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Small hypothalamic hamartomas and gelastic seizures. [Published with videosequences]. Volume 4, issue 2, June 2002

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  • Small hypothalamic harmatomas and gelastic seirues

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Seizures characterized by laughing (gelastic seizures (GSs) [1, 2]) are rare. They can occur mixed with other seizure types, including complex partial (CPS) or generalized tonic-clonic seizures (GTCS) sometimes with unusual types such as cursive or dacrystic, seizures [3-5]); or they can be found just as transient phenomena, during the clinical evolution of an epileptic syndrome. GSs are found in patients suffering from symptomatic partial epilepsies, originating from the temporal [4, 6] or frontal lobes [7], or, more often, in patients with a hypothalamic hamartoma (HH) [8-13]. In particular, "early onset GSs, HH and precocious puberty (PP)", is a rare but well recognized severe childhood epileptic syndrome, frequently resulting in catastrophic epileptic encephalopathy [9, 10]. However, GSs, with similar electro-clinical features, can sometimes be found in patients with a less severe epilepsy disorder, related to a small HH or without any demonstrable lesion, and, thereafter, considered as "cryptogenic" [12]. Sturm et al. recently described episodes of "pressure to laugh" rather than actual laughing seizures in patients with small HHs [14].

It is likely that a certain number of epileptic syndromes with GSs, at the moment classified as cryptogenic, may be actually be related to small HHs, which were not detected by early-generation magnetic resonance imaging (MRI), or by a neuroradiological study not specifically directed to the hypothalamic region.

The aim of this paper is to report three patients affected by epilepsy with GSs, related to a small HH, in order to show some video-EEG (VEEG) recordings of these infrequent seizures, and to stress once again the need for an accurate MRI study in patients with GSs.

Materials and methods

According to Gascon and Lombroso [8], GSs are defined as "stereotypic recurrence of ictal laughter inadapted to context, associated with other signs compatible with seizure and with ictal/interictal EEG abnormalities".

Patients were included in this study if:

- GSs were the only seizure type;

- or onset of epilepsy had been characterized by GSs;

- or GSs had been the most clinically relevant ictal phenomena for at least 1 year;

- at least one GS had been recorded by VEEG or had been recorded by EEG and directly observed by one of the authors.

All patients with GSs underwent at least one cerebral MRI using a 0.5 or 1.5 tesla superconductive magnet. The examination was performed with a spin-echo multiecho sequence and T1-PD- and T2- weighted images, using thin slice (3 mm) sections, with axial, transverse and coronal planes. An additional T1- weighted sequence was used after intravenous paramagnetic contrast medium injection (Gd-DTPA) (for further information about MRI procedures see in [15]). Sessile HHs, less than 1 cm diameter, were defined as "small".

All patients included in the study underwent neuropsychological evaluation and interictal Tc99m- HMPAO SPECT.

Case reports

Since 1986 we have observed six patients with GSs associated with HHs; in this paper we describe three of them, in which a small HH was observed. Two of these patients have been previously reported (cases 3 and 4 of [12]).

Case 1 (case 3 of [12])

This is a 52 year-old, right-handed man, with unremarkable familial and personal history. No PP was reported. His academic career was quite satisfactory. GSs with face-flushing began at the age of 20. Laughing attacks were very frequent and sometimes recurring in brief clusters; they were described by the patient as unpredictable and inadapted to the context. The patient did not feel amused during GSs but rather embarassed, so that he tried to conceal the laughter, e.g., by feigning a sneeze. At the age of 33, CPS appeared, with feeling of unreality, loss of contact, and oro-masticatory automatisms. At the time of our observation, CPS were well controlled by polytherapy (CBZ + TPM), while GSs persisted. MRI showed a sessile, 0.8 cm diameter HH, pressing on the floor of the third ventricle (figure 1). Neuropsychological assessment was normal; EEG showed mild, interictal left temporal abnormalities, while ictal recordings of GSs were invariably accompanied by EEG flattening. A VEEG of a typical brief cluster of GS (at age 48), without impairment of consciousness, is showed in the videosequence.

Case 2

This 37 year-old, right-handed man had no family history of epilepsy. No PP was reported. Seizure onset was at the age of 7, with very frequent GSs and face flushing, tonic or GTCS during sleep; later, sporadic diurnal CPS also occurred. GSs were totally refractory to medical therapy, whereas other seizure types were controlled. EEG was diffusely slowed with focal (frontal and temporal) interictal paroxysmal activity (PA); interictal SPECT showed left temporo-parietal hypoperfusion. Ictal EEGs invariably showed flattening of cerebral activity. MRI revealed an approximately 1 cm diameter, sessile HH (figure 2). Neuropsychological assessment was normal, but the high frequency of episodes led to some difficulties at work.

