ORCID Profile
0000-0003-4580-841X
Current Organisations
CNRS Délégation Midi-Pyrénées
,
University of Melbourne
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Psychology | Sensory Processes, Perception and Performance | Music Performance | Quantitative Genetics (incl. Disease and Trait Mapping Genetics) | Biological Psychology (Neuropsychology, Psychopharmacology, | Neurology And Neuromuscular Diseases | Health, Clinical And Counselling Psychology |
Learner and Learning Achievement | Expanding Knowledge in Psychology and Cognitive Sciences | Music | Preventive medicine | Evaluation of health outcomes | Behaviour and health
Publisher: Wiley
Date: 05-2009
DOI: 10.1111/J.1528-1167.2008.01893.X
Abstract: To examine the nature and determinants (biologic and psychological) of cognitive complaints in first-seizure patients. We analyzed this in the context of our previous findings that a sense of loss of control after a newly diagnosed seizure (limited or pervasive) predicts subsequent psychological adjustment trajectories. Eighty-five consecutive First Seizure Clinic patients were assessed at 1 and 3 months. Cognitive complaints were evaluated qualitatively, with a semistructured interview, and quantitatively, with the A-B Neuropsychological Assessment Schedule (ABNAS). Objective attentional processing was assessed with reaction time tasks and the Wechsler Adult Intelligence Scale-3rd edition (WAIS-III) Processing Speed Index. Mood was assessed with the Hospital Anxiety and Depression Scale (HADS). Psychological adjustment trajectories were represented by previous classification of patients into limited and pervasive groups, as derived from semistructured interview. Cognitive complaints at 1 and 3 months were strongly associated with mood, and unrelated to objective attentional processing. Psychological adjustment trajectories influenced the longitudinal course of cognitive complaints, and these effects were partially mediated by mood differences between the limited and pervasive groups. The course of cognitive complaints was also altered by commencing antiepileptic drugs. Patients experiencing seizure recurrence reported greater cognitive complaints, even before their seizure recurred. Mediation analyses showed this effect was likely attributable to increased mood disturbance in the seizure recurrence group, and was unrelated to objective attentional processing. Understanding cognitive complaints in first-seizure patients requires a longitudinal perspective that takes into account the patients' changing psychological and medical contexts. Patients presenting with extensive cognitive complaints may warrant assessment for mood and adjustment issues.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-10-2002
Abstract: Although precipitation of seizures by exercise has been described, the reproducible induction of temporal lobe seizures by exercise is unusual. The authors report two patients with left temporal lobe seizures induced by exercise. In one patient the family history suggested autosomal-dominant inheritance. Prolonged hyperventilation, simple movements, and visualization of a competitive game did not produce epileptiform discharges on the interictal EEG.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1993
Abstract: We evaluated ictal 99mtechnetium hexamethyl propylene-amine-oxime single-photon emission computed tomography (SPECT) in 22 children with electroclinical features of frontal lobe epilepsy (FLE). Ictal SPECT demonstrated unilateral frontal hyperperfusion in 20 of 22 children (91%) (one lobar, two frontocentral, six dorsolateral, six frontopolar, three orbitofrontal, one medial frontal, and one insula), concordant with electroclinical lateralization in 19 of 20 (95%). Hyperperfusion was evident in the ipsilateral basal ganglia in 16 of 22 (73%) and the contralateral cerebellum in 14 of 22 children (64%). Interictal SPECT showed unilateral, localized frontal hypoperfusion concordant with electroclinical lateralization in only two of 22 children (9%). Ictal SPECT localization to the frontocentral, media frontal, or dorsolateral regions was associated with asymmetric tonic posturing, contralateral head/eye deviation, and unilateral clonic jerking (p or = 0.05). Ictal SPECT has the potential to (1) localize seizures in patients with intractable FLE, and (2) advance understanding of the in vivo anatomico-clinical relationships of frontal lobe seizures.
Publisher: Oxford University Press (OUP)
Date: 15-10-2005
DOI: 10.1093/HMG/DDI355
Abstract: Common idiopathic epilepsies are, clinically and genetically, a heterogeneous group of complex seizure disorders. Seizures arise from periodic neuronal hyperexcitability of unknown cause. The genetic component is mostly polygenic, where each susceptibility gene in any given in idual is likely to represent a small component of the total heritability. Two susceptibility genes have been so far identified, where genetic variation is associated with experimentally demonstrated changes in ion channel properties, consistent with seizure susceptibility. Rare variants and a polymorphic allele of the T-type calcium channel CACNA1H and a polymorphic allele and a rare variant of the GABA(A) receptor delta subunit gene have differential functional effects. We speculate that these and other as yet undiscovered susceptibility genes for complex epilepsy could act as 'modifier' loci, affecting penetrance and expressivity of the mutations of large effect in those 'monogenic' epilepsies with simple inheritance that segregate through large families. Discovery of epilepsy-associated ion channel defects in these rare families has opened the door to the discovery of the first two susceptibility genes in epilepsies with complex genetics. The susceptibility genes so far detected are not commonly involved in complex epilepsy suggesting the likelihood of considerable underlying polygenic heterogeneity.
Publisher: Oxford University Press (OUP)
Date: 11-05-2004
DOI: 10.1093/HMG/DDH146
Publisher: AMPCo
Date: 04-2000
Publisher: Elsevier BV
Date: 09-2010
Publisher: Elsevier BV
Date: 08-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1999
Abstract: Seven untreated patients with idiopathic generalized epilepsy were studied with recovery curve analysis using transcranial magnetic stimulation and compared with 16 controls. Patients had a shorter period of inhibition of the test response following a conditioning stimulus and demonstrated a period of increased facilitation of the test response at interstimulus intervals of 200 to 300 msec, which was similar to the mean interdischarge interval of spike-wave activity on EEG. This provides further evidence of cortical hyperexcitability in idiopathic generalized epilepsy.
Publisher: Wiley
Date: 05-1997
Abstract: We describe 5 women and 5 men with periventricular nodular heterotopia and electroclinical features suggestive of temporal lobe epilepsy, who were surgically treated for control of medically refractory seizures. Magnetic resonance imaging revealed bilateral periventricular nodular heterotopia in 7 of the 10 patients. Because of the lack of clear localization, 6 patients were studied with intracranial depth electrode recordings. Seizures were of hippoc al onset (3 patients), regional temporal lobe onset (2 patients), or occipital-temporal onset (1 patient). Anterior temporal lobectomy was performed in 6 patients selective amygdalohippoc ectomy, in 1 and anterior temporal lobectomy plus resection of the heterotopic tissue, in 3. None of the 9 patients followed for more than 12 months postoperatively were seizure free. Two patients were initially seizure free for approximately 18 months, but then seizures recurred. One patient had a major reduction in seizure frequency at a 39-month follow-up after most of the unilateral heterotopic tissue was included in the temporal resection. Temporal resection did not lead to a long-term favorable outcome in this group of patients with periventricular nodular heterotopia and epileptogenic discharges involving the temporal lobe. This suggests a more widespread disorder with epileptogenic activity possibly originating in or near the heterotopic tissue. The clinical and electrographic features of periventricular nodular heterotopia pointing to temporal lobe origin are misleading and temporal resection does not result in long-term cessation of seizures.
Publisher: Wiley
Date: 11-05-2018
DOI: 10.1111/EPI.14087
Publisher: Wiley
Date: 03-2006
DOI: 10.1111/J.1528-1167.2006.00466.X
Abstract: Benign rolandic epilepsy (BRE) is considered a genetically determined idiopathic partial epilepsy. We analyzed a large s le of twins from four international twin registers to probe the genetics of BRE. We also aim to synthesize the apparently conflicting family and twin data into a model of BRE etiology. Large population-based twin registries of epilepsies from Odense (Denmark), Richmond, Virginia (United States), and Oslo (Norway) were reviewed for BRE cases and added to our Australian twin data. Diagnosis of classic BRE was based on electroclinical criteria with normal neurologic development. Cases with a compatible electroclinical picture but abnormal neurologic development were termed non-classic BRE. Eighteen twin pairs were identified (10 monozygous eight dizygous) of whom at least one twin was diagnosed with classic BRE among a total s le of 1,952 twin pairs validated for seizures, and all were discordant for BRE. The estimated monozygous pairwise concordance for BRE in this s le was 0.0 [95% confidence interval (CI), 0.0-0.3). Four twin pairs (one monozygous, three dizygous) had non-classic BRE, and all co-twins had seizures. The twin data showing an absence of any concordant twin pairs with classic BRE suggest that noninherited factors are of major importance in BRE. Modelling the data shows that the familial occurrence of centrotemporal spikes makes only a minor contribution to the familial aggregation of BRE. Genetic factors are probably more important in non-classic BRE. The etiology and mode(s) of inheritance of BRE are much more complicated than initially conceptualized.
Publisher: Elsevier BV
Date: 10-1993
Publisher: Wiley
Date: 02-2002
DOI: 10.1046/J.1528-1157.2002.19498.X
Abstract: We analyzed databases on chromosomal anomalies and epilepsy to identify chromosomal regions where abnormalities are associated with clinically recognizable epilepsy syndromes. The expectation was that these regions could then be offered as targets in the search for epilepsy genes. The cytogenetic program of the Oxford Medical Database, and the PubMed database were used to identify chromosomal aberrations associated with seizures and/or EEG abnormalities. The literature on selected small anomalies thus identified was reviewed from a clinical and electroencephalographic viewpoint, to classify the seizures and syndromes according to the current International League Against Epilepsy (ILAE) classification. There were 400 different chromosomal imbalances described with seizures or EEG abnormalities. Eight chromosomal disorders had a high association with epilepsy. These comprised: the Wolf-Hirschhorn (4p-) syndrome, Miller-Dieker syndrome (del 17p13.3), Angelman syndrome (del 15q11-q13), the inversion duplication 15 syndrome, terminal deletions of chromosome 1q and 1p, and ring chromosomes 14 and 20. Many other segments had a weaker association with seizures. The poor quality of description of the epileptology in many reports thwarted an attempt to make precise karyotype-phenotype correlations. We identified certain chromosomal regions where aberrations had an evident association with seizures, and these regions may be useful targets for gene hunters. New correlations with specific epilepsy syndromes were not revealed. Clinicians should continue to search for small chromosomal abnormalities associated with specific epilepsy syndromes that could provide important clues for finding epilepsy genes, and the epileptology should be rigorously characterized.
Publisher: Wiley
Date: 21-05-2019
DOI: 10.1111/EPI.16020
Abstract: Certification by treating physicians of fitness to drive in people with epilepsy creates a conflict of interest that may result in unsafe decisions, damage the doctor-patient relationship, expose the physician to legal liability and prevent optimal treatment. Ideally, the treating physician should provide objective clinical information to the driver licensing authority (DLA), which then determines fitness or otherwise. However, DLAs in Australia do not employ medical staff and the national standards are complex. Fitness is determined by the treating physician, according to published national standards. The purpose of this study was to determine the feasibility of using a decision tree to determine fitness, according to the Australian standards. A decision tree was constructed to use clinical data to determine whether a patient met the national standard to drive a private motorcar, failed to meet it or required further assessment. A form was designed to collect the necessary clinical data from the treating physician. A computerized version of the decision tree was then used in a pilot in two Australian states in parallel with the existing certification system. Four hundred thirty-nine drivers with declared epilepsy and their treating physicians were invited to participate when their annual driver licence review was due. Two hundred fifty-three (58%) forms were returned. All patients were considered fit to drive by their physician. Seventy-six percent had not had a seizure for over two years. In 88.1%, there was agreement between the decision tree and treating physician, with 3.6% identified by the decision tree as requiring review. Although considered fit by their physician, 6.3% did not meet the national standard to drive. The decision tree model is a practical alternative to fitness certification by treating physicians. This Australian pilot can serve as a model for applying objective standards to driving assessments in other jurisdictions, using local driving standards. It has the potential to improve road safety by avoiding the negative effects of certification by treating physicians and can cope with complex standards. It is now in use in two states of Australia.
Publisher: Elsevier BV
Date: 1996
DOI: 10.1016/S0896-6273(00)80025-2
Abstract: Periventricular heterotopia (PH) involves dramatic malformations of the human cerebral cortex. Here we show that PH is closely linked to markers in distal Xq28 (maximal two-point lod score = 4.77 for F8C at theta = 0 maximal multipoint lod score = 5.37), so that affected females are obligatory mosaics for the mutation that PH is lethal to at least some affected males that PH malformations consist of well-differentiated cortical neurons filling the adult subependymal zone and that in iduals with PH are at high risk for epilepsy, though they have no other neurological or external stigmata. The PH gene may represent an important epilepsy susceptibility locus in addition to playing a key role in normal cortical development.
Publisher: BMJ
Date: 14-09-2007
Publisher: Elsevier BV
Date: 09-2002
Publisher: Wiley
Date: 04-2022
DOI: 10.1111/EPI.17228
Abstract: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All s les were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger s le sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.
Publisher: Wiley
Date: 13-01-2012
DOI: 10.1111/J.1528-1167.2011.03379.X
Abstract: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.
