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Somatosensory evoked potentials and eeg findings in siblings of juvenile myoclonic epilepsy patients Volume 1, issue 3, Septembre 1999

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Juvenile myoclonic epilepsy (JME) is a specific and common form of nonprogressive idiopathic generalised epilepsy characterised by onset in adolescence and the presence of myoclonic jerks, tonic-clonic or clonic- tonic-clonic convulsions and absence seizures. Hereditary factors play a major role in the aetiology of JME [1-7]. It is also well known that the clinically unaffected family members of JME patients can demonstrate specific or nonspecific EEG abnormalities [7]. In 1957, Janz and Christian reported somatosensory-evoked potential (SEP) abnormalities in JME [8]. A subsequent study in which the SEP of patients with JME and idiopathic generalised epilepsy (IGE) were analysed, showed significantly higher P25 and N33 amplitudes as well as a 'giant SEP' rate of 14% in the JME group [9].

In order to demonstrate cortical hyperexitability and to determine the efficacy of HASEP in detecting asymptomatic relatives of JME patients , we evaluated the EEG findings and SEP in asymptomatic siblings of JME patients.

Method

We analysed the EEG and SEP findings of 37 JME patients and 48 asymptomatic siblings of 27 patients. All index cases met the diagnostic criteria for JME according to Panayiotopoulos [10]. Since the mean age of JME patients was significantly lower than that of the healthy siblings, we had to use two different, age matched control groups of healthy volunteers for each study group. Control groups of JME patients and healthy siblings consisted of 14 and 42 subjects, respectively.

All patients were identified during a clinic visit, and a detailed family history and further clinical history were taken at the time of the study, from the patient as well as from every participating family member. All cranial CT or MR investigations performed in 24 of the 37 JME patients were normal. All patients were receiving valproate monotherapy with a dosage between 1,000 and 2,500 mg/day.

All asymptomatic siblings included in the study underwent psychological and neurological examinations which were within normal limits. None of them had CT or MR investigations.

Conventional EEG recordings along with activating methods (hyperventilation and photic stimulation) were performed using an 18 -channel Medelec 1118 device. Electrodes were placed according to the international 10-20 system. Recordings were made under the supervision of a neurologist (DA). During each paroxysmal event, the reaction of the subjects to verbal stimuli was observed in order to determine whether these were subclinical or ictal discharges. Two different authors (D.A., B.A.) evaluated the EEG using both bipolar and referential montages.

SEP examinations were performed using a 4- channel Medelec Sapphire 4 ME device. Multiple Ag/AgCl cup electrodes were placed to Erb's point, cervical 7 level, C3' and C4' (approximately 2 cm. posterior to C3 and C4 in 10-20 system) for recordings. All electrodes were referred to Fz. Electrode impedance was kept below 5 kohm. SEP were obtained by stimulating the median nerve, at the wrist, with electric shocks delivered at a rate of 5/s as a square wave pulse of 0.2 ms duration. Stimulus intensity was set to produce a muscle contraction causing a visible twitch. The filter bandpass was 10 Hz-2,000 Hz. At least 128 responses were averaged and two runs were performed for each patient. The N20 latencies and the peak to peak N20/P25 amplitude of cortical SEP responses were measured. SEP were considered as HASEP when the amplitude was higher than + 3 SD of the average of the control group.

For statistical evaluation, chi-square - and t- test was used.

Results

The JME group consisted of 12 male and 25 female patients with a mean age of 20.33 ± 5.28 years, while the asymptomatic sibling group consisted of 25 male and 23 female individuals with a mean age of 24.17 ± 1.34 years. The control groups for JME patients and their siblings consisted of 14 and 42 individuals, with a mean age of 21.85 ± 6.2 and 26.91 ± 7.2, respectively (p = 0.42; p = 0.18). The mean age of siblings who exhibited either SEP- or both EEG and SEP abnormalities was 20.4 ± 9.6 and 20.3 ± 10.9, respectively. The mean age of subjects with EEG and/or SEP abnormalities was lower than that of the whole study group.

Of 13 asymptomatic siblings with EEG abnormalities (27.1%), 5 had pathognomic 4-6 Hz spike/polyspike and wave paroxysms between 1-3 sec duration (10.4%),
5 had high amplitude slow wave paroxysms between 1-2 sec duration (10.4%), and the remaining 3 patients exhibited focal spike and wave activity in the temporal region
(T3 = 2,T4 = 1) during hyperventilation (6.25%).

