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.     

Efficacy of Thyrotropin-Releasing Hormone in the Treatment of Intractable Epilepsy

Purpose : The ictal EEG and magnetoencephalogram (MEG) for gelastic seizures were recorded in a 4-year-old girl with tuberous sclerosis. The sites of origin for the seizure activities were investigated by using an equivalent current dipole (ECD) with the MEG.
Methods : EEG and MEG were recorded simultaneously under the administration of diazepam (DZP). The MEG recording was performed on a system consisting of an array of 64 sensors uniformly distributed over the patient's whole head (CTF, Canada), and the estimated ECDs were superimposed on the magnetic resonance imaging (MRI) images (Siemens, 1.5 Tesla).
Results : Two laughing attacks lasting 5 s each were documented. The ictal EEG showed gradually increasing 11–Hz rhythmic α activities with dominance over the frontocentral areas bilaterally, followed by irregular spike-and-wave discharges. The ictal MEG detected bilateral frontal rhythmic sharp waves before the appearance of the activities on the EEG. The estimated ECDs were localized in the deep white matter of the right frontal lobe on the MRI. However, those dipoles did not coincide with the locations of her cortical tubers.
Conclusions : Although gelastic seizures accompanied with hypothalamic hamartomas are well known, several reports have suggested a temporal or frontal lobe origin for gelastic seizures. In this patient, the ECD indicated that the seizures originated in the frontal lobe, although ictal scalp EEG recordings could not determine the precise focus. Thus, in cases in which the use of ictal scalp EEG fails to show the sites of origin for the seizures, it is recommended that the origins be estimated by using the non-invasive method of ictal MEG analysis.     

Gelastic seizures: Incidence,clinical and EEG features in adult patients undergoing video‐EEG telemetry

This study aimed to determine clinical features of adult patients with gelastic seizures recorded on video –electroencephalography (EEG) over a 5‐year period. We screened video‐EEG telemetry reports for the occurrence of the term “gelastic” seizures, and assessed the semiology, EEG features, and duration of those seizures. Gelastic seizures were identified in 19 (0.8%) of 2,446 admissions. The presumed epileptogenic zone was in the hypothalamus in one third of the cases, temporal lobe epilepsy was diagnosed in another third, and the remainder of the cases presenting with gelastic seizures were classified as frontal, parietal lobe epilepsy or remained undetermined or were multifocal. Gelastic seizures were embedded in a semiology, with part of the seizure showing features of automotor seizures. A small proportion of patients underwent epilepsy surgery. Outcome of epilepsy surgery was related to the underlying pathology; two patients with hippocampal sclerosis had good outcomes following temporal lobe resection and one of four patients with hypothalamic hamartomas undergoing gamma knife surgery had a good outcome.     

Psychogenic gelastic seizures in a patient with hypothalamic hamartoma

Gelastic seizures are classically associated with hypothalamic hamartoma. The most effective treatment for gelastic epilepsy is surgery, although confirming that a hypothalamic hamartoma is an epileptic lesion prior to surgical intervention is challenging. Here, we report the case of a patient with a hypothalamic hamartoma who was diagnosed with psychogenic non-epileptic gelastic seizures using video-EEG monitoring. [Published with video sequences].     

Intractable gelastic seizures during infancy: ictal positron emission tomography (PET) demonstrating epileptiform activity within the hypothalamic hamartoma

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.     

A note on gelastic epilepsy

Laughter epilepsy or gelastic seizures have been described in various epilepsies arising from the temporal or frontal lobes, but most commonly from hypothalamic hamartomata. Gelastic seizures also arise from temporal and frontal lobe tumours and atrophic lesions. The essential clinical features are: stereotyped recurrence; absence of external precipitants; concomitance of other manifestations generally accepted as epileptic; presence of interictal or interictal EEG epileptiform discharges, and absence of conditions in which pathological laughter might occur. The history and clinical significance are discussed.     

Gelastic seizure with tectal tumor, lobar holoprosencephaly, and subependymal nodules: clinical report

Gelastic seizures are characterized by inappropriate, stereotyped laughter and are often first recognized when other epileptic manifestations occur. They are frequently associated with hypothalamic hamartomas. Central nervous system developmental abnormalities are rarely reported with gelastic seizures. There is only one case report of gelastic seizure caused by holoprosencephaly. We report a 2-year-old girl with multiple brain structural abnormalities including tectal tumor (possibly hamartoma), multiple subependymal nodules, and holoprosencephaly. She developed seizures during the newborn period and presented with gelastic seizure and simple partial seizure at 3 months of age.     