Publisher: Elsevier BV
Date: 02-2006
Publisher: Elsevier BV
Date: 04-2009
Publisher: Informa UK Limited
Date: 02-1996
DOI: 10.1080/01688639608408266
Abstract: The present study evaluated the hypothesis (Mayeux et al., 1980) that visual confrontation naming deficits may underlie the memory complaint in patients with temporal lobe epilepsy (TLE). Thirty-nine patients with medically refractory left (n = 23) and right (n = 16) TLE were compared with an epilepsy control group with idiopathic primary generalized epilepsy (n = 38). All subjects completed selected subtests of the Multilingual Aphasia Examination and Wechsler Memory Scale (Form 1) together with a measure specifically designed for quantification of the memory complaint in TLE. Objective verbal memory test performance, confrontation naming, repetition, and comprehension were unrelated to memory self-report. Controlled Oral Word Association was the only measure to exert an influence on memory self-ratings, and this relationship was specific to the TLE group. The hypothesis of Mayeux et al. (1980) was not specifically supported, but the present findings do suggest that cognitive processes reflected in orthographically based and internally generated word retrieval play a role in memory self-report.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-02-2000
DOI: 10.1212/WNL.54.4.971
Abstract: Gelastic seizures are the hallmark of the epilepsy syndrome associated with hypothalamic hamartomas. Patients typically develop cognitive deterioration and refractory seizures. The authors describe three patients with small hypothalamic hamartomas without these features and thus identify a mild end to the clinical spectrum. All had the unusual symptom of "pressure to laugh," often without actual laughter. This symptom could be dismissed as psychogenic but should be recognized as a clue to the presence of this unusual lesion.
Publisher: BMJ
Date: 03-2004
Abstract: A proposal that an endogenous benzodiazepine-like agent named endozepine-4 might be responsible for presentations of recurrent stupor has gained wide acceptance. A case of recurrent stupor over two decades is presented with many similarities to previous cases of "endozepine stupor". This case, however, was caused by exogenous benzodiazepine administration and serves as a warning to clinicians to beware of this diagnosis.
Publisher: Oxford University Press (OUP)
Date: 02-1991
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-03-2013
Publisher: Wiley
Date: 12-2008
DOI: 10.1111/J.1528-1167.2008.01652.X
Abstract: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a relatively benign epilepsy syndrome with few comorbidities. Here we describe two families with unusually severe ADNFLE, with associated psychiatric, behavioral, and cognitive features. Detailed clinical data on 17 affected in iduals were obtained, and genotyping of microsatellite markers, linkage analysis, and sequencing of candidate genes was performed. The severe ADNFLE phenotype in these families was often refractory to treatment, with status epilepticus occurring in 24% of subjects. Psychiatric or behavioral disorders occurred in 53%, with intellectual disability in 24%, and developmental regression in two in iduals. No mutations were identified in alpha4, alpha2, or beta2 nAChR subunits. In one family there was evidence of linkage to a region of 15q24 without nAChR subunit genes. In conclusion, severe ADNFLE has significant medical, psychiatric, and intellectual morbidity. The molecular basis of severe ADNFLE is unknown but may involve non-nAChR-related mechanisms.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-1987
DOI: 10.1212/WNL.37.6.993
Abstract: There are two current approaches to the clinical conceptualization of the generalized epilepsies. The syndromic approach attempts to sub ide the patient population into relatively homogeneous groups, largely on the basis of clinical and EEG criteria. In contrast, the neurobiological approach aims to formulate a unique profile for each patient by incorporating particulars of the patient onto the background of knowledge regarding the etiologic factors important in generalized epilepsy. The value of these two approaches is discussed with regard to the dual aims of, first, improving the understanding of generalized epilepsy, and second, providing a precise diagnosis, an accurate prognosis, and optimal treatment for the patient.
Publisher: Wiley
Date: 04-1994
DOI: 10.1111/J.1445-5994.1994.TB00556.X
Abstract: Point mutations in the mitochondrial (mt) genome underlie a number of neurological disorders. Some are well defined including the myoclonus epilepsy ragged red fibre syndrome (MERRF) and the mitochondrial encephalopathy lactic acidosis stroke like episode syndrome (MELAS). However, other clinical phenotypes are less distinctive and mitochondrial studies are often included in the workup in complex neurological syndromes of uncertain aetiology. We investigated 27 consecutive patients with varied clinical phenotypes referred to our laboratory for mtDNA studies to determine the incidence of recognised point mutations in a patient group with a range of phenotypes including many where mt disease was possible but did not fall into a classical syndrome. The recognised point mutations were detected by lification of the appropriate DNA fragment by PCR followed by restriction-endonuclease digestion of the normal and mutant species. The A-G base substitution mutation at nucleotide (nt)3243 in the tRNA(Leu) gene of mtDNA which is present in the majority of cases of MELAS syndrome, was detected in four cases, only one of whom had typical MELAS symptoms. Their clinical manifestations ranged from mild deafness to a mixture of chronic progressive external ophthalmoplegia symptoms (CPEO) and stroke like episodes. The nt3243 mutation was also identified in one of seven mtDNA deletion negative CPEO cases. The presentation of the mtDNA mutation at nt3243 appears therefore to be quite variable with some mild phenotypes as well as severe phenotypes observed. In general, the chance of finding a mitochondrial point mutation in a patient with an atypical clinical phenotype is small.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 1993
DOI: 10.1212/WNL.43.1_PART_1.186
Abstract: In progressive myoclonus epilepsy (PME), responses to afferent input are frequently abnormal. It is unclear whether the abnormality lies at the cortical, subcortical, or segmental level. To obtain evidence for an exaggerated effect on motor cortical excitability, we used peripheral nerve and transcranial magnetic stimulation in controls and subjects with idiopathic generalized epilepsy and PME. Mean threshold intensity was higher in those with idiopathic generalized epilepsy and PME than in controls, probably as a result of anticonvulsant treatment. A long-latency response to peripheral stimulation and an exaggerated facilitatory effect of peripheral stimulation on the motor evoked potential was present in subjects with PME. Latency differences between the late responses in the upper and lower limbs provided evidence against a segmental reflex and implicated rapidly conducting fibers in the spinal cord. Both the late response and the facilitatory effect had onset latencies consistent with a transcortical pathway, suggesting an exaggerated effect of afferent input on motor cortical excitability in PME.
Publisher: Proceedings of the National Academy of Sciences
Date: 30-10-2007
Abstract: Mutations in the GABA A receptor γ2 subunit are associated with childhood absence epilepsy and febrile seizures. To understand better the molecular basis of absence epilepsy in man, we developed a mouse model harboring a γ2 subunit point mutation (R43Q) found in a large Australian family. Mice heterozygous for the mutation demonstrated behavioral arrest associated with 6-to 7-Hz spike-and-wave discharges, which are blocked by ethosuximide, a first-line treatment for absence epilepsy in man. Seizures in the mouse showed an abrupt onset at around age 20 days corresponding to the childhood nature of this disease. Reduced cell surface expression of γ2(R43Q) was seen in heterozygous mice in the absence of any change in α1 subunit surface expression, ruling out a dominant-negative effect. GABA A -mediated synaptic currents recorded from cortical pyramidal neurons revealed a small but significant reduction that was not seen in the reticular or ventrobasal thalamic nuclei. We hypothesize that a subtle reduction in cortical inhibition underlies childhood absence epilepsy seen in humans harboring the R43Q mutation.
Publisher: Wiley
Date: 09-1989
Abstract: Limbic P3 event-related potentials were recorded from mesial temporal electrodes implanted for presurgical investigation in 70 patients with intractable focal seizures. In 46 (81%) of 57 patients with unilateral temporal lobe epilepsy, the limbic P3 potential was absent or rudimentary ipsilateral to the seizure focus and a robust P3 potential was always elicited from the nonepileptogenic temporal lobe. Bilateral P3 potentials were recorded in 6 patients (10%) with unilateral temporal lobe epilepsy. In the remaining 5 patients in the group with unilateral temporal lobe epilepsy, results showed P3 bilaterally absent (2 patients), P3 present in a unilateral investigation (1 patient), P3 absent contralateral to the seizure focus (1 patient), and technically unsatisfactory recordings (1 patient). Bilaterally absent P3 potentials were noted in 2 patients with bilateral temporal lobe epilepsy. In 6 patients with technically adequate P3 studies and extratemporal seizures, bilaterally present P3 potentials were noted. Sensitivity and specificity of P3 absence as a predictor of an epileptogenic temporal lobe were 87% and 95%, respectively. Tissue specimens of the hippoc us were available in 22 patients (43%). Thirteen hippoc i showed sclerosis, all of which were associated with unilaterally absent P3 potentials. Nine hippoc i were normal (5 patients with the P3 absent, 4 with P3 present). Sensitivity and specificity of an absent limbic P3 as a function of hippoc al pathological findings were 100% and 44%, respectively. Absent limbic P3 potentials in temporal lobe epilepsy thus indicate structural or functional hippoc al abnormality and may add important information in presurgical evaluation with depth electrodes of patients who have temporal lobe epilepsy.
Publisher: BMJ
Date: 23-10-2010
Abstract: The ring chromosome 20 syndrome (R20) is a rare genetic disorder associated with a refractory electroclinical epilepsy syndrome and variably expressed comorbidities of intellectual disability and dysmorphism. To understand the structure and composition of the ring chromosome 20 (r(20)) in this patient cohort, blood specimens from 28 affected in iduals were analysed by cytogenetic, fluorescence in situ hybridisation, and/or high resolution whole genome single nucleotide polymorphism array analysis. These studies revealed two distinct groups of patients. Group 1 (N=21) was mosaic for the r(20) and a normal cell line with no detectable deletions or duplications of chromosome 20 in either cell line. The mosaic nature of these rings suggests a postzygotic origin with formation of the ring by fusion of the telomeric regions with no apparent loss of subtelomeric or telomeric DNA. Group 2 (N=7) had non-mosaic ring chromosomes with a deletion at one or both ends of the chromosome, near the ring fusion point. The non-mosaic nature of these rings is consistent with a meiotic origin. The age of onset of seizures was significantly lower in the non-mosaic patients (group 2, median age of onset 2.1 years) than in the mosaic patients (group 1, median age of onset 6.0 years). Patients from group 2 had more extensive comorbidities. These studies demonstrate that r(20) is molecularly heterogeneous and formed by two distinct mechanisms, which, in turn, produce different phenotypic spectrums.
Publisher: Wiley
Date: 08-1996
DOI: 10.1111/J.1528-1157.1996.TB00653.X
Abstract: We studied cerebral perfusion patterns in the various subtypes of TLE, as determined by pathology and good outcome after temporal lobectomy (as confirmation of temporal origin). We studied clinical features and ictal technetium 99m hexamethyl-propyleneamineoxime (99mTc-HM-PAO) single-photon emission-computed tomography (SPECT) in four subgroups of patients with intractable temporal lobe epilepsy (TLE) treated with surgery: hippoc al sclerosis (group 1, n = 10), foreign-tissue lesion in mesial temporal lobe (group 2, n = 8), foreign-tissue lesion in lateral temporal lobe (group 3, n = 7), and normal temporal lobe tissue with good surgical outcome (group 4, n = 5). No major clinical differences in auras, complex partial seizures or postictal states were identified among the groups. Ictal SPECT showed distinct patterns of cerebral perfusion in these subtypes of TLE. In groups 1 and 2, hyperperfusion was seen in the ipsilateral mesial and lateral temporal regions. In group 3, hyperperfusion was seen bilaterally in the temporal lobes with predominant changes in the region of the lesion. Hyperperfusion was restricted to the ipsilateral anteromesial temporal region in group 4. Ipsilateral temporal hyperperfusion in mesial onset seizures can be explained by known anatomic projections between mesial structures and ipsilateral temporal neocortex. Bilateral temporal hyperperfusion in lateral onset seizures can be explained by the presence of anterior commissural connections between lateral temporal neocortex and the contralateral amygdala. We conclude that the perfusion patterns seen on ictal SPECT are helpful for subclassification of temporal lobe seizures, whereas clinical features are relatively unhelpful. These perfusion patterns provide an insight into preferential pathways of seizure propagation in the subtypes of TLE.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-04-2000
Abstract: To describe the motor and convulsive manifestations in acute sports-related head injury. A total of 234 cases of concussive injuries during the 1995 through 1997 football seasons were obtained from the Australian Football League Medical Officers Association injury survey. Of these, 102 cases were recorded adequately on television videotape and were analyzed by two independent observers using a standardized recording form detailing injury mechanics and clinical features of the episodes. Motor and convulsive features were correlated with mechanical variables and with duration of loss of consciousness using linear modeling techniques. Tonic posturing occurred in 25 subjects, clonic movements in 6, righting movement in 40, and gait unsteadiness in 42. In one subject the tonic and clonic features were sufficiently prolonged to be deemed a concussive convulsion. The only risk factor for tonic posturing using logistic regression was the presence of loss of consciousness (p = 0.0001). There was a trend toward facial impact being an independent predictor of tonic posturing but this did not reach significance. No other independent variable predicted the development of clonic movements, righting movements, or gait unsteadiness. Subtle motor manifestations such as tonic posturing and clonic movements commonly occur in concussion the main predictive factor for tonic posturing is the presence of loss of consciousness. The authors speculate that these clinical features are due to brainstem dysfunction secondary to biomechanical forces inducing a transient functional decerebration.