SEP findings are summarised in table I.

Our normal SEP values were consistent with normal laboratory values.

There was no significant difference in N20 latencies between JME patients, asymptomatic siblings and control groups (p = 0.78, p = 0.76). N20/P25 amplitudes were significantly higher in both the JME group and asymptomatic siblings than those of control cases (p < 0.0001, p < 0.002).

N20/P25 amplitudes higher than 8.51 µV in JME patients and 7.93 µV in asymptomatic siblings were considered as HASEP. HASEP were observed in 8 of 37 patients with JME (21.6%), and in 10 out of 48 healthy siblings (20.8%). None of the control cases exhibited HASEP of high amplitude (figure 1).

Among 16 families of patients having at least one asymptomatic sibling with EEG and/or SEP abnormality, 5 couples were consanguinous in the 1st degree, 2 couples in the 2nd degree, 4 in the 3rd degree: 5 couples were not consanguinous. Conversely, among the remaining 11 families of patients having asymptomatic siblings without EEG or SEP abnormalities, consanguinity (1st degree) was noted in only one. The consanguinity rate was significantly higher in parents of patients having at least one asymptomatic sibling with EEG and/or SEP abnormalities compared with parents of siblings having no EEG and SEP abnormalities (68.7% versus 9.9%, p = 0.0022) (table II).

Discussion

JME is a clearly defined form of idiopathic generalised epilepsy with a high aggregation in family members. Eighty percent of symptomatic and 6% of asymptomatic siblings have EEG that show abnormalities in the form of 4-6 Hz multiple spike/slow waves or sharp and slow waves, and some abnormalities may also be observed in asymptomatic parents of probands [11]. In a study which evaluated 390 JME relatives, EEG recordings showed specific discharges in 15% and nonspecific paroxysmal changes in 39.7% of cases [12]. In another study, Oflazoglu et al. found that out of 71 first or second-degree relatives, 6 (8.4%) had pathognomonic EEG abnormalities [13]. In our study, 27.1% of asymptomatic siblings had EEG abnormalities: 10.4% had specific discharges and 6.25% had focal spike and wave activity (only during hyperventilation), while the remaining patients (10.4%) exhibited slow wave paroxysms. Our specific discharge rate was lower than in the Janz's study, but higher than in Oflazoglu's study. Although we have evaluated the same ethnic group, we found higher EEG abnormality rates than in Oflazoglu's study which may be explained by the restriction of our study to the first-degree relatives. Our nonspecific discharge rate was also lower than in Janz's study.

HASEP was present in 21.6% of our JME patients. This rate was slightly higher than that in Salas-Puig's study [9]. At the time SEP was performed, the patient group was receiving valproate monotherapy which is known not to produce changes in SEP [9]. The asymptomatic sibling group showed 20.8% HASEP which was similar to the JME group. We also found higher N20/P25 amplitudes in both JME patients and asymptomatic siblings compared to those of control cases.

Greenberg's study showed that the finding of linkage is stable within a wide range of assumptions of penetrance and modes of inheritance, and that the EEG traits seen in unaffected family members reflect the action of the same gene that is involved in the expression of JME [14].

In spite of strong evidence that a dominantly inherited gene is found on chromosome 6, some newer linkage studies have also revealed evidence indicating that some families classified as having JME, may have another syndrome unrelated to the chromosome 6 locus [7]. Recent results, therefore, favour genetic heterogeneity for JME and common idiopathic generalised epilepsies [6, 15-21]. The SEP trait might also reflect the involvement of one of the many loci affected in this heterogenous genetic disorder, and could therefore be used to distinguish its various genotypic forms.

In our study, there were two types of family. In the first group, asymptomatic siblings had abnormal EEG and/or SEP findings as well as higher consanguinity rates; in the second group, asymptomatic siblings had no EEG and SEP abnormalities, and the consanguinity rate was lower than the first group. On the other hand, asymptomatic siblings having abnormal SEP findings had a lower mean age than those without HASEP. Although the amplitudes of SEP may decrease with advanced age, we believe that genetic heterogeneity may have played a role in these two different family groups.