Journal of Pediatric Neurology, Vol. 1, No. 2, 2003, pp. 69-73
Retired, The Children's Hospitals, Manchester , United Kingdom
Received: May 21, 2003 .
Code Number: pn03013
The symptoms associated with gelastic seizures are discussed, as well as their most frequent origin in hypothalamic hamartoma. Complications, especially cognitive and behaviour disorders, often occur, and causes for these are suggested. Sometimes the laughter is accompanied by feeling of mirth, and sometimes it is not, and this seems to depend on the parts of the cerebral cortex affected by the epileptic discharges. Precocious puberty often occurs in affected patients. Some of the possible causes for this are considered, and findings which suggest the diagnosis. The pathology responsible for gelastic seizures can vary, but most commonly it is a developmental anomaly in the hypothalamic area, and rarely a neoplasm. Other structural lesions in the central nervous system may well occur. The differential diagnosis is considered, and the possibilities of treatment. Surgery should be considered at an early age, particularly if the seizures do not respond to medical treatment, as if successful the child's quality of life can be greatly improved. The decision on the type of operation to be used may best be made on an individual basis depending on the type and site of the lesion; and the risks involved. The development of stereotactic radiosurgery may be the best hope for the future. (J Pediatr Neurol 2003; 1(2): 69-73).
Key words: gelastic seizures, hypothalamic hamartoma, symptoms, diagnosis, treatment.
The characteristics of epileptic seizures can sometimes indicate their origins within the brain. This is especially true of gelastic seizures, when unexplained, uncontrollable mirthless laughter and giggling occurs followed by some kind of fit (1). When these occur the presence of a hypothalamic hamartoma is highly likely, and especially if there are signs of precocious puberty (2), although such fits can result from foci in other parts of the brain such as the frontal or temporal lobes (3,4).
Symptoms and Signs
Gelastic seizures can be strongly suspected when the attacks are recurrent and stereotyped with no apparent precipitating cause, and the laughter is followed by epileptic manifestations such as tonic and clonic movements, disturbances of consciousness and automatisms; and when the electroencephalogram (EEG) shows ictal and interictal epileptic discharges (1). A study by Freeman et al (5) confirmed that the gelastic seizures originated in a hypothalamic hamartoma, but that the evolution of the EEG abnormalities, the development of generalised seizures after the onset of the former, and the postoperative resolution of both the interictal spike-wave discharges and the generalised seizures, may be the effect of secondary epileptogenesis. The epileptic activity seems to spread from the hypothalamic hamartoma to the limbic structures via the hypothalamus thus activating the noradrenergic system and the hypothalanic-pituitary axis, the former causing increased blood pressure and heart rate and raised norepinephrine levels in the plasma and the latter raised prolactin levels in the plasma (6).
Cognitive deficits have been found in children with gelastic seizures and hypothalamic hamartoma. Frattali et al (7) examined eight such children with a battery of tests, and all of them showed failures ranging from mild to severe. There were correlations with both seizure severity and frequency and the extent of the deficits; and the effects of anti-epileptic drugs may have also been a factor. The findings suggested that the learning difficulties, and the emotional states of the children, were due to impaired function of conduction pathways of the hypothalamus involving cortical association areas, the amygdala, and hippocampal formation. Deonna and Ziegler (8) have concluded from their studies that there is a close link between the location of the malformation, the epilepsy and the neurobehavioral syndrome. It may be that the epileptic activity in the hypothalamic-amygdala-frontal systems at an early age upsets the evolution of these functions; resulting in developmental and attention deficit disorders. Berkovic et al (10) consider that the progressive intellectual decline in these patients may aries from, or be closely associated with, the mamillary bodies, and excitotoxic damage to the mamillary bodies and adjacent medial thalamus.
Sturm et al (10) have stressed the diversity of the clinical spectrum of children with hypothalamic hamartoma. Those with sessile tumours usually having not only gelastic seizures refractory to treatment but cognitive deterioration and behavioural difficulties. However if the tumours are small the symptoms can be mild. They record three such children whose fits consisted of only a desire or pressure to laugh, and with normal intelligence, a presentation which is bound to cause considerable diagnostic difficulties. The studies of Iwasa et al (11) showed that in one patient with interical spikes in the anterior frontal region corresponding to the cingulate gyrus the seizures were without a sense of mirth, and in two patients when the spikes were in the medial temporal region the seizures were associated with laughter and a subjective feeling of mirth. This suggests that neural activity in the hippocampal region is involved with the generation of gelastic seizures with a sense of mirth and those in the cingulate areas may be associated with the motor act of laughter. Biraben et al (12) also found that in seizures with a frontal focus the laughter is a forced motor behaviour or an automatism, and that mirth associated with the laughter only occurs when the temporal lobes are involved with their role in generating emotion.
