Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Advances in imaging and surgical techniques have improved the recognition, treatment, and understanding of gelastic seizures due to hypothalamic hamartomas. It is now clear that in many cases the hamartoma is critical in generating the laughing seizures. Ictal laughter, however, can also occur in the absence of a hamartoma and is typically associated with frontal or temporal lobe epilepsy. The authors review the clinical presentation and differential diagnosis of paroxysmal laughter and comment on what the various etiologies may be able to tell us about the neuroanatomy of laughter. New and promising therapies such as MRI-guided laser interstitial thermal therapy are also reviewed.
• Gelastic seizures are characterized by recurrent bouts of unprovoked and stereotyped laughter.
• The differential diagnosis for gelastic seizures includes pseudobulbar laughter, gelastic cataplexy, and gelastic syncope.
• Gelastic seizures are classically associated with hypothalamic hamartoma but may also be secondary to focal pathology in the frontal or temporal lobes, and rarely the parietal lobe.
• When they are associated with hypothalamic hamartomas, gelastic seizures are typically intractable to medical therapy and may be 1 of the first manifestations of a syndrome characterized by multiple seizure types, precocious puberty, and an epileptic encephalopathy.
• The most effective treatments for gelastic seizures associated with hypothalamic hamartoma involve removal or ablation of the hamartoma, rarely the parietal lobe.
• When they are associated with hypothalamic hamartomas, gelastic seizures are typically intractable to medical therapy and may be one of the first manifestations of a syndrome characterized by multiple seizure types, precocious puberty, and an epileptic encephalopathy.
Daly and Mulder coined the term "gelastic epilepsy" from the Greek word gelos, meaning “laughter,” to emphasize the main character of these seizures (28). The possibility of sudden emotions as a manifestation of an epileptic seizure had been recognized since the end of the 19th century (130). These emotions were usually characterized as unpleasant. Emotions of fear were most often described. Laughing seizures were first described by Trousseau (147). Gowers observed emotions "with a cheerful character" as part of a seizure (50). Gascon and Lombroso suggested the following criteria for the diagnosis of gelastic epilepsy: stereotyped recurrence; absence of external precipitants; concomitance of other manifestations generally accepted as epileptic; presence of interictal or ictal epileptiform discharges on EEG; and absence of conditions in which pathologic laughter might occur (47). Arguments were raised against the concept of gelastic seizures as an epileptic syndrome because the definition of the syndrome was based on a single symptom (77). Currently, the ILAE classifies gelastic seizures as a type of focal seizure, which may be a component of various epilepsy syndromes (35; 36). The updated ILAE proposal recognizes gelastic seizures associated with hypothalamic hamartomas as a specific epilepsy constellation (121).
Gelastic seizures are classically associated with hypothalamic hamartomas, but ictal laughing has also been described in different epileptic conditions associated with the temporal or frontal lobes.
• The most effective treatments for gelastic seizures associated with hypothalamic hamartomas involve removal or ablation of the hamartoma.
The clinical spectrum and etiology of gelastic seizures has been primarily defined by case series and single case reports. Tassinari and colleagues compiled a literature review of 60 cases of patients with a hypothalamic hamartoma and gelastic seizures as well as another 60 cases of patients with gelastic seizures that were not associated with hypothalamic hamartomas (141). In the latter group, 37 patients had a suspected or proven temporal epileptogenic focus and 6 had a frontal focus. Many of these patients had focal pathology such as tumors, encephalomalacia, or hemispheric atrophy. The remaining patients had non-localizing, multifocal, or no EEG abnormalities. It is possible that some of the cases may have been due to an unrecognized hypothalamic abnormality.
Gelastic seizures are usually the first seizure type to present in patients with epilepsy related to a hypothalamic hamartoma and typically present before the age of 5 (141; 101). Subsequently, during school age, other seizure types develop, and cognitive deterioration occurs. Severe behavior problems are common, and the seizures are usually intractable (08; 151; 139). A few cases of epilepsy in adult patients with hypothalamic hamartoma have been described. Gelastic seizures are less common in this age group and the epileptic syndrome, including behavior problems and learning difficulties, seems to be milder (90; 90).
When gelastic seizures are associated with frontal lobe or temporal lobe pathology, onset is usually after the age of 5 years; gelastic seizures usually present in close relation to or later than, other seizure types. The oldest reported case of gelastic seizures occurred in an 83-year-old man with right frontal lobe epilepsy (19).
Gelastic seizures associated with hypothalamic hamartomas often appear several times daily or even hourly. This differs from the less frequently appearing gelastic seizures associated with other localizations. Occasional cases of gelastic status epilepticus have been reported in patients with (95; 104; 108) and without (48; 114; 19; 81) hypothalamic hamartoma.
Marashly and colleagues reported a 3-year-old patient with new onset refractory status epilepticus (NORSE) in the form of recurrent and intractable gelastic seizures arising from the right frontal lobe (81). No response was obtained with aggressive medical treatment but subsequent resection of the right frontal lobe sparing eloquent cortex resulted in seizure control and excellent outcome (81).
