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OBJECTIVE The purpose of this study is to investigate the outcomes of epilepsy surgery targeting the subcentimeter-sized resting state functional magnetic resonance imaging (rs-fMRI) epileptogenic onset zone (EZ) in hypothalamic hamartoma (HH). METHODS Fifty-one children with HH-related intractable epilepsy received anatomical MRI-guided stereotactic laser ablation (SLA) procedures. Fifteen of these children were control subjects (CS) not guided by rs-fMRI. Thirty-six had been preoperatively guided by rs-fMRI (RS) to determine EZs, which were subsequently targeted by SLA. The primary outcome measure for the study was a predetermined goal of 30% reduction in seizure frequency and improvement in class I Engel outcomes 1 year postoperatively. Quantitative and qualitative volumetric analyses of total HH and ablated tissue were also assessed. RESULTS In the RS group, the EZ target within the HH was ablated with high accuracy (>87.5% of target ablated in 83% of subjects). There was no difference between the groups in percentage of ablated hamartoma volume (P = 0.137). Overall seizure reduction was higher in the rs-fMRI group: 85% RS versus 49% CS (P = 0.0006, adjusted). The Engel Epilepsy Surgery Outcome Scale demonstrated significant differences in those with freedom from disabling seizures (class I), 92% RS versus 47% CS, a 45% improvement (P = 0.001). Compared to prior studies, there was improvement in class I outcomes (92% vs 76%-81%). No postoperative morbidity or mortality occurred. SIGNIFICANCE For the first time, surgical SLA targeting of subcentimeter-sized EZs, located by rs-fMRI, guided surgery for intractable epilepsy. Our outcomes demonstrated the highest seizure freedom rate without surgical complications and are a significant improvement over prior reports. The approach improved freedom from seizures by 45% compared to conventional ablation, regardless of hamartoma size or anatomical classification. This technique showed the same or reduced morbidity (0%) compared to recent non-rs-fMRI-guided SLA studies with as high as 20% permanent significant morbidity.

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 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.

International audience; Gamma Knife radiosurgery (GK) is an effective treatment for hypothalamic hamar-toma. No precise data are available on the risk of endocrine side effects of this treatment. In this study, 34 patients with hypothalamic hamartoma (HH) were followed prospectively at the Department of Endocrinology, La Timone Hospital, Marseille, France, for a mean follow-up of >2 years (mean AE standard deviation [SD] 3.6 AE 2 years). Initial pre-and post-GK radiosurgery evaluations were performed, including weight, body mass index (BMI), and a complete endocrinological workup. At diagnosis, eight patients presented with central precocious puberty at a mean age of 5.4 AE 2.4 years. At the time of GK (mean age 18.2 AE 11.1 years), two patients previously treated with surgery presented with luteinizing hormone/follicle-stimulating hormone (LH/FSH) deficiency. After GK, only one patient presented with a new thy-rotropin-stimulating hormone (TSH) deficiency, 2 years after the procedure. The other pituitary axes remained normal in all but two patients (who had LH/FSH deficiency prior to GK). There was no significant difference between pre-and post-GK mean BMI (26.9 vs. 25.1 kg/m 2 , p = 0.59). To conclude, in this group of 34 patients, GK did not induce major endocrinologic side effects reported with all the other surgical techniques in the literature. It is, thus, a safe and effective procedure in the treatment of hypothalamic hamartoma.

Summary The clinical appearance of patients with hypothalamic hamartomas is very heterogeneous, and interindividual variability of intellectual abilities is not completely understood. We retrospectively investigated cerebral dysfunction as indicated by reduced regional glucose metabolism in 29 patients (age range 7–49 years) with epilepsy due to hypothalamic hamartomas. Brain metabolism assessed by [18F]FDG-PET was compared between patients with and without cognitive impairment controlled for unevenly distributed hamartoma lateralization seen on magnetic resonance imaging (MRI). Due to the broad age range, the variable “age” was included in the imaging analyses as a covariate. Additional voxel-wise analysis with hamartoma volume, disease duration, seizure severity, seizure frequency, and antiepileptic drug (AED) load as well as dosage and gender as further covariates was accomplished. Furthermore, global visual ratings on laterality of hypometabolism patterns were assessed according to clinical standards and related to hamartoma lateralization on MRI as well as lateralization of electroencephalography (EEG) abnormalities. Cognitively impaired patients showed significantly reduced glucose metabolism in bilateral frontal as well as right parietal and posterior midline cortices (p

