Lamotrigine associated with exacerbation or de novo myoclonus in idiopathic generalized epilepsies.

Five patients with idiopathic generalized epilepsies (IGE) treated with lamotrigine (LTG) experienced exacerbation or de novo appearance of myoclonic jerks (MJ). In three patients, LTG exacerbated MJ in a dose-dependent manner with early aggravation during titration. MJ disappeared when LTG dose was decreased by 25 to 50%. In two patients, LTG exacerbated MJ in a delayed but more severe manner, with myoclonic status that only ceased after LTG withdrawal.

[Neurogenesis in the adult brain: the demise of a dogma and the advent of new treatments]. / La neurogénèse dans le cerveau adulte: de l'effondrement des dogmes vers de nouvelles thérapies?

Since the early sixties, many concepts concerning neurogenesis have been progressively ruled out. Proof of the persistence of a physiological neurogenesis in adult mammals, including humans, raised the concept of a unique precursor cell giving birth to neurons and glial cells. According to this concept, a real continuum between neuroepithelial cells, radial glia and astrocytes exists from the embryonic period to adult age and generates both neurons and glial cells. Different factors, either secreted in situ or transported by blood, can influence this physiological neurogenesis process. The targets and role of newborn neurons are not clearly understood. In pathological conditions (ischemia, epilepsy, lesions), the physiological neurogenesis process is enhanced; however the significance of this neurogenesis excess (beneficial or deleterious) is not completely known. Advances in understanding the regulation of neurogenesis in these different conditions represent hopes of new therapeutic procedures, not only by improving the control of differentiation and survival of transplanted stem cells, but also by the possibility of modifying the processes of "endogenous neurogenesis".

[What organisation to improve health care management of patients with partial refractory epilepsy?]. / Quelle organisation de soins pour améliorer la qualité de la prise en charge des patients avec une épilepsie partielle pharmaco-résistante?

Management of refractory epilepsy requires a comprehensive approach with cooperation between primary care physicians, neurologists or neuropaediatricians and specialist epilepsy centres. A regional or interregional network organisation may provide improved access to care provision including inpatient facilities for emergencies, early referral to an epilepsy specialist centre. Such organisation should be appropriate to quality standards for neurophysiology and neuroimaging assessment, epilepsy surgery programme and psychological and social counselling services.

[Bupropion-induced epileptic seizures]. / Crises d'épilepsie induites par le bupropion.

INTRODUCTION: Bupropion hydrochloride (Zyban) is prescribed for smoking cessation. It is contraindicated in patients with seizure disorders. We report three patients with generalized tonic-clonic seizure that occurred a few days after the intake of this drug. OBSERVATIONS: The first two patients had no personal or family seizure history. They had generalized tonic-clonic seizure after taking bupropion (300 mg per day) for a few days. Acute symptomatic seizures were diagnosed in both cases. The third patient suffered from myoclonic jerks during adolescence, had a history of seizure after high dose codeine treatment and a family seizure history. She had generalized tonic-clonic seizure after taking bupropion 300 mg per day. EEG showed paroxystic generalized activity and photosensitivity, consistent with the diagnosis of juvenile myoclonic epilepsy. DISCUSSION: Bupropion can lower seizure threshold. The incidence of seizure at 300 mg per day is 1/1000 patients treated. CONCLUSION: Many commonly prescribed drugs can trigger epileptic seizure, bupropion is one of them. When prescribing this drug, this adverse effect must be acknowledged and health practitioners should be aware of this risk.

Dramatic effect of levetiracetam on epileptic negative myoclonus.

OBJECTIVE: To investigate the properties of levetiracetam in a patient with severe epileptic negative myoclonus. Treatment of epileptic negative myoclonus relies on the drugs that are effective in focal epilepsies, but it is usually pharmacoresistant. Levetiracetam is a new antiepileptic drug with a broad-spectrum activity that includes efficacy against positive myoclonus. CASE REPORT: This woman had had epileptic falls since the age of 2 years. In 2000, she was on phenobarbital (100 mg/day) and valproate (2000 mg/day) and had two drop attacks per month. Clinical examination showed negative myoclonus of the arms clearly predominating on the left side, which was confirmed by a polygraphic EEG. Levetiracetam (1000 mg/day in the first week, increased to 2000 mg/day thereafter) was added. During the first 2 months, the patient experienced four minor seizures without fall. A polygraphic EEG confirmed that the patient's epileptic negative myoclonus disappeared during levetiracetam treatment. At 1-year follow-up, this patient had had only one seizure. CONCLUSIONS: The result of levetiracetam treatment in this patient is encouraging, but efficacy should be confirmed in larger series. A long-term follow-up is also necessary to establish that this antimyoclonic effect of levetiracetam is maintained over a period of years.