The characteristic clinical manifestation of a gelastic seizure is laughter. Other clinical features vary depending on the associated pathology and epileptic syndrome. Some patients have experienced both gelastic and crying seizures, termed "dacrystic” (102) or “quiritarian” seizures (127). The initial gelastic seizures in infants and young children with hypothalamic hamartomas are typically uncomplicated spurts of laughter without impaired consciousness that last less than 30 seconds and recur frequently (93; 101). Although inappropriate, the laughter exhibited early in the syndrome can be so similar to the patient’s natural laughter that it can go without diagnosis for a long period of time. Berkovic and colleagues reported on 1 case in which a baby with a hypothalamic hamartoma won a “happy baby” contest on account of his laughter (08). In infants with hypothalamic hamartomas, the frequent intermittent unprovoked episodes of laughing or crying have also been misdiagnosed as gastroesophageal reflux disease (Sandifer syndrome) (140).
A gelastic component can occur as part of several kinds of seizures, such as axial tonic seizures, flexor spasms, generalized tonic-clonic seizures, atypical absence seizures, as well as focal seizures with impairment of awareness (previously termed complex partial seizures) (77). When it occurs as part of another seizure, the laughing component can be prolonged and associated with impaired consciousness. Over time, patients with hypothalamic hamartomas and gelastic epilepsy typically develop several seizure types, which can occur with and without ictal laughter (101). As opposed to the early gelastic seizures, the laughing in these later seizures is usually clearly inappropriate without emotional valence (141). In patients with gelastic seizures without a hypothalamic hamartoma, such as patients with frontal or temporal epilepsies, the laughter is typically associated with automatisms, motor signs, or autonomic changes. In these cases, laughter can occur with or without a change in awareness (04; 141). The experience and expression of mirth also varies in neocortical gelastic seizures and may suggest their site of origin (see the “Localization” section for further discussion).
The prognosis of gelastic seizures originating from frontal lobes, temporal lobes, or other regions of the brain is dependent on the underlying pathology. They usually have a better outcome than those associated with a hypothalamic origin. Children with gelastic seizures due to hypothalamic hamartomas typically develop intractable seizures and a secondary epileptic encephalopathy characterized by cognitive deterioration and severe behavior problems (08; 40; 15; 138). The development of other seizure types correlates with the duration of epilepsy and not the size of the hamartoma (106; 137). Larger hamartomas, however, are more likely to be associated with cognitive impairment (106). In the rare adult onset cases of gelastic seizures associated with a hypothalamic hamartoma, epilepsy seems to be milder (90; 90).
A 37-year-old right-handed man with mild mental retardation was evaluated for intractable epilepsy. He was born at 34 weeks with no perinatal complications. He had normal or near normal development until the age of 6 months, when he developed infantile spasms with hypsarrhythmia. Following ACTH treatment, he became seizure-free until the age of 8, when initially nocturnal gelastic seizures developed. These were characterized by an arousal with giggling. He subsequently developed multiple seizure types including focal aware seizures (autonomic auras), focal seizures with impairment of awareness and unilateral automatisms, and focal seizures that evolved to bilateral motor seizures. The latter 2 seizure types occasionally included laughter. Seizures were refractory to over 8 different antiseizure medications. Interictal EEG demonstrated mild to moderate background slowing, frequent generalized 2 to 3 Hz sharp-and-wave and spike-and-wave discharges, and left anterior temporal (F7-T3) spikes. Ictal EEG during gelastic seizures was characterized by a 1- to 2-second burst of generalized spike-and-wave activity followed by a few seconds of diffuse attenuation. MRI demonstrated a non-enhancing 1 cm lesion in or abutting the left hypothalamus, protruding into third ventricle consistent with a hypothalamic hamartoma.
The patient underwent endoscopic resection of the hypothalamic hamartoma via a right frontal horn approach.
Seizures became less frequent (decreased from daily to monthly) but persisted for 3 years before abating completely. He was then seizure-free for at least 2 years. Surgery was complicated by memory impairment (initially severe) and transient hyperphagia with significant weight gain.
Localization of hypothalamic hamartoma. Nonneoplastic malformations resembling gray matter can be seen on these MRIs:
Gelastic seizures are classically associated with hypothalamic hamartomas, but ictal laughing has also been described in many patients without hamartomas. These cases are typically associated with frontal or temporal lobe epilepsies, many of which have definitive cortical pathology. A series of 19 cases with gelastic seizures found that one third were related to hypothalamic hamartomas, one third had temporal lobe epilepsy, and the rest were variable or undetermined (69). Gelastic epilepsy has been associated with temporal lobe tumors (25; 28; 77; 22; 127; 30), atrophy (47; 22), cortical tubers in tuberous sclerosis (162), and postinfectious foci (22). Frontal lobe lesions that have been associated with gelastic epilepsy include tumors (85; 136; 04; 148; 98) and cortical dysplasia (84; 123; 23; 150; 55). Frontal hypermotor seizures with a gelastic component have also been reported in a patient with ring chromosome 20 syndrome (33). The frontal lobe regions most typically involved in gelastic seizures include the orbitofrontal cortex (11; 58; 148) and anterior cingulate cortex (77; 04; 31; 84). However, there are at least 2 reports of intracranial EEGs during gelastic seizures suggesting the involvement of the superior frontal gyrus. Intracranial EEG during the gelastic component of the seizures in 1 adult and 1 child, respectively, suggested that the symptomatogenic zone responsible for the ictal laughter was in the right superior frontal gyrus (150; 81).
