Novel susceptibility locus at chromosome 6q16.3-22.31 in a family with GEFS+.

BACKGROUND: Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with extremely variable expressivity. Mutations in 5 genes that raise susceptibility to GEFS+ have been discovered, but they account for only a small proportion of families. METHODS: We identified a 4-generation family containing 15 affected individuals with a range of phenotypes in the GEFS+ spectrum, including febrile seizures, febrile seizures plus, epilepsy, and severe epilepsy with developmental delay. We performed a genome-wide linkage analysis using microsatellite markers and then saturated the potential linkage region identified by this screen with more markers. We evaluated the evidence for linkage using both model-based and model-free (posterior probability of linkage [PPL]) analyses. We sequenced 16 candidate genes and screened for copy number abnormalities in the minimal genetic region. RESULTS: All 15 affected subjects and 1 obligate carrier shared a haplotype of markers at chromosome 6q16.3-22.31, an 18.1-megabase region flanked by markers D6S962 and D6S287. The maximum multipoint lod score in this region was 4.68. PPL analysis indicated an 89% probability of linkage. Sequencing of 16 candidate genes did not reveal a causative mutation. No deletions or duplications were identified. CONCLUSIONS: We report a novel susceptibility locus for genetic epilepsy with febrile seizures plus at 6q16.3-22.31, in which there are no known genes associated with ion channels or neurotransmitter receptors. The identification of the responsible gene in this region is likely to lead to the discovery of novel mechanisms of febrile seizures and epilepsy.

Classification of partial seizure symptoms in genetic studies of the epilepsies.

OBJECTIVES: To develop standardized definitions for classification of partial seizure symptoms for use in genetic research on the epilepsies, and evaluate inter-rater reliability of classifications based on these definitions. METHODS: The authors developed the Partial Seizure Symptom Definitions (PSSD), which include standardized definitions of 41 partial seizure symptoms within the sensory, autonomic, aphasic, psychic, and motor categories. Based on these definitions, two epileptologists independently classified partial seizures in 75 individuals from 34 families selected because one person had ictal auditory symptoms or aphasia. The data used for classification consisted of standardized diagnostic interviews with subjects and family informants, and medical records obtained from treating neurologists. Agreement was assessed by kappa. RESULTS: Agreement between the two neurologists using the PSSD was "substantial" or "almost perfect" for most symptom categories. CONCLUSIONS: Use of standardized definitions for classification of partial seizure symptoms such as those in the Partial Seizure Symptom Definitions should improve reliability and accuracy in future genetic studies of the epilepsies.

LGI1 mutations in autosomal dominant partial epilepsy with auditory features.

OBJECTIVE: S: Mutations in LGI1 cause autosomal dominant partial epilepsy with auditory features (ADPEAF), a form of familial temporal lobe epilepsy with auditory ictal manifestations. The authors aimed to determine what proportion of ADPEAF families carries a mutation, to estimate the penetrance of identified mutations, and to identify clinical features that distinguish families with and without mutations. METHODS: The authors sequenced LGI1 in 10 newly described ADPEAF families and analyzed clinical features in these families and others with mutations reported previously. RESULTS: Three of the families had missense mutations in LGI1 (C42R, I298T, and A110D). Penetrance was 54% in eight families with LGI1 mutations the authors have identified so far (five reported previously and three reported here). Excluding the original linkage family, the authors have found mutations in 50% (7/14) of tested families. Families with and without mutations had similar clinical features, but those with mutations contained significantly more subjects with auditory symptoms and significantly fewer with autonomic symptoms. In families with mutations, the most common auditory symptom type was simple, unformed sounds (e.g., buzzing and ringing). In two of the newly identified families with mutations, some subjects with mutations had idiopathic generalized epilepsies. CONCLUSIONS: LGI1 mutations are a common cause of autosomal dominant partial epilepsy with auditory features. Current data do not reveal a clinical feature that clearly predicts which families with autosomal dominant partial epilepsy with auditory features have a mutation. Some families with LGI1 mutations contain individuals with idiopathic generalized epilepsies. This could result from either an effect of LGI1 on risk for generalized epilepsy or an effect of co-occurring idiopathic generalized epilepsy-specific genes in these families.