Publisher: Elsevier BV
Date: 10-2010
Publisher: Wiley
Date: 12-2020
DOI: 10.1002/ALZ.041347
Publisher: Wiley
Date: 11-1992
DOI: 10.1111/J.1528-1157.1992.TB01760.X
Abstract: A detailed questionnaire has been devised for diagnosis of seizure type. It is suitable for administration by trained interviewers, either directly or by telephone. A comparison of physician-based and questionnaire-based diagnoses showed almost perfect agreement in classification of patients into those with seizures of either generalized or focal origin. Substantial to almost-perfect agreement was reached in diagnosis of patients with most in idual seizure types. Disagreement in differentiation between simple and complex partial seizures (CPS) probably reflects the limitations of the clinical method rather than of the questionnaire itself. The questionnaire should be of value in large-scaled clinical and epidemiologic studies.
Publisher: Therapeutic Guidelines Limited
Date: 12-2003
Publisher: Elsevier BV
Date: 2023
Publisher: Elsevier BV
Date: 03-1977
DOI: 10.1016/0005-2787(77)90350-1
Abstract: 1. Suspensions of avian erythroid nuclei, of high purity, were prepared. Acetylation of histones was observed when nuclei were incubated in the presence of [1-14C]acetyl CoA, but not in the presence of sodium [3H]acetate. 2. The acetylation reaction was very heat labile and reproduced the in vivo reaction with high fidelity. The reaction was strongly inhibited by alent cations and cysteine. 3. Studies, in which intact cells were pre-incubated with cycloheximide prior to the isolation of nuclei, suggested that histone acetylation in isolated erythroid nuclei was largely independent of histone synthesis. 4. The pH profile suggested the presence of at least two histone acetyltransferases, with pH optima at 8.0 and 8.6. Acetylation of histone H4 appeared to be favoured at pH 8.0. 5. Studies on histone acetylation in isolated nuclei should be very useful in correlating observations on histone acetylation in vivo, with experiments using purified histone acetyltransferases.
Publisher: Wiley
Date: 19-06-2003
DOI: 10.1046/J.1528-1157.2003.59102.X
Abstract: Hypothalamic hamartomas may be associated with gelastic seizures, focal seizures, and a generalized epileptic encephalopathy, with severe seizures and cognitive and behavior decline. Despite earlier views to the contrary, good evidence now exists that all these clinical features are caused, directly or indirectly, by the hamartoma. Resection of these lesions was long regarded as too hazardous and unlikely to benefit seizure control. It is now clear that hypothalamic hamartomas can be effectively treated with a variety of surgical approaches with sustained seizure control and often seizure freedom. Qualitative observations suggest that behavior and cognition also improve with treatment, but quantitative validation is required. The specific approach should be tailored according to the surgical anatomy of the lesion and the experience of the surgeon. Choices include a transcallosal approach (good for intraventricular lesions), a pterional approach (useful for interpeduncular lesions), a transventricular endoscopic approach, or destruction of the lesion with radiofrequency probes or gamma knife radiosurgery. The previously dismal outlook for children with severe seizures associated with this lesion has now dramatically changed. These insights may have implications for other epileptic encephalopathies of childhood.
Publisher: Wiley
Date: 12-1998
DOI: 10.1111/J.1528-1157.1998.TB01332.X
Abstract: Lamotrigine (LTG) is recognised as effective add-on therapy for focal epilepsies, but this is the first double-blind, placebo-controlled, crossover study in treatment-resistant generalised epilepsy. The study consisted of 2 x 8-week treatment periods followed by a 4-week washout period. Patients received doses of either 75 or 150 mg daily, depending on their concomitant antiepileptic drugs (AEDs). Long-term continuation was offered at the end of the study with open-label LTG. Five centres in Australia recruited 26 patients who were having absence, myoclonic, or generalized tonic-clonic seizures or a combination of these. Twenty-two patients completed the study. There was a significant reduction in frequency of both tonic-clonic and absence seizure types with LTG. A 350% decrease in seizures was observed for tonic-clonic seizures in 50% of cases and for absence seizures in 33% of evaluable cases. Rash was the only adverse effect causing discontinuation. Twenty-three of 26 opted for open-label LTG, with 20 still receiving LTG for a mean of 26 months. In these 20, 80% had > or =50% seizure reduction and five (25%) were seizure free. This study shows that LTG is effective add-on therapy in patients with refractory generalised epilepsies. Statistically significant reduction in seizures in both absence and tonic-clonic seizure types was seen even with low doses of LTG.
Publisher: Wiley
Date: 10-2002
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-06-2016
Publisher: Wiley
Date: 09-1993
Abstract: Observations on experimental models suggest that diffuse cortical hyperexcitability is an important abnormality in the generalized epilepsies. We used the threshold for transcranial magnetic stimulation as an index of motor cortical excitability in 89 neurologically normal control subjects and 56 patients with idiopathic generalized epilepsy (20 untreated and 36 chronically treated with anticonvulsants). Magnetic stimulation was repeated in 10 patients after valproate monotherapy had been commenced and in 23 control subjects. The threshold intensity was significantly lower in the untreated patients (46 +/- 5% [mean +/- 95% confidence interval]) than in the control subjects (56 +/- 2%). Treated patients had significantly higher thresholds (64 +/- 4%) than did untreated patients and control subjects. A significant increase in threshold intensity (8 +/- 2%) occurred in patients retested after starting valproate there was no significant change in retested control subjects (-1 +/- 2%). Threshold intensity was positively correlated with plasma valproate levels (rs = 0.37). The findings suggest that cortical excitability is increased in idiopathic generalized epilepsy and is reduced following anticonvulsant treatment. Transcranial magnetic stimulation is of use in examining the pathophysiology of generalized epilepsy. Furthermore, changes in threshold intensity in response to anticonvulsant treatment may prove useful in guiding therapy.
Publisher: Wiley
Date: 04-2007
DOI: 10.1111/J.1528-1167.2007.00977.X
Abstract: Although complex idiopathic generalized epilepsies (IGEs) are recognized to have a significant genetic component, as yet there are no known common susceptibility variants. It has recently been suggested that variation in the BRD2 gene confers increased risk of juvenile myoclonic epilepsy (JME), which accounts for around a quarter of all IGE. Here we examine the association between the candidate causal SNP (the promoter variant rs3918149) and JME in five independent cohorts comprising in total 531 JME cases and 1,390 healthy controls. The strongest candidate causal variant from the original report (rs3918149) was genotyped across all five cohorts. In an effort to identify novel candidate causal polymorphisms, previously unscreened regions of UTR were resequenced. We observed a significant effect in a small s le recruited in Britain (genotype p = 0.001, allele p = 0.001), a borderline significant effect in a s le recruited in Ireland and no association in larger s les of German, Australian, and Indian populations. There was no association with other common forms of epilepsy or any other clear candidate casual variants in or near the BRD2 region. The replication of an effect in the British cohort and suggestive evidence from that recruited in Ireland but lack of replication from the larger German, Australian, and Indian cohorts is surprising and difficult to explain. Further replication in carefully matched populations is required. Results presented here do not, however, support a strong effect for susceptibility to JME across populations of European descent.
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.EJMG.2017.06.002
Abstract: Knobloch syndrome [OMIM: (KNO1) #267750] is a rare and clinically heterogeneous autosomal recessive disorder caused by mutations in COL18A1. Knobloch syndrome is characterised by abnormalities of the eye and occipital skull defects however the full phenotypic spectrum is yet to be defined. This report describes a family of four affected sisters with polymicrogyria, refractory seizures, and intellectual impairment of varying severity with a Lennox-Gastaut phenotype, and complex eye abnormalities where a syndromic diagnosis was not initially made. Whole exome sequencing of two affected sisters followed by filtering for rare and potentially disease causing variants in all genes identified compound heterozygous variants in NM_030582.3 (COL18A1): c.3690G > A: p.(Trp1230*) and NM_030582.3 (COL18A1): c.4063_4064delCT: p.(Leu1355Valfs*72). The two variants co-segregated with the affected in iduals in the family. Identification of COL18A1 mutations in in iduals with a Lennox-Gastaut phenotype and anterior polymicrogyria but lacking the classical occipital encephalocele expands the COL18A1 clinical spectrum.
Publisher: S. Karger AG
Date: 1999
DOI: 10.1159/000017399
Abstract: i Introduction: /i We performed hippoc al T sub /sub relaxometry as part of a routine magnetic resonance imaging (MRI) examination in 50 normal controls and 127 consecutive patients referred because of suspected seizures. i Methods: /i On the basis of T sub /sub values in controls (100.2 ± 4.2 ms) we defined normal as ms ( mean + 2 SD), borderline as 110–113 ms (mean + 2 SD to mean + 3 SD) and abnormal as ms ( mean + 3 SD). i Results: /i After detailed investigation, 103 of these 127 patients had epilepsy and 24 did not. In the nonepilepsy group, none had abnormal hippoc al T sub /sub values. Twenty-seven of the 103 patients in the epilepsy group had abnormal values, 7 were borderline and 69 were normal. Only 5 patients with abnormal T sub /sub values did not have temporal lobe epilepsy: 1 had extratemporal lobe epilepsy, 1 had generalized epilepsy and 3 had unclassified epilepsy. Twenty-two of 27 (81%) patients with abnormal hippoc al T sub /sub values had intractable epilepsy [compared with 32 of 69 (46%) patients with normal values p 0.05, χ sup /sup test]. Two thirds of patients with abnormal values had a history of a major antecedent event (compared to only 7% of those with normal values, p 0.05, χ sup /sup test). i Conclusion: /i Abnormal T sub /sub relaxometry is significantly associated with intractable epilepsy as well as with major antecedent events.
Publisher: Elsevier BV
Date: 06-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-10-2000
Abstract: The idiopathic generalized epilepsies (IGE) are classically regarded as due to a functional abnormality. However, microscopic microdysgenetic changes have been reported in the majority of cases by one group. To independently evaluate the microscopic microdysgenetic changes in a controlled, blinded study. Five brains with IGE and five age-matched control brains were collected. Blocks were taken from nine standardized Brodmann areas, both hippoc i, and cerebellum. Slides were examined independently by two neuropathologists blinded to patient group, who qualitatively scored microdysgenetic features on standardized data sheets. The results were compared and any discrepancies were rescored by the pathologists together using a double-header microscope. Quantitative neuronal profile counts in the molecular layer in standardized Brodmann areas of frontal cortex and in deep frontal white matter were performed. Microdysgenetic features in nine Brodmann areas, hippoc i, and cerebellum were not increased in brains from subjects with IGE compared with control brains. Quantitative neuronal profile counts in the molecular layer of frontal cortex and deep frontal white matter were not increased in IGE compared with controls. This controlled, blinded study did not replicate the results of previous reports of microdysgenesis in IGE. Although factors such as syndrome heterogeneity and s le size may explain the discrepancy, technical factors could also play a role. The current ion channel hypothesis for the pathogenesis of IGE does not preclude microscopic or ultramicroscopic abnormalities and the search for these should continue.
Publisher: Elsevier BV
Date: 12-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-1998
DOI: 10.1212/WNL.50.3.677
Abstract: Diffuse cerebral swelling with delayed catastrophic deterioration, a known complication of brain trauma, has been postulated to occur after repeated concussive brain injury in sports--the "second impact syndrome" (SIS). Certain current concussion management guidelines are contingent upon this assumption. We established criteria for definite, probable, and possible SIS and analyzed all published cases. A total of 17 cases were identified in which the reports described the cases as being consistent with SIS. Of these, only five probable cases of SIS were found based on our diagnostic criteria. We also studied the accuracy of recalled episodes of minor concussion in football players by their teammates because the diagnosis of SIS is usually based on such accounts. We found overreporting of recalled episodes of concussion in teammates when compared with self reports and videotape analysis. Based on case reports, the claim that SIS is a risk factor for diffuse cerebral swelling is not established. Prevention strategies for sports-related cerebral swelling are difficult to implement in the absence of established risk factors.
Publisher: Wiley
Date: 17-07-2022
DOI: 10.1111/EPI.17332
Abstract: The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics increased access to genetic testing and counseling fuller understanding of natural histories agility and rigor in preclinical research, including strategic use of emerging model systems and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable ex les of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.
Publisher: Wiley
Date: 09-2010
DOI: 10.1111/J.1528-1167.2010.02537.X
Abstract: Temporal lobe epilepsy (TLE) is not a unitary electroclinical imaging syndrome. We asked if seizures arising from the parahippoc al-inferior temporal (PIT) region differ from those associated with hippoc al sclerosis (HS). The electroclinical features of 22 patients with HS and 14 patients with lesions in the PIT region who underwent epilepsy surgery and were seizure free for at least 2 years postoperatively were analyzed retrospectively. Patients with PIT lesions had a higher frequency of hypermotor and bilateral features and a lower frequency of behavioral arrest at the onset of seizure compared to cases with HS, suggesting that TLE originating in the PIT area can mimic frontal lobe epilepsy or contralateral mesial TLE.