Is there a lamotrigine withdrawal syndrome?

OBJECTIVES: To report a peculiar observation of a patient who developed a psychomotor inhibition state after a rapid cessation of lamotrigine (LTG). RESULTS: This man was referred to us at the age of 26 years for presurgical evaluation. His treatment [valproate (VPA), 1200 mg/day and LTG, 200 mg/day] was quickly decreased and discontinued after 4 days in order to record seizures. Because LTG was ineffective on seizures control, it was decided to stop it definitively. After a few days, he became anhedonic. He had a tremor, a slight tachycardia and an important hyperhydrosis of the hands. He was considered as having a withdrawal reaction to LTG which was confirmed by spontaneous resolution after a few days. CONCLUSIONS: Withdrawal syndrome caused by anti-epileptic drugs has been rarely reported. However, in our personal experience of patients monitored for epilepsy surgery, many patients complained of minor reactions when the treatments were quickly decreased. Severe reactions are exceptional and may be explained in this case by the pharmacodynamic effects of LTG. It has indeed been suggested that LTG could have psychostimulant and antidepressive effects.

[Optimal use of lamotrigine in clinical practice: results of an open multicenter trial in refractory epilepsy]. / Utilisation optimale de la lamotrigine en pratique clinique.

The study was designed to evaluate optimal use of add-on lamotrigine in the treatment of children and adults with refractory epilepsy of any type. Because of the available evidence from controlled studies, indicating the large spectrum of action of lamotrigine, we designed this prospective study to investigate the efficacy and safety of lamotrigine in everyday clinical practice, to collect useful information on its action in specific epilepsy syndromes and on the clinical results of specific co-medications. We studied 566 patients with a diagnosis of refractory epilepsy of any type currently receiving stable conventional regimens of antiepileptic therapy. Efficacy analysis was limited to 510 patients (388 patients aged 12 years or more, 122 patients aged 2 to 12 years) for which the exact number of seizures could be evaluated. Seizure characteristics were: simple and/or complex partial seizures in 298 (58p. cent) patients, partial seizures with secondary generalisation in 85 (17p. cent), generalised seizures of any type in 226 (44 percent). Syndromic diagnosis was partial symptomatic or cryptogenic epilepsy in 302 patients (59 percent), generalised symptomatic or cryptogenic epilepsy in 116 (23 percent) and idiopathic generalised epilepsy in 50 (10 percent). The percentage of patients who achieved at least 50 percent reduction in the frequency of seizures was evaluated around 40p. cent for all epilepsy categories, and up to 61 percent in idiopathic generalised epilepsies. Response to treatment with lamotrigine was usually obtained by the end of titration (4 weeks) and remained stable at 48 weeks. Thirty-three patients (7 percent) remained seizure-free at 48 weeks. In the group of patients with partial epilepsy, 19p. cent presented a more than 75 percent reduction in seizure frequency. A more than 50 percent reduction in secondary generalisation of partial seizures was observed in 45 percent of the patients. Efficacy results were similar in both the adult and paediatric age groups. They were better for patients receiving valproate co-medication (45 percent of the responders) as compared to other co-medications (37 percent of the responders), suggesting a synergistic action. Safety has been evaluated for all the patients having received lamotrigine (n=566). The incidence of adverse events attributed to lamotrigine was similar to the results of controlled studies, with somnolence reported in 10p. cent, a cutaneous reaction in 8 percent and episodes of transitory diplopia in 8 percent. A cutaneous reaction was more frequent in patients receiving carbamazepine (10 percent) as compared to valproate comedication (5 percent). However, the adverse event was sufficiently serious to necessitate hospitalisation in 3 patients receiving valproate. Dose escalation was not respected in two. Rash was reversible in all of the patients following discontinuation of the drug. The results of this study contribute to the overall understanding of the spectrum of lamotrigine effectiveness across seizure types and epileptic syndromes. Lamotrigine was well tolerated in children and adults.