The clinical spectrum and natural history of gelastic epilepsy-hypothalamic hamartoma syndrome.

PURPOSE: To delineate the clinical spectrum and patterns of evolution of epilepsy with gelastic seizures related to hypothalamic hamartoma (HH). PATIENTS AND METHODS: We evaluated patients with HH, observed between 1986 and 2002 for whom at least one ictal video-EEG or EEG recording of gelastic seizures was available. RESULTS: Six subjects (four male, two female) with sessile HH between 0.8 and 1.7 cm in diameter were identified. The onset of gelastic seizures was between 2 months and 20 years. It evolved to secondary generalized epilepsy in one case, and to drug-resistant partial epilepsy in the other five from 2 to 13 years after onset. No patient showed precocious puberty. Severe cognitive impairment developed in the patient with secondary generalized epilepsy, and a mild cognitive defect in two others. Patients with an HH below 1cm did not show neuropsychological or behavioural disturbances. Drug resistance occurred in all cases. Surgical removal of HH markedly improved the clinical evolution in two patients. CONCLUSIONS: Gelastic epilepsy-HH syndrome can differ in severity and evolution. A catastrophic evolution and drug resistance can be reversed by surgical or by gamma-knife ablation of HH.     

Gelastic seizures: not always hypothalamic hamartoma.

Gelastic seizures are often associated with hypothalamic hamartomas. However, focal cortical dysplasias can also cause "laughing seizures", and such cases can be difficult to localize with EEG. This case report presents a 29-year-old woman who was successfully rendered free of gelastic seizures after resection of a frontal cortical dysplasia, localized through MRI and SPECT imaging.[Published with video sequences].     

Analysis of the dynamics and origin of epileptic activity in patients with tuberous sclerosis evaluated for surgery of epilepsy

OBJECTIVE: The epilepsies associated with the tuberous sclerosis complex (TSC) are very often refractory to medical therapy. Surgery for epilepsy is an effective alternative when the critical link between the localization of seizure onset in the scalp and a particular cortical tuber can be established. In this study we perform analysis of ictal and interictal EEG to improve such link. METHODS: The ictal and interictal recordings of four patients with TSC undergoing surgery for epilepsy were submitted to independent component analysis (ICA), followed by source analysis, using the sLORETA algorithm. The localizations obtained for the ictal EEG and for the average interictal spikes were compared. RESULTS: The ICA of ictal EEG produced consistent results in different events, and there was good agreement with the tubers that were successfully removed in three of the four patients (one patient refused surgery). In some patients there was a large discrepancy between the localization of ictal and interictal sources. The interictal activity produced more widespread source localizations. CONCLUSIONS: The use of ICA of ictal EEG followed by the use of source analysis methods in four cases of epilepsy and TSC was able to localize the epileptic generators very near the lesions successfully removed in surgery for epilepsy. SIGNIFICANCE: The ICA of ictal EEG events may be a useful add-on to the tools used to establish the connection between epileptic scalp activity and the cortical tubers originating it, in patients with TSC considered for surgery of epilepsy.     

Intrinsic epileptogenesis of hypothalamic hamartomas in gelastic epilepsy

Hypothalamic hamartomas and gelastic seizures are often associated with cognitive deterioration, behavioral problems, and poor response to anticonvulsant treatment or cortical resections. The origin and pathophysiology of the epileptic attacks are obscure. We investigated 3 patients with this syndrome and frequent gelastic seizures. Ictal single-photon emission computed tomography performed during typical gelastic seizures demonstrated hyperperfusion in the hamartomas, hypothalamic region, and thalamus without cortical or cerebellar hyperperfusion. Electroencephalographic recordings with depth electrodes implanted in the hamartoma demonstrated focal seizure origin from the hamartoma in 1 patient. Electrical stimulation studies reproduced the typical gelastic events. Stereotactic radiofrequency lesioning of the hamartoma resulted in seizure resulted in seizure remission without complications 20 months after surgery. The functional imaging findings, electrophysiological data, and results of radiofrequency surgery indicate that epileptic seizures in this syndrome originate and propagate from the hypothalamic hamartoma and adjacent structures.     

Sensitivity of recordings at sphenoidal electrode site for detecting seizure onset: evidence from scalp, superficial and deep foramen ovale recordings.

