[The behavioral disorders in epilepsy]. / Troubles comportementaux des épileptiques.

The behavioral disorders are more frequent in the epilepsy patients, children and adults, than in the general population. They have been extensively studied by numerous authors, as well as the underlying various factors. These factors are neurobiological and psychological. From the neurobiological point of view, the importance of the brain damages, their nature, their topography, their lateralization, their date of occurrence during the development have been underlined. Specific personality and behavior features have been linked to the temporal localization of the epilepsy, but many controversies continue about this topic and a behavioral temporal syndrome is not proven. The frontal epilepsies are also responsible for psychological and behavioral disturbances. The epilepsy per se is an etiologic factor, through the ictal events and the interictal changes in the neuronal functioning. One example is that of the endogenous production of opioïd substances during the seizures. However the organic factors cannot be dissociated from the psychological ones. The neuropsychological deficits are significantly linked to the appearance of behavioral disorders in children. The stigma stuck to the epilepsy and the imprevisible character of the seizures have a deep resounding upon the subject, his family and his environment. The pharmacological medications are useful for the depressive and psychotic episodes, but have little efficacy on the character disorders, the aggressiveness and the psychogenic seizures. They need a careful assessment of the situation and a strict super vision of the seizure number (risk of worsening) and of the pharmacocinetic interactions. A comprehensive, social and psychological management of the epilepsy patients is always indicated, knowing that every person is unique and has to be understood and helped in his singularity.

Absence epilepsy with fast rhythmic discharges during sleep: an intermediary form of generalized epilepsy?

PURPOSE: To describe a particular form of absence epilepsy (AE) characterized by an atypical EEG pattern (fast rhythmic discharges) during sleep and an unfavorable course with the persistence of seizures at a late age and drug resistance. METHODS: We reviewed the medical files of 31 patients diagnosed with AE at our institution been 1995 and 1999 for whom an EEG during sleep had been recorded. Patients with fast rhythmic discharges during sleep were selected for the study. RESULTS: Five patients showed the usual criteria of childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE), but with fast discharges of rhythmic spikes (10-15 Hz) during sleep. such as those typically observed in Lennox-Gastaut syndrome. Four patients were of adult age at the time of the last examination. Intellectual capacities were "borderline" in each case, with visible social and learning handicaps. Absences were the initial seizure event in all patients, but four patients developed generalized tonic-clonic seizures during the course of the disease. Treatment using a combination of antiabsence drugs such as valproate and lamotrigine led to only marginal improvement. CONCLUSIONS: These findings illustrate the utility of sleep EEG in detecting the fast rhythmic discharges that are markers of drug resistance in AE and suggest the existence of transitional forms of AE that are intermediate between idiopathic and cryptogenic/symptomatic generalized epilepsies.

Incidence of drug-induced aggravation in benign epilepsy with centrotemporal spikes.

PURPOSE: Benign epilepsy with centrotemporal spikes (BECTS) is characterized by an excellent prognosis. Drug therapy is necessary in only a minority of patients. Carbamazepine (CBZ) and phenobarbital (PB) have been reported to cause electroclinical aggravation in some cases. The incidence of drug-induced aggravation in BECTS has never been established. METHODS: We retrospectively studied 98 consecutive cases of BECTS, examined at the Centre Saint Paul between 1984 and 1999; 82 patients had received one or more treatments, often successively and in association. RESULTS: We found only one case of electroclinical aggravation with CBZ among 40 patients exposed to CBZ (35 in monotherapy, five in polytherapy). An additional case showed a marked EEG aggravation on CBZ + PB among 14 patients taking PB (nine with monotherapy and five with polytherapy), and PB was apparently responsible. No patient treated with valproate or benzodiazepines showed aggravation. CONCLUSIONS: Aggravation of BECTS caused by antiepileptic drugs happens only rarely. There is a minor risk of aggravation with CBZ and also probably with PB. Drug-induced aggravation may occur only during certain periods coinciding with spontaneous worsening of BECTS.