Publisher: Oxford University Press (OUP)
Date: 03-1997
Abstract: The clinical and genetic relationships of febrile seizures and the generalized epilepsies are poorly understood. We ascertained a family with genealogical information in 2000 in iduals where there was an unusual concentration of in iduals with febrile seizures and generalized epilepsy in one part of the pedigree. We first clarified complex consanguineous relationships in earlier generations and then systematically studied the epilepsy phenotypes in affected in iduals. In one branch (core family) 25 in iduals over four generations were affected. The commonest phenotype, denoted as 'febrile seizures plus' (FS+), comprised childhood onset (median 1 year) of multiple febrile seizures, but unlike the typical febrile convulsion syndrome, attacks with fever continued beyond 6 years, or afebrile seizures occurred. Seizures usually ceased by mid childhood (median 11 years). Other phenotypes included FS+ and absences, FS+ and myoclonic seizures, FS+ and atonic seizures, and the most severely affected in idual had myoclonic-astatic epilepsy (MAE). The pattern of inheritance was autosomal dominant. The large variation in generalized epilepsy phenotypes was not explained by acquired factors. Analysis of this large family and critical review of the literature led to the concept of a genetic epilepsy syndrome termed generalized epilepsy with febrile seizures plus (GEFS+). GEFS+ has a spectrum of phenotypes including febrile seizures, FS+ and the less common MAE. Recognition of GEFS+ explains the epilepsy phenotypes of previously poorly understood benign childhood generalized epilepsies. In in idual patients the inherited nature of GEFS+ may be overlooked. Molecular genetic study of such large families should allow identification of genes relevant to febrile seizures and generalized epilepsies.
Publisher: Public Library of Science (PLoS)
Date: 09-07-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-01-2016
Publisher: Oxford University Press (OUP)
Date: 07-2022
Abstract: Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for the largest number of cases. The genetic alterations involved in focal epilepsy are far from being fully elucidated. Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B, encoding for the class II phosphatidylinositol 3-kinase PI3K-C2β, underlie focal epilepsy in humans. We demonstrate that patients’ variants act as loss-of-function alleles, leading to impaired synthesis of the rare signalling lipid phosphatidylinositol 3,4-bisphosphate, resulting in mTORC1 hyperactivation. In vivo, mutant Pik3c2b alleles caused dose-dependent neuronal hyperexcitability and increased seizure susceptibility, indicating haploinsufficiency as a key driver of disease. Moreover, acute mTORC1 inhibition in mutant mice prevented experimentally induced seizures, providing a potential therapeutic option for a selective group of patients with focal epilepsy. Our findings reveal an unexpected role for class II PI3K-mediated lipid signalling in regulating mTORC1-dependent neuronal excitability in mice and humans.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2018
DOI: 10.1212/NXG.0000000000000297
Abstract: To examine the genotype to phenotype connection in glucose transporter type 1 (GLUT1) deficiency and whether a simple functional assay can predict disease outcome from genetic sequence alone. GLUT1 deficiency, due to mutations in SLC2A1 , causes a wide range of epilepsies. One possible mechanism for this is variable impact of mutations on GLUT1 function. To test this, we measured glucose transport by GLUT1 variants identified in population controls and patients with mild to severe epilepsies. Controls were reference sequence from the NCBI and 4 population missense variants chosen from public reference control databases. Nine variants associated with epilepsies or movement disorders, with normal intellect in all in iduals, formed the mild group. The severe group included 5 missense variants associated with classical GLUT1 encephalopathy. GLUT1 variants were expressed in Xenopus laevis oocytes, and glucose uptake was measured to determine kinetics (V max ) and affinity (K m ). Disease severity inversely correlated with rate of glucose transport between control (V max = 28 ± 5), mild (V max = 16 ± 3), and severe (V max = 3 ± 1) groups, respectively. Affinities of glucose binding in control (K m = 55 ± 18) and mild (K m = 43 ± 10) groups were not significantly different, whereas affinity was indeterminate in the severe group because of low transport rates. Simplified analysis of glucose transport at high concentration (100 mM) was equally effective at separating the groups. Disease severity can be partly explained by the extent of GLUT1 dysfunction. This simple Xenopus oocyte assay complements genetic and clinical assessments. In prenatal diagnosis, this simple oocyte glucose uptake assay could be useful because standard clinical assessments are not available.
Publisher: Wiley
Date: 21-11-2017
DOI: 10.1002/ANA.25084
Abstract: Differential diagnosis of autosomal recessive cerebellar ataxias can be challenging. A ranking algorithm named RADIAL that predicts the molecular diagnosis based on the clinical phenotype of a patient has been developed to guide genetic testing and to align genetic findings with the clinical context. An algorithm that follows clinical practice, including patient history, clinical, magnetic resonance imaging, electromyography, and biomarker features, was developed following a review of the literature on 67 autosomal recessive cerebellar ataxias and personal clinical experience. Frequency and specificity of each feature were defined for each autosomal recessive cerebellar ataxia, and corresponding prediction scores were assigned. Clinical and paraclinical features of patients are entered into the algorithm, and a patient's total score for each autosomal recessive cerebellar ataxia is calculated, producing a ranking of possible diagnoses. Sensitivity and specificity of the algorithm were assessed by blinded analysis of a multinational cohort of 834 patients with molecularly confirmed autosomal recessive cerebellar ataxia. The performance of the algorithm was assessed versus a blinded panel of autosomal recessive cerebellar ataxia experts. The correct diagnosis was ranked within the top 3 highest-scoring diagnoses at a sensitivity and specificity of >90% for 84% and 91% of the evaluated genes, respectively. Mean sensitivity and specificity of the top 3 highest-scoring diagnoses were 92% and 95%, respectively. The algorithm outperformed the panel of ataxia experts (p = 0.001). Our algorithm is highly sensitive and specific, accurately predicting the underlying molecular diagnoses of autosomal recessive cerebellar ataxias, thereby guiding targeted sequencing or facilitating interpretation of next-generation sequencing data. Ann Neurol 2017 :892-899.
Publisher: Radiological Society of North America (RSNA)
Date: 12-2016
DOI: 10.1148/RADIOL.2016150852
Abstract: Purpose To investigate whether it is possible in patients with periventricular nodular heterotopia (PVNH) to detect abnormal fiber projections that have only previously been reported in the histopathology literature. Materials and Methods Whole-brain diffusion-weighted (DW) imaging data from 14 patients with bilateral PVNH and 14 age- and sex-matched healthy control subjects were prospectively acquired by using 3.0-T magnetic resonance (MR) imaging between August 1, 2008, and December 5, 2012. All participants provided written informed consent. The DW imaging data were processed to generate whole-brain constrained spherical deconvolution (CSD)-based tractography data and super-resolution track-density imaging (TDI) maps. The tractography data were overlaid on coregistered three-dimensional T1-weighted images to visually assess regions of heterotopia. A panel of MR imaging researchers independently assessed each case and indicated numerically (no = 1, yes = 2) as to the presence of abnormal fiber tracks in nodular tissue. The Fleiss κ statistical measure was applied to assess the reader agreement. Results Abnormal fiber tracks emanating from one or more regions of heterotopia were reported by all four readers in all 14 patients with PVNH (Fleiss κ = 1). These abnormal structures were not visible on the tractography data from any of the control subjects and were not discernable on the conventional T1-weighted images of the patients with PVNH. Conclusion Whole-brain CSD-based fiber tractography and super-resolution TDI mapping reveals abnormal fiber projections in nodular tissue suggestive of abnormal organization of white matter (with abnormal fibers both within nodules and projecting to the surrounding white matter) in patients with bilateral PVNH.
Publisher: Wiley
Date: 12-1992
Abstract: Two children are reported with acute uveitis during the early progressive phase of chronic encephalitis (Rasmussen's syndrome). In both children, the side of the uveitis was ipsilateral to the side of cerebral inflammation, although in 1 child there were milder inflammatory changes in the contralateral eye. This association adds weight to the viral hypothesis of chronic encephalitis and raises the possibility of primary ocular infection and neurotropic spread to the brain.
Publisher: Wiley
Date: 03-08-2021
DOI: 10.1002/ANA.26174
Abstract: Psychoses affecting people with epilepsy increase disease burden and diminish quality of life. We characterized postictal psychosis, which comprises about one quarter of epilepsy‐related psychoses, and has unknown causation. We conducted a case–control cohort study including patients diagnosed with postictal psychosis, confirmed by psychiatric assessment, with available data regarding epilepsy, treatment, psychiatric history, psychosis profile, and outcomes. After screening 3,288 epilepsy patients, we identified 83 with psychosis 49 had postictal psychosis. Controls were 98 adults, matched by age and epilepsy type, with no history of psychosis. Logistic regression was used to investigate clinical factors associated with postictal psychosis univariate associations with a p value 0.20 were used to build a multivariate model. Polygenic risk scores for schizophrenia were calculated. Cases were more likely to have seizure clustering (odds ratio [OR] = 7.59, p 0.001), seizures with a recollected aura (OR = 2.49, p = 0.013), and a family history of psychiatric disease (OR = 5.17, p = 0.022). Cases showed predominance of right temporal epileptiform discharges (OR = 4.87, p = 0.007). There was no difference in epilepsy duration, neuroimaging findings, or antiseizure treatment between cases and controls. Polygenic risk scores for schizophrenia in an extended cohort of postictal psychosis cases (n = 58) were significantly higher than in 1,366 epilepsy controls ( R 2 = 3%, p = 6 × 10 −3 ), but not significantly different from 945 independent patients with schizophrenia ( R 2 = 0.1% , p = 0.775). Postictal psychosis occurs under particular circumstances in people with epilepsy with a heightened genetic predisposition to schizophrenia, illustrating how disease biology (seizures) and trait susceptibility (schizophrenia) may interact to produce particular outcomes (postictal psychosis) in a common disease. ANN NEUROL 2021 :464–476
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-07-2013
Publisher: Elsevier BV
Date: 10-2014
Publisher: Wiley
Date: 16-04-2018
DOI: 10.1111/EPI.14077
Abstract: Epilepsy has a strong genetic component, with an ever-increasing number of disease-causing genes being discovered. Most epilepsy-causing mutations are germ line and thus present from conception. These mutations are therefore well positioned to have a deleterious impact during early development. Here we review studies that investigate the role of genetic lesions within the early developmental window, specifically focusing on genetic generalized epilepsy (GGE). Literature on the potential pathogenic role of sub-mesoscopic structural changes in GGE is also reviewed. Evidence from rodent models of genetic epilepsy support the idea that functional and structural changes can occur in early development, leading to altered seizure susceptibility into adulthood. Both animal and human studies suggest that sub-mesoscopic structural changes occur in GGE. The existence of sub-mesoscopic structural changes prior to seizure onset may act as biomarkers of excitability in genetic epilepsies. We also propose that presymptomatic treatment may be essential for limiting the long-term consequences of disease-causing mutations in genetic epilepsies.
Publisher: Cambridge University Press (CUP)
Date: 07-2000
DOI: 10.1017/S1355617700655029
Abstract: We studied a group of 31 temporal lobe epilepsy patients (25 left, 6 right) with unilateral hippoc al sclerosis evident on magnetic resonance imaging. Single slice T2 relaxation times were acquired for the left and right hippoc i. Principal components analysis of preoperative memory data resulted in two factors that reflect a distinction between arbitrary and semantic forms of verbal recall. The former component correlated with left hippoc al T2 relaxation time, while the latter component did not. This study suggests that variation in left hippoc al integrity is more related to the acquisition of arbitrary associates than semantically structured material, and reinforces the possibility that the left temporal lobe is functionally heterogeneous with respect to memory. ( JINS , 2000, 6 , 529–538.)
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-07-2007
DOI: 10.1212/01.WNL.0000268699.34614.D3
Abstract: To assess the efficacy and tolerability of adjunctive levetiracetam in patients with uncontrolled generalized tonic-clonic (GTC) seizures associated with idiopathic generalized epilepsies (IGE). This multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled adults and children (4 to 65 years) with IGE experiencing >or=3 GTC seizures during the 8-week baseline period (4-week retrospective and 4-week prospective), despite receiving stable doses of one or two antiepileptic drugs (AEDs). Patients were randomized to levetiracetam (target dose 3,000 mg/day for adults 60 mg/kg/day for children) or placebo and a 4-week titration period was followed by a 20-week evaluation period. Of 229 patients screened, 164 were randomized (levetiracetam, n = 80 placebo, n = 84). Levetiracetam produced a greater mean reduction in GTC seizure frequency per week over the treatment period (56.5%) than placebo (28.2% p = 0.004). The percentage of patients who had >or=50% reduction of GTC seizure frequency per week (responders) during the treatment period was 72.2% for levetiracetam and 45.2% for placebo (p < 0.001 OR 3.28 95% CI 1.68 to 6.38). During the first 2-week treatment 64.6% of patients on levetiracetam and 45.2% on placebo (p = 0.018) were classified as responders. During the evaluation period the percent of patients free of GTC seizures (34.2% vs 10.7% p < 0.001) and all seizure types (24.1% vs 8.3% p = 0.009) was greater for levetiracetam than placebo. Levetiracetam was well tolerated with 1.3% of patients discontinuing therapy due to adverse events vs 4.8% on placebo. Adjunctive levetiracetam is an effective and well-tolerated antiepileptic drug for treating generalized tonic-clonic seizures in patients with idiopathic generalized epilepsies.
