Epilepsy & Behavior 37 (2014) 87–90

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Brief Communication

Gelastic epilepsy without hypothalamic hamartoma: Three additional cases Salvatore Savasta a, Mauro Budetta b, Maria Valentina Spartà a, Maria Luisa Carpentieri b, Guido Trasimeni c, Niki Zavras a, Maria Pia Villa d, Pasquale Parisi d,⁎ a

Department of Pediatrics, Pavia University Fondazione, IRCCS Policlinico San Matteo, Pavia, Italy Paediatric and Child Neurology Unit, Cava de' Tirreni AOU S. Giovanni di Dio e Ruggiero d'Aragona Hospital, Salerno, Italy NESMOS Department, Chair of Neuroradiology, Faculty of Medicine & Psychology, La Sapienza University, c/o Sant' Andrea Hospital, Rome, Italy d NESMOS Department, Child Neurology, Chair of Pediatrics, Faculty of Medicine & Psychology, Sant' Andrea Hospital, La Sapienza University, Rome, Italy b c

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Article history: Received 20 April 2014 Revised 6 June 2014 Accepted 9 June 2014 Available online xxxx Keywords: Gelastic seizures Gelastic epilepsy Cryptogenic epilepsy Focal epilepsy Hypothalamic hamartoma

a b s t r a c t We describe three children with gelastic seizures without hypothalamic hamartoma whose seizures were characterized by typical laughing attacks associated or not with other seizure types. Ictal/interictal EEG and magnetic resonance imaging were performed. All three subjects showed a good response to carbamazepine therapy with complete seizure control in addition to a benign clinical and cognitive outcome. These three cases confirm that gelastic epilepsy without hypothalamic hamartoma, both in cryptogenic or symptomatic patients (one child showed a dysplastic right parietotemporal lesion), usually has a more benign natural history, and carbamazepine seems to be the most efficacious therapy to obtain both immediate and long-term seizure control. These findings need to be confirmed in a larger sample of children affected by gelastic epilepsy without hypothalamic hamartoma. © 2014 Elsevier Inc. All rights reserved.

1. Introduction The main sign/symptom of gelastic epilepsy (GE) is gelastic seizure (GS), characterized by a sudden burst of laughter (lasting usually for less than a minute) with no apparent cause, occurring often when the child is falling asleep, although it may also occur throughout the day or night [1–5]. Gelastic seizures (GSs) are quite rare and usually associated with other seizure types or observed only as a transient phenomenon in the clinical evolution of an epileptic syndrome. They are rarely diagnosed early, although they begin in infancy in over one-third of documented patients [3–5]. Gelastic seizures can occur with very high frequency and amazing regularity and, in many children, only with the development of the more devastating and recognizable seizures (absence seizures, focal seizures, generalized tonic–clonic and atonic seizures) is a correct diagnosis eventually posed. Usually, when other seizure types begin, behavior and cognitive issues become more obvious [2–6].

⁎ Corresponding author at: Child Neurology, Headache Pediatric Center, Paediatric Sleep Disorders, Chair of Paediatrics, NESMOS Department, Faculty of Medicine & Psychology, La Sapienza University, c/o Sant' Andrea Hospital, Via di Grottarossa, 10351039, 00189 Rome, Italy. Fax: +39 6 33775941. E-mail addresses: [email protected], [email protected] (P. Parisi).

http://dx.doi.org/10.1016/j.yebeh.2014.06.012 1525-5050/© 2014 Elsevier Inc. All rights reserved.