Clinical factors of drug resistance in juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy is a comparatively benign form of idiopathic generalised epilepsy. Little is known about the prevalence of difficult to treat or drug resistant patients. Among 155 consecutive patients with newly diagnosed juvenile myoclonic epilepsy evaluated between 1981 and 1998 and followed up for at least 1 year (61 men, 94 women; aged 15-70 years, mean 33 (SD 10.3); onset of juvenile myoclonic epilepsy at the age of 14.5 (SD 3.7), range 6-26; follow up 1-52 years, mean 13.5 (SD 9.9)), there were 15 pseudoresistant patients (9.7%: lack of compliance (eight), insufficient treatment (three), abnormal lifestyle (four)) and 24 patients (15.5%) who had persisting seizures despite adequate therapy and lifestyle. Clinical features associated with drug resistance were (1) the presence of psychiatric problems (58.3% v 19%; chi(2) p<0.001) and (2) independently, the combination of seizure types (Fischer's exact 2 by 4, p=0.0026). Three types were present in 62.5% of resistant patients versus 23.3% in non-resistant patients (chi(2), p=0.0001). None of the resistant patients had myoclonic jerks as the only seizure type or a combination of absences and myoclonic jerks. Family history of epilepsy, age at onset of seizures, sex, presence of photoparoxysmal response, results of conventional neuroimagings (CT and MRI), and delayed diagnosis were not significantly associated with drug resistance. There is thus a significant subgroup of patients with juvenile myoclonic epilepsy who pose difficult therapeutic problems, and the prevalence of resistant cases may be increased in the experience of a referral epilepsy centre.

Do carbamazepine and phenytoin aggravate juvenile myoclonic epilepsy?

BACKGROUND: Juvenile myoclonic epilepsy is a frequent form of idiopathic generalized epilepsy that is usually and easily controlled by valproate monotherapy. However, juvenile myoclonic epilepsy is often misdiagnosed, and some drugs, especially carbamazepine and phenytoin, may have an aggravating effect. OBJECTIVES: To determine the risk of aggravation of juvenile myoclonic epilepsy in patients treated with carbamazepine and phenytoin. METHODS: Among 170 consecutive patients with juvenile myoclonic epilepsy (104 female, 66 male) referred between 1981 and 1998, the authors retrospectively found 40 patients (23%) who had received carbamazepine or phenytoin (duration of epilepsy at referral, 1 to 34 years; mean +/- SD, 13.8 +/- 8.5 years; follow-up, 3 to 50 years; mean +/- SD, 16.4 +/- 11 years). RESULTS: Twenty-three patients (57.5%) experienced aggravation of seizures, whereas 6 (15%) apparently benefited from these drugs. There was no effect in the remaining 11 cases (27.5%). Carbamazepine was prescribed to 28 patients: 19 (68%) had aggravated symptoms, including myoclonic status in two; 4 (14%) were improved, one in association with valproate and one in association with valproate and phenobarbital. Phenytoin was prescribed in 16 cases: 6 (38%) had aggravation and 2 (12%) were improved, including one in association with phenobarbital. Vigabatrin was given in only one case, in association with carbamazepine, and provoked a mixed absence and myoclonic status. CONCLUSIONS: Among commonly prescribed anticonvulsants, carbamazepine appears to have the strongest aggravating potential in patients with juvenile myoclonic epilepsy, whereas the aggravating effect of phenytoin is less prominent. Aggravation was mostly in the form of increased myoclonic jerks.

Cost minimization analysis of antiepileptic drugs in newly diagnosed epilepsy in 12 European countries.

A recent United Kingdom cost minimization analysis (CMA) of four antiepileptic drugs (AEDs) used to treat newly diagnosed adult epilepsy demonstrated that a new drug, lamotrigine (LTG), incurred higher costs than carbamazepine (CBZ), phenytoin (PHT), and valproate (VPA), whose costs were similar. This analysis took account of each drug's side-effect and tolerability profile. The present analysis investigated the costs of treatment with LTG, CBZ, PHT, and VPA in 12 European countries. Data were derived from published sources and from a panel of locally based experts. When no published data were available, estimates were obtained using expert opinion by a consensus method. These data were incorporated into a treatment pathway model, which considered the treatment of patients during the first 12 months after diagnosis. The primary outcome considered was seizure freedom. Randomized controlled trials demonstrate that the drugs considered are equally effective in terms of their ability to achieve seizure freedom, and thus the most appropriate form of economic evaluation is a CMA. These trials provided data on the incidence of side effects, dosages, and retention rates. The economic perspective taken was that of society as a whole and the analysis was calculated on an "intent-to-treat" basis. Only direct medical costs were considered. In each country considered, LTG was twofold to threefold more expensive than the other drugs considered. A sensitivity analysis demonstrated that varying each of the assumptions (range defined by expert panels) did not significantly alter the results obtained.