Electrocortical stimulation of both the supplementary motor area (42) and the anterior cingulate (135) has been able to generate laughter. There have also been rare reports of gelastic seizures involving the parietal lobe (131; 80). Cases of gelastic epilepsy of unknown etiology have also been reported (21; 19).
Tran and colleagues summarized the localization of cortical gelastic seizures in 16 cases from their institution and 77 cases reported in the literature (145). Specific localization was determined in 9 institutional cases and 18 from the literature. Of these 27 cases, 13 localized to the frontal lobes (10 medial frontal), 8 to the temporal lobes, 2 to the parietal lobes, and 4 to the opercular/insular region. Nine cases localized to the left hemisphere and 18 to the right. Overall, the authors concluded that ictal laughter, when not associated with a hypothalamic hamartoma, is a poorly localizing semiology.
There is some controversy as to whether the anatomic origin of gelastic seizures can be determined by the qualitative features of the laughter and the patient’s subjective experience during the seizure. It has been suggested that normal laughter results from the integration of at least 2 separate neural networks. In this model, 1 network, involving the temporal cortex, particularly the posterior temporal cortex, the amygdala, and the dorsal brainstem, is responsible for the perception of mirth and emotionally driven laughter. A second network, involving the frontal lobe, particularly the cingulate, premotor, and opercular regions, as well as the pyramidal tract, basal ganglia, and ventral brainstem, controls the “motor program” involved in laughing (78; 04; 156). In concert with this hypothesis, gelastic seizures generated from the frontal lobe typically appear unnatural, forced, and without emotions or feelings of mirth (11; 123; 68). The experience of mirth during gelastic seizures usually occurs with ictal involvement of the temporal lobe (75; 47; 02; 57; 04; 26; 100); however, emotional content is not reported by the majority of patients with gelastic seizures of temporal lobe origin (11). In fact, the gelastic seizures in some patients with temporal lobe tumors have also been described as being of a forced and unnatural nature (Bancuad et al 1974; 127). Gelastic seizures generated from hypothalamic hamartoma are usually also devoid of emotional content (04). Most patients with hypothalamic hamartomas and gelastic seizures are conscious of the laughter but do not experience a sensation of mirth (93), though some exceptions have been reported (04; 139; 101). A sensation of a “pressure to laugh” is common (Strum et al 2000; 137).
Prior to advances in surgical and neuroimaging techniques of the last 2 decades, it was hypothesized that the manifestation of gelastic epilepsy in patients with hypothalamic hamartomas was due to associated epileptogenic regions in the temporal or frontal lobes. This assumption was in part due to the fact that interictal and ictal EEGs in patients with hypothalamic hamartomas typically demonstrate focal frontal and temporal epileptiform discharges as well as generalized spike-and-wave discharges. In a retrospective review of 12 patients with hypothalamic hamartomas who had temporal or frontal surgery, however, Cascino and colleagues demonstrated that resections that exclude the hamartoma are not sufficient to eliminate or reduce seizure frequency (18). The concept that the hypothalamic hamartoma itself is the generator of gelastic seizures is supported by the fact that removal of the tumor is necessary and often sufficient to improve or cure these seizures, even if the EEG suggests temporal or frontal involvement (99; 151; 71; 105; 149; 95). Palmini and colleagues reported a case of status gelasticus following a left temporal lobectomy in a patient with a hypothalamic hamartoma (104). Gelastic seizures improved only after removal of the hamartoma.
