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PubMed2005

Current treatments of epilepsy.

Medical therapy is the mainstay for epilepsy, with most patients well controlled on a single antiepileptic drug (AED). In this non-refractory group, many patients have medication side effects and occasional seizures. Approximately 30% of patients with partial epilepsy and 25% of patients with generalized epilepsy are not well controlled on medications. These patients are often receiving multiple AEDs, with disabling seizures and side effects. Although second-generation AEDs are safer and better tolerated than the older AEDs, there are scant data to support significant advantages in efficacy. In VA studies with older AEDS, therapy with two AEDs improved seizure control in 40% of patients but seizure freedom was achieved in only 9%. A meta-analysis of the second-generation AEDs used as adjunctive therapies shows that 12% to 29% of patients had a 50% or greater reduction in seizure frequency. Surgery and the vagus nerve stimulator provide important therapeutic options in patients whose seizures are not controlled by AEDs. Special considerations about epilepsy care must be made in pediatric populations, those with developmental delays, women, and the elderly.

Adult↗
PubMedDate not supplied

[Cases of idiopathic and cryptogenic epilepsias in a regional referral neuropediatric unit].

INTRODUCTION AND OBJECTIVES: Advances in genetics, techniques for diagnosis and treatment, and increasing concern for the quality of life and neuropsychological aspects of epileptic children and the possible repercussions of treatment lead to changes in the approach to epilepsy and require continual adaptation. In this study we analysed a series of cases of idiopathic and cryptogenic epilepsy attended by the Neuropaediatric Department of the Hospital Miguel Servet in Zaragoza (Spain). PATIENTS AND METHODS: We studied the cases diagnosed as having idiopathic or cryptogenic epilepsy between May 1990 and December 1999. RESULTS: We assessed 4,507 children. In 1,794 (39.8%) consultation was for a paroxystic disorder. Epilepsy was diagnosed in 466 children (10.3%) and 103 cases were considered possibly or probably epilepsy but the diagnosis remains in doubt (2.3%). In 111 cases (23.8%) the epilepsy was considered idiopathic, in 122 (26.2%) cryptogenic and in 233 cases (50%) symptomatic. The following epileptic syndromes were identified: epilepsy-absence attacks in 28 cases (6%), benign myoclonic infantile epilepsy in 4 cases, other idiopathic generalized epilepsies in 61 cases (13%), benign Rolandic epilepsy in 18 cases (3.9%), 2 cases of cryptogenic Ohtahara syndrome, 6 cases of cryptogenic West syndrome, 1 severe case of infantile myoclonic epilepsy, 1 case of continuous wave epilepsy during slow eye movement sleep and 1 case of Landau-Kleffner syndrome. CONCLUSION: Current requirements and the rate of advances in epilepsy make it essential for neuropaediatric teams to include experts in epilepsy.

Adolescent↗
PubMed2001

[Surgery for intractable epilepsy in children: pre- and perioperative evaluations with special reference to dipole tracing method estimated from interictal spike].

Methods of preoperative and perioperative evaluation methods for surgical treatment of intractable epilepsy in children are described. Among non-invasive diagnostic methods, EEG-video monitoring is the most fundamental. Amygdalohippocampal volume measurement by MR was useful for the differential diagnosis of mesial temporal lobe epilepsy (TLE) from lateral TLE and generalized epilepsy. The dipole tracing method with a realistic head model was useful for identification of epileptic foci from the interictal spikes of scalp EEG, when an abnormal electric source was estimated as an equivalent current dipole (ECD) in the brain of patients with organic lesion and TLE. ECD concentration ratio ranged from 70 to 90% within 20 mm around the lesion. After lesionectomy seizures disappeared in every patient. The mean distance between the centers of the ECD and epileptic focus (identified by subdural electrode recording) was 14 mm (range: 8 to 18 mm). ECDs of mesial TLE were located in the temporal base rather than mesial temporal lobe, whereas those of lateral TLE in the lateral cortex precisely. In unilateral, intermediate and bilateral TLE, 76%, 52% and 36% of ECDs were localized in the ictal onset zone respectively (p = 0.007). Electrical cortical stimulation with chronically placed intracranial electrodes was used to accurately identify eloquent areas to avoid postsurgical complications. Immediately after operation, 10 to 20% of patients showed better or deteriorated results in neuropsychological examinations, which recovered in all patients after one year. Postoperative seizures were absent in three fourths of patients. Further efforts are needed to obtain better seizure control in future.