Genetic influences on myoclonic and absence seizures.

OBJECTIVE: To examine the relationship between genotype and phenotype in idiopathic generalized epilepsies (IGEs) using a novel approach that focuses on seizure type rather than syndrome. METHODS: The authors evaluated whether the genetic effects on myoclonic seizures differ from the genetic effects on absence seizures. For this purpose, they studied 34 families containing 2 or more members with IGEs and assessed whether the number of families concordant for seizure type exceeded that expected by chance. The authors performed a similar analysis to examine the genetic contributions to juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and childhood absence epilepsy (CAE). RESULTS: The observed number of families concordant for seizure type (myoclonic, absence, or both) was greater than expected (20 vs 7.51; p < 0.0001). The observed number of families concordant for syndrome was greater than expected when JME was compared with absence epilepsies (JAE+CAE) (17 vs 11.9; p < 0.012) but not when JAE was compared with CAE (8 vs 6.82; p = 0.516). CONCLUSIONS: These results provide evidence for distinct genetic effects on absence and myoclonic seizures, suggesting that examining the two seizure types separately would be useful in linkage studies of idiopathic generalized epilepsies. The approach presented here can also be used to discover other clinical features that could direct division of epilepsies into groups likely to share susceptibility genes.

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Status epilepticus arising de novo in hospitalized patients: an analysis of 41 patients.

Most of the information on predisposing factors and mortality in status epilepticus (SE) arises from data obtained from patients presenting to the casualty department. However, another population which is frequently seen by consultative neurologists are medically ill patients who develop SE while in hospital. These patients are often notoriously difficult to treat once SE arises. We sought to characterize patients at risk for SE arising when they are hospitalized for other reasons. By doing this, risk factors for developing SE and prognostic indicators might be determined. We retrospectively reviewed records from three urban hospitals in the United States to identify hospitalized patients developing SE over a 1 year period. SE was defined as a clinical seizure lasting 30 minutes or longer, or repeated seizures without recovery. Patients who were admitted in SE or for an epilepsy-related problem, or who were less than 1 year old were excluded from the study. Forty-one patients with in-hospital SE were identified. There were 28 males and 13 females with an age range from 1 to 91 years (mean: 60 years, median: 65 years). The mean interval from hospital admission to the onset of status epilepticus was 26 days. Nineteen (46%) patients had a prior history of either epilepsy or symptomatic seizures, and of these, 10 were inadequately treated as judged by serum anticonvulsant levels at the time SE developed. Focal brain abnormality was present in 26 (63%) patients, the most common of which was stroke (17 patients ). Major metabolic derangements including hypoxia, electrolyte imbalance, hepatic encephalopathy, and sepsis were present in 23 (56%) patients. Eleven (27%) patients were being treated with theophylline preparations at the time SE developed. Mortality in this group of patients with in-hospital SE was 61% (25 deaths), with about one-third dying while in status, and two-thirds dying subsequently in hospital. In this retrospective study, there was no clear relationship between mortality and the duration of SE in this group of patients. In-hospital development of SE is usually related to underlying focal brain abnormality, especially stroke, in combination with systemic metabolic derangement. Prognosis is poor, and appears to be more related to underlying conditions rather than to status duration. More accurate prospective studies are warranted.

A unilateral, prolonged, nonconvulsive seizure in a patient treated with bilateral ECT.

We report on a case of a 45-year-old man in an episode of major depression with psychotic features treated with bilateral electroconvulsive therapy (ECT). At the eighth treatment, he manifested unilateral, prolonged, nonconvulsive seizure activity on the left side, which lasted 351 seconds longer than seizure activity on the right, and was terminated with intravenous diazepam. This is the first report of a unilateral prolonged seizure. Its occurrence following bilateral ECT was particularly noteworthy. This case also highlights the importance of two-channel EEG recording during ECT. Without two recording channels we doubt that this event would have been detected, perhaps resulting in nonconvulsive status epilepticus.