In addition to these surgical cases, there is substantial neurophysiologic and radiologic evidence that the hamartoma itself is intrinsically epileptogenic and critical in the generation of gelastic seizures: analysis of the scalp EEG dynamics of epileptic activity in gelastic seizures produced isolation of epileptic rhythms in gelastic seizures; subcortical deep generators were found to be activated earlier than the superficial ones, suggesting a consistent subcortical origin of the rhythmical activity (72). Dipole source localization also suggested that gelastic seizures likely originate in the hypothalamic hamartoma (54). An fMRI study of gelastic seizures demonstrated involvement of the hamartoma, as well as the cingulate gyrus, the precuneus, and the prefrontal cortex (67). Furthermore, ictal SPECT performed during typical gelastic seizures in patients with hypothalamic hamartomas demonstrates hyperperfusion in the hamartoma, hypothalamic region, and thalamus, without cortical or cerebellar hyperperfusion (05; 71; 62), and ictal FDG-PET during episodes of status gelasticus demonstrates ictal hypermetabolism localized to the hamartoma (104; 128). However, not all nuclear medicine studies have been this specific (56; 15). Finally, stereo-EEG techniques, which allow for extraoperative intracranial recordings directly from the hypothalamic hamartoma, neighboring hypothalamic structures, and other bilateral cortical areas, have shown that gelastic seizures are associated with ictal discharges localized in the hamartoma (92; 71; 60; 152; 153). Using stereo-EEG with electrodes implanted in the hypothalamic hamartomas of 15 patients with gelastic seizures refractory to treatment, Wang and colleagues evaluated 20 gelastic seizures and recorded both interictal and ictal intrahypothalamic discharges (153). These studies also demonstrated that electrical stimulation of the hamartoma can reproduce attacks of laughing (71; 60). Interestingly, in 1 case, differences were found among electrically induced clinical symptoms from different parts of the same hamartoma (60). Intraoperative scalp and intrahamartoma recordings have also demonstrated that interictal scalp EEG findings such as temporal sharp waves, often seen in patients with hypothalamic hamartoma, can correspond to synchronous epileptiform abnormalities within the hamartoma (134).
Parvizi and colleagues reviewed the anatomical localization of hypothalamic hamartomas in 100 patients with gelastic seizures. The authors found that all of the hamartomas involved the posterior aspect of the hypothalamus at the level of the mamillary bodies, and they speculate that future pathological studies may be able to identify unique nuclei in this region responsible for the generation of ictal laughter (106). In contrast, hypothalamic hamartomas that connect to the anterior hypothalamus in the region of the tuber cinereum are associated with central precocious puberty (71; 52). However, both epilepsy and precocious puberty commonly occur in concomitance in patients with hypothalamic hamartomas. Amongst 26 patients undergoing surgical treatment of drug-resistant epilepsy due to hypothalamic hamartomas, 11 (42%) had associated central precocious puberty (96).
Hypothalamic hamartomas are a developmental malformation that arises from the inferior hypothalamus. The origin of the hamartoma is not known. Epileptogenesis within the hamartoma appears to be driven by large immature pyramidal neurons that are paradoxically activated by GABA.
As described above, various etiologies have been shown to be associated with gelastic epilepsy that is not related to a hypothalamic hamartoma. Some of these are structural, including neoplasms and cortical dysplasia. Many cases remain cryptogenic.
Cell biology. The mechanisms underlying the epileptogenesis of gelastic seizures are not fully understood (158; 160; 159). Some advances in surgical techniques for the treatment of hypothalamic hamartomas have allowed for a better understanding of this highly epileptogenic tissue. Hamartomas typically consist of clusters of small neurons, scattered large neurons, and glial cells. It is believed that hypothalamic hamartomas have intrinsic epileptic properties and involve mechanisms that modulate GABAergic neurons (161; Kim et al 2008). Single-cell recordings demonstrate that the small cells contain predominantly GABA-ergic inhibitory neurons exhibiting intrinsic “pacemaker-like” behavior (161). Similar to what occurs during early development (89; 07), under pathological conditions GABA-A receptors signaling may promote neuronal excitability rather than inhibition. The depolarizing activity of GABA-A receptors signaling in immature neurons occurs when there is a decrease in the expression and activity of neuron specific potassium-chloride cotransporter (KCC2) and an increase in sodium-potassium cotransporter (NKCC1) (116; 38; 44; 45). Kim and colleagues investigated the role of GABA-A receptors in human hypothalamic hamartoma tissue and found that that 84% of large hypothalamic hamartoma neurons expressed solely or relatively more NKCC1, which suggests that these GABAergic neurons behave as immature neurons (Kim et al 2008).
In order to better understand the paradoxical reaction, Semaan and colleagues compared these immature large hamartoma cells to control hypothalamic tissue from cadavers and found an increase in expression of brain-derived neurotrophic factor (BDNF), which downregulates expression of KCC2 (126). In the immature large hamartoma cell, the decreased expression of KCC2 leads to increased intracellular Cl-concentrations, increasing GABAergic excitability. These authors proposed a model of epileptogenesis in the hamartoma in which the small pacemaker-like cells provide tonic activation of the large cells, which may project to and excite the adjacent cerebral cortex (126). Therefore, hypothalamic hamartomas have intrinsic epileptic properties enabling generation and propagation of gelastic seizures.