Structural brain lesions do not influence the prognosis of juvenile myoclonic epilepsy.

OBJECTIVES: In juvenile myoclonic epilepsy (JME) neuroimaging procedures are usually unnecessary but are often performed following the first generalized tonic-clonic seizure before a specific diagnosis has been reached. Our aim was to evaluate the influence of abnormal findings on the clinical presentation and prognosis of JME. MATERIAL AND METHODS: We retrospectively analyzed all medical records of JME patients first referred in two epilepsy centers (Marseilles, Nice) between 1981 and 1998. RESULTS: Among 170 consecutive unselected newly diagnosed JME patients, neuroimaging was performed in 82 cases (MRI: 22, CT: 75, including MRI+CT: 15). In 4 subjects, specific neurological abnormalities had justified neuroimaging: severe head trauma after the onset of JME (2, both with lesions related to the trauma), multiple sclerosis with onset after JME (1, with normal MRI before the onset of multiple sclerosis and abnormal, specific findings later), severe mental retardation (1, with diffuse MRI changes but a typical electro-clinical presentation and evolution). In the other 78 cases, 9 had abnormal findings: common arachnoid cyst (3), mild diffuse cerebral atrophy and ventricular enlargement (1), mild ventricular enlargement only (3), septum lucidum cavum (1), mildly increased T2 signal in the left temporal lobe (1). Abnormal neuroimaging did not influence therapeutic decisions or prognosis. CONCLUSIONS: These data confirm that neuroimaging procedures should not be routinely performed in patients with typical JME, unless additional neurological problems, that are unrelated to the diagnosis of epilepsy, occur.

Is it juvenile myoclonic epilepsy?

A 21-year old man with marked developmental delay was referred for the diagnosis of myoclonic jerks (MJ), which were sometimes responsible for sudden falls without loss of consciousness, that had begun 2 years before, and for a recent generalized tonic-clonic seizure preceded by a cluster of MJ. Physical examination revealed a small stature, bilateral pyramidal signs, severe mental retardation, and retinis pigmentosa. Etiological factors for this encephalopathy were not found (muscle and skin biopsies, karyotype and extensive blood chemistry). Waking interictal EEG showed a normal background activity and generalized poly-spike-and wave (PSW) discharges. Photic stimulation disclosed a marked photoparoxysmal response, sometimes associated with myoclonic jerks. Three spontaneous jerks accompanied by a burst of generalized PSW were recorded on awakening from a nap. The MRI disclosed wide ventricles, a thin corpus callosum, brainstem atrophy and a so-called "redundant gyration"; these changes were evocative of acquired perinatal damage. Juvenile myoclonic epilepsy (JME) was diagnosed and valproate was started resulting in complete control of seizures. During a 5-year follow-up, the patient has remained seizure-free and the EEG consistently normal. In our opinion, JME can be diagnosed in very uncommon settings, including patients with significant brain damage, as long as all the other criteria for the diagnosis are present.

Gamma knife surgery for mesial temporal lobe epilepsy.

PURPOSE: Gamma knife radiosurgery (GK) allows precise and complete destruction of chosen target structures containing healthy and/or pathologic cells, without significant concomitant or late radiation damage to adjacent tissues. All the well-documented radiosurgery of epilepsy cases are epilepsies associated with tumors or arteriovenous malformations (AVMs). Results prompted the idea to test radiosurgery as a new way of treating epilepsy without space-occupying lesions. METHODS: To evaluate this new method, we selected seven patients with drug-resistant "mesial temporal lobe epilepsy" (MTLE). The preoperative evaluation program was the one we usually perform for patients selected for microsurgery of TLE [video-EEG analysis of seizures, foramen ovale electrode recording, magnetic resonance imaging (MRI) positron emission tomography (PET) scan, neuropsychological testing]. In lieu of microsurgery, the amygdalohippocampectomy was performed by using GK radiosurgery. RESULTS: Morphologic (MRI) signs of destruction of the target took place at 9 months after GK surgery. Since the treatment day, the first patient has been seizure free. Seizure improvement came more gradually for the following patients, and complete cessation of seizures occurred around the tenth month (range, 8-15 months). MRI shows that the amygdaloentorhinohippocampal target was selectively injured. No significant side effect (except one case of homologous quadrantanopia) or morbidity and no mortality was observed. The current follow-up is 24-61 months, and all (but one) patients are seizure free. CONCLUSIONS: This initial experience proves clearly the short-to middle-term efficiency and safety of GK for MTLE surgery. These results need further confirmation of long-term efficiency, but the introduction of GK surgery into epilepsy surgery can reduce dramatically its invasiveness and morbidity.