Publisher: Wiley
Date: 09-05-2018
DOI: 10.1111/EPI.14193
Abstract: This is the second of a 2-part primer on the genetics of the epilepsies within the Genetic Literacy Series of the Genetics Commission of the International League Against Epilepsy. In Part 1, we covered types of genetic variation, inheritance patterns, and their relationship to disease. In Part 2, we apply these basic principles to the case of a young boy with epileptic encephalopathy and ask 3 important questions: (1) Is the gene in question an established genetic etiology for epilepsy? (2) Is the variant in this particular gene pathogenic by established variant interpretation criteria? (3) Is the variant considered causative in the clinical context? These questions are considered and then answered for the clinical case in question.
Publisher: Wiley
Date: 09-2009
DOI: 10.1002/ANA.21724
Abstract: Absence epilepsies of childhood are heterogeneous with most cases following complex inheritance. Those cases with onset before 4 years of age represent a poorly studied subset. We screened 34 patients with early-onset absence epilepsy for mutations in SLC2A1, the gene encoding the GLUT1 glucose transporter. Mutations leading to reduced protein function were found in 12% (4/34) of patients. Two mutations arose de novo, and two were familial. These findings suggest GLUT1 deficiency underlies a significant proportion of early-onset absence epilepsy, which has both genetic counseling and treatment implications because the ketogenic diet is effective in GLUT1 deficiency.
Publisher: Wiley
Date: 02-2010
DOI: 10.1002/ANA.21968
Publisher: EMBO
Date: 25-03-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-12-2001
Abstract: Concussion is a well-recognized clinical entity however, its pathophysiologic basis remains a mystery. One unresolved issue is whether concussion is associated with lesser degrees of diffuse structural change seen in severe traumatic brain injury, or is the mechanism entirely caused by reversible functional changes. This issue is clouded not only by the lack of critical data, but also by confusion in terminology, even in contemporary literature. This confusion began in ancient times when no distinction was made between the transient effects of concussion and severe traumatic brain injury. The first clear separate recognition of concussion was made by the Persian physician, Rhazes, in the 10th century. Lanfrancus subsequently expanded this concept as brain "commotion" in the 13th century, although other Renaissance physicians continued to obscure this concept. By the 18th century, a variety of hypotheses for concussion had emerged. The 19th century discovery of petechial hemorrhagic lesions in severe traumatic brain injury led to these being posited as the basis of concussion, and a similar logic was used later to suggest diffuse axonal injury was responsible. The neuropathology and pathophysiology of concussion has important implications in neurology, sports medicine, medicolegal medicine, and in the understanding of consciousness. Fresh approaches to these questions are needed and modern research tools, including functional imaging and experimental studies of ion-channel function, could help elucidate this puzzle that has evolved over the past 3,000 years.
Publisher: Wiley
Date: 25-03-2022
DOI: 10.1111/EPI.17217
Abstract: Around 30% of patients undergoing surgical resection for drug‐resistant mesial temporal lobe epilepsy (MTLE) do not obtain seizure freedom. Success of anterior temporal lobe resection (ATLR) critically depends on the careful selection of surgical candidates, aiming at optimizing seizure freedom while minimizing postoperative morbidity. Structural MRI and FDG‐PET neuroimaging are routinely used in presurgical assessment and guide the decision to proceed to surgery. In this study, we evaluate the potential of machine learning techniques applied to standard presurgical MRI and PET imaging features to provide enhanced prognostic value relative to current practice. Eighty two patients with drug resistant MTLE were scanned with FDG‐PET pre‐surgery and T1‐weighted MRI pre‐ and postsurgery. From these images the following features of interest were derived: volume of temporal lobe (TL) hypometabolism, % of extratemporal hypometabolism, presence of contralateral TL hypometabolism, presence of hippoc al sclerosis, laterality of seizure onset volume of tissue resected and % of temporal lobe hypometabolism resected. These measures were used as predictor variables in logistic regression, support vector machines, random forests and artificial neural networks. In the study cohort, 24 of 82 (28.3%) who underwent an ATLR for drug‐resistant MTLE did not achieve Engel Class I (i.e., free of disabling seizures) outcome at a minimum of 2 years of postoperative follow‐up. We found that machine learning approaches were able to predict up to 73% of the 24 ATLR surgical patients who did not achieve a Class I outcome, at the expense of incorrect prediction for up to 31% of patients who did achieve a Class I outcome. Overall accuracies ranged from 70% to 80%, with an area under the receiver operating characteristic curve (AUC) of .75–.81. We additionally found that information regarding overall extent of both total and significantly hypometabolic tissue resected was crucial to predictive performance, with AUC dropping to .59–.62 using presurgical information alone. Incorporating the laterality of seizure onset and the choice of machine learning algorithm did not significantly change predictive performance. Collectively, these results indicate that "acceptable" to "good" patient‐specific prognostication for drug‐resistant MTLE surgery is feasible with machine learning approaches utilizing commonly collected imaging modalities, but that information on the surgical resection region is critical for optimal prognostication.
Publisher: Springer Science and Business Media LLC
Date: 17-11-2015
DOI: 10.1038/NG.3144
Publisher: Elsevier BV
Date: 12-2018
Publisher: Elsevier BV
Date: 08-2003
Publisher: Cold Spring Harbor Laboratory
Date: 18-04-2019
DOI: 10.1101/613075
Abstract: The binding of GABA to extra-synaptic GABA A receptors generates tonic inhibition that acts as a powerful modulator of cortical network activity. Despite GABA being present at low levels throughout the extracellular space of the brain, previous work has shown that GABA may differentially modulate the excitability of neuron subtypes through variation in chloride gradient. Here, we introduce a distinct mechanism through which extracellular GABA can differentially modulate the excitability of neuron subtypes through variation in neuronal electrophysiological properties. Using biophysically-detailed computational models, we found that tonic inhibition enhanced the responsiveness (or gain) of models with electrophysiological features typically observed in somatostatin (Sst) interneurons and reduced gain in models with features typical for parvalbumin (Pv) interneurons. These predictions were experimentally verified using patch-cl recordings. Further analysis revealed that differential gain modulation is also dependent upon the extent of outward rectification of the GABA A receptor-mediated tonic current. Our detailed neuron models demonstrate two subcellular consequences of tonic inhibition. First, tonic inhibition enhances somatic action potential repolarisation by increasing current flow into the dendritic compartment. This enhanced repolarisation then reduces voltage-dependent potassium currents at the soma during the afterhyperpolarisation. Finally, we show that reductions of potassium current selectively increase gain within neurons exhibiting action potential dynamics typical for Sst interneurons. Potassium currents in Pv-type interneurons are not sensitive to this mechanism as they deactivate rapidly and are unavailable for further modulation. These findings introduce a neuromodulatory paradigm in which GABA can induce a state of differential interneuron excitability through differences in intrinsic electrophysiological properties.
Publisher: Elsevier BV
Date: 12-1997
DOI: 10.1016/S0140-6736(05)63684-7
Abstract: Psychiatric nurses often face abuse, attacks, escape, suicides, and other situations related to the care of patients with mental disorders, which are more likely to induce psychological distress. This study aimed to examine the relationship between coping styles and psychological distress among Chinese psychiatric nurses in Shandong and the significance of sleep quality as a mediating factor. A total of 812 psychiatric nurses in Shandong, China, were investigated using the Psychological Distress Scale (K10), Simplified Coping Style Questionnaire (SCSQ), Pittsburgh Sleep Quality Index (PSQI) and self-compiled general information questionnaire. Psychological distress was detected in 571 psychiatric nurses (70.3%). The psychological distress of psychiatric nurses was significantly different with respect to professional title (χ Psychiatric nurses have a high rate of psychological distress, which is closely related to coping styles, and sleep quality has a certain regulatory effect.
Publisher: Informa UK Limited
Date: 14-06-2014
DOI: 10.1586/14737175.2014.928203
Abstract: Juvenile myoclonic epilepsy (JME) is a clinically and genetically heterogenous, generalized epilepsy syndrome usually starting in adolescence. An age-related, predominantly frontocortical-subcortical network dysfunction is likely to be the substrate of bilateral myoclonic seizures occurring at full consciousness within hours after awakening, which are the clinical hallmark of JME. Although essential features of JME were recognized by Herpin more than 140 years ago, it is still an enigmatic epilepsy syndrome in many ways advanced imaging techniques reveal multi-focal abnormalities in this paradigmatic generalized epilepsy syndrome clinical studies reveal a major role of genetics in etiology, but the underlying molecular changes are likely to be highly heterogeneous many JME patients have psycho-social issues, even though their intelligence is normal antiepileptic drugs (AEDs), notably valproic acid, achieve seizure remission in two thirds of patients, but more patients seem to relapse after stopping AEDs than in any other epilepsy syndrome. This pessimistic outlook has been challenged in recent population-based studies and needs to be assessed in randomized AED withdrawal trials. This review summarizes recent focus neuroimaging, genetic, and behavioral aspects of JME and re-appraises the entrenched view that remission off AEDs is exceptionally rare in JME.
Publisher: Elsevier BV
Date: 03-1991
DOI: 10.1016/0022-510X(91)90098-R
Abstract: The functional consequences of large heteroplasmic mtDNA deletions were investigated in a group of 6 patients with chronic progressive external ophthalmoplegia (CPEO) syndromes. State III respiration rates corrected for age were low with site I and II substrates in all cases and cytochrome oxidase activity was depressed. The severity of impairment varied and is consistent with inclusion of a variable percentage of non-functioning mitochondria (with deleted mtDNA) in the pellet. Western blot studies with a holocomplex antibody battery revealed no abnormalities in subunit content of complexes III and IV. A deficiency of several complex I subunits in 3 cases suggests that abnormal nuclear-mitochondrial regulation of complex I assembly may follow large mtDNA deletions.
Publisher: Wiley
Date: 30-05-2019
DOI: 10.1002/AJMG.A.61216
Abstract: Pathogenic variants in the X-chromosome Aristaless-related homeobox (ARX) gene contribute to intellectual disability, epilepsy, and associated comorbidities in affected males. Here, we report a novel splice variant in ARX in a family with three affected in iduals. The proband had early onset developmental and epileptic encephalopathy, his brother and mother had severe and mild intellectual disability, respectively. Massively parallel sequencing identified a novel c.1449-1G>C in intron 4 of the ARX gene, predicted to abolish the splice acceptor site, retaining intron 4 and leading to a premature termination codon immediately after exon 4. As exon 5 is the last exon of the ARX gene, the premature termination codon at position p.L484* would be predicted to escape nonsense-mediated mRNA decay, potentially producing at least some C-terminally truncated protein. Analysis of cDNA from patient lymphoblastoid cells confirmed retention of intron 4 and loss of detectable expression of ARX mRNA across exon 4 to exon 5. We review published cases of variants that lead to altered or early termination of the ARX protein, but not complete loss of function, and are associated with phenotypes of intellectual disability and infantile onset developmental and epileptic encephalopathies, including Ohtahara and West syndromes. Taken together, this novel splice variant retaining intron 4 is likely to be the cause of the early onset developmental and epileptic encephalopathy in the proband.
Publisher: Wiley
Date: 04-2009
DOI: 10.1111/J.1528-1167.2009.02023.X
Abstract: SCN1A is the most clinically relevant epilepsy gene and is associated with generalized epilepsy and febrile seizure plus (GEFS+) and Dravet syndrome. We postulated that earlier onset of febrile seizures in the febrile seizure (FS) and febrile seizure plus (FS+) phenotypes may occur in the presence of a SCN1A mutation. This was because of the age-related onset of Dravet syndrome, which typically begins in the first year of life. We found that patients with FS and FS+ with SCN1A mutations had earlier median onset of febrile seizures compared to the population median. Patients with GABRG2 mutations had a similar early onset in contrast to patients with SCN1B mutations where onset was later. This study is the first to demonstrate that a specific genetic abnormality directly influences the FS and FS+ phenotype in terms of age of onset.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-08-2023
DOI: 10.1212/CPJ.0000000000200187
Abstract: Myoclonus is often approached in different ways by epileptologists and movement disorder specialists, leading to confusion in the literature. Multiplicity and inconsistency over the past 2 centuries resulted in a lack of precision and ambiguity of the terminology. We show that this is a current problem in which one phenomenon has been described with many terms and vice versa. Of more importance, we discuss the conceptualization of myoclonus from perspectives of both fields and focus on the borderland that exists, especially in the spectrum of cortical and epileptic myoclonus. By giving 2 ex les, we illustrate the conundrum: the spectrum of progressive myoclonus epilepsies and progressive myoclonic ataxias and “cortical tremor” observed in familial cortical myoclonic tremor with epilepsy or familial adult myoclonic epilepsy. We attempt to facilitate to bridge these subspecialties and form the base for a uniform understanding to take this issue forward toward future classifications, discussions, and scientific research.