As described above, the majority of imaging, neurophysiology, and molecular studies have indicated that cases of gelastic seizures that occur early in the course of patients with hypothalamic hamartomas are likely generated by the hamartomas themselves. However, over time patients with hypothalamic hamartomas frequently develop an epileptic encephalopathy with multiple seizure types and cognitive decline. Epileptic activity in the hamartoma may spread via limbic pathways, recruiting secondary epileptogenic zones. In support of this theory, a morphometric MRI study demonstrated that hamartoma patients who developed multiple seizure types had greater white-matter density in the temporal lobes and cerebellum than those who had only gelastic seizures (79). Using intracranial EEG, Valentin and colleagues found that single pulse electrical stimulation of the left cingulate gyrus elicited generalized epileptiform discharges in a 38-year-old patient with a hypothalamic hamartoma and seizures since infancy (152). Although the seizures themselves began in the hamartoma, these interictal discharges could only be elicited from the cingulate cortex, indicating independent cortical irritability in this region. In their stereo-EEG study, Kahane and colleagues found that in 3 cases in which the ictal discharge was seen outside of the hamartoma, the cingulate gyrus was involved (60). They proposed that the “mamillo-thalamo-cingulate” tract could serve as a relay of hypothalamic hamartoma discharges towards the cortex, and that the excitability of the cortex could progressively increase until eventually seizures of cortical origin were established (60). Leal and colleagues proposed that the fornix and cingulate fasciculus may be a tract utilized for propagation of gelastic seizures (74). This was based on simultaneous EEG and fMRI in 1 patient, which allowed for temporal resolution of his gelastic seizures. The ictal fMRI suggested generation of the ictal discharge within the hamartoma with subsequent propagation to the left hypothalamus and left posterior temporal-occipital area followed by spread to the ipsilateral frontal lobe.
The concept of secondary epileptogenesis in patients with hypothalamic hamartomas is also supported by 2 cases described by Scholly and colleagues (124). Both patients had longstanding (> 35 years) epilepsy associated with hypothalamic hamartomas. Gelastic seizures improved after endoscopic resection of the hamartomas, but independent temporal lobe seizures with loss of consciousness persisted in both patients, only resolving after left temporal lobe resections.
Gelastic seizures are rare, making determination of their incidence and the frequency of associated etiologies difficult. Three studies have attempted to define the prevalence of gelastic seizures. Chen and Forster reviewed 5000 cases of adults and children with epilepsy referred to a tertiary care center and identified 10 cases of gelastic epilepsy (0.2% of referred patients) (22). The majority of these cases were attributed to head injury or infection. There were no recognized hypothalamic hamartomas in this cohort, which may reflect the limitations of neuroimaging at the time. Shahar and colleagues identified 10 cases of gelastic epilepsy in a review of 2400 children referred to any of the pediatric neurology centers in Israel for evaluation of a potential seizure disorder (0.4% of referred patients) (129). Based on this data, they estimated the prevalence of gelastic seizures among all Israeli children to be 0.4 in 100,000. Of these 10 cases, 4 were associated with a hypothalamic hamartoma. Three patients had cortical dysplasia, and 3 cases were considered idiopathic. In Sweden, looking at only patients with gelastic seizures and hypothalamic hamartomas, Brandberg and colleagues estimated the prevalence of this syndrome among Swedish children to be 0.5 in 100,000 (15). A review of all patients in a single epilepsy monitoring unit over 5 years identified 19 cases (0.8%) with gelastic seizures, one third with hypothalamic hamartomas (69).
There are no known methods of preventing the development of hypothalamic hamartoma or gelastic epilepsy. Early removal, disconnection, or destruction of a hypothalamic hamartoma associated with gelastic epilepsy is the best way to prevent the development of intractable epilepsy and neuropsychiatric comorbidities.
Pathologic laughter is not always epileptic. Other causes of pathologic laughter or abnormal responses to appropriately induced laughter include the following:
Pseudobulbar laughter. Emotional disinhibition in patients with pseudobulbar affect can lead to pathologic laughter. As opposed to the pathologic laughter of gelastic seizures, which is unprovoked and unpredictable, pseudobulbar laughter usually occurs in response to an external trigger and is mood-congruent but inappropriate in its intensity. Pseudobulbar affect can be seen following strokes and in association with many neurodegenerative conditions such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer disease (122).
Gelastic cataplexy. Strong emotions and laughter can trigger atonic events in patients with cataplexy and these laughter-induced events can be mistaken for seizures. Gelastic cataplexy (cataplexy induced by laughter or emotions associated with laughter) is actually a relatively common symptom early in the course of late-infantile and juvenile Niemann-Pick C (64; 111; 110; 112).
Gelastic syncope. Vigorous but appropriate laughter has been noted to induce vasovagal syncope in a handful of patients (144; 13; 118; 143; 34; 107). There is also a single case report of pathologic laughter and associated syncope or presyncopal symptoms, both of which resolved after the removal of an ependymoma in the cerebellar vermis, which abutted the floor of the fourth ventricle (37).
Psychogenic non-epileptic events. One case of psychogenic non-epileptic gelastic events has been reported by 1 of the authors (120).
Gelastic seizures are known to occur in the following syndromes and diseases: hypothalamic hamartoma, frontal lobe epilepsy, temporal lobe epilepsy, and Niemann-Pick disease type C (though there is debate if the events in Niemann-Pick disease type C are gelastic cataplexy vs. gelastic seizures) (51; 59).