Photic reflex myoclonus: a neurophysiological study in progressive myoclonus epilepsies.

PURPOSE: To investigate the neurophysiological features of photic reflex myoclonus (PRM) in patients with progressive myoclonus epilepsies (PMEs) of different types (Unverricht-Lundborg disease, Lafora's disease, cryptogenic). METHODS: All patients underwent computerized video-polygraphic recordings, collecting electromyographic (EMG) activity from several cranial and limb muscles. PRM was elicited by intermittent photic stimulation (IPS). RESULTS: IPS could evoke PRM with a 1:1 relation at frequencies up to 12 Hz. Back-average of the EEG, triggered from the onset of PRM at the upper limbs, showed a contralateral positive-negative transient in central region, preceded by approximately 10 ms by a similar, ipsilateral occipital wave. When IPS induced bilateral jerking, a time lag of approximately 10 ms between the homologous muscles of the two sides was observed, paralleled by a similar delay between the associated contralateral EEG transients in the two central regions, suggesting spread of cortical myoclonic activity from one hemisphere to the other via transcallosal fibers. PRM propagated in different cranial and limb muscles according to a rostrocaudal pattern, with latencies compatible with a transmission along fast-conducting corticospinal motor pathways. CONCLUSIONS: In our PME patients, PRM presented uniform neurophysiological features, indicating the participation of both occipital and motor cortices, with bilateral spread presumably mediated by transcallosal connections and propagation down the spinal cord via fast-conducting corticospinal pathways.

Are there generalised spike waves and typical absences in benign rolandic epilepsy?

Generalised 3 Hz spike wave (SW) discharges with or without absences have been described in children with benign epilepsy with centrotemporal spikes (BECTS), leading to speculations about a continuum between childhood absence epilepsy (CAE) and BECTS. We thus decided to evaluate the prevalence of absence seizures (AS) and generalised 3 Hz SW in patients with BECTS. All patients with BECTS first referred since 1986 have been identified prospectively. Their medical and electroencephalograph (EEG) records were analysed retrospectively, in the search for AS and generalised SW discharges. Over a period of 11 years, we found typical rolandic spikes in 66 newly referred patients; 64 had seizures typical for the condition (18 female, 46 male), two were asymptomatic and were not further analysed. All had routine waking EEG recordings, and 49 children (76%) had at least one sleep EEG. AS or classical generalised 3 Hz SW were never recorded from history or EEG data, respectively. However, 17 patients had some diffuse SW discharges, lasting 1-5 s, which appeared as grossly symmetrical in only seven children, with a clearly asymmetrical aspect in the others. Among these seven patients, the discharges were only seen on awakening in one, both during waking and nREM sleep stage I or II in one and only during nREM sleep stage I or II in five. They were apparently subclinical in all. We thus found neither AS nor classical 3 Hz SW discharges among 64 consecutive patients with BECTS. Brief bursts of bilateral abnormalities occur in about 25% of the cases, mostly with sleepiness. Such findings do not substantiate the existence of a continuum between CAE and BECTS.

Late-onset epilepsy associated with regional brain cortical dysplasia.