Adolescent↗
PubMed2004

[Genetic approach to the pathogeneses of epilepsy].

Recently, genetic causes have been identified in certain epilepsy syndromes in which the phenotypes are similar to common idiopathic epilepsies. Interestingly, almost all such genetic abnormalities were detected in genes encoding ion channels expressed in the brain. Thus such epilepsy syndromes are disorders of ion channels, i.e., "channelopathies". The list of ion channel abnormalities that are associated with childhood epilepsy is expanding and includes the followings. Mutations of the genes encoding two subunits of the neuronal nicotinic acetylcholine receptor, a ligand-gated ion channel, were found in autosomal dominant nocturnal frontal lobe epilepsy. Mutations of two KCNQ K+-channel genes were identified in benign familial neonatal convulsions. Mutations of the genes encoding several subunits of the voltage-gated Na+-channel and GABA(A) receptor, a ligand-gated ion channel, were also identified as underlying causes of various epilepsy syndromes, such as autosomal dominant epilepsy with febrile seizures plus or generalized epilepsy with febrile seizures plus, benign familial neonatal infantile seizures and autosomal dominant juvenile myoclonic epilepsy. Mutations within the same gene can result in different epilepsy phenotypes. Abnormalities of Na+-channel alpha1 subunit were also associated with severe myoclonic epilepsy in infancy. Epilepsy syndromes mentioned above, except for severe myoclonic epilepsy in infancy, were familial epilepsy syndromes showing dominant inheritance with high penetrance while common idiopathic epilepsies do not show obvious inheritance. However, the similarities in symptomatology between such familial epilepsies and common idiopathic epilepsy may provide us with clues to the genetics of common idiopathic epilepsies.

Epilepsy↗
PubMed1976

[The epileptic heredity in several comitial children].

For most authors, hereditary epilepsy is restricted to a certain number of neuropsychiatric diseases liable to be transmitted and associated to epileptic seizures : such as the progressive epilepsy myoclonia of Ramsay-Hunt, or some neuroectodermoses (Bourneville's tuberous sclerosis). But those diseases are quite rare compared to the majority of the epileptic population we meet everyday. Yet it seems to us that there is a genetic predisposition in some patients suffering from epilepsy, generalized from the start, called idiopathic epilepsy (grand mal, petit mal, massive myoclonias), where no cerebral lesion can be found. For this research, we have undertaken the study of two families, one with three children, the other with two homozygous twins. All the children were suffering from clinical epilepsy. The altered state of the E.E.G. of the parents who do not have obvious apparent epileptic seizures, confirms the genetic role of certain idiopathic epilepsies. A study of bibliography accompanies the topic of this presentation.

Adolescent↗
PubMed1982

Classification of partial epilepsies according to the symptomatology of seizures: practical value and prognostic implications.

Among 1,000 outpatient epileptics who visited the Epilepsy Center of Bologna consecutively from 1974 to 1978, 596 cases of partial epilepsy (PE) were chosen, representing 62.9% of all cases classified according to the International Classification of epilepsies. Fifty-four of these cases (5.7%) of those classifiable) that were affected by benign infantile epilepsy with rolandic spikes were not analyzed further. The remaining cases were divided up into three groups based on the symptomatology of the seizures: (1) partial elementary epilepsy (PEE), 102 cases (10.8%); (2) partial complex epilepsy (PCE), 332 cases (35%); and (3) partial secondarily generalized epilepsy (PSGE), 108 cases (11.4%). The three groups were compared according to the parameters that distinguish recognized epileptic syndromes, in order to see whether they constitute autonomous nosographic entities. Among the three groups, significant differences did not arise with regard to the incidence of single lesional etiological factors, the age of onset of the epilepsy, the neurological context, and the general features of interictal EEG. PSGE instead differs significantly from the other two forms for the minor severity of the epilepsy at first examination and for its more favorable course: after at least 2 years of follow-up under treatment, the epilepsy appeared to be controlled in 60.6% of the cases with PSGE, in 31.6% of those with PEE, and in 37.5% of those with PCE (p less than 0.05). For those with PE, globally considered, only three parameters have a favorable prognostic value: the brief duration of the epilepsy at the first observation, the rarity of the seizures, and the presence of only one type of seizure.