Daly and Mulder [1] first coined the term gelastic epilepsy (GE) (from gelos: “mirth”) to describe GSs where laughter represents the predominant ictal semiology. Gelastic seizures with early onset, in association with hypothalamic hamartoma (HH) and occasionally precocious puberty (PP), are rare but well-recognized childhood epileptic syndromes, usually with a severe long-term prognosis [3]. Gelastic seizures may also be observed in association with other seizure types in epileptic disorders attributable to lesions in other brain areas. In fact, this ictal phenomenon has also been described in some epilepsies arising from the temporal, parietal, or frontal lobes [7–11]. Moreover, GSs in patients without any evidence of structural lesions of the central nervous system (i.e., cryptogenic cases) are rarely reported. In these latter cases, clinical EEG and ictal semiology findings are similar to those observed in symptomatic cases, but the clinical evolution is usually more benign [3–6,10–13]. Since small and not easily recognizable, HHs may be present in patients with GS; thus, a careful MRI study of the hypothalamic, infundibular, and mammillary body areas is mandatory [14]. Further, some patients with GE may also experience only the impulse to laugh [14]. Here, we report on three children in whom GSs (not associated with HHs, two cryptogenic and one showing a dysplastic frontoparietal lesion) associated with other seizure types showed a good response to carbamazepine and a clinically benign evolution even from a cognitive point of view.

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2. Case report 2.1. Case number 1 A 3.5-year-old male child, with a healthy personal and familial history, came to our attention following reports of sudden episodes of inappropriate laughter at kindergarten. These episodes were of short duration (few seconds), and he reported that these episodes were not connected with pleasure or satisfaction but rather as unmotivated or incidental. At the onset, it was not possible to obtain an ictal EEG recording of these episodes, which were sporadic (about once a week). An interictal EEG showed rare and suspicious anomalies in the frontal regions. The first MRI performed appeared normal, and no therapy was prescribed. The episodes of laughter increased slightly during the day and began to occur even at night, causing awakening. During a video sleep-EEG, it was possible to record an ictal episode. Subsequently, the interictal EEG began to reveal clear paroxysmal EEG abnormalities of the left frontal region. At the onset of the recorded seizure, a recruiting rhythm appeared at the left frontal region (Fig. 1) followed by a generalized flattening of the EEG. The seizure began with atypical laughter associated with some random and gross movements of the lower limbs causing the awakening of the child. Another MRI was performed which was also negative. Carbamazepine treatment was introduced with complete and immediate disappearance of the seizures. After 13 months, the parents decided to stop the anticonvulsant therapy, without initial reappearance of the seizures, but 8 months after discontinuation, the seizures recurred. Another brain MRI was obtained which failed to disclose any epileptogenic lesion, and carbamazepine therapy was restarted with immediate good response. After two years, carbamazepine therapy was stopped, and the patient is seizure-free until now. The boy attends school with good results, and his cognitive performance is normal at the age of seven (WISC-R: total IQ = 110). 2.2. Case number 2 A 9-year-old male child with a negative family history for epilepsy presented with daytime episodes of inappropriate laughter during school hours. Two months after the onset, he suffered two generalized tonic–clonic seizures (GTCSs); therefore, anticonvulsant therapy with oxcarbazepine was introduced with complete seizure control. Unfortunately, one year later, episodes of inappropriate laughter with