There is a rare autosomal dominant disorder, Pallister-Hall syndrome, that consists of hypothalamic hamartoma and other CNS malformations, polydactyly, dysplastic nails, syndactyly, hypopituitarism, craniofacial abnormalities such as bifid epiglottis, and visceral anomalies, including imperforate anus and congenital heart and pulmonary and renal defects (10). The association between Pallister-Hall syndrome and mutations in the GLI3 gene made by Kang and colleagues in 1997 generated the search for somatic GLI3 mutations in the hamartoma tissue (Kang et al 1997; 27; 53). Hildebrand and associates identified somatic mutations of the sonic hedgehog pathway in 14 (37%) of 38 patients with hypothalamic hamartoma and gelastic seizures (53). Currently, a few genes have been associated with hypothalamic hamartomas, including Shh gene, GLI3, and PRKACA (27; 53; 117). They speculate that the interest in the sonic hedgehog pathway, which led to development of therapeutic agents for treatment of cancers (17), could ultimately be investigated for the treatment of hypothalamic hamartoma associated with these gene mutations (53).
High-resolution MRI is of the utmost importance to reveal the origin of gelastic seizures. Sometimes, where a hypothalamic hamartoma has been revealed, other malformations of cortical development can also be found (86; 133; 15; 104). Video EEG should also be considered in patients with paroxysmal laughter. This can help confirm the diagnosis of gelastic seizures based on ictal semiology and can also help screen for other seizure types. It is important to keep in mind, however, that in patients with a hypothalamic hamartoma, scalp EEG recordings have limited localizing value. In 1 series of 68 patients with hypothalamic hamartoma, EEG recordings during gelastic seizures typically did not show an obvious ictal pattern (146). Occasionally, the seizures correlated with generalized abnormalities or focal seizures, likely representing seizure spread to neocortex. The same study demonstrated that video EEG monitoring in patients with hypothalamic hamartomas did not improve surgical outcome. Some authors have suggested that in specific cases, dipole analysis of scalp EEG and MEG may be helpful (73; 49). Diffusion tensor imaging has also been reported to be useful (88). The performance of interictal and ictal SPECT may be of interest (32) as well as ictal FDG-PET (104). Finally, some have reported utility of fMRI to localize spikes or seizures (74). These studies may influence the clinical picture and surgical approach. If intracranial recordings are done as part of a surgical approach, one should strongly consider including a depth electrode recording from the hypothalamic hamartoma (93; 60).
Up to 50% of patients with hypothalamic hamartomas and epilepsy have precocious puberty, and other endocrine abnormalities have been reported (109). Patients with confirmed hypothalamic hamartomas should also undergo a complete endocrinological workup for signs of precocious puberty. This includes measurement of height, weight, and height velocity, as well as pubertal staging and bone age. Gonadotropin assays may also be indicated.
Treatment of gelastic seizures associated with hypothalamic hamartomas (see Table 1).
Surgery. Gelastic seizures associated with hypothalamic hamartomas are typically refractory to antiseizure medications (103; 15). In these cases, there is now mounting evidence that through an individually tailored surgical approach the condition is a treatable epileptic encephalopathy (105; 76; 103; 09; 29; 39). Complete removal, ablation, or disconnection of the hamartoma is usually necessary to achieve complete or substantial seizure reduction and decrease the chances of developing an epileptic encephalopathy. There are several possible surgical approaches for resection or disconnection of a hypothalamic hamartoma; the choice of surgical technique is based on the tumor’s size and anatomical site of attachment. Hypothalamic hamartomas can be classified as pedunculated or sessile. Most of the hypothalamic hamartomas associated with epileptic seizures are sessile lesions, whereas pedunculated lesions are most commonly associated with isolated precocious puberty. As opposed to the pedunculated tumors, which have a narrow-based connection to the hypothalamus and can be surgically approached from below the third ventricle, the sessile lesions have a broad-based connection to the hypothalamus and may extend into the third ventricle. These tumors are best approached from above. A transcallosal anterior interforniceal approach is thought to be the optimal way to visualize and resect the intraventricular component of a sessile hamartoma. Using frameless stereotaxy, sessile tumors less than 1.5 cm in diameter can be resected endoscopically via a less invasive transcortical transventricular route through the foramen of Monro (142; 41). These surgical procedures are associated with reasonably good outcomes when performed by experienced surgeons in selected patients. Case series from the Barrow Neurological Institute report a substantial (more than 90%) seizure reduction in 70% to 80% of surgical cases with 50% achieving seizure freedom (96; 97).
Although a transcallosal or endoscopic resection offers patients with hypothalamic hamartomas and gelastic epilepsy the best chance of seizure freedom and cognitive stabilization, these surgical procedures are not without substantial risks.
One of the most significant complications of these procedures is transient or permanent memory loss due to injury to the fornices, mamillary bodies, or connections within this important memory circuit (Papez circuit) (03). Other serious complications include third nerve palsies, strokes, hyperphagia, and endocrine abnormalities, particularly diabetes insipidus.