RATIONALE: Cortical dysplasia (CD) designates a diverse group of malformations resulting from one or more abnormalities in the development of the cerebral cortex. The clinical manifestations of CD are varied, probably depending on the type, location and extent of CD. Epilepsy is a potential late manifestation of any cortical malformation. To our knowledge, however, no study has focused specifically on late onset of epilepsy in patients with localized CD. MATERIAL AND METHODS: We studied patients with localized CD confirmed by MRI. Patients were divided into 2 groups according to age at onset of epilepsy. Group 1 included patients in whom the first seizure occurred up to the age of 12 (early-onset group) and group 2 included patients in whom the first seizure occurred after the age of 12 (late-onset group). The two groups were compared with regard to the type of CD, clinical findings and EEG findings. RESULTS: Thirty-three patients with various forms of CD were studied. Onset of epilepsy occurred in adolescence or adulthood in 9 cases (37%). In 6 of these (17% overall), the first seizure occurred in adulthood. CD were posterior bilateral pachygyria (1), unilateral polymicrogyria (3), focal dysplasia with subcortical gray matter heterotopia (1), perisylvian bilateral polymicrogyria (1), bioccipital polymicrogyria (1) and bilateral nodular periventricular gray matter heterotopia (2). The incidence of neurological signs was lower in the late-onset group. Mental retardation was moderate or absent, thus allowing a fairly normal lifestyle. All patients presented partial seizures with a lower incidence of drug resistance (p < 0.01). EEG demonstrated preservation of background activity and absence of diffuse or multifocal abnormalities. CONCLUSION: Onset of epilepsy with various forms of CD may be delayed until adolescence or adulthood. Prognosis of epilepsy is usually more favorable in these cases.

Radiosurgery for trigeminal neuralgia and epilepsy.

The role of Gamma Knife surgery in the field of functional surgery recently has evolved dramatically. For treatment of trigeminal neuralgia, Gamma Knife surgery is the least invasive procedure, with a low rate of hypesthesia. If a rate of complete relief similar to that of other surgical techniques could be achieved, this approach will become one of the main techniques used to treat the disease initially. The authors present their experience with a group of 16 patients with mesial temporal lobe epilepsy who have been treated successfully (15 completely seizure-free and 1 with rare, nondisabling seizures) without significant complication. After additional follow-up to demonstrate the absence of long-term consequences, this fascinating new approach could change epilepsy surgery practice dramatically.

A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2).

Progressive myoclonus epilepsy of the Lafora type or Lafora disease (EPM2; McKusick no. 254780) is an autosomal recessive disorder characterized by epilepsy, myoclonus, progressive neurological deterioration and glycogen-like intracellular inclusion bodies (Lafora bodies). A gene for EPM2 previously has been mapped to chromosome 6q23-q25 using linkage analysis and homozygosity mapping. Here we report the positional cloning of the 6q EPM2 gene. A microdeletion within the EPM2 critical region, present inhomozygosis in an affected individual, was found to disrupt a novel gene encoding a putative protein tyrosine phosphatase (PTPase). The gene, denoted EPM2, presents alternative splicing in the 5' and 3' end regions. Mutational analysis revealed that EPM2 patients are homozygous for loss-of-function mutations in EPM2. These findings suggest that Lafora disease results from the mutational inactivation of a PTPase activity that may be important in the control of glycogen metabolism.

Familial epilepsy with unilateral and bilateral malformations of cortical development.

PURPOSE: To describe a family in whom two sisters with epilepsy, mental retardation, and microcephaly had different malformations of cortical development detected by magnetic resonance imaging (MRI). METHODS: Clinical investigation of the patients and their family. High-resolution MRI, cognitive testing, and repeated EEG recording in both patients. RESULTS: In one patient, the malformation was bilateral and diffuse but much more pronounced in the parietal and occipital regions, with MRI characteristics indicating pachygyria-polymicrogyria. In the other patient, the abnormality involved the right hemisphere, predominating around the perisylvian region, with MRI more clearly indicative of polymicrogyria. A brother also had severe epilepsy, diffuse EEG abnormalities, mental retardation, and microcephaly, but could not be studied neuroradiologically. CONCLUSIONS: Lack of MRI studies in the parents and brother does not allow a precise hypothesis on the mode of transmission. However, findings from this family indicate that unilateral malformations of cortical development detected during investigations after seizure onset may be genetically based, suggesting that a single genetic abnormality could be responsible for bilateral or unilateral malformations.

Multilobar polymicrogyria, intractable drop attack seizures, and sleep-related electrical status epilepticus.