Difficulties can also occur when seizures start in the neonatal period. DiFazio and Davis (13) describe a three months-old child with a large hypothalamic mass who had spells from birth. These occurred frequently, with bursts of hypernea, cooing respirations, giggling and smiling, and they stressed that if surgical intervention is possible cognitive and behavioural disorders may be prevented. Children with gelastic seizures and hypothalamic hamartoma often show an increase in psychiatric conditions, especially the oppositional defiant disorder and the attention deficit hyperactivity disorder. Aggression can also occur. Healthy siblings on the other hand were not affected in this way (14).
Children with gelastic seizures may often show evidence of precocious puberty, defined in girls as the onset of secondary sexual characteristics before the age of eight years, and central if due to premature activation of the hypothalamic-pituitary-gonodal axis. Often no lesion is discovered, although this is not so in boys. Ng et al (15) found that with the use of magnetic resonance imaging (MRI) scans lesions could be found in ten (15%) of the girls investigated, although there were no neurological symptoms or signs on presentation. Six of them had hypothalamic hamartoma; so that this was considered a justifiable investigation in such patients. In the studies of Debeneix et al (16) precocious puberty was associated with small and pedunculated hamartoma and sessile ones with seizures. Precocious puberty may be due to premature disappearance of normal inhibitory factors on the thalamus which results in luteinising hormone releasing factor activating the pituitory-gonodal axis (17). Jung and Ojeda (18) found that in some patients with hypothalamic hamartoma the lesion induced precocious puberty by stimulating this hormone from the hypothalamus via the secretion of glial factors, such as the transforming growth factors; but this may only occur if the hamartoma is in close proximity to either luteinizing hormone releasing factor neurons or to their axonal processes in the median eminence. There seems to be no disturbance of hypothalamic-pituitary function (16). Elevated basal and stimulated luteinizing hormone levels and luteinizing hormone:follicle stimulating hormone ratio suggest central precocious puberty due to hypothalamic hamartoma, which must be differentiated from other neurogenic causes such as neurotuberculosis, pituitary adenoma, hydrocephalus, and other malformations (19).
Pathology of Gelastic Seizures and Their Propagation
The commonest lesion associated with seizures of this type is a hypothalamic hamartoma, which by definition should not grow (20). However, different pathologies are possible. For example other types of cerebral tumours can occur in the hypothalamic region, such as astrocytomas (21). Also the aetiology may be non-malignant. In the case of the girl with gelastic seizures described by Bellman et al (1) EEG and MRI scans were normal, and it was suggested that there could be a defect in the temporal lobe as she also suffered from a language disorder, or perinatal hypoxia might have resulted in a small hemorrhage or infarction in the limbic system. Gelastic seizures have also been reported in a child with West's syndrome due to perinatal hypothalamic hemorrhage (22).
Associated cerebral abnormalities can occur, and Gulati et al (23) have reported an infant with gelastic seizures and precocious puberty who on investigation showed agenesis of corpus callosum, the Dandy-Walker complex, and diffuse cerebral dysgenesis. Widespread cortical abnormalities have also been recorded in two patients with gelastic seizures and hypothalamic hamartoma by Sisodiya et al (24) using MRI brain scans; this form of dysgenesis possibly being the reason for the persistence of epileptic seizures after successful surgery on the primary lesion. Arpino et al (25) have described these seizures as part of the Pallister-Hall syndrome with pituitary dysfunction, polydactyly, and imperforate anus.
Apart from hypothalamic hamartoma, similar congenital malformations can occur in the floor of the forth ventricle in children. Delande et al (26) report two such patients who were operated on with relief of seizures, consisting of motor and dysautonomic manifestations. It was considered, as in other types, the seizures arose from inside the lesion with spread to other areas of the brain. Gelastic seizures can also rarely be associated with other central nervous system developmental abnormalities. Akman et al (27) presented a 2-year-old girl with gelastic and simple partial seizures which started at the age of three months. She was found to have multiple brain structural abnormalities, including a tectal tumour which may have been a hamartoma, multiple subependymal nodules, and holoprosencephaly.
Certainly such dysplastic tissues can act as an epileptic focus, but perhaps more likely abnormal discharges emanating from a hamartoma triggers a secondary epileptogenic cortical zone associated with a local tissue anomaly, for example in the frontal or temporal regions (28). When, as already mentioned, there are lesions in other parts of the cortex another possibility is a spread of the discharges from the cortex to the temporal lobe and hypothalamus via the cingulate gyrus (29).