[Localizing and prognosis value of 99Tcm-ECD spect in patients with refractory temporal lobe epilepsies]. / Valeur localisatrice et pronostique de la tomographie d'émission monophotonique par injection de 99mTc-ECD dans les épilepsies temporales réfractaires.

Interictal and ictal 99Tcm ECD-SPECT were retrospectively studied in 46 patients with refractory temporal lobe epilepsy. Forty two of these patients underwent an anterior temporal lobectomy with amygdalo-hippocampectomy or a cortical resection. SPECT findings as indicator of localization for the epileptogenic zone (EZ) and surgical prognosis were validated by comparison with other investigations including video-EEG monitoring with surface electrodes in all the patients, intracranial electrodes in 18 patients and the results of post-surgery outcome. Reliability of SPECT for localizing the epileptogenic zone (EZ) was found for mesial temporal epilepsy (28 patients) and the presumed bilateral temporal epilepsies (7 patients). In these latter cases, ECD-SPECT findings may serve to replace invasive methods with use of intracranial electrodes. SPECTs were unreliable when EZ was undetermined whether mesial or lateral by other non invasive investigations. Unilateral mesial temporal hyperperfusion associated with hypoperfusion of contralateral mesial structures evidenced by ictal SPECTs appear to be preoperative criteria for a successful outcome after surgery.

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.

[Pathophysiology of epileptic seizures and status epilepticus]. / Physiopathologie des crises et des états de mal épileptiques.

Primary and secondary epileptogenesis involves multiple genetic and acquired factors. Epileptogenesis is a complex result of combined factors including membrane factors, neurotransmitter and environmental factors. Ion channel-related diseases, GABA and glutamate dysfunction, and glial reaction intervene in different epileptic conditions. The understanding of the mechanisms which emphasize initiation and maintenance of status epilepticus (SE) are in progress. Prognosis of SE is related to the duration of epileptic activity and to the acute cerebral and systemic consequences. Delayed cellular and molecular alterations after SE are responsible for secondary epileptogenesis. Glutamate receptor activation is the main key point leading to an excessive intraneuronal accumulation of ionic calcium by which a cascade of reactions is induced. Apoptotic neuronal death, glial reaction axonal sprouting and neurogenesis contribute to a state of hyperexcitability and hypersynchrony. A better understanding of underlying mechanisms of epileptogenesis may serve the development of new drugs with both anticonvulsant and antiepileptic (prevention or neuroprotection) actions.

[Recent insights about genetics of human idiopathic epilepsies and febrile seizures]. / Données récentes sur la génétique des épilepsies idiopathiques et des convulsions fébriles.

We present here recent insight into idiopathic epilepsies and febrile convulsions. For each case, main clinical features are presented, concomitantly with genetic advances (transmission, penetrance and expressivity, locus, gene, gene function, identified mutations).

Sleep influence on seizures and epilepsy effects on sleep in partial frontal and temporal lobe epilepsies.

OBJECTIVES: A reciprocal effect is observed between sleep and epilepsy. Sleep effect on epilepsy is protective and facilitating. Reciprocally epilepsy alters sleep organization and microarchitecture. This interelationship is well established for some epilepsies but remains undefined for cryptogenic and symptomatic frontal and temporal lobe epilepsies. In order to research sleep influence on seizures and epilepsy effects on sleep we carried out two studies in patients with cryptogenic/symptomatic frontal or temporal lobe epilepsies. METHODS: The occurrence of seizures in relation to the state of alertness was analyzed in patients with (1) mesial temporal and frontal lobe epilepsy, and (2) in patients with mesio-lateral temporal and mesial temporal lobe epilepsy in several conditions. Sleep analysis (organization and microarchitecture) was realized. RESULTS: We found: (1) a precise relationship between sleep and seizures in frontal lobe epilepsy (FLE); (2) a precise relationship between wakefulness and seizures in temporal lobe epilepsy (TLE); (3) sleep organization was normal in FLE and altered in TLE; (4) alterations of sleep microarchitecture in FLE and TLE. CONCLUSIONS: Seizure occurrence was mainly in relation to sleep for FLE and to wakefulness for TLE. Sleep organization appeared more altered for TLE than FLE. These results allow practical applications to localize and study FLE and TLE.