Publisher: Springer Science and Business Media LLC
Date: 07-2016
DOI: 10.1007/S00439-016-1700-8
Abstract: Familial adult myoclonus epilepsy (FAME) is a rare autosomal dominant disorder characterized by adult onset, involuntary muscle jerks, cortical myoclonus and occasional seizures. FAME is genetically heterogeneous with more than 70 families reported worldwide and five potential disease loci. The efforts to identify potential causal variants have been unsuccessful in all but three families. To date, linkage analysis has been the main approach to find and narrow FAME critical regions. We propose an alternative method, pedigree free identity-by-descent (IBD) mapping, that infers regions of the genome between in iduals that have been inherited from a common ancestor. IBD mapping provides an alternative to linkage analysis in the presence of allelic and locus heterogeneity by detecting clusters of in iduals who share a common allele. Succeeding IBD mapping, gene prioritization based on gene co-expression analysis can be used to identify the most promising candidate genes. We performed an IBD analysis using high-density single nucleotide polymorphism (SNP) array data followed by gene prioritization on a FAME cohort of ten European families and one Australian/New Zealander family eight of which had known disease loci. By identifying IBD regions common to multiple families, we were able to narrow the FAME2 locus to a 9.78 megabase interval within 2p11.2-q11.2. We provide additional evidence of a founder effect in four Italian families and allelic heterogeneity with at least four distinct founders responsible for FAME at the FAME2 locus. In addition, we suggest candidate disease genes using gene prioritization based on gene co-expression analysis.
Publisher: Wiley
Date: 03-11-2022
DOI: 10.1002/ACN3.51687
Abstract: The objectives of this study were to define the clinical and biochemical spectrum of spinal muscular atrophy with progressive myoclonic epilepsy (SMA‐PME) and to determine if aberrant cellular ceramide accumulation could be normalized by enzyme replacement. Clinical features of 6 patients with SMA‐PME were assessed by retrospective chart review, and a literature review of 24 previously published cases was performed. Leukocyte enzyme activity of acid ceramidase was assessed with a fluorescence‐based assay. Skin fibroblast ceramide content and was assessed by high performance liquid chromatography, electrospray ionization tandem mass spectroscopy. Enzyme replacement was assessed using recombinant human acid ceramidase (rhAC) in vitro. The six new patients showed the hallmark features of SMA‐PME, with variable initial symptom and age of onset. Five of six patients carried at least one of the recurrent SMA‐PME variants observed in two specific codons of ASAH1 . A review of 30 total cases revealed that patients who were homozygous for the most common c.125C T variant presented in the first decade of life with limb‐girdle weakness as the initial symptom. Sensorineural hearing loss was associated with the c.456A C variant. Leukocyte acid ceramidase activity varied from 4.1%–13.1% of controls. Ceramide species in fibroblasts were detected and total cellular ceramide content was elevated by 2 to 9‐fold compared to controls. Treatment with rhAC normalized ceramide profiles in cultured fibroblasts to control levels within 48 h. This study details the genotype–phenotype correlations observed in SMA‐PME and shows the impact of rhAC to correct the abnormal cellular ceramide profile in cells.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 02-05-2008
Abstract: Certain mutations in specific parts of the neuronal nicotinic acetylcholine receptor (nAChR) subunit genes CHRNA4, CHRNB2, and probably CHRNA2, can cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). All but one of the known causative mutations are located in the second transmembrane region (TM2), which serves as the major ion poreforming domain of the receptor. Functional characterization of these ADNFLE mutations has shown that although each mutant exhibits specific properties, they all confer a gain of function with increased sensitivity to acetylcholine. In this work, we characterize the second and third ADNFLE-associated mutations that are external to TM2 but affect different amino acid residues within the third transmembrane region (TM3). The two new CHRNB2 mutations were identified in three families of Turkish Cypriot, Scottish, and English origin. These TM3 mutations elicit the same gain of function pathomechanism as observed for the TM2 mutations with enhanced acetylcholine sensitivity, despite their unusual localization within the gene. Electrophysiological experiments, including single channel measurements, revealed that incorporation of these new mutant subunits does not affect the conductance of the ionic pore but increases the probability of opening. Determination of the sensitivity to nicotine for nAChRs carrying mutations in TM2 and TM3 showed clear differences in the direction and the extent to which the window current for nicotine sensitivity was shifted for in idual mutations, indicating differences in pharmacogenomic properties that are not readily correlated with increased ACh affinity.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 02-2018
Publisher: Wiley
Date: 09-05-2018
DOI: 10.1111/EPI.14042
Abstract: The genetic generalized epilepsies (GGEs) are mainly genetically determined disorders. Although inheritance in most cases appears to be complex, involving multiple genes, variants of a number of genes are known to contribute. Pathogenic variants of SLC2A1 leading to autosomal-dominant GLUT1 deficiency account for up to 1% of cases, increasing to 10% of those with absence seizures starting before age 4 years. Copy number variants are found in around 3% of cases, acting as risk alleles. Copy number variation is much more common in those with comorbid learning disability. Common variant associations are starting to emerge from genome-wide association studies but do not yet explain a large proportion of GGEs. Although currently genetic testing is not likely to yield a diagnosis for most patients with GGEs, it can be of great importance in specific clinical situations. Providers should consider the in idual patient's history in determining the utility of genetic testing.
Publisher: Elsevier BV
Date: 10-2009
Publisher: Wiley
Date: 09-03-2023
DOI: 10.1111/EPI.17547
Abstract: “How many epilepsy genes are there?” is a frequently asked question. We sought to (1) provide a curated list of genes that cause monogenic epilepsies, and (2) compare and contrast epilepsy gene panels from multiple sources. We compared genes included on the epilepsy panels (as of July 29, 2022) of four clinical diagnostic providers: Invitae, GeneDx, Fulgent Genetics, and Blueprint Genetics and two research resources: PanelApp Australia and ClinGen. A master list of all unique genes was supplemented by additional genes identified via PubMed searches up until August 15, 2022, using the search terms “genetics” AND/OR “epilepsy” AND/OR “seizures”. Evidence supporting a monogenic role for all genes was manually reviewed those with limited or disputed evidence were excluded. All genes were annotated according to inheritance pattern and broad epilepsy phenotype. The comparison of genes included on epilepsy clinical panels revealed high heterogeneity in both number of genes (range: 144–511) and content. Just 111 genes (15.5%) were included on all four clinical panels. Subsequent manual curation of all “epilepsy genes” identified monogenic etiologies. Almost 90% of genes were associated with developmental and epileptic encephalopathies. By comparison only 5% of genes were associated with monogenic causes of “common epilepsies” (i.e., generalized and focal epilepsy syndromes). Autosomal recessive genes were most frequent (56% of genes) however, this varied according to the associated epilepsy phenotype(s). Genes associated with common epilepsy syndromes were more likely to be dominantly inherited and associated with multiple epilepsy types. Our curated list of monogenic epilepsy genes is publicly available: ahlolab/genes4epilepsy and will be regularly updated. This gene resource can be utilized to target genes beyond those included on clinical gene panels, for gene enrichment methods and candidate gene prioritization. We invite ongoing feedback and contributions from the scientific community via genes4-epilepsy@unimelb.edu.au .
Publisher: Wiley
Date: 12-1998
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1996
Publisher: Oxford University Press (OUP)
Date: 24-02-2017
DOI: 10.1093/BRAIN/AWW346
Publisher: Wiley
Date: 02-1983
DOI: 10.1111/J.1445-5994.1983.TB04554.X
Abstract: PHIP and SABRE hyperpolarized NMR methods are used to follow the unexpected metal-catalysed hydrogenation of quinazoline (Qu) to 3,4-dihydroquinazoline as the sole product. A solution of [IrCl(IMes)(COD)] in dichloromethane reacts with H2 and Qu to form [IrCl(H)2(IMes)(Qu)2] (2). The addition of methanol then results in its conversion to [Ir(H)2(IMes)(Qu)3]Cl (3) which catalyses the hydrogenation reaction. Density functional theory calculations are used to rationalise a proposed outer sphere mechanism in which (3) converts to [IrCl(H)2(H2)(IMes)(Qu)2]Cl (4) and neutral [Ir(H)3(IMes)(Qu)2] (6), both of which are involved in the formation of 3,4-dihydroquinazoline via the stepwise transfer of H+ and H-, with H2 identified as the reductant. Successive ligand exchange in 3 results in the production of thermodynamically stable [Ir(H)2(IMes)(3,4-dihydroquinazoline)3]Cl (5).
Publisher: Wiley
Date: 02-1999
DOI: 10.1002/1531-8249(199902)45:2<146::AID-ANA3>3.0.CO;2-N
Abstract: Mutations in the X-linked gene doublecortin, which encodes a protein with no dear structural homologues, are found in pedigrees in which affected females show "double cortex" syndrome (DC also known as subcortical band heterotopia or laminar heterotopia) and affected males show X-linked lissencephaly. Mutations in doublecortin also cause sporadic DC in females. To determine the incidence of doublecortin mutations in DC, we investigated a cohort of eight pedigrees and 47 sporadic patients with DC for mutations in the doublecortin open reading frame as assessed by single-stranded conformational polymorphism analysis. Mutations were identified in each of the eight DC pedigrees (100%), and in 18 of the 47 sporadic DC patients (38%). Identified mutations were of two types, protein truncation mutations and single amino acid substitution mutations. However, pedigrees with DC displayed almost exclusively single amino acid substitution mutations, suggesting that patients with these mutations may have less of a reproductive disadvantage versus those patients with protein truncation mutations. Single amino acid substitution mutations were tightly clustered in two regions of the open reading frame, suggesting that these two regions are critical for the function of the Doublecortin protein.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-12-2022
DOI: 10.1212/WNL.0000000000201469
Abstract: Mosaic pathogenic variants restricted to the brain are increasingly recognized as a cause of focal epilepsies. We aimed to identify a mosaic pathogenic variant and its anatomical gradient in brain DNA derived from trace tissue on explanted stereoelectroencephalography (SEEG) electrodes. We studied a patient with nonlesional multifocal epilepsy undergoing presurgical evaluation with SEEG. After explantation, the electrodes were ided into 3 pools based on their brain location (right posterior quadrant, left posterior quadrant, hippoc us/temporal neocortex). Tissue from each pool was processed for trace DNA that was whole genome lified prior to high-depth exome sequencing. Droplet digital PCR was performed to quantify mosaicism. A brain-specific glial fibrillary acidic protein (GFAP) assay enabled cell-of-origin analysis. We demonstrated a mosaic gradient for a novel pathogenic KCNT1 loss-of-function variant (c.530G A, p.W177X) predicted to lead to nonsense-mediated decay. Strikingly, the mosaic gradient correlated strongly with the SEEG findings because the highest variant allele frequency was in the right posterior quadrant, reflecting the most epileptogenic region on EEG studies. An elevated GFAP level indicated enrichment of brain-derived cells in SEEG cell suspension. This study demonstrates a proof of concept that mosaic gradients of pathogenic variants can be established using trace tissue from explanted SEEG electrodes.