associated GTCSs recurred. Consequently, an MRI was performed with negative results, and anticonvulsant treatment with levetiracetam was started. One year later, five other gelastic seizures associated with secondary GTCSs occurred (Fig. 2) (moreover, during treatment with levetiracetam, his parents reported numerous episodes of “inappropriate laughter”), so it was decided to gradually withdraw levetiracetam, and carbamazepine was then introduced. Since the initiation of therapy with carbamazepine, the GS and GTCS episodes completely disappeared. Two years later, anticonvulsant therapy was tapered, and the boy is currently seizure-free and attends school with good results. The cognitive development is adequate (WISC-R = total IQ = 103). 2.3. Case number 3 A 15-year-old boy, with a healthy personal and familial history, at the age of three, began to have “unmotivated outbursts of laughter”. These episodes were of short duration (lasting for about 3–10 s) which he reported as not associated with pleasure or satisfaction. He came to our attention two years later (at the age of five) following frequent reported episodes of inappropriate laughter (Fig. 3), two of which were followed by secondary GTCSs. Consequently, anticonvulsant therapy with topiramate (5 mg/kg/day) was introduced with good seizure control for about six months, while a brain MRI and positron emission tomography (PET) showed a dysplastic right parietotemporal lesion (Figs. 4 a, b, c). Interestingly, although the dysplastic area was in the right temporal cortex (see Figs. 4 a, b, c), the focal onset of the EEG anomalies clearly originated in the left frontal region (Fig. 3). In particular, as soon as the EEG discharges became generalized, the clinical manifestations (gelastic seizure) appeared. After about seven months, GSs (gelastic seizures with secondary left focal sensory–motor seizures) reappeared. Carbamazepine was introduced, and topiramate was stopped with complete immediate and long-term seizure control. After three seizure-free years, carbamazepine therapy was gradually stopped, and the boy is still seizure-free with normal cognitive performance (WISC-R = total IQ = 100) and school achievements. 3. Discussion The epileptic syndrome characterized by early-onset GSs, HHs, precocious puberty PP, and a poor long-term prognosis with cognitive

Fig. 1. Gelastic seizure: At the onset of the recorded seizure, a recruiting rhythm appeared in the left frontal region followed by a generalized flattening of the EEG.

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Fig. 2. Gelastic seizure: The ictal EEG recording showed diffuse slow discharges during clinical manifestations. Rhythmical delta activity was observed over the anterior regions.

deterioration is now well recognized [3–6]. In this report, we present a small series of three children indicating that GE without HH, both in cryptogenic (case numbers 1 and 2) and symptomatic (case number 3) patients, has a more benign natural history and shows good response to anticonvulsant therapy compared with GE associated with HH [3–6]. It is possible that the presence of an associated HH represents an

intrinsic epileptogenic factor [12], and this could explain why surgical ablation of HH has been reported to achieve seizure control in the “classical syndromic” presentation. Nonetheless, it should be underlined that good cognitive outcome was achieved in all three children whose epilepsy responded well to carbamazepine anticonvulsant therapy. Therefore, carbamazepine

Fig. 3. Gelastic seizure: EEG recording: Although the dysplastic area was evident in the right temporal cortex (see Figs. 4 a, b, c), the focal onset of the EEG anomalies originated in the contralateral (left frontal) region followed by prompt diffusion; in particular, as the EEG discharges became generalized, the clinical manifestations (gelastic seizure) appeared.

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Fig. 4. a: Coronal inversion recovery image shows a thickened dysplastic cortex at the right superior temporal gyrus and insulae (arrow). b: Axial flair image shows thin linear hyperintensity in the subcortical white matter representing associated gliosis (large arrows). c: Axial FDG PET image shows the area of marked hypometabolism corresponding with the dysplastic zone (large arrows).

appears to be the best choice in these cases (children affected by GEs without HH) to obtain both immediate and long-term seizure control. Obviously, these findings need to be confirmed in a larger sample of children affected by GE without HH. In particular, in case number 1, carbamazepine was introduced as a first-line anticonvulsant therapy while in the other two cases (numbers 2 and 3), other first-line therapies (levetiracetam and topiramate) failed in both cases. Conversely, carbamazepine was effective in all three reported cases. As we stated above, some patients with GE experience an impulse to laugh, but in our children, we carefully excluded the occurrence of “subtle seizures” [14]. In conclusion, this small series of three children described here, compared with cases reported in the literature [1–12], underscores that (a) GSs associated with HH (the “syndromic form”) often have a later onset, long-term cognitive/psychiatric impairment, and a drugresistant natural course; (b) there is a more benign cognitive outcome with normal school performance when a HH is not present; and (c) carbamazepine seems to be more effective than other anticonvulsant drugs, although this finding needs to be confirmed in a larger sample. Conflict of interest We have no conflicts of interest to disclose with regard to this study.

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