The videosequences show a VEEG, recorded at the age of 32, and a video, at the age of 37, of typical GSs, with face- flushing but no impairment of consciousness.

Case 3 (case 4 of [12])

This 23 year-old, right-handed woman had no family history of epilepsy. No PP was reported. GSs and, more rarely, dacrystic seizures occurred in the first years of life. After a seizure free interval, GSs, CPS, and rare GTCS recurred at the age of 6. Her academic career was poor, but her IQ was 90. GSs were totally unresponsive to AED therapy, whereas CPS and TCS were well controlled. Interictal EEG was diffusely slowed with bilateral, asynchronous temporal or frontal PA. Ictal EEG showed a diffuse flattening. MRI revealed a sessile, 0.94 cm diameter HH, extended upward, with slight hypothalamic displacement (figure 3).

Discussion

There is a growing accumulation of data demonstrating that, in patients with HH, GSs originate in the hamartoma itself. This has been demonstrated by stereo-EEG recordings of ictal discharges from the hypothalamic lesion [16], and suggested by dipole source localization of epileptiform discharges [18], by ictal SPECT hyperperfusion observed in this area [17, 19-21] and by good seizure control resulting from surgical ablation [12, 19, 22-24]. Conversely, no substantial improvement has been observed after frontal, temporal or callosal resections [9, 24, 25]. The older literature had already suggested the role of diencephalic-hypothalamic structures in the release of affective and emotional responses [26-29]; the close connections between HH and these structures can also explain the autonomic symptoms (such as the face flushing, frequently observed during the laughing attacks) and hormonal changes accompanying GSs [30, 31].

The typical, complete expression of this condition characterises the "early onset GSs, HH and PP syndrome" [10].

Despite its rarity, this epileptic syndrome is of extraordinary interest, presenting as a fully refractory, epileptic encephalopathy, with cognitive stagnation or deterioration and severe behavioral problems [32]. Its drug-resistance and its catastrophic clinical course warrant an early surgical [24] (or maybe, radiosurgical [23]) approach. In addition, this syndrome provides new, important clues to the mechanisms of human epileptogenesis: GSs are true "diencephalic" seizures; the discharges may spread, by hypothalamic-amygdala connections, to mesiotemporal and orbital structures, causing temporal or frontal partial seizures; and by thalamus and cortical projections, presenting as symptomatic generalized epilepsy (SGE) mimicking Lennox-Gastaut syndrome [13, 33]. However, the syndrome may be incomplete: PP is an inconsistent (and probably not very frequent) symptom [11, 12], and so is the evolution towards an SGE; cognitive and behavioural problems may be absent or mild; GSs can start later, in late infancy or in childhood, and, in the less severe cases, may be abortive and consist only of an ictal "pressure to laugh" [14].

It is likely that this clinical variability correlates with the size and the location of the HH. In this paper, we have defined as "small" HHs which are less than 10 mm in diameter (volume < 0.5 cm3). Our concept of "small" is obviously arbitrary: the three patients reported by Sturm et al. [14] had very small HHs (5-6 mm diameter, volume 0.06-0.11 cm3). In our patients, GSs are the prominent feature through out the whole epileptic history, even if other seizure types invariabily occur; PP is absent and cognitive development is normal or nearly normal. The seizures in the cases of Sturm et al., presented as a desire or pressure to laugh, rather than actual GSs, thus representing the mildest end of the clinical spectrum of epilepsies related to HHs. At the other extreme, patients with larger HHs (1.5-2 cm), show a more severe partial epilepsy with cognitive impairment or a progressive catastrophic epilepsy as described by Berkovic et al. [10]. However, these observations stress the necessity of a careful examination of the diencephalon, tuber cinereum and mammillary body regions in patients showing GSs; diagnosis of HH may have, in fact, relevant therapeutic and prognostic implications: epilepsy related to HH is invariably drug-resistant and can have a great impact on quality of life of the patient; nowadays, a neurosurgical approach can be considered for small HHs, provided that complete or nearly complete excision can be safely achieved, e.g., via transcallosal-interforniceal route to the third ventricle [24]; or, alternatively, gamma-knife surgery can be envisaged [34].

Videosequence caption

Frame 1. Case 1: brief cluster of GSs. To witness the preserved consciousness, the pt repeats "I had a seizure", and reads the time aloud. EEG shows only a diffuse depression.

Frame 2. Case 2 (at age of 32): VEEG of a typical GS. Note the diffuse flattening of EEG, with no evident paroxysmal activity.

Frame 3. Case 2 (at age of 37): Video of a GS, accompanied by face-flushing. The pt feels the imminent laugh; consciousness is preserved during the seizure.

Received November 23, 2001 / Accepted April 3, 2002