Age Factors↗
PubMed2005

Ion channel defects in idiopathic epilepsies.

Idiopathic epilepsies are genetically determined diseases of the central nervous system characterized by typical epileptic seizures and EEG abnormalities but not associated with structural brain lesions. In recent years, an increasing number of mutations associated with idiopathic epilepsy syndromes were identified in genes encoding subunits of voltage- or ligand-gated ion channels. These encouraging results provide a plausible pathophysiological concept, since ion channels form the basis for neuronal excitability and are the major targets for anticonvulsive pharmacotherapy. The first epilepsy genes were identified for rare autosomal dominant syndromes within large pedigrees. Recently, a few mutations were also found for the frequent classical forms of idiopathic generalized epilepsies (IGE), for example absence or juvenile myoclonic epilepsy. The mutations can affect ion channels which on one hand have been known since several decades to be crucial for neuronal function, such as the voltage-gated sodium channel or the GABA(A) receptor, or on the other hand were newly identified within the last decade as KCNQ potassium channels or the ClC-2 chloride channel. Functional studies characterizing the molecular defects of the mutant channels point to a central role of GABAergic synaptic inhibition in the pathophysiology of IGE. Furthermore, newly discovered genes may be suitable as novel targets for pharmacotherapy such as KCNQ channels for the anticonvulsant drug retigabine. Altogether, these genetic and pathophysiological investigations will enhance our knowledge about the understanding of epileptogenesis and can help to improve anticonvulsive therapy.

Animals↗
PubMed1993

[The antioxidant system in the dynamic combined treatment of epilepsy patients with traditional anticonvulsant preparations and an antioxidant--alpha-tocopherol].

Examination of 13 patients suffering from generalized epilepsy has shown about 20-25% decreases in the activity of superoxide dismutase (SOD) and glutathione peroxidase (GP) in red blood cells. Out of them 9 patients were treated with the antioxidant alpha-tocopherol (600 mg daily). Prior to alpha-tocopherol treatment all patients showed abnormal electroencephalographic (EEG) changes; 4 weeks later the effects of the antioxidant appeared as positive EEG changes, reduced frequency of epileptic seizures, increased SOD activity and patients' improved general state. Thus, the addition of the antioxidant to the multitherapy of epilepsy enhances antioxidative activity and therapeutical effects.

Adult↗
PubMed2002

Modulation of sodium current in mammalian cells by an epilepsy-correlated beta 1-subunit mutation.

The syndrome of generalized epilepsy with febrile seizure plus (GEFS+) is associated with a single point mutation on the gene SCN1B that results in a substitution of the cysteine 121 with a tryptophane in the sodium channel beta 1-subunit protein. We have studied, in the HEK cells permanently transfected with the skeletal muscle sodium channel alpha-subunit (SkM1), the effects of a transient transfection of the wild type (WT) or C121W mutant beta 1-subunit. Coexpression of the WT beta 1 produces two effects on the sodium currents expressed in mammalian cells: the increase in the density of sodium channels, and the modulation of the inactivation of the sodium currents, inducing a hastening of the recovery from the inactivation. This modulation is less severe as observed when sodium channels are expressed in frog oocytes. We have observed that mutant C121W lacks this modulatory property, but maintains its property to increase the current density. Our observation suggests a possible involvement of this lack of modulation in the development of the GEFS+, providing the first hypothesis based on the observation of the functional properties of the beta 1-subunit C121W mutant in mammalian cells, which certainly represents a more physiological preparation, instead of in Xenopus oocytes, where the modulatory properties of the beta 1-subunit are artificially amplified.

Animals↗
PubMed2006

Eye rolling as a manifestation of clobazam toxicity in a child with epilepsy.