OBJECTIVES: Some authors have recently stressed that the position of the tip of sphenoidal electrodes plays a crucial role in their efficacy in detecting ictal onset. An opportunity to test this hypothesis is provided by recordings from the most superficial contacts of foramen ovale (FO) electrode bundles because these contacts are located at the FO, in a position equivalent to that of optimally located sphenoidal electrodes. To simplify wording, recordings obtained by superficial FO electrodes will hereafter be called sphenoidal recordings, although they have not been obtained with standard sphenoidal electrodes. The sensitivities of simultaneous scalp and sphenoidal recordings for detecting ictal onset have been compared with each other, and with a 'gold standard' provided by simultaneous deep intracranial FO recordings from the mesial aspect of the temporal lobe. METHODS: Three hundred and fourteen seizures obtained from 110 patients under telemetric presurgical assessment for temporal lobe epilepsy have been studied. Scalp electrodes included anterior temporal placements. All scalp electrodes were considered when identifying seizure onset but the anterior temporal electrodes were most frequently involved. RESULTS: Ictal onset time at sphenoidal and scalp recordings: initial ictal changes appeared simultaneously in scalp and sphenoidal recordings in 123 seizures (39.2%). Initial changes occurred earlier in sphenoidal recordings in 63 seizures (20.1%), whereas they were seen earlier on the scalp in 76 seizures (24.2%). Artefacts prevented the comparison between sphenoidal and scalp recordings in 16 seizures (5.1%) and no ictal changes were seen on the scalp and/or sphenoidal recordings in 36 seizures (11.5%). In most of the 63 seizures where ictal changes appeared earlier in sphenoidal recordings, a delayed ipsilateral scalp onset was seen as the signal amplitude increased or scalp changes could be identified retrospectively on the scalp with an onset which appeared simultaneous and ipsilateral to the initial sphenoidal changes. Sphenoidal recordings supplied additional information when compared to scalp recordings in only 22 seizures (7%): in 5 seizures with artefacts on the scalp, in 6 seizures with no changes on the scalp and in 11 seizures with discrepant laterality at onset. Congruence in laterality with respect to deep intracraneal FO recordings: of the 61 seizures with unilateral onset on the scalp, onsets at sphenoidal recordings and deep FO electrodes were ipsilateral in most cases. In only 3 of these 61 seizures (4.9%), sphenoidal recordings lateralized ipsilateral to the deep FO electrodes in the presence of a contralateral onset on the scalp. In 14 among the 122 seizures (11.5%) with bilateral asymmetrical onset on the scalp, sphenoidal recordings lateralized seizure onset ipsilateral to the deep FO electrodes in the presence of a contralateral scalp onset. Thus, when compared with scalp EEG, sphenoidal recordings increased laterality congruence with respect to deep FO electrodes in 17 seizures (5.4%). CONCLUSIONS: Extracranial electrodes located next to the FO at the sphenoidal electrode site yield an improvement over suitable surface electrodes in the identification of ictal onset in only 5.4-7% of seizures. Such improvement derives from the fact that the low amplitude signals often seen at seizure onset may show higher amplitude on sphenoidal than on scalp recordings.     

Intracranial EEG Substrates of Scalp Ictal Patterns from Temporal Lobe Foci

Summary: Purpose: To determine the intracranial EEG features responsible for producing the various ictal scalp rhythms, which we previously identified in a new EEG classification for temporal lobe seizures. Methods: In 24 patients, we analyzed simultaneous intracranial and surface ictal EEG recordings (64 total channels) obtained from a combination of intracerebral depth, subd-ural strip, and scalp electrodes. Results: Four of four patients with Type 1 scalp seizure patterns had mesial temporal seizure onsets. However, discharges confined to the hippocampus produced no scalp EEG rhythms. The regular 5- to 9-Hz subtemporal and temporal EEG pattern of Type 1a seizures required the synchronous recruitment of adjacent inferolateral temporal neocortex. Seizure discharges confined to the mesiobasal temporal cortex produced a vertex dominant rhythm (Type 1c) due to the net vertical orientation of dipolar sources located there. Ten of 13 patients with Type 2 seizures had inferolateral or lateral, temporal neocortical seizure onsets. Initial cerebral ictal activity was typically a focal or regional, low voltage, fast rhythm (20–40 Hz) that was often associated with widespread background flattening. Only an attenuation of normal rhythms was reflected in scalp electrodes. Irregular 2- to 4-Hz cortical ictal rhythms that commonly followed resulted in a comparably slow and irregular scalp EEG pattern (Type 2a). Type 2C seizures showed regional, periodic, 1– to 4-Hz sharp waves following intracranial seizure onset. Seven patients had Type 3 scalp seizures, which were characterized by diffuse slowing or attenuation of background scalp EEG activity. This resulted when seizure activity was confined to the hippocampus, when there was rapid seizure propagation to the contralateral temporal lobe, or when cortical ictal activity failed to achieve widespread synchrony. Conclusions: Type 1, 2, and 3 scalp EEG patterns of temporal lobe seizures are not a reflection of cortical activity at seizure onset. Differences in the subsequent development, propagation, and synchrony of cortical ictal discharges produce the characteristic scalp EEG rhythms.     

