic kindling, may be useful for studying secondary subcortico-cortical epileptogenesis. Using intracollicular and intracortical recordings, we studied an ictal electrographic pattern of focal subcortical seizures induced by repeated sound stimulation in Wistar audiogenic-susceptible rats. The audiogenic seizures, representing brief attacks of paroxysmal unidirectional running, were accompanied by epileptiform abnormalities in the IC, mostly on the side ipsilateral to run direction, and enhanced rhythmic 8–9Hz activity in the cortex. With repetition of the subcortical seizures and kindling development, a secondary cortical discharge began to follow the IC seizure. The secondary discharge initially involved the cortex homolateral to the side of dominant subcortical epileptiform abnormalities and behaviorally expressed as limbic (partial) clonus. Kindling progression was associated with bilateralization of the secondary cortical discharge, an increase in its amplitude and duration, intensification of associated behavioral seizures (from partial clonus to generalized tonic–clonic convulsions). Thus, ictal recordings during brief audiogenic running seizures showed their focal subcortical origin. Repetition of the subcortical seizures may result in secondary subcortico-cortical epileptogenesis manifested by emergence and progressive intensification of epileptiform discharges in the cortex.

Stereotactic radiofrequency thermocoagulation for giant hypothalamic hamartoma.

OBJECTIVE The authors undertook this study to validate the feasibility and safety of stereotactic radiofrequency thermocoagulation (SRT) for the surgical treatment of giant hypothalamic hamartoma (HH). METHODS Of the 109 patients who underwent SRT for hypothalamic hamartoma (HH) at the authors' institution between 1997 and 2013, 16 patients (9 female, 7 male) had giant HHs (maximum diameter ≥ 30 mm). The clinical records of these 16 patients were retrospectively reviewed. RESULTS The patients' age at first SRT ranged from 1 to 22 years (median 5 years). The maximum diameter of their HHs was 30-80 mm (mean 38.5 mm). Eleven HHs had bilateral attachments to the hypothalamus. All patients had gelastic seizures (GS), and 12 had types of seizures other than GS. Some of these patients also had mental retardation (n = 10, 62.5%), behavioral disorders (n = 8, 50.0%), and precocious puberty (n = 11, 68.8%). A total of 22 SRT procedures were performed; 5 patients underwent repeat SRT procedures. There was no mortality or permanent morbidity. After 17 of the 22 procedures, the patients experienced transient complications, including high fever (n = 7), hyperphagia (n = 3), hyponatremia (n = 6), disturbance of consciousness (n = 1), cyst enlargement (n = 1), and epidural hematoma (n = 1). Thirteen patients (81.3%) achieved freedom from GS after the final SRT procedure during a follow-up period ranging from 6 to 60 months (mean 23 months). Twelve patients had nongelastic seizures in addition to GS, and 7 (58.3%) of these 12 patients experienced freedom from their nongelastic seizures. CONCLUSIONS SRT provided minimal invasiveness and excellent seizure outcomes even in patients with giant HHs. Repeat SRT is safe for residual GS. SRT is a feasible single surgical strategy for HH regardless of the tumor's size or shape.

Study progress of pathogenesis and clinical treatment of gelastic epilepsy

Gelastic epilepsy is a special refractory epilepsy accompany with ictal laughing and/or crying which can be divided into cortical induced gelastic epilepsy and hypothalamic hamartomas induced gelastic epilepsy according to their epileptogenic focus.Currently, domestic scholars had lack of systematic understanding of the mechanism and clinical treatment involved in gelastic epilepsy.Recently, foreign scholars had achieved great progress in the research of gelastic epilepsy which included the ictal laughing mechanism in gelastic epilepsy, the primary molecular mechanism in hypothalamic hamartomas induced gelastic epilepsy, the secondary epileptogenesis mechanism in hypothalamic hamartomas induced gelastic epilepsy and the clinical treatment of gelastic epilepsy.Now, the study progress of pathogenesis and clinical treatment of gelastic epilepsy were reviewed. Key words: Gelastic epilepsy; Clinical treatment; Child