The Diagnosis of Hamartoma
The EEG may show focal cortical abnormalities, either from spread of the discharges from the cenrtral areas, or as indicating a focal lesion, and can be the only evidence of the origin of the gelastic seizures (4).
Using imaging techniques hypothalamic hamartomas produce characteristic soft tissue masses, iso-intense to the grey matter. They are homogeneous and sharply demarcated by the surrounding cerebreospinal fluid (CSF). There is no enhancement on contrast due to the blood-brain barrier (17). Striano et al (30) have emphasised that, when the hamartoma is small, magnetic resonance imaging of the hypothalamic, infundibular, and mammillary bodies areas may not show the lesion unless it is used with great care.
When single photon emission computed tomography is used there may be a dramatic ictal uptake in the area of the tumour, with normalisation during the interictal phase (13). Also positron emission tomography can help to show areas of hypometabolism, and confirm for example the spread of the epileptic discharge to the temporal lobe (31). The differential diagnosis is from craniopharyngioma, optic and hypothalamic gliomas, and gangliogliomas, which all enhance with contrast (32).
In most instances treatment for tumours in the hypothalamic region will be surgical, and it has been shown that resection of the lesion can alleviate both the seizures and the behavioural and cognitive abnormalities; although there can be serious complications such as cerebral infarcts. In view of the different presentations of the tumour the exact technique used is best judged on an individual patient basis (32). For example, Rosenfeld et al (33) have used the transcallosal-interforniceal route to the third ventricle to remove the hamartoma, with improvement of the patient's epilepsy, development and behaviour, Watanabe et al (34) using the interhemispheric trans-lamina terminalis approach reported control of seizures after only a partial resection of the lesion, and Delalande and Fohlen (35) found it relatively safe and effective in reducing the number of seizures if the intraventricular tumour was disconnected from other areas. Parrent (36) has reported a patient with gelastic seizures associated with a hypothalamic hamartoma whose seizures failed to respond to partial resection of the hamartoma, temporal lobectomy, and orbitofrontal cortiectomy, but showed progressive improvement after lesions were produced by radiofrequency ablation. Another potentially successful technique which can be used, when the hypothalamic tumour is inaccessible and the seizures are intractable, is stereotactic gamma knife radiosurgery (20,37,38). Régis et al (39) have used this technique with success, and they advocate marginal doses greater than, or equal to 17 Gy, and partial dose-planning when necessary to avoid damaging surrounding structures. Small hypothalamic hamartoma located inside the third ventricle or in the floor are the best candidates for gamma knife surgery. Such techniques cannot entirely replace more radical surgery, but in many instances will have fewer side effects, and can achieve good seizure control (40).
Zaatreh et al (41) have suggested that long-acting gonadotropin releasing hormone analogue should be considered as a possible therapy for gelastic seizures in patients with hypothalamic hamartoma when they found that such a patient, whose fits were resistant to conventional anti-epileptic drugs, responded dramatically to this treatment. It was suggested that this analogue might cause seizure remission by its influence on the origins of the epileptic activity within the hamartoma, and it can preserve the growth potential of those with central precocious puberty (16).
Precocious puberty can be treated with medroxy progesterone acetate, especially if surgery is not possible (17). However precocious puberty associated with hamartoma can usually be successfully treated surgically when patients fail to respond to medical treatment, when the length of the treatment cannot be tolerated by the children and their families, and when there are uncontrolled gelastic seizures (42).
In selected cases it may be possible to treat gelastic seizures with steroids, for example an infant with tuberous sclerosis developed such attacks which were controlled with adrenocorticotropic hormone (43). The patient reported by Gulati et al (23) was given a gonadotropin releasing hormone agonist analogue which resulted in regression of pubertal development, and subsequently treatment with phenytoin markedly reduced the incidence of gelastic seizures.
Unusual seizures can by their manifestations, not only suggest the probable site of their origin, but help to indicate the function of different parts of the brain; and gelastic seizures are a good example and are worthy of further study. As so often in such cases the correct diagnosis often depends on an accurate history, with confirmation by imaging studies.
Gelastic seizures are known to be refractory to medical treatment, no surgery should be considered at an early stage in an effort to improve the child's quality of life, and prevent developmental and behavioural disorders. A number of different techniques have been used, some with greater risks than others. Pedunculated growths are more easily removed than sessile ones, and those located in the region of the tuber cinereum and the mamillary bodies are more readily resected than those which lie on the floor of the third ventricle (44). The further development of stereotactic radiosurgery may help to improve the outcome for these patients.
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