Some authors have proposed that disconnection of the hypothalamic hamartoma may be similarly effective and less risky than complete resection of the abnormal tissue (24; 113; 16). The largest series reported by Procaccini and colleagues involved 32 disconnection surgeries (6 pterional approaches, 15 endoscopic, and 11 combined approaches) (113). Seizure freedom was achieved in 48.5% of patients and another 48.5% improved. The authors concluded that the endoscopic disconnection approach is most effective for patients with vertically inserted hamartomas above the floor of the third ventricle (type 2). In this subgroup, 90% achieved seizure freedom. Neurologic complications occurred in 2 patients disconnected by pterional approach and endocrinological complications occurred in 3 patients (see Table 1). Many patients reported neuropsychological improvement; memory impairment was not reported. Calisto and colleagues (from the same center) compared endoscopic disconnection by monopolar coagulation to disconnection by thulium laser disconnection (16). At 1-year follow-up, 42% of each group achieved Engel class I, Ia, or Ib (5/12 with coagulation disconnection, 3/7 with laser disconnection). Acute postoperative complications included oculomotor deficits, electrolyte alterations, memory deficits, and mutism in the monopolar coagulation disconnection cases. Among the laser disconnection cases 1 patient had drowsiness and a possible subcortical infarct on CT and another patient had memory deficits. The authors reported there were no persistent complications by 1-year follow-up.
Radiosurgical intervention is less often associated with the complications mentioned above but can result in substantial intracranial edema. Radiosurgery typically takes 1 to 2 years to reach full effect and is typically reserved for smaller hamartomas. In the 2 largest series of gamma-knife surgery and interstitial radiosurgery, the rate of Engel class I outcomes was 37% (with interstitial radiosurgery 12.5% were completely seizure free but 37% were class I). Significant seizure reduction occurred in 50% to 60% (115; 125). Smaller studies of radiosurgery have yielded similar results (01; 83).
Other alternative methods such as MRI-guided stereotaxic radiofrequency thermoregulation, laser interstitial thermal therapy, and stereo electroencephalography-guided radiofrequency thermocoagulation were introduced. These minimally invasive and promising techniques aim to disconnect the hypothalamic hamartoma to prevent seizure propagation while avoiding serious complications. The disadvantage of these less invasive procedures is the fact that patients may need to undergo repeated treatment to obtain relief of the symptoms. A few outcome studies investigated the efficacy and safety of these minimally invasive techniques for treatment of hypothalamic hamartoma and gelastic seizures in adults and children (61; 154; 157; 63; Gadgil et al 2019; 132).
In 1 series of radiofrequency thermocoagulation, 76% of patients achieved seizure freedom, with intellectual and behavioral improvement also reported (61). Although this procedure is less invasive than open surgical resection, transient endocrinological changes and memory problems have been reported. For larger hamartomas, the need for multiple trajectories to ablate the lesion increases risk to nearby vascular structures (87).
Wilfong and Curry reported the outcomes of 14 cases treated with a laser thermal ablation technique (157). A significant advantage of this technique is that the laser probe can be inserted and the thermal ablation carried out with the patient in the MRI scanner, allowing for visualization of the placement and procedure. Overall seizure freedom among 14 patients with 1 to 24 months of follow-up was 79% after first procedure and 86% overall when including 1 patient who required a second procedure. Of 10 patients with 6-month follow-up, 80% were seizure free after a first procedure and 90% were seizure free after a second procedure. One patient had subclinical and self-resolving subarachnoid hemorrhage. No neuroendocrine complications, neurologic deficits, or memory problems were reported.