BACKGROUND AND OBJECTIVE: Patients with cortical malformations often have intractable seizures and are candidates for epilepsy surgery. Within an unselected series of patients with various forms of cortical malformation, nine patients with multilobar polymicrogyria had electrical status epilepticus during sleep (ESES) accompanied by infrequent focal motor seizures. Eight patients also had intractable atonic drop attack seizures. Because ESES usually is accompanied by a good long-term seizure prognosis, the objective of this study was to examine ESES outcome among patients with a structural lesion that is usually highly epileptogenic and has a low seizure remission trend. METHODS: The nine patients had follow-up periods lasting 4 to 19 years. All underwent brain MRI, serial sleep EEG recordings, and cognitive testing during and after ESES. RESULTS: ESES and drop attack seizures appeared between the ages of 2 and 5 years (mean, 4 years) and ceased between the ages of 5 and 12 years (mean, 8 years). At the last visit patients were 8 to 23 years of age (mean, 14.5 years) and were either seizure free or had very infrequent focal motor seizures during sleep. Three patients were free from antiepileptic drugs. In no patient was definite cognitive deterioration apparent after ESES in comparison with earlier evaluations. CONCLUSIONS: Age-related secondary bilateral synchrony underlying ESES may be facilitated in multilobar polymicrogyria. The good seizure outcome contrasts with that usually found in the presence of cortical malformations. For children with polymicrogyria and drop attack seizures, surgical treatment of the epilepsy should be considered cautiously, and sleep EEG recordings should be performed systematically.

A PCR amplification method reveals instability of the dodecamer repeat in progressive myoclonus epilepsy (EPM1) and no correlation between the size of the repeat and age at onset.

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is a rare, autosomal recessive disorder characterized by onset at age 6-16 years, generalized seizures, incapacitating myoclonus, and variable progression to cerebellar ataxia. The gene that causes EPM1, cystatin B, encodes a cysteine proteinase inhibitor. Only a minority of EPM1 patients carry a point mutation within the transcription unit. The majority of EPM1 alleles contain large expansions of a dodecamer repeat, CCC CGC CCC GCG, located upstream of the 5' transcription start site of the cystatin B gene; normal alleles contain two or three copies of this repeat. All EPM1 alleles with an expansion were resistant to standard PCR amplification. To precisely determine the size of the repeat in affected individuals, we developed a detection protocol involving PCR amplification and subsequent hybridization with an oligonucleotide containing the repeat. The largest detected expansion was approximately 75 copies; the smallest was approximately 30 copies. We identified affected siblings with repeat expansions, of different sizes, on the same haplotype, which confirms the repeat's instability during transmissions. Expansions were observed directly; contractions were deduced by comparison of allele sizes within a family. In a sample of 28 patients, we found no correlation between age at onset of EPM1 and the size of the expanded dodecamer. This suggests that once the dodecamer repeat expands beyond a critical threshold, cystatin B expression is reduced in certain cells, with pathological consequences.

Lamotrigine and seizure aggravation in severe myoclonic epilepsy.

PURPOSE: In severe myoclonic epilepsy of infancy (SME), multiple drug-resistant focal and generalized seizure types occur. Lamotrigine (LTG), found effective in many generalized and partial seizures, has been little used in severe childhood epilepsy syndromes with multiple seizure types. We studied the effects of LTG in SME. METHODS: Twenty-one patients with SME, aged 2-18 years, were treated with LTG, 20 in add-on and one in monotherapy. LTG was started at 0.2-2.5 mg/kg/day and increased to 2.5-12.5 mg/kg/day. For each seizure type, excluding atypical absences, >50% variations compared with the 2 months preceding LTG were considered indicators of response, also taking into account the degree of disability each seizure type produced. RESULTS: LTG induced worsening in 17 (80%) patients, no change in three, and improvement in one. There was >50% increase in convulsive seizures in eight (40%) of 20 patients. Myoclonic seizures worsened in six (33%) of 18 patients. Of five patients improving in at least one seizure type, four had concomitant worsening of more invalidating seizures. Clear-cut worsening appeared within 3 months in most patients but was insidious in some. LTG was suspended in 19 patients after 15 days-5 years (mean, 14 months) with consequent improvement in 18. CONCLUSIONS: The pronounced seizure deterioration during LTG treatment was not attributable to the natural course of the disease and could be a direct effect of therapeutic LTG doses. LTG treatment seems inappropriate in SME.