Ictal Laughter Associated with Paroxysmal Hypothalamopituitary Dysfunction

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.     

Scalp EEG in temporal lobe epilepsy surgery

Electroencephalography (EEG) with standard scalp and additional noninvasive electrodes plays a major role in the selection of patients for temporal lobe epilepsy surgery. Recent studies have provided data supporting the value of interictal and postictal EEG in assessing the site of ictal onset. Scalp ictal rhythms are morphologically complex but at least one pattern (a five cycles/second rhythm maximum at the sphenoidal or anterior temporal electrode) occurs in >50% of patients and has a high predictive value and interobserver reliability for temporal lobe originating seizures. Thorough interictal and ictal scalp EEG evaluation, in conjunction with modern neuroimaging, is sufficient for proceeding to surgery without invasive recordings in some patients. Further studies are required to define the scalp ictal characteristics of mesial vs. lateral temporal lobe epilepsy.     

Gelastic seizures involving the right parietal lobe.

Gelastic seizures have been described in various epilepsies arising from the temporal or frontal lobes, although the most commonly encountered form is related to the presence of an hypothalamic hamartoma. We report a patient with gelastic seizures involving the right parietal lobe. Our patient, a 32-year-old man, underwent video-EEG monitoring, interictal and ictal brain SPECTs during gelastic seizures. Subtraction ictal SPECT co-registered to MRI (SISCOM), was performed to localize any ictal hyperperfusion during these gelastic seizures. The seizures consisted of brief staring followed by smiling and laughing. Electroencephalography during the gelastic seizures showed rhythmic sharp waves in the right parietal lobe. SISCOM showed ictal hyperperfusion in the right parietal lobe and medial portions of right cerebellum. Our findings suggest that the right parietal lobe may actively participate in the particular epileptogenic network generating gelastic seizures.     

The clinical usefulness of ictal surface EEG in neocortical epilepsy

PURPOSE: Localizable scalp EEGs, during ictal episodes, appear to be rare in neocortical epileptic syndromes. However, studies based on large numbers of patients are also rare. This study aims to identify the characteristic patterns of variable neocortical epilepsies and to evaluate their clinical usefulness in the localization of epileptogenic focuses. METHODS: We retrospectively assessed 394 noninvasive ictal recordings from 86 patients who subsequently underwent invasive study and resective surgery. Ictal EEGs were recorded using a video-EEG monitoring system with electrodes placed according to the International 10-20 system, with additional anterior temporal electrodes. The ictal recordings were analyzed according to localizing accuracy and frequency characteristics. The durations of discrete or regional ictal rhythms were also measured. RESULTS: The percentage of discrete or regional EEGs was 23% in frontal lobe epilepsy, 52% in lateral temporal lobe epilepsy, 70% in occipital lobe epilepsy, and 10% in parietal lobe epilepsy. In order of frequency, the localizable ictal rhythms were theta, beta, alpha, delta, and rhythmic spike-and-wave. The duration of discrete or regional ictal rhythms was significantly shorter in frontal lobe epilepsy and parietal lobe epilepsy than in other epilepsies. Ictal beta activity was the most common rhythm in discrete-patterned EEGs. Structural lesions found on MRI did not significantly affect the localization of epileptogenic focuses in the patients. The type of seizure was not related to the degree of localization, with the exception of simple partial seizure. CONCLUSIONS: Ictal surface EEG was clinically helpful in the localization of epileptogenic focuses in at least some neocortical epileptic syndromes.     