Autosomal dominant partial epilepsy with auditory features: defining the phenotype.

The authors previously reported linkage to chromosome 10q22-24 for autosomal dominant partial epilepsy with auditory features. This study describes seizure semiology in the original linkage family in further detail. Auditory hallucinations were most common, but other sensory symptoms (visual, olfactory, vertiginous, and cephalic) were also reported. Autonomic, psychic, and motor symptoms were less common. The clinical semiology points to a lateral temporal seizure origin. Auditory hallucinations, the most striking clinical feature, are useful for identifying new families with this synome.

Prospective magnetic resonance imaging identification of focal cortical dysplasia, including the non-balloon cell subtype.

The purpose of this study was to determine the role of high-resolution T2-weighted fast multiplanar inversion-recovery (FMPIR) magnetic resonance (MR) imaging in detecting and delineating microscopic focal cortical dysplasia (FCD). We performed MR scans with FMPIR on 42 patients with suspected neocortical epilepsy. Ten MR studies were read prospectively as showing FCD; these case histories, electroencephalographic studies, and neuroimaging data were reviewed. Eight of these patients subsequently underwent focal cortical resection guided by intraoperative electrocorticography. The MR findings were correlated with pathological findings in these 8 patients. For purposes of radiological-pathological correlation, the FCD lesions were divided into two classes. Radiological classification was based on the absence (type A) or presence (type B) of T2 prolongation of the subcortical white matter. Pathological grading as type I or type II was based on a previously described pathological grading system. Specific MR findings associated with FCD included focal blurring of the gray-white matter interface (n = 9), thickening of the cortical ribbon (n = 7), and T2 prolongation of the subcortical white matter (n = 4). In 3 patients, the only MR finding that suggested FCD was localized blurring of the gray-white matter junction. In 2 of these 3 patients, the MR diagnosis of FCD could be made only by FMPIR. FCD was confirmed histologically in 7 of 8 patients, with insufficient tissue for complete histopathological evaluation in 1 case. Radiological classification of FCD agreed with pathological classification in 5 of 7 cases. Correlation of MR findings with intraoperative electrocorticography results indicated that the MR study localized the epileptogenic lesion correctly in 8 of 8 cases. Scalp ictal electroencephalographic studies localized the epileptogenic lesion in 5 of 8 cases; positron emission tomographic scans were focally abnormal in 3 of 3 cases. FMPIR MR imaging permitted accurate diagnosis and localization of FCD in all patients with pathologically proved FCD. MR identification of FCD aided presurgical planning and intraoperative management of these patients.

Advances in the medical treatment of epilepsy.

Treatment options for epilepsy, especially using antiepileptic drugs, have increased substantially in the past five years. Since 1993, four novel antiepileptic drugs have been approved and marketed in the United States: felbamate, gabapentin, lamotrigine, and topiramate. Two others, tiagabine and vigabatrin, are likely to be approved in the near future. For many patients, these agents offer the realistic promise of improved seizure control, often with fewer adverse effects and less significant drug interactions compared with older agents. In addition, fosphenytoin, a water-soluble phenytoin prodrug with a number of advantages over intravenous phenytoin, has been released. There are new administration options for carbamazepine, diazepam, and valproic acid. For drug-resistant or -intolerant patients, there has been renewed interest in alternative therapies, especially the ketogenic diet. Taken together, these represent significant therapeutic advances that are benefiting patients with epilepsy. At the same time, improved understanding of the basic mechanisms of epileptogenesis, and of the cellular and molecular actions of available antiepileptic drugs, creates a framework for designing unique therapeutic strategies that are targeted at key sites of vulnerability involved in the development and maintenance of the epileptic state.