Epilepsy and other neurological disorders
Michel Mazzuca, Florian Lesage, Michel Lazdunski
These defects range from nonsense and missense point mutations to insertion, truncation and splice site mutations producing altered, non-functional or negative-dominant channel subunits. To date, 12 mutated genes have been identified. They code for Na
<sup>+</sup> (SNC1A, SNC2A, SNC1B), K
<sup>+</sup> (KCNA1, KCNQ2, KCNQ3) and Cl
<sup>-</sup> (CLCN2) channel subunits, as well as neurotransmitter receptor subunits including Cl
<sup>-</sup> channel GABAA receptor (GABRA1, GABRG2) and cationic channel acetylcholine receptor (CHRNA4, CHRNB2). One ion transporter Na
<sup>+</sup> ATPase gene (ATP1A2) has also been identified. The epilepsy syndromes related to these genes are as diverse as benign familial neonatal (BFNC - KCNQ2 and 3) and infantile (BFNIC - SNC2A and ATP1A2) convulsions, episodic ataxia with seizures (AE2 - KCNA1), generalized epilepsy with febrile seizure plus (GEFS+ - SCN2A, 1A, 1B and GABRG2), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE - CHRNA4 and B2), severe myoclonic epilepsy of infancy (SMEI - SNC1A), juvenile myoclonic epilepsy (JME - GABRA1 and CLCN2), and childhood and juvenile absence epilepsy (CAE, JAE - SNC1B, GABRG2 and CLCN2). Despite the difficulty to correlate genotypes and phenotypes, these studies have increased our understanding of causal mechanisms of epilepsy and open a wide range of possibilities for developing better antiepileptic drugs and treatments.
Nathalie Bednarek, Jacques Motte
the consequence of the underlying neurological pathology (encephalopathy with epilepsy); it is therefore not the only factor responsible for delay. Within the framework of encephalopathies with epilepsy a rigorous diagnosis is necessary with, in particular a cutaneous examination (neuro-cutaneous syndromes), a precise clinical examination (anoxo-ischaemic sequelae of the perinatal period), an EEG, a cerebral magnetic resonance imaging (MRI) as well as the search for associated abnomalities (cardiac, renal…). There are also epileptogenic encephalopathies such as age-related syndromes: Hemiconvulsions-Hemiplegia-Epilepsy syndrome; Rasmussen’s syndrome; Dravet’s syndrome; myoclono-astatic epilepsy (Doose). Age at onset and type of seizures, as well as ictal and interictal EEG finding provide valuable hints for a specific diagnosis, while other investigation are usually not contributive. Developmental delay and epilepsy are frequently associated. One of the first steps to diagnosis consists in trying to establish the eventual causal role of the epilepsy. Answering this question may prove to be of primary importance for the choice of a therapeutic strategy and/or further etiological investigations.
Marie-Odile Livet, Nathalie Villeneuve, Géraldine Daquin, Marie-Anne Cournelle, Joselle Mancini, Anne Moncla
Some genetic syndromes with intellectual disability may also be associated with specific dysmorphic features, behavioural patterns or electro-clinically recognizable epilepsy syndromes. Identifying the epilepsy syndrome may prove to be an important clue for the diagnosis of the associated genetic syndrome. Moreover, the implicated chromosomal regions may be useful targets when searching for epilepsy genes. We review and discuss available data on some genetic syndromes (Angelman syndrome, duplication of the 15q11-q13 region, Wolf-Hirschorn syndrome, ring chromosome 20, fragile X syndrome) also presenting specific epilepsy features.
Bernard Echenne, Agathe Roubertie, Véronique Humbertclaude, François Rivier
to the characteristics of the epilepsy (generalized, partial or poorly defined), the successive steps of the clinical and biological investigations are described, taking into account the patient’s age and the type of seizure; the importance of some metabolic diseases and of some chromosomal abnormalities is underlined.
Pierre Genton, Michelle Bureau
the category of PME has been retained by the latest classification scheme proposal of the International League Against Epilepsy. PMEs are defined by: 1) generalized epileptic seizures (focal seizures may also occur in certain etiologies), 2) a sometimes invalidating myoclonus, and 3) other neurological symptoms (ataxia, dementia, sensory deficits) that vary according to etiology. Indeed, PMEs are a heterogenous group of conditions, with diverse etiologies. Their prevalence varies according to the ethnic context, and PMEs may appear as fairly frequent in some settings, because of genetic factors (isolate and/or inbreeding, for instance, in PMEs with recessive inheritance). The genetic and biochemical mechanisms underlying PMEs are increasingly recognized. We must nowadays follow a logical diagnostic scheme that will take into account the ethnic and genetic context, the age at onset of symptoms and the respective weight of symptoms. New therapeutic approaches are under development, and the available purely symptomatic treatments can be used to best possible effect. It is thus possible to recognize PMEs as a group of conditions appearing either as epilepsy, or as a movement disorder, or still under the mask of various neurological or cognitive symptoms. It is also possible to organize a logical, comprehensive care for patients with PME.
to an increase of epilepsy cases in the elderly. For example, in Alzheimer’s disease, almost 10% of the patients present with seizures, eventually necessitating an antiepileptic treatment. We review available data on epidemiology, diagnosis and treatment of the epilepsies when associated with major neurodegenerative disorders. Controlled, prospective studies are lacking.
in the cortex and juxtacortical white matter. Partial epilepsies with focal seizures often with atypical symptoms and with or without secondary generalisation are the usual pattern. Seizures can be observed as the first symptom of multiple sclerosis, or during relapses, with a direct correlation between paroxysmal phenomena and plaques demonstrated by brain MRI. Infrequently, it can start during the progressive phase, without active inflammation, generally associated with brain atrophy and high lesion load. Generally, the prognosis of epilepsy in multiple sclerosis patients is estimated to be good, without special recommendations or consensus for the choice of anti-epileptic drug. Non-epileptic paroxysmal symptoms may be confused with epileptic seizures. It usually responds to many different antiepileptic drugs.
Hervé Vespignani, A Al Najjar, Stéphane Kremer, Louis Maillard
infections (meningitis, encephalitis, single or multiple abscesses, sub-dural empyema). The occurrence of status epilepticus (SE) from an infection is a serious factor to be considered in therapeutic management. Brain CT-scan or MRI examinations are used to establish its parasitic, mycotic, bacterial or viral etiology. These studies also serve to confirm or modify the clinical diagnosis and the topographical origin of the infection. Nevertheless normal morphological examinations do not rule out a recent infection as a causative factor in epileptic seizures. This is especially true for meningitis in all age groups but particularly in children. Indeed, epileptic seizure onset in patients with meningitis is an indication of the presence of a cerebral abscess. In the acute phase, antiepileptic treatments are the rule of thumb. Their indication in the follow up phase with the purpose of preventing further seizures will depend upon the nature of the infection and availability of access to antiinfectious treatments. The risk of subsequent epileptic seizures is most common in patients with encephalitis and cerebral abscesses. In cases of trauma, infections affecting the central nervous system increase the risk of posttraumatic epileptic seizures.
withdrawal seizures” (AWS). However, experimental and clinical data strongly suggest that withdrawal is not the only mechanism by which the chronic absorption of alcohol may act. Specific epileptogenesis may underlie seizures unrelated to withdrawal (SUW). Epileptogenesis in this context involves several mechanisms including alterations of excitation/inhibition systems and a kindling-like effect. A classification scheme was proposed in which patients presenting with seizures unrelated to any cause other than alcohol are classified in several successive stages of “alcoholic epilepsy”, the first being characterized by AWS, the second by SUW and the last by persistent chronic seizures.