Publisher: American Medical Association (AMA)
Date: 05-2006
DOI: 10.1001/ARCHNEUR.63.5.705
Abstract: Abnormal paroxysmal events in sleep may be parasomnias or epileptic seizures. In nocturnal frontal lobe epilepsy (NFLE), the unusual seizure features often lead to diagnostic confusion with nonepileptic parasomnias video-electroencephalography monitoring is usually required to make the diagnosis. To examine the reliability of the clinical history in diagnosing NFLE, using the Frontal Lobe Epilepsy and Parasomnias (FLEP) scale. The FLEP scale, comprising specific questions reflecting the diagnostic features of NFLE and parasomnias, was developed by an expert panel following review of the literature. It was then validated in a s le of in iduals with firmly diagnosed nocturnal events. Patients were recruited after appropriate diagnostic workup in tertiary sleep and epilepsy referral centers in Melbourne, Australia. Sixty-two patients (45 males) [corrected] with paroxysmal nocturnal events. Intervention Two independent interviews were conducted in each case, with the patient and a witness, by researchers blinded to the diagnosis. The diagnosis obtained from scores on the FLEP scale was compared with the confirmed diagnosis in each patient. Nocturnal frontal lobe epilepsy was correctly diagnosed from the FLEP score in 31 of 31 patients, with a sensitivity of 1.0 (95% confidence interval [CI], 0.85-1.00), specificity of 0.90 (95% CI, 0.73-0.97), positive predictive value of 0.91 (95% CI, 0.75-0.97), and negative predictive value of 1.00 (95% CI, 0.85-1.00). A diagnosis of NFLE can be made reliably using the clinical features identified in the FLEP scale. This may reduce the requirement for tertiary referral and extensive inpatient monitoring.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-1998
Publisher: Oxford University Press (OUP)
Date: 1989
Abstract: Electrophysiological studies (EEG, evoked potentials, nerve conduction and EMG) in 13 patients with myoclonus epilepsy with ragged red fibres (MERRF) are presented. The most notable findings are the presence of atypical irregular generalized spike and wave discharges arising from an abnormal EEG background (9 patients), focal epileptiform abnormalities (6 patients) most commonly over the occipital regions and giant cortical SEPs (4 of 6 patients tested). Similar findings of disturbed EEG background activity, generalized spike and wave discharges and giant cortical SEPs appear to be shared by the group of diseases characterized by progressive myoclonus epilepsy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-1998
Publisher: Oxford University Press (OUP)
Date: 11-1997
DOI: 10.1093/BRAIN/120.11.1921
Abstract: We sought to determine whether patterns of ictal hyperfusion demonstrated using [99mTC]HMPAO (hexamethylpropylene amine oxime) single photon emission computed tomography (SPECT) predict outcome of temporal lobectomy in particular, whether the more extensive patterns of ictal hyperperfusion are associated with poor outcome. We studied 63 patients who had ictal SPECT studies prior to temporal lobectomy. Hyperperfusion on ictal SPECT scans was lateralized, and classified into: (i) 'typical', (ii) 'typical with posterior extension', (iii) 'bilateral' and (iv) 'atypical' patterns. Outcome (minimum of 2 years follow-up) was classified as either seizure free, or not seizure free. Actuarial analysis was used to test the relationship of SPECT patterns with outcome. There were 35 cases with the typical ictal SPECT pattern, 13 posterior, nine bilateral and six atypical cases. The atypical pattern was associated with lack of pathology in the surgical specimen. Outcome was similar for the typical, posterior and bilateral with 60%, 69% and 67% seizure free, respectively. In contrast, the atypical group had a worse outcome with only 33% seizure free. Actuarial analysis showed a significant difference in outcome between patients with the typical pattern, and patients with the atypical pattern (P = 0.04). We conclude that extended patterns of ictal perfusion in temporal lobe epilepsy do not predict poor outcome, indicating that extended hyperperfusion probably represents seizure propagation pathways rather than intrinsically epileptogenic tissue. Atypical patterns of hyperperfusion are associated with poor outcome and may indicate diffuse or extra-temporal epileptogenicity.
Publisher: Elsevier BV
Date: 03-2008
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-07-2009
Publisher: Wiley
Date: 04-2010
DOI: 10.1002/ANA.21909
Publisher: Elsevier BV
Date: 03-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-12-2018
DOI: 10.1212/WNL.0000000000006729
Abstract: To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1 . We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%) high pain threshold (72%) eating problems, including oral aversion (68%) hypotonia (67%) sleeping problems (62%) autism spectrum disorder (54%) and ataxia or gait abnormalities (51%). SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-09-2004
DOI: 10.1212/01.WNL.0000137051.33486.C7
Abstract: Alteration of ATP-binding cassette subfamily B member 1 transporter (ABCB1) can plausibly cause drug-resistant epilepsy as it influences brain penetration of drugs. The CC genotype at the ABCB1 C3435T polymorphism was reported to be associated with multidrug resistance. A replication study in 401 drug-resistant and 208 drug-responsive subjects with epilepsy showed no significant association between the CC genotype and drug-resistant epilepsy. The authors suggest the initial association may have arisen by chance.
Publisher: Wiley
Date: 12-03-2020
DOI: 10.1111/EPI.16475
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.MCN.2007.03.003
Abstract: Seizure susceptibility is high in human infants compared to adults, presumably because of developmentally regulated changes in neural excitability. Benign familial neonatal-infantile seizures (BFNIS), characterized by both early onset and remission, are caused by mutations in the gene encoding a human sodium channel (NaV1.2). We analyzed neonatal and adult splice forms of NaV1.2 with a BFNIS mutation (L1563V) in human embryonic kidney cells. Computer modeling revealed that neonatal channels are less excitable than adult channels. Introduction of the mutation increased excitability in the neonatal channels to a level similar to adult channels. By contrast, the mutation did not affect the adult channel variant. This "adult-like" increased excitability is likely to be the mechanism underlying BFNIS in infants with this mutation. More generally, developmentally regulated NaV1.2 splicing may be one mechanism that counters the normally high excitability of neonatal neurons and helps to reduce seizure susceptibility in normal human infants.
Publisher: Wiley
Date: 14-11-2022
DOI: 10.1111/EPI.17440
Abstract: Anterior temporal lobectomy (ATL) for medication‐resistant localized epilepsy results in ablation or reduction of seizures for most patients. However, some in iduals who attain an initial extended period of postsurgical seizure freedom will experience a later seizure recurrence. In this study, we examined the prevalence and some risk factors for late recurrence in an ATL cohort with extensive regular follow‐up. Included were 449 patients who underwent ATL at Austin Health, Australia, from 1978 to 2008. Postsurgical follow‐up was undertaken 2–3 yearly. Seizure recurrence was tested using Kaplan–Meier analysis, log‐rank test, and Cox regression. Late recurrence was qualified as a first disabling seizure years postsurgery. We examined risks within the ATL cohort according to broad pathology groups and tested whether late recurrence differed for the ATL cohort compared to patients who had resections outside the temporal lobe ( n = 98). Median post‐ATL follow‐up was 22 years (range = .1–38.6), 6% were lost to follow‐up, and 12% had died. Probabilities for remaining completely seizure‐free after surgery were 51% (95% confidence interval [CI] = 53–63) at 2 postoperative years, 36% (95% CI = 32–41) at 10 years, 32% (95% CI = 27–36) at 20 years, and 30% (95% CI = 25–34) at 25 years. Recurrences were reported up to 23 years postoperatively. Late seizures occurred in all major ATL pathology groups, with increased risk in the "normal" and "distant lesion" groups ( p ≤ .03). Comparison between the ATL cohort and patients who underwent extratemporal resection demonstrated similar patterns of late recurrence ( p = .74). Some first recurrences were very late, reported decades after ATL. Late recurrences were not unique to any broad ATL pathology group and did not differ according to whether resections were ATL or extratemporal. Reports of these events by patients with residual pathology suggest that potentially epileptogenic abnormalities outside the area of resection may be implicated as one of several possible underlying mechanisms.
Publisher: BMJ
Date: 04-1992
Publisher: Elsevier BV
Date: 12-1998
Publisher: Elsevier BV
Date: 12-1999
DOI: 10.1086/302649
Publisher: Wiley
Date: 24-09-2010
DOI: 10.1111/J.1528-1167.2010.02712.X
Abstract: Early onset absence epilepsy (EOAE) starting before the age of 4 years constitutes a rare subgroup of the idiopathic generalized epilepsies (IGEs). A strong genetic component in IGE has been suggested by twin and family studies. We describe a boy with absence seizures starting at the age of 9 months whose parents both had childhood absence epilepsy. A 192-kb duplication in 1q21.3 was identified in the proband and his father, encompassing the gene CHRNB2 coding for the β-2 subunit of the nicotinic acetylcholine receptor and the gene ADAR coding for adenosine deaminase, an enzyme responsible for RNA editing. Both are candidate genes for seizure disorders. The duplication was not identified in 191 independent IGE patients (93 EOAE 98 classical IGE) or in 1,157 population controls.
Publisher: Wiley
Date: 25-02-2018
DOI: 10.1111/JSR.12669
Abstract: The aim of this study was to evaluate the efficacy and tolerability of open-label lacosamide in patients with refractory sleep-related hypermotor epilepsy. The study was a case review of eight patients with refractory sleep-related hypermotor epilepsy treated with lacosamide. Seizure diaries compared the mean baseline seizure frequency with the most recent 3 months of follow-up. Five (62.5%) patients were responders, defined as ≥50% reduction in seizure frequency, over a mean duration of exposure of 21.5 months. The mean maintenance dose of lacosamide was 400 mg/day. No-one reported worsening of seizures. Lacosamide was well tolerated with initial fatigue being the main side-effect. Lacosamide is a potentially efficacious adjunctive therapy in patients with refractory sleep-related hypermotor epilepsy. A double-blind placebo-controlled study would determine its efficacy.
Publisher: Wiley
Date: 09-03-2023
DOI: 10.1111/EPI.17557
Abstract: The progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders, typically presenting in late childhood. An etiologic diagnosis is achieved in about 80% of patients with PME, and genome‐wide molecular studies on remaining, well‐selected, undiagnosed cases can further dissect the underlying genetic heterogeneity. Through whole‐exome sequencing (WES), we identified pathogenic truncating variants in the IRF2BPL gene in two, unrelated patients presenting with PME. IRF2BPL belongs to the transcriptional regulators family and it is expressed in multiple human tissues, including the brain. Recently missense and nonsense mutations in IRF2BPL were found in patients presenting with developmental delay and epileptic encephalopathy, ataxia, and movement disorders, but none with clear PME. We identified 13 other patients in the literature with myoclonic seizures and IRF2BPL variants. There was no clear genotype–phenotype correlation. With the description of these cases, the IRF2BPL gene should be considered in the list of genes to be tested in the presence of PME, in addition to patients with neurodevelopmental or movement disorders.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-05-2003
DOI: 10.1212/01.WNL.0000061479.59789.10
Abstract: The authors describe three patients with refractory temporal lobe epilepsy (TLE) following an episode of hypertensive encephalopathy as their only identified antecedent event. All patients had typical MR features of hippoc al sclerosis (HS), and the two operated cases had typical HS histology and became seizure-free postoperatively. These cases suggest that hypertensive encephalopathy may be a rare form of initial precipitating injury, leading to TLE and HS.
Publisher: Elsevier BV
Date: 07-2002
DOI: 10.1016/S0028-3908(02)00067-9
Abstract: The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby these mutations produce seizures is unknown. Three mutations of the alpha(4) subunit of the neuronal nicotinic acetylcholine receptor (nAChR) have been identified in autosomal dominant nocturnal frontal lobe epilepsy. In vitro studies of two mutations suggest an alteration of receptor function resulting in decreased ion channel current flow. We investigated the response of alpha(4) nAChR subunit knockout mice to the gamma-aminobutyric acid (GABA) receptor antagonists pentylenetetrazole (PTZ) and bicuculline (BIC), the glutamate receptor agonist kainic acid (KA), the glycine receptor antagonist strychnine and the K(+) channel blocker 4-aminopyridine (4-AP). Mutant (Mt) mice had a greater sensitivity to PTZ and BIC, with an increase in major motor seizures and seizure-related deaths. Furthermore, Mt mice were more sensitive to KA and strychnine, but the effects were much smaller compared to those seen with the GABA receptor antagonists. Paradoxically, Mt mice appeared to be relatively protected from 4-AP-induced major motor seizures and death. The results show that a functional deletion of the alpha(4) nAChR subunit in vivo is associated with a major increase in sensitivity to GABA receptor blockers.
Publisher: Springer Science and Business Media LLC
Date: 21-04-2021
DOI: 10.1186/S13023-021-01813-5
Abstract: CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition. An expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. In iduals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria. Twenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality). This program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease and other neurodegenerative disorders. This addresses the clinical need to complement other information available.
Publisher: Elsevier BV
Date: 07-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-12-2006
Publisher: Elsevier BV
Date: 02-2000
DOI: 10.1086/302768
Publisher: Elsevier BV
Date: 12-1997
Publisher: Elsevier BV
Date: 02-1989
DOI: 10.1016/S0140-6736(89)91769-8
Abstract: To assess the health-related economic burden attributable to smoking in China for persons aged 35 and older. A prevalence-based, disease-specific approach was used to estimate the smoking attributable direct costs, indirect morbidity costs, and costs of premature deaths caused by smoking-related diseases. The primary data source was the 1998 China National Health Services Survey, which contains the smoking status, medical utilisation, and expenditures for 216,101 in iduals. The economic costs of smoking in 2000 amounted to $5.0 billion (measured in 2000, USD) in total and $25.43 per smoker (> or = age 35). The share of the economic costs was greater for men than women, and greater in rural areas than in urban areas. Of the $5.0 billion total costs, direct costs were $1.7 billion (34% of the total), indirect morbidity costs were $0.4 billion (8%), and indirect mortality costs were $2.9 billion (58%). The direct costs of smoking accounted for 3.1% of China's national health expenditures in 2000. The adverse health effects of smoking constitute a huge economic burden to the Chinese society. To reduce this burden in the future, effective tobacco control programmes and sustained efforts are needed to curb the tobacco epidemic and economic losses.