The discovery of intrinsic epileptogenicity of the hypothalamic hamartoma (HH) marked a new area in understanding the associated clinical syndrome, often manifesting as progressive epileptic encephalopathy. However, therapeutic procedures targeting the HH proved to be inefficient to cure seizures in up to 50% of cases, whereas in cases with partial improvement, the electroclinical patterns of persisting seizures suggest an involvement of distant cortical regions. The concept of kindling-like secondary epileptogenesis has been suggested as a possible underlying mechanism. Yet the role of the hypothalamic lesion in the pathophysiology of the syndrome remains debatable. In the Strasbourg-Kork series, the best outcomes were obtained when the duration of epilepsy before endoscopic HH surgery did not exceed 10 years. In two patients with HH ablation followed at a later time by a temporal lobectomy, only this second surgical step allowed complete seizure freedom. These findings suggest the existence of an independent, third stage of secondary epileptogenesis in human. In the Grenoble series, stereotactic intracerebral recordings (stereo electroencephalography [SEEG]) of five HH cases demonstrated that gelastic/dacrystic seizures were correlated with discharges within the HH, whereas other seizure types were related to discharges affecting cortical regions, which sometimes seemed to be triggered by HH. In the Marseille series, two cases explored by SEEG provided evidence of extended epileptogenicity outside the limits of the HH, forming complex epileptogenic networks, with HH still triggering clusters of neocortical seizures in the first, but not obligatory involved in spontaneous seizures in the second case. Taken together, our data argue for the existence of dynamic ictal network organization, with possible "kindling-like" relationships between the HH and the neocortex or widespread epileptogenesis. Despite the existence of secondary epileptogenesis, the epileptogenic zone could still be limited to the hamartoma, for which early surgical treatment should be pragmatically considered as a first surgical step.

Hypothalamic hamartoma (HH) is a relatively rare cause of epilepsy, mainly affecting children. Nearly all patients develop gelastic seizures, often followed by other focal seizure types. Our case illustrates the mechanisms of epileptogenesis in HH. The patient developed gelastic attacks as a baby, and secondarily generalized seizures and drop attacks at 9 years of age. Magnetic resonance imaging (MRI) confirmed the presence of a HH. Presurgical assessment with intracranial electroencephalography (EEG) monitoring recorded gelastic seizures with generalized epileptiform activity. Functional stimulation of the hamartoma provoked gelastic attacks. Single pulse electrical stimulation (SPES) was used to identify epileptogenic cortex. SPES of the left cingular cortex provoked generalized responses similar to the spontaneous generalized discharges. Our results suggest that long-standing history of epilepsy in patients with HH may be related to additional sources of epileptogenic activity. Electrical stimulation performed in this patient provided additional data to favor the hypothesis of secondarily epileptogenesis in the cingulate gyrus independently from the primary origin in the HH.

Hypothalamic hamartomas (HHs) have beendemonstrated as the cause of gelastic epilepsy,both by intracranial electrodes and functionalimaging. The neocortex becomes secondarilyinvolved, through poorly characterized propaga-tion pathways. The detailed dynamics of seizurespread have not yet been demonstrated, owing tothe limited spatial–temporal resolution of avail-able functional mapping. We studied a patientwith epilepsy associated with HH and gelasticepilepsy. Simultaneous electroencephalography(EEG) and functional magnetic resonance imaging(fMRI) of several seizure events were obtained,with blood oxygen level dependent (BOLD)activation of the hamartoma, and left hemispherehypothalamus, hippocampus, parietal–occipitalarea, cingulate gyrus, and dorsal–lateral frontalarea. Integration of regional BOLD kinetics andEEG power dynamics strongly suggests propaga-tion of the epileptic activity from the HH throughthe left fornix to the temporal lobe, and laterthrough the cingulate fasciculus to the left frontallobe. The EEG⁄fMRI method has the spatial–tem-poral resolution to study the dynamics of seizureactivity, with detailed demonstration of origin andpropagationpathways.KEY WORDS: Hypothalamic hamartoma, Epi-lepsy, BOLD, EEG-fMRI, Seizure, Functionalmapping.Epilepsy associated with hypothalamic hamartomas(HHs) has generated a lot of interest since the work ofBerkovic et al. (1988), which described the peculiar fea-tures of the syndrome. More recent studies have demon-strated the intrinsic epileptic character of the hamartoma(Munari et al., 1995; Kuzniecky et al., 1997), as well asthe excellent outcome of cases where surgical removalwas possible (Nishio et al., 1994; Fohlen et al., 2003;RosenfeldFRyvlinetal.,2003),with epileptic spikes involving predominantly the frontalor temporal areas, most often in a single hemisphere (Lealetal.,2003).Thisandthemonotonouscharacterofclinicalseizure manifestations in the first years of the syndromesuggest the existence of selective and stable propagationpathways from the hamartoma to the neocortex, whichnevertheless remain poorly characterized. The positronemission tomography (PET) and single-photon emissioncomputed tomography (SPECT) brain mapping tech-niques can show the participation of the hamartoma in theseizure events (Arroyo et al., 1997; Kuzniecky et al.,1997), as well as the neocortical dysfunction (Ryvlinet al., 2003), but their lack of temporal resolution does notallow insight into the dynamics of the propagation. Thescalp EEG has therequiredtime resolution,but itis insen-sitive to the activity in the hamartoma and deep neocorti-cal structures in general, and, therefore, has not allowed acomplete characterization of the ictal events (Leal et al.,2006). A full understanding ofthe dynamicsofthe epilep-tic activity throughout the seizure will require brain map-ping methods with both good spatial and temporal