Validity of diagnosis using the French translation of the semi-structured interview for seizure classification.

PURPOSE: The purpose of this study was to assess the acceptability and validity of the French cross-cultural translation of a semistructured interview for seizure classification (SISC). We used the first revised version, the original of which was validated in 1990. METHODS: We administered the French SISC to a sample of 67 adults older than 15 years, comprising 17 controls and 50 patients with epilepsy (without provoked or isolated seizures). A cross-cultural translation was made from American English into French. Medical records were reviewed by epileptologists, who classified seizures, syndromes, and risk factors in accordance with the International League Against Epilepsy (ILAE) classifications. Agreement between interview- and physician-based diagnoses was assessed with a kappa coefficient (kappa) at each level of the recognized schemes for the classification of seizures (both broad and specific categories), syndromes, and risk factors. RESULTS: The sensitivity of the French SISC in diagnosing an epileptic seizure was 100%, with a specificity of 94%. Interview-based diagnoses agreed with those of physicians in 90% of patients for broad seizure categories [i.e., generalized or focal in origin (kappa = 0.74)]. When diagnoses agreed on focal origin, the agreement on seizure types-simple or complex-was 91% (kappa = 0.84). Among generalized seizures, the agreement was 73% (kappa = 0.60). Agreement on epilepsy syndromes was excellent for generalized epilepsy but moderate for focal epilepsy. Agreement on identified risk factors was 93%. CONCLUSIONS: The kappa coefficients demonstrated a good level of reliability. These results support the acceptability of this type of interview and the validity of the French version of the SISC.

[Effect of awakening and sleep deprivation in triggering idiopathic generalized epilepsy]. / Effet de la privation de sommeil et du réveil dans le déclenchement des crises des épilepsies généralisées idiopathiques.

The facilitating effect of awakening and sleep deprivation on seizure production and EEG abnormalities is characteristic of idiopathic generalized epilepsies (IGE). This effect is particularly patent in awakening epilepsy. Paroxysmal events occurring in non-REM sleep, related to spindle production during transitional periods or awakening are characteristic of IGE. Because IGEs are particularly sensitive to sleep, sleep deprivation, and awakening, the association of these three conditions is particularly helpful in exploration protocols, especially when no wakefulness abnormalities are seen on the EEG. These observations in IGE suggest a dysfunction of awakening control systems. Awakening epilepsies may be differentiated from sleep-induced seizures observed in other IGE and in partial epilepsies.

Alterations of metallothionein II and apolipoprotein J mRNA levels in kainate-treated rats.

Although different mechanisms have been proposed, it has been suggested that apolipoprotein J (ApoJ) and metallothionein II (MTII), expressed by astrocytes, are protective proteins. Alterations in their expression may contribute to the involvement of astrocytes in epileptogenesis. We studied the expression of MTII and ApoJ genes 7 days following status epilepticus induced in rats by intra-amygdala injection of kainate (KA). ApoJ mRNA levels were increased in both cortex (77%, p < 0.01) and hippocampus (64%, p < 0.02), whereas, in contrast to previous findings 3 days after KA injection, DNA fragmentation was not detected on agarose gel electrophoresis. These results show that ApoJ is induced along with early genes during massive apoptosis, and remains induced after the acute phase. MTII mRNA levels were altered only in hippocampus (62%, p < 0.05), whereas KA-treated rats had no seizure for 7 days. The sustained induction of MTII mRNA shows that zinc homeostasis is not returned to normal or alternatively that astrocytes maintain an altered phenotype in spite of normal zinc release. Polyadenylated RNA and beta-actin mRNA levels were in contrast unaltered in cortex or hippocampus at this time point. These specific variations in ApoJ and MTII mRNA expression during the latent period suggest that they are part of long term biochemical and/or phenotypic alterations in astrocytes, following a single episode of severe seizures.

The relationship between sleep and epilepsy in frontal and temporal lobe epilepsies: practical and physiopathologic considerations.