A four-year-old male with symptomatic generalized epilepsy presented with ataxia, eye rolling, and episodes of back arching which were of non-epileptic origin following the introduction of clobazam at 0.75mg/kg/day. Concurrent antiepileptic medication was lamotrigine at 13mg/kg/day. Clobazam plasma levels were within the normal range, while N-desmethylclobazam (DCLB) concentrations were between five and seven times above the upper limit of the normal range. The plasma elimination half-life for DCLB was prolonged, suggesting a genetic variability in DCLB metabolism leading to toxicity. Reduction in the dose of clobazam to 0.3mg/kg/day was associated with resolution of the non-epileptic neurological symptoms, reduction in DCLB plasma levels, and maintenance of seizure control.

Anticonvulsants↗
PubMed2003

Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures.

A group of infant onset epilepsies manifest very frequent generalized tonic-clonic seizures (GTC) intractable to medical therapy, which may or may not be accompanied by minor seizures such as myoclonic seizures, absences and partial seizures. They include severe myoclonic epilepsy in infancy (SMEI) and intractable childhood epilepsy with GTC (ICEGTC). They are commonly associated with fever-sensitivity, family history of seizure disorders and developmental decline after seizure onset. Mutations of the neuronal voltage-gated sodium channel alpha subunit type 1 gene (SCN1A) were recently reported in SMEI patients. To clarify the genotypic differences in this group of epilepsies, we searched for SCN1A abnormalities in 25 patients with SMEI and 10 with ICEGTC, together with the family members of 15 patients. Frameshift mutations in SCN1A were observed in four patients, nonsense mutations in five patients, missense mutations in 21 patients, other mutations in two patients and no mutation in five patients. SMEI patients showed nonsense mutations, frameshifts, or missense mutations, while ICEGTC patients showed only missense mutations. Study of both parents of 11 patients revealed that the mutations in these patients were de novo. However, two mothers had the same missense mutations as their ICEGTC children, and they had generalized epilepsy with febrile seizures plus. Here we suggest that SMEI and ICEGTC represent a continuum with minor phenotypic and genotypic differences.

Adolescent↗
PubMed1987

Thalamocortical mechanisms of state-dependent seizures during amygdala kindling and systemic penicillin epilepsy in cats.

Somatomotor system-evoked potential data suggested that thalamus and cortex provide a final common pathway for the timing of generalized seizures in the sleep-wake cycle. Results indicated thalamic mediation of sleep-activated seizures in the amygdala kindling model of secondary generalized epilepsy; in contrast, cortical hyperexcitability was implicated in the timing of seizures with the systemic penicillin model of primary generalized, petit mal epilepsy. Even though thalamic or cortical hyperexcitability peaked during seizure prone sleep or awakening states in the two models, increased, 'subclinical' levels of hyperexcitability persisted during seizure resistant states, notably rapid-eye-movement (REM) sleep. This finding suggested a chronic, if often latent neuropathology for both epilepsy models and upon which the sleep-wake state modulation of seizures is superimposed.

Amygdala↗
PubMed2005

Neonatal epilepsy syndromes and GEFS+: mechanistic considerations.

Genetic analyses of familial epilepsies over the past decade have identified mutations in several different ion channel genes that result in neonatal or early-onset seizure disorders, including benign familial neonatal convulsions (BFNC), generalized epilepsy with febrile seizures plus (GEFS+), and severe myoclonic epilepsy of infancy (SMEI). These genes encode voltage-gated Na+ channel subunits (SCN1A, SCN2A, SCN1B), voltage-gated K+ channel subunits (KCNQ2, KCNQ3), and a ligand-gated neurotransmitter receptor subunit (GABRG2). While the opportunity to genotype patients for mutations in these genes can have an immediate and significant impact on our ability to diagnose and provide genetic counseling to patients, the ultimate goal is to use this molecular knowledge to develop effective treatments and cures for each disorder. This will necessitate elucidation of the molecular, cellular, and network mechanisms that translate ion channel defects into specific epilepsy phenotypes. The functional analysis of epileptogenic channel mutations in vitro and in vivo has already provided a vast amount of raw biophysical data, but attempts to interpret these data to explain clinical phenotypes so far appear to raise as many questions as they answer. Nevertheless, patterns are beginning to emerge from these early studies that will help define the full scope of the challenges ahead while simultaneously providing the foundation of future efforts to overcome them. Here, I discuss some of the potential mechanisms that have been uncovered recently linking mutant ion channel genes to neonatal epilepsy syndromes and GEFS+.