Summary: Purpose: To present the results of transcallosal surgical resection of hypothalamic hamartoma (HH) in 26 patients with refractory epilepsy in a prospective outcome study. Methods: Patients with refractory epilepsy symptomatic to HH were referred for surgical resection of their HH (mean age, 10.0 years; range, 2.1–24.2 years). A transcallosal, interforniceal approach was used to remove and/or disconnect the hamartoma. Volumetry was obtained on pre- and postoperative brain MRI scans to determine percentage of resection. Outcome assessment included determination of postoperative seizure frequencies in comparison to baseline and the incidence of postoperative complications. Postoperative changes in cognitive and behavioral functioning, in comparison to baseline, were elicited by parental report. Results: The average postoperative follow-up interval was 20.3 months (range, 13–28 months). Fourteen (54%) patients were completely seizure free, and nine (35%) had at least a 90% improvement in total seizure frequency. Parents reported postoperative improvement in behavior in 23 (88%) patients and in cognition in 17 (65%) patients. Transient postoperative memory disturbance was seen in 15 (58%) patients, but persisted in only two (8%). Two (8%) patients had persisting endocrine disturbance requiring hormone replacement therapy (diabetes insipidus and hypothyroidism in one each). With univariate analysis, the likelihood of a seizure-free outcome correlated with younger age, shorter lifetime duration of epilepsy, smaller preoperative HH volume, and 100% HH resection. Conclusions: Refractory epilepsy associated with HH can be safely and effectively treated with surgical resection by a transcallosal, interforniceal approach. Short-term memory deficits appear to be transient for most patients, and family perception of the impact of surgery on cognitive and behavioral domains is favorable. Complete resection yields the best result.

Summary: Purpose: To present the first ictal fluorodeoxyglucose–positron emission tomography (FDG-PET) evidence of the hypothalamic origin of gelastic seizures in a patient with a hypothalamic hamartoma (HH) and to raise the issue of true dual pathology related to this entity. Methods: Ictal FDG-PET was acquired during an episode of status gelasticus with preserved consciousness, in a patient previously operated on for complex partial seizures (CPSs) due to a temporal lobe epileptogenic cyst. Results: Ictal hypermetabolism was localized to the region of the HH during the status gelasticus. CPSs had been completely eliminated after temporal lobe surgery. Conclusions: Ictal FDG-PET independently confirmed that gelastic seizures in patients with HH do originate in the diencephalic lesion. An HH may coexist with another epileptogenic lesion, in a context of dual pathology.