Kameyama and colleagues reported excellent seizure outcomes after stereotaxic radiofrequency thermoregulation (SRT) in 100 patients with hypothalamic hamartoma. Repeat stereotaxic radiofrequency thermoregulations led to freedom from gelastic seizures in 32 patients (63). In a retrospective review of 150 patients with residual hypothalamic hamartoma, Shirozu and associates reported the response to treatment with repeated stereotaxic radiofrequency thermoregulations in 206 patients: 43 (28.7%) underwent 1 repeat SRT; 33 (22.0%) underwent 2 repeat SRTs; 7 (4.7%) underwent 3 repeat SRTs; and 3 (2.0%) underwent 4 repeat SRTs (132). Overall, 73% of these patients became seizure free, 90% were free from gelastic seizures, and 74% were free from nongelastic seizures after 1 or multiple repeat stereotaxic radiofrequency thermoregulations (132). Transient complications did not differ between first and repeat stereotaxic radiofrequency thermoregulations. However, persistent complications were more frequently seen after repeat stereotaxic radiofrequency thermoregulation, including memory disturbance, hypopituitarism, hemiparesis, and diabetes insipidus (132). Gadgil and colleagues retrospectively reviewed 58 pediatric patients that underwent MRI-guided laser interstitial thermal therapy for treatment of hypothalamic hamartoma; 18 (31%) of these patients had undergone prior surgeries, including open resection of hypothalamic hamartoma in 13.8% and gamma knife surgery in 12.1% (43). All patients underwent laser interstitial thermal therapy and 16 had repeat laser interstitial thermal therapy, and 12 (20.7%) had 2 ablations and 4 (6.9%) had 3 ablations (43). There were transient postoperative complications such as disorders of sodium metabolism (n = 4), transient short-term memory dysfunction (n = 4), and transient worsened seizures (n=4); 1 of these patients with seizures developed status epilepticus and respiratory failure but had a full recovery (43). Only 1 patient had permanent memory deficits (43). The majority (81%) of patients were free of gelastic seizures at 6 months or more of follow-up and the percentage of residual hamartoma was smaller (43%) in patients free of gelastic seizures when compared to those with refractory, persistent seizures (71%) (43). Resting state functional MRI (rs-fMRI) was used to localize the epileptogenic zone within the hypothalamic hamartoma prior to performing stereotaxic laser ablation in 51 pediatric patients with intractable epilepsy (14). Patients were allocated to the control group or rsfMRI group based on the success of the rsfMRI data acquisition (14). Overall seizure reduction was high in the rsfMRI group (85%) with class I Engel outcome classification seen in 92% when compared to the control group with 49% of seizure reduction and 47% with class I Engel outcome classification (14). No postsurgical morbidity or mortality were reported with this surgical approach (14).
Neurostimulation. Deep brain stimulation has been attempted in a few patients with hypothalamic seizures and intractable epilepsy (155; 65; 82). Of 4 reported patients in these series, 3 showed improvement in seizure frequency in short-term follow-up. One receiving high-frequency stimulation of the mamillothalamic tract became seizure free for 10 months (65). Future research as to the long-term outcomes and risks of deep brain stimulation for hypothalamic hamartoma patients is needed before it is considered over surgical interventions.
Vagal nerve stimulation has also been tried in several children with gelastic seizures and hypothalamic hamartoma. The majority did not have any significant clinical improvement in their seizures (94; Brandenberg et al 2004; 155; 12), though behavior may have been improved in 4 children with autistic symptoms (94).
Alternative therapies. Although gelastic seizures associated with hypothalamic hamartomas are usually intractable to antiseizure medications, there is an evolving body of research identifying alternative therapies. One case series reported that 4 of 6 patients with seizures and hypothalamic hamartoma had a positive response to the ketogenic diet (20). Cases of precocious puberty and gelastic seizures successfully treated with long-acting GnRH analogues have been described (163). These novel approaches are not FDA-approved therapies or indications.
Treatment of gelastic epilepsy not associated with hypothalamic hamartomas. For gelastic seizures not associated with hypothalamic hamartomas, treatment depends on the underlying etiology. Nonhamartoma-related gelastic epilepsy has been reported to respond to various antiepileptic drugs (56; 26; 46; 19) as well as surgical resection (06; 04; 70; 21; 69). Antiepileptic drug treatment is the first-line of therapy in most cases. In 1 case series of 3 children with normal intelligence and gelastic seizures (2 apparently cryptogenic and 1 associated with right parieto-temporal cortical dysplasia), Savasta and associates reported a good response to carbamazepine, with seizure remission persisting after withdrawal of the drug (119). Epilepsy surgery should be considered in neoplastic or vascular causes of gelastic seizures and in patients who are intractable to 2 or more antiepileptic drugs. In a review of 10 cases of gelastic epilepsy of frontal lobe origin, 3 patients responded to medical management and 2 responded to surgical treatment (11).
Early surgical intervention provides the best seizure outcomes and the best chance at preventing progression to intractable epilepsy with neuropsychiatric comorbidities. As discussed above, neurosurgical resection does have significant treatment-related complications such as neuroendocrine and neurologic sequelae, including memory loss. The development of new minimally-invasive surgical techniques has introduced hope of better long-term outcomes in the syndrome of hypothalamic hamartomas and gelastic seizures. As with most surgical procedures, the experience of the surgeon plays an important role in a patient’s outcome.
Women with gelastic epilepsy can carry healthy pregnancies. Management of reproductive-age women with gelastic seizures should be similar to that of women with other types of epilepsy. Antiepileptic drugs with a relatively low risk of structural and teratogenesis should be used as first-line drugs and folic acid (0.4 to 4 mg daily) should be recommended. In women with intractable gelastic seizures, surgical resection should be considered well in advance of attempts to conceive.
Gelastic seizures pose no specific contraindications to anesthesia.
Diosely C Silveira MD PhD
Dr. Silveira of the Hackensack University Medical Center and JFK Neuroscience Institute has no financial relationships to disclose.See Profile
Suman Bharath MD
Dr. Bharath of Hackensack University Medical Center and JFK Neuroscience Institute has no relevant financial relationships to disclose.See Profile
Solomon L Moshé MD
Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
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