Age of Onset↗
PubMed2000

Correlation of EEG, neuroimaging and histopathology in an epilepsy patient with diffuse cortical dysplasia.

The correlation between scalp EEG, intraoperative electrocorticogram, neuroimaging and histopathology was examined in an epileptic child with diffuse cortical dysplasia. The 6-year-old girl with moderate mental retardation had suffered from intractable complex partial and generalized epilepsies since the age of 2 years. MR images demonstrated unilateral large macrogyria/polymicrogyria and schizencephaly in the right occipital lobe. The epileptic focus was detected on the macrogyria by EEG and single photon emission tomography. However, the intraoperative electrocorticogram showed frequent spikes from the polymicrogyria and no paroxysmal activity in the macrogyria. The polymicrogyria and the macrogyric lesion were resected, using an image-guided system. The histological findings revealed that the macrogyria was covered with and separated by glial bundles. It has been reported that epileptogenicity is produced from abnormal neurons and their arrangement in cortical dysplasia; in this case, however, the major dysplastic lesion had no epileptogenicity; rather the focus might be in the polymicrogyria around the lesion.

Cerebral Cortex↗
PubMed2003

Channelopathies as a genetic cause of epilepsy.

PURPOSE OF REVIEW: This review describes the significant number of new gene associations with epilepsy syndromes that have emerged during the past year, together with additional mutations and new electrophysiological data relating to previously known gene associations. RECENT FINDINGS: Autosomal dominant juvenile myoclonic epilepsy was demonstrated to be a channelopathy associated with a GABA(A) receptor, alpha1 subunit mutation. Benign familial neonatal infantile seizures were delineated as another channelopathy of infancy, by molecular characterization of sodium channel, alpha2 subunit defects. A sodium channel, alpha2 subunit defect was previously found to be associated with generalized epilepsy with febrile seizures plus. Similarly, the clinical spectrum associated with potassium channel, KQT-like mutations was extended to include the channelopathy myokymia and neonatal epilepsy. Mutations in the non-ion channel genes, leucine-rich, glioma inactivated 1 gene and Aristaless related homeobox gene, have emerged as important causes of their specific syndromes, with mutations in the latter gene frequently underlying X-linked mental retardation with epilepsy. SUMMARY: All but one of the idiopathic epilepsies with a known molecular basis are channelopathies. Where the ion channel defects have been identified, however, they generally account for a minority of families and sporadic cases with the syndrome in question. The data suggest that ion channel mutations of large effect are a common cause of rare monogenic idiopathic epilepsies, but are rare causes of common epilepsies. Additive effects of genetic variation, perhaps within the same ion channel gene families, are likely to underlie the common idiopathic generalized epilepsies with complex inheritance. The genetics of epilepsy is progressing rapidly toward a more detailed molecular dissection and definition of syndromes.

Calcium Channels↗
PubMed2002

Social communication in children with epilepsy.

BACKGROUND: This study examined measures of social communication that involve the use of language in formulating and organizing thoughts and its relationship with seizure-related, developmental, cognitive, and behavioral variables in 92 children with complex partial seizure disorder (CPS), 51 with primary generalized epilepsy (PGE), and 117 normal children, aged 5.1-16.9 years. METHODS: Coding the children's speech samples with the Kiddie Formal Thought Disorder Rating Scale (Caplan et al., 1989) and Halliday and Hasan's (1976) analysis of cohesion demonstrated social communication deficits in both seizure disorder groups. RESULTS: The CPS patients had both formal thought disorder and cohesion deficits and the PGE group had mild cohesion deficits. IQ, as well as fronto-temporal and bilateral spike and wave activity were associated with the severity of the social communication deficits of the CPS group. The social communication deficits of the PGE group, however, were related to IQ and seizure control. CONCLUSIONS: Recurrent CPS and PGE and fronto-temporal localization of epileptic activity might impair the development of children's communication skills.

Adolescent↗