Summary: Purpose: Hamartomas of the hypothalamus (HH) cause an uncommon and unusual epilepsy syndrome. The condition is recognized to affect children, but the presentation in adults is not well understood. We present 19 children and adult patients with HH, including three patients whose epilepsy began in adult life. The patterns of clinical presentation, evolution of the epilepsy from childhood to adult life, and electroclinical diagnostic features are presented. Methods: Nineteen patients, both children and adults with HH and epilepsy, were evaluated clinically, with EEG, videoEEG, and magnetic resonance imaging (MRI) scanning. Seven patients underwent surgical resection of the hamartoma. Stereotactic thermocoagulation of the hamartoma was performed in two patients. Results: Gelastic seizures occurred at onset of epilepsy in 15 of 16 early-onset cases. Subsequently, multiple seizures types occurred, which then evolved to mainly partial epilepsy with tonic or complex partial seizures (five of eight adults), or became entrenched symptomatic generalized epilepsy with atypical absences, drop attacks, and secondarily generalized seizures, and cognitive impairment (three of eight adults). In the adult-onset patients, gelastic seizures were not prominent, the epilepsy was milder, and they functioned normally. Stereotactic thermocoagulation of the hamartoma resulted in improvement in seizure control in two patients. Conclusions: Gelastic seizures are not a prominent feature of epilepsy in adult patients with HH. The epilepsy associated with HH, although severe at onset, can evolve into a milder syndrome in later life. For less severely affected patients, minimally invasive alternatives to the traditionally difficult open surgical treatment should be considered. Key Words: Hypothalamus hamartoma—Gelastic seizures—Precocious puberty— Stereotactic thermocoagulation.

Summary: Purpose: The epilepsy associated with hypothalamic hamartomas (HHs) has typical clinical, electrophysiologic, and behavioral manifestations refractory to drug therapy and with unfavorable evolution. It is well known that only sessile lesions produce epilepsy, but no correlation has been established between the different types of sessile hamartomas and the diverse manifestations of the epilepsy. We correlate anatomic details of the hamartoma and the clinical and neurophysiologic manifestations of the associated epilepsy. Methods: HHs of seven patients with epilepsy (ages 2– 25 years) were classified as to lateralization and connection to the anteroposterior axis of the hypothalamus by using high-resolution brain magnetic resonance imaging. We correlated the anatomic classification with the clinical and neurophysiologic manifestations of the epilepsy as evaluated in long-term (24 h) video-EEG recordings. Results: HHs ranged in size from 0.4 to 2.6 cc, with complete lateralization in six of seven patients. Ictal manifestations showed good correlation with the lobar involvement of ictal/interictal EEGs. These manifestations suggest the existence of two types of cortical involvement, one associated with the temporal lobe, produced by hamartomas connected to the posterior hypothalamus (mamillary bodies), and the other associated with the frontal lobe, seen in lesions connecting to the middle hypothalamus. Conclusions: A consistent clinical and neurophysiologic pattern of either temporal or frontal lobe cortical secondary involvement was found in the patients of our series. It depends on whether the hamartoma connects to the mamillary bodies (temporal lobe cases) or whether it connects to the medial hypothalamus (frontal lobe cases).

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. 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.

SUMMARY We report the case of a 3-year-old boy with status gelasticus symptomatic to a giant hypothalamic hamartoma despite two previous hypothalamic hamartoma surgeries using pterional approaches from each side. Following his third resection employing an endoscopic, transventricular approach, he has been seizure free for 6 months with significant cognitive, behavioral, and electroencephalographic improvement. This case reinforces the importance of surgery for a form of status epilepticus and in addition that repeat (three) surgeries can be successful, indeed life changing. The optimal surgical approaches and management plan for hypothalamic hamartoma surgery—including subtemporal, subfrontal, transcallosal, and endoscopic approaches—are discussed, including how these treatment decisions have evolved as a result of our large series experience.

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.

Summary: Hypothalamic hamartomas are rare developmental malformations of the inferior hypothalamus. Typically they result in symptomatic, refractory mixed seizure disorder with trademark gelastic or laughing seizures. We present a 30-month-old boy with a hypothalamic hamartoma and a nearly 2-month history of near-continuous gelastic seizures, which we have labeled “status gelasticus.” The seizures were refractory to multiple antiepileptic drugs (AEDs), and emergency transcallosal resection of the hypothalamic hamartoma was performed with resultant near-immediate cessation of the seizures. At 12-month follow-up, the patient was averaging one brief gelastic seizure every 2 weeks, with a longest seizure-free period of 2 months.