PURPOSE: The influence of sleep on the incidence of seizures and the reciprocal effects of epilepsy on sleep were analyzed in 30 patients with intractable partial seizures, all candidates for surgery. METHODS: The patients were classified into two groups of 15 patients according to the documented site of the epileptogenic zone: frontal lobe epilepsy (FLE) and medial temporal lobe epilepsy (TLE). Frequency and waking-sleep distribution of seizures were evaluated by continuous video-EEG monitoring for 5 days, under defined antiepileptic drug (AED), sleep, and sleep deprivation regimens. Sleep organization was analyzed by polysomnography prior to the presurgical protocol. RESULTS: Significant differences were found between the two groups in sleeping-waking distribution of seizures under varied conditions, and in the quality of sleep organization. In FLE patients, seizures most often occurred during sleep, although sleep organization was normal. In TLE patients, most seizures occurred while patients were awake, and sleep organization was characterized by a low efficiency index. The difference in seizure distribution between FLE and TLE persisted under all conditions investigated, i.e., after AED discontinuation and sleep deprivation. CONCLUSIONS: Sleep recording may be useful for diagnosis of FLE, and monitoring after sleep deprivation for that of TLE. We speculate that sleep-related seizures in FLE may depend on interaction between frontal lobe areas with the thalamus cortical synchronization system and the acetylcholine regulatory system of waking.

Therapeutic strategies against epilepsy in Mediterranean countries: a report from an international collaborative survey.

A collaborative survey was performed to compare prescribing strategies for the treatment of epilepsy in Mediterranean countries, based on analysis of 500 questionnaires compiled by physicians in 14 different countries. For partial seizures, carbamazepine was the drug of choice in most countries, whereas the second choice of drug differed widely. For primarily generalized tonic-clonic seizures, valproic acid was usually preferred, but other drugs used widely in some countries included phenobarbital, phenytoin and carbamazepine. Lamotrigine was the most popular second-line drug for primarily generalized tonic-clonic seizures in the European countries. In patients where the initial drug failed, switching to an alternative monotherapy was usually the preferred strategy, but advocates of early use of combination therapy exceeded 30% in the respondents of seven countries. Most respondents, in all countries except Turkey, did not prescribe drugs to prevent recurrence of febrile seizures; however, intermittent prophylaxis with a benzodiazepine was advocated by a considerable number of physicians, and continuous prophylaxis was prescribed by a significant minority of respondents in France, Syria and Tunisia. New drugs were rarely used as first-line treatment due to high cost and inadequate experience. Overall, this survey indicates that there is a wide variability in therapeutic practices between and within countries. This information may be useful for the implementation of national educational activities and for the design of pragmatic trials aimed at comparing different therapeutic strategies.

[Clinical study of familial forms of amyotrophic lateral sclerosis. Review of the literature]. / Etude clinique des formes familiales de sclérose latérale amyotrophique. Revue de la littérature.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving both upper and lower motor neurons. The disease is possibly due to several factors, including a genetic one. This is supported by the existence of 5 to 10 p. 100 familial cases. In these pedigrees, the transmission is autosomal dominant, with a high penetrance (> 90 p. 100). We studied the phenotypes of these familial cases, in reviewing the literature on familial ALS (FALS). It has been noted that FALS are heterogeneous, with different age of onset, site of onset and disease duration. Moreover, in FALS, onset is earlier than in the sporadic form (48 vs 60 years, as usually reported in the literature). We also frequently noted sensory disorders (20 p. 100), onset on the lower limbs (46 p. 100) and decreased or absent ankle-jerks (75 p. 100) in FALS patients.

Allelic heterogeneity of Mediterranean myoclonus and the cystatin B gene.

Mediterranean myoclonus is a progressive myoclonus epilepsy with autosomal recessive inheritance. Another form has been described in Finland, the so-called Baltic myoclonus. Mediterranean myoclonus and Baltic myoclonus are also known as Unverricht-Lundborg disease. Linkage analyses have shown that the genes for both these forms of myoclonus are closely linked to 21q22.3 DNA markers, suggesting that they are caused by mutations at the same locus (EPM1). Recently, two heterozygous mutations were found in the cystatin B gene in patients with Unverricht-Lundborg disease. We report recombinational and linkage disequilibrium mapping of EPM1, and cystatin B gene sequencing, in 14 consanguineous pedigrees with Mediterranean myoclonus. Linkage to 21q22.3 DNA markers was observed in all these families. Haplotype analysis suggests that a common mutation segregates within these pedigrees, and that this mutation is different from the common one responsible for the Finnish form of Unverricht-Lundborg disease. No mutation was found in the exons or splice junctions of the cystatin B gene in the 14 pedigrees.