Publisher: Elsevier BV
Date: 1998
DOI: 10.1016/S0092-8674(00)80899-5
Abstract: X-linked lissencephaly and "double cortex" are allelic human disorders mapping to Xq22.3-Xq23 associated with arrest of migrating cerebral cortical neurons. We identified a novel 10 kb brain-specific cDNA interrupted by a balanced translocation in an XLIS patient that encodes a novel 40 kDa predicted protein named Doublecortin. Four double cortex/X-linked lissencephaly families and three sporadic double cortex patients show independent doublecortin mutations, at least one of them a de novo mutation. Doublecortin contains a consensus Abl phosphorylation site and other sites of potential phosphorylation. Although Doublecortin does not contain a kinase domain, it is homologous to the amino terminus of a predicted kinase protein, indicating a likely role in signal transduction. Doublecortin, along with the newly characterized mDab1, may define an Abl-dependent pathway regulating neuronal migration.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-07-2017
DOI: 10.1212/NXG.0000000000000163
Abstract: To assist the interpretation of genomic data for common epilepsies, we asked whether variants implicated in mild epilepsies in autosomal dominant families are present in the general population. We studied 12 genes for the milder epilepsies and identified published variants with strong segregation support (de novo germline mutation or ≥4 affected family members). These variants were checked in the Exome Aggregation Consortium (ExAC), a database of genetic variation in over 60,000 in iduals. We subsequently evaluated variants in these epilepsy genes that lacked strong segregation support. To determine whether the findings in epilepsies were representative of other diseases, we also assessed the presence of variants in other dominant neurologic disorders (e.g., CADASIL). Published epilepsy variants with strong segregation support (n = 65) were absent (n = 61) or present once (n = 4) in ExAC. By contrast, of 46 published epilepsy variants without strong segregation support, 8 occurred recurrently (2–186 times). Similarly, none of the 45 disease-associated variants from other neurologic disorders with strong segregation support occurred more than once in ExAC. Reanalysis using the larger ExAC V2 plus gnomAD reference cohort showed consistent results. Variants causing autosomal dominant epilepsies are ultra-rare in the general population. Variants observed more than once in ExAC were only found among reports without strong segregation support, suggesting that they may be benign. Clinicians are increasingly faced with the interpretation of genetic variants of unknown significance. These data illustrate that variants present more than once in ExAC are less likely to be pathogenic, reinforcing the valuable clinical role of ExAC.
Publisher: Cold Spring Harbor Laboratory
Date: 23-02-2023
Publisher: Elsevier BV
Date: 03-2008
Publisher: Wiley
Date: 12-03-2015
DOI: 10.1002/ACN3.191
Publisher: CRC Press
Date: 20-09-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-07-2015
Publisher: Wiley
Date: 03-1998
DOI: 10.1111/J.1528-1157.1998.TB05115.X
Abstract: Generalized epilepsies are treatable with a number of antiepileptic drugs (AEDs) that are effective in different seizure types and epilepsy syndromes. The mechanisms of action of these AEDs are incompletely understood but include inhibition of low-threshold calcium currents and of voltage-gated sodium channels and facilitation of GABA(A) receptor currents. The mechanisms of aggravation are also unknown but could include elevation of brain GABA, blockade of voltage-gated sodium channels, and idiosyncratic toxicity reactions. Anecdotal reports suggest that aggravation of generalized epilepsy can occur with virtually all AEDs. The best-documented ex les are aggravation of absences by carbamazepine and aggravation of symptomatic generalized epilepsies by vigabatrin. Therefore, the physician must be constantly aware of the problem of aggravation of seizures by AEDs. With careful diagnosis of the epileptic syndrome and an awareness of the problem, aggravation of seizures can be minimized.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-08-2003
DOI: 10.1212/01.WNL.0000049457.05670.7D
Abstract: To better understand the epileptogenesis of symptomatic generalized epilepsy in patients with hypothalamic hamartoma and intractable epilepsy, many of whom experience remission of generalized seizures and slow spike-wave discharges following surgery. The authors documented the evolution of symptomatic generalized epilepsy in 12 of 20 children who underwent transcallosal microsurgical hypothalamic hamartoma resection. In seven patients they recorded intraoperative EEG from the hamartoma and simultaneously from the scalp and frontal cortex before, during, and after resection. Gelastic seizures began on average at 6 months of age (range birth to 3 years) tonic seizures began at 6 years (range 2 months to 9 years). Normal EEG were reported in early childhood thereafter, abnormalities were progressive. Interictal spike-wave was recorded intraoperatively over the scalp and cortex in six patients, but not from the hypothalamic hamartoma. Hamartoma resection had no immediate effect on cortical spike-wave, but waking spike-wave was absent in seven patients on subsequent postoperative EEG. Tonic seizures ceased in 11 of 12 patients, but 6 of these had postoperative generalized seizures that resolved over 1 to 6 months. Gelastic seizures in hypothalamic hamartoma arise from the hamartoma itself the interictal spike-wave does not. The evolution of EEG abnormalities, the development of generalized seizures years after onset of gelastic seizures, and the postoperative running down of interictal spike-wave and generalized seizures in these patients may reflect secondary epileptogenesis.
Publisher: Wiley
Date: 31-12-2016
DOI: 10.1111/EPI.13291
Abstract: We report on a quantitative analysis of data from a study that acquired continuous long-term ambulatory human electroencephalography (EEG) data over extended periods. The objectives were to examine the seizure duration and interseizure interval (ISI), their relationship to each other, and the effect of these features on the clinical manifestation of events. Chronic ambulatory intracranial EEG data acquired for the purpose of seizure prediction were analyzed and annotated. A detection algorithm identified potential seizure activity, which was manually confirmed. Events were classified as clinically corroborated, electroencephalographically identical but not clinically corroborated, or subclinical. K-means cluster analysis supplemented by finite mixture modeling was used to locate groupings of seizure duration and ISI. Quantitative analyses confirmed well-resolved groups of seizure duration and ISIs, which were either mono-modal or multimodal, and highly subject specific. Subjects with a single population of seizures were linked to improved seizure prediction outcomes. There was a complex relationship between clinically manifest seizures, seizure duration, and interval. These data represent the first opportunity to reliably investigate the statistics of seizure occurrence in a realistic, long-term setting. The presence of distinct duration groups implies that the evolution of seizures follows a predetermined course. Patterns of seizure activity showed considerable variation between in iduals, but were highly predictable within in iduals. This finding indicates seizure dynamics are characterized by subject-specific time scales therefore, temporal distributions of seizures should also be interpreted on an in idual level. Identification of duration and interval subgroups may provide a new avenue for improving seizure prediction.
Publisher: Elsevier BV
Date: 05-2011
Publisher: AMPCo
Date: 2005
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.NEUROIMAGE.2005.09.052
Abstract: Data from animal studies suggest that serotonin release promotes wakefulness and suppresses REM sleep, but there are dangers in extrapolating these findings to humans. Binding of the radioligand [18F]MPPF to 5HT1A receptors is sensitive to levels of endogenous serotonin. In this study, we aimed to demonstrate changes in serotonin receptor availability in the human brain in wakefulness and sleep using [18F]MPPF and positron emission tomography. 14 subjects with narcolepsy cataplexy underwent [18F]MPPF PET scans in wakefulness and in sleep. Subjects who used the stimulant methylphenidate took their normal medication for the wake scan but omitted it prior to the sleep scan. The change in binding potential (BP) between the sleep and wake scans was examined using paired t test. Methylphenidate is thought to have little or no effect on serotonergic neurotransmission, and in order to confirm the absence of an effect on [18F]MPPF binding, a concurrent study was performed using a beta-microprobe technique to examine the effect of methylphenidate administration on [18F]MPPF binding in Sprague-Dawley rats. The human study showed a significant increase in [18F]MPPF binding in sleep compared to wakefulness in the whole brain and all regions of interest examined (temporal cortex, mesial temporal region and cingulate cortex). The beta-microprobe study confirmed that methylphenidate administration had no effect on [18F]MPPF binding. These findings indicate that serotonin receptor availability is increased in sleep compared to wakefulness in narcoleptic humans.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.PHARMTHERA.2010.07.003
Abstract: Epilepsy is a common and serious neurological disorder. Despite recent advances in drug therapy, treatment for epilepsy is still largely empirical and rational prescribing based on the mechanism of action in an in idual patient is generally not possible. Genetic studies have identified an increasing collection of disease-causing genes providing a fundamental molecular foundation on which to build this understanding, at least for some forms of epilepsy. The impact of these genetic discoveries is likely to be wide reaching-from the discovery and validation of new drug targets to the potential to enable rational prescribing based on genetic makeup and even further through animal experimentation to tease out molecular and cellular mechanisms that lead to hyperexcitable neuronal networks causing epilepsy. Here we discuss how we can use knowledge of genetic mechanisms to improve treatment strategies now and into the future.
Publisher: Cambridge University Press
Date: 13-12-2001
Publisher: Wiley
Date: 09-03-2001
Publisher: Wiley
Date: 05-2000
Publisher: Oxford University Press (OUP)
Date: 12-08-2014
DOI: 10.1093/BRAIN/AWU194
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.AUTNEU.2014.03.008
Abstract: Vasovagal syncope (VVS) is the most frequent type of syncope and affects about 25% of the population. The role of genetic factors in VVS has long been debated. In this review we will discuss the current evidence that strongly suggests a major genetic component. Family aggregation studies have consistently shown that in iduals with VVS more frequently have affected family members with VVS than unaffected controls. Clear evidence for the relevance of genetic factors was provided by a twin study that showed significantly higher concordance rates in monozygous compared to dizygous twins for frequent syncope and syncope associated with typical vasovagal triggers. Analysis of the family history of the concordant monozygous twins revealed that complex inheritance is operative in the majority but rarer families with autosomal dominant inheritance also exist. Several autosomal dominant families have been described in the literature with the largest including 30 affected in iduals. Candidate gene association studies have so far been disappointing as they have revealed either negative or unconfirmed results. However, in an autosomal dominant family the first locus for VVS was identified on chromosome 15q26. The underlying gene has not been identified yet. Genetic factors play a role in VVS. Most cases follow complex inheritance autosomal dominant inheritance occurs less frequently. Identification of the underlying genes will improve our understanding of pathophysiology and may lead to new therapeutic strategies.
Publisher: Wiley
Date: 2010
DOI: 10.1002/ANA.21806
Abstract: Approximately 30% of patients with newly diagnosed epilepsy do not respond to antiepileptic drugs (AEDs), but this is not predictable. We used transcranial magnetic stimulation to determine the effect of AEDs on cortical excitability in patients with epilepsy and correlated this with a successful response to treatment. Ninety-nine drug-naïve patients with newly diagnosed epilepsy (55 idiopathic generalized epilepsy, 44 focal epilepsy) were evaluated. Motor threshold and cortical excitability on recovery curve analysis were measured before and 4 to 16 weeks after starting medication. After 1 year of treatment, 43 of 55 idiopathic generalized epilepsy and 26 of 44 focal epilepsy patients were seizure free. A decrease in cortical excitability occurred in the seizure-free group as indicated by an increase in motor threshold (p < 0.05) and intracortical inhibition on recovery curve analysis, maximum at the 250-millisecond interstimulus interval (p < 0.01) compared with pretreatment values. These changes were not present in the group with ongoing seizures. Seizure freedom is marked by a reduction in transcranial magnetic stimulation measures of cortical excitability, evident shortly after beginning therapy. This virtual normalization of cortical excitability occurred regardless of the seizure characteristics or AED used. Failure to show this response to AED treatment may be valuable as an early predictor of pharmacoresistance in in idual patients.
Publisher: Elsevier BV
Date: 03-2008
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.EJMG.2015.09.002
Abstract: Juvenile neuronal-ceroid-lipofuscinosis (JNCL) is a lysosomal storage disease caused by mutations in CLN3. The most frequent mutation is a 1.02-kb deletion that, when homozygous, causes the classical clinical presentation. Patients harboring mutations different than the major deletion show a marked clinical heterogeneity, including protracted disease course with possible involvement of extraneuronal tissues. Cardiac involvement is relatively rare in JNCL and it is usually due to myocardial storage of ceroid-lipofuscinin. Only recently, histopathological findings of autophagic vacuolar myopathy (AVM) were detected in JNCL patients with severe cardiomyopathy. We describe a 35-year-old male showing a delayed-classic JNCL with visual loss in childhood and neurological manifestations only appearing in adult life. He had an unusual CLN3 genotype with an unreported deletion (p.Ala349_Leu350del) and the known p.His315Glnfs*67 mutation. Autophagic vacuolar myopathy was shown by muscle biopsy. At clinical follow-up, moderately increased CPK levels were detected whereas periodic cardiac assessments have been normal to date. Adult neurologists should be aware of protracted JNCL as cause of progressive neurological decline in adults. The occurrence of autophagic vacuolar myopathy necessitates periodic cardiac surveillance, which is not usually an issue in classic JNCL due to early neurological death.
Publisher: Wiley
Date: 06-2002
DOI: 10.1046/J.1528-1157.43.S.5.16.X
Abstract: The linkage between autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and neuronal nicotinic acetylcholine receptor has been strongly reinforced by the report of five distinct mutations in the two genes coding for the major brain alpha4beta2 nicotinic acetylcholine (ACh) receptors. As a first step toward understanding the basic mechanisms underlying this genetically transmissible neurologic disorder, we examined the similarities and differences of the functional properties displayed by naturally occurring mutant forms of this ligand-gated channel. Functional studies of neuronal nicotinic ACh receptors reconstituted in Xenopus oocytes were designed to analyze the common traits displayed by the different mutations associated with ADNFLE. Coexpression of the control and mutated alleles harboring the alpha4S248F mutation obtained from patient DNAs yielded ACh-evoked currents of litude comparable to the control responses but with a higher sensitivity and desensitization to the natural agonist. Alternatively, the other mutants (alpha4L