Summary: A 6.5-year-old boy developed seizures at age 2.8 years consisting of episodes of unconsciousness and laughing attacks. By age 6 years, multiple seizure types, including generalized tonic-clonic (GTC), complex partial (CPS) and akinetic seizures, and drop attacks were occurring several times daily. EEG showed multifocal epileptic discharges. Antiepileptic drugs (AEDs) did not control the seizures. With progression of the epilepsy, cognitive deterioration developed. There were no manifestations of precocious puberty. Neuroimaging disclosed a suprasellar mass in continuity with the hypothalamus, and a diagnosis of hypothalamic hamartoma was made. After surgical resection of the hamartoma, the seizures were completely alleviated, and the epileptic EEG discharges disappeared. Improvement of mental function was also noted. ReSUMe Un petit garcon âge de 6.5 ans a presente des crises a l'tige de 2.8 ans, representees par des pertes de connaissance et des attaques de rire. A l'âge de 6 ans, les crises avaient evolue et avaient differents types, incluant des crises generalisees tonicocloniques, des crises partielles complexes et des crises aeineiques ainsi que des drop-attaces qui survenaient plusieurs fois par jour. L'EEG mettait en evidence des decharges epileptiques multifocales. Les medicaments antiepileptiques (MEA) ne reussissaient pas a controler les crises. Une deterioration des fonctions cognitives avait ete constatee avec la progression de l'epilepsie. Il n'y avait pas de manifestations de puberte precoce. La neuroimagerie avait mis en evidence une masse suprasellaire en continuite avec l'hypothalamus, et le diagnostic d'hamartohypothalamique a ete porte. Apres resection chirurgicale de l'hamartome, les crises furent supprimees, les decharges epileptiques disparurent. Une amelioration du fonctionnement intellectuel a egalement ete notee. RESUMEN A la edad de 2.8 anos un muchacho de 6.5 anos de edad desarrollo ataques que consistian en episodios de perdida de conocimiento y de risa involuntaria. A los 6 anos tenia ataques varias veces a1 dia y de multiples manifestaciones incluyendo crisis generalizadas tonico-clonicas, ataques parciales y crisis acineticas con caidas bruscas. Los EEG mostraron descargas epilepticas multifocales y las medicaciones antiepilepticas no controlaron estos episodios. A medida que la epilepsia progresaba se observo un deterioro cognitivo sin que aparecieran manifestaciones de pubertad precoz. Los estudios de neuroimagen revelaron una masa supreselar en continuidad con el hipotalamo por lo que se diagnostico un hamartoma hipotalBmico. Despues de la excision quirurgica del hamartoma los ataques mejoraron completamente y las descargas en el EEG desaparecieron. Tambien se observo una mejoria de las funciones mentales. ZUSAMMENFASSUNG Ein 6.5 Jahre alter Junge hatte seit dem 3. Lebensjahr Anfalle mit Bewuβtlosigkeit und Lachen. Im Alter von 6 Jahren ereigneten sich verschiedene Anfallstypen mit generalisierten tonisch-klonischen Anfallen, komplex-partialen und akinetischen Anfallen, Sturzanfallen jeweils mehrfach pro Tag. Im EEG fanden sich multifokale epileptische Entladungen. Die Anfalle waren gegenuber Antiepileptika therapieresistent. Mit Zunahme der Epilepsie traten kognitive Einbuβen auf. Kein Hinweis fur eine Pubertas praecox. Das NMR zeigte eine suprasellare Verdichtung mit Ubergang in den Hypothalamus, so daβ die Diagnose hypothalamisches Hamartom gestellt wurde. Nach operativer Enfernung des Hamartoms waren die Anfalle vollstandig beseitigt, und die epileptischen Entladungen im EEG verschwunden. Ebenso besserten sich die mentalen Funktionen.

Summary: Purpose: We tested the hypothesis that widespread extralesional abnormalities of cerebral structure exist in association with apparently isolated hypothalamic hamartomata, providing a structural basis for the poor response of seizures to removal of the hamartoma or other apparently focal epilepto-genic zones present. Methods: High-resolution magnetic resonance imaging (MRI) brain scans of 2 patients with hypothalamic hamartomata were quantified by determination of regional distribution and symmetry of distribution of cortical gray matter and subcortical matter volumes. The results were compared with normal ranges for the distribution of such tissues in 33 controls. Results: Both patients had abnormalities of distribution of gray and subcortical matter, whereas control subjects did not. These abnormalities were beyond the hamartoma itself, in areas of cerebrum that on visual inspection alone appeared completely normal. Conclusions: Extralesional abnormalities of cerebral structure are present in the cerebrum of patients with hypothalamic hamartoma, as in most patients with other dysgeneses. These abnormalities may explain the poor outcome of epilepsy surgery in patients with this form of dysgenesis. These preliminary findings require further investigation.