Dacrystic seizures: Demographic,semiologic, and etiologic insights from a multicenter study in long‐term video‐EEG monitoring units

Purpose: To provide an estimate of the frequency of dacrystic seizures in video‐electroencephalography (EEG) long‐term monitoring units of tertiary referral epilepsy centers and to describe the clinical presentation of dacrystic seizures in relationship to the underlying etiology. Methods: We screened clinical records and video‐EEG reports for the diagnosis of dacrystic seizures of all patients admitted for video‐EEG long‐term monitoring at five epilepsy referral centers in the United States and Germany. Patients with a potential diagnosis of dacrystic seizures were identified, and their clinical charts and video‐EEG recordings were reviewed. We included only patients with: (1) stereotyped lacrimation, sobbing, grimacing, yelling, or sad facial expression; (2) long‐term video‐EEG recordings (at least 12 h); and (3) at least one brain magnetic resonance imaging (MRI) study. Key Findings: Nine patients (four female) with dacrystic seizures were identified. Dacrystic seizures were identified in 0.06–0.53% of the patients admitted for long‐term video‐EEG monitoring depending on the specific center. Considering our study population as a whole, the frequency was 0.13%. The presence of dacrystic seizures without other accompanying clinical features was found in only one patient. Gelastic seizures accompanied dacrystic seizures in five cases, and a hypothalamic hamartoma was found in all of these five patients. The underlying etiology in the four patients with dacrystic seizures without gelastic seizures was left mesial temporal sclerosis (three patients) and a frontal glioblastoma (one patient). All patients had a difficult‐to‐control epilepsy as demonstrated by the following: (1) at least three different antiepileptic drugs were tried in each patient, (2) epilepsy was well controlled with antiepileptic drugs in only two patients, (3) six patients were considered for epilepsy surgery and three of them underwent a surgical/radiosurgical or radioablative procedure. Regarding outcome, antiepileptic drugs alone achieved seizure freedom in two patients and did not change seizure frequency in another patient. Radiosurgery led to moderately good seizure control in one patient and did not improve seizure control in another patient. Three patients were or are being considered for epilepsy surgery on last follow‐up. One patient remains seizure free 3 years after epilepsy surgery. Significance: Dacrystic seizures are a rare but clinically relevant finding during video‐EEG monitoring. Our data show that when the patient has dacrystic and gelastic seizures, the cause is a hypothalamic hamartoma. In contrast, when dacrystic seizures are not accompanied by gelastic seizures the underlying lesion is most commonly located in the temporal cortex.     

Gelastic seizures of neocortical origin confirmed by resective surgery

Ictal laughter is a relatively unusual phenomenon that appears to arise from within hypothalamic hamartomas. Gelastic seizures of neocortical origin are rare and when reported typically originate from temporofrontal regions in proximity to the hypothalamus, raising the possibility of a subtle lesion in the hypothalamus. A girl with gelastic seizures originating in a dysembryoblastic neuroepithelial tumor at the cranial vertex had resolution of her seizures following surgical resection. Electrical propagation of seizures via the cingulate gyrus appears to be an alternative mechanism underlying gelastic seizures.     

Interictal spike EEG source analysis in hypothalamic hamartoma epilepsy.

OBJECTIVE: The epilepsy associated with the hypothalamic hamartomas constitutes a syndrome with peculiar seizures, usually refractory to medical therapy, mild cognitive delay, behavioural problems and multifocal spike activity in the scalp electroencephalogram (EEG). The cortical origin of spikes has been widely assumed but not specifically demonstrated. METHODS: We present results of a source analysis of interictal spikes from 4 patients (age 2-25 years) with epilepsy and hypothalamic hamartoma, using EEG scalp recordings (32 electrodes) and realistic boundary element models constructed from volumetric magnetic resonance imaging (MRIs). Multifocal spike activity was the most common finding, distributed mainly over the frontal and temporal lobes. A spike classification based on scalp topography was done and averaging within each class performed to improve the signal to noise ratio. Single moving dipole models were used, as well as the Rap-MUSIC algorithm. RESULTS: All spikes with good signal to noise ratio were best explained by initial deep sources in the neighbourhood of the hamartoma, with late sources located in the cortex. Not a single patient could have his spike activity explained by a combination of cortical sources. CONCLUSIONS: Overall, the results demonstrate a consistent origin of spike activity in the subcortical region in the neighbourhood of the hamartoma, with late spread to cortical areas.