Hypothalamic hamartomas are rare malformations containing neurons that can be associated with a remark- able epileptic syndrome. This syndrome is characterized by laughing (gelastic) seizures beginning in early child- hood, often in the neonatal period. Usually there is later development of both focal seizures including complex partial seizures (CPS) and a pattern of symptomatic gen- eralized epilepsy with tonic, atonic and other seizure types in association with slow spike-and-wave discharge

Summary: Purpose: Seizures with ictal laughter (also termed gelastic seizures) have been associated with hypothalamic hamartomas and precocious puberty. It is not known, however, where in the brain such seizures originate. We describe a child with gelastic seizures and a hypothalamic lesion (probably a hamartoma) in whom two dysfunctional phenomena were observed. Results: First, there was a hyperperfusion in the hypothalamopituitary areas shown by ictal [99m]Tc hexamethyl-propyleneamine oxime (HM-PAO) single photon-emission computed tomography (SPECT). Second, there was an ictal pulse of gonadotropins, 17β-estradiol, and growth hormone well above the normal limits in one of the seizures. Conclusion: These findings suggest that gelastic seizures associated with hypothalamic hamartomas are generated in the hypothalamus or in its neighboring regions and that these seizures may cause paroxysmal dysfunction of the hypothalamo-pitutary axis.

Purpose: Seizures caused by hypothalamic hamartomas are usually difficult to control. Surgical removal of the lesion has been reported to be an effective therapy to control the seizures. However, surgical treatment can potentially damage the cranial nerves or the hypothalamus. Case Report: This is a report of a patient who had intractable epilepsy due to an inaccessible hypothalamic hamartoma and was subsequently treated with stereotactically directed irradiation by using a gamma-knife unit. This 25-year-old man had a history of intractable gelastic and tonic-clonic seizures for the last 23 years. His seizures started with a transient atony of his trunk and extremities at age 6 months. Soon they became associated with gelastic attacks with utterances followed by short generalized tonic-clonic seizures and prolonged postictal drowsiness. He was referred to our department in August 1995, just after a seizure-related car accident. Usually, the seizures were generalized tonic-clonic convulsions following a gelastic attack, occurring 3–6 times a month while taking anticonvulsants such as carbamazepine (CBZ; 1,200 mg), valproate (VPA; 1,800 mg), and zonisamide (ZNS; 600 mg) daily. He also had automatic seizures presenting as oral automatisms, vomiting, and spitting, and these occurred once or twice a month. The blood levels of these drugs were above the minimal effective concentrations, There was no evidence of precocious puberty or any apparent mental retardation. Electroencephalography (EEG) revealed diffuse and dysrhythmic slow background activities and sporadic spike or spike-and-wave activities preferentially in the left frontal and parietal leads. Video-EEG monitoring showed generalized tonic-clonic seizures after a transient laughing attack accompanied by diffuse spike-and-wave bursts, which did not show any laterality. The current magnetic resonance imaging (MRI) as well as the MRI performed 30 months ago demonstrated a nonenhancing and non-progressive spherical mass -10 mm in diameter on the right side at the floor of the third ventricle. The lesion was irradiated with 36 Gy to the center and 18 Gy (50% isodose line) to the margin through a 4–mm and an 8–mm collimator. Two months after the irradiation, the frequency of the seizure attacks transiently increased. However, he has not had any seizures since 3 months after the therapy. Antiepileptic drugs (AEDs) have been reduced since 1 year after the irradiation. The MRI performed 1 year after the irradiation demonstrated a complete disappearance of the lesion. The patient has been seizure free for the last 17 months, with no neurologic or endocrinologic complications. The MRI examination 12 months after the irradiation showed a complete disappearance of the lesion. Conclusions: Stereotactic irradiation by-,using a gamma-knife unit appears to be a promising therapeutic option for surgically inaccessible hypothalamic hamartomas associated with intractable seizures.

Purpose: In five patients with refractory seizures due to a hypothalamic hamartoma recently examined in our institute, we analyzed the electroclinical and the neuroimaging findings in detail. Methods: Three patients were men and two were women, and their ages at the time of the investigation ranged from 16 to 49 years (mean, 26 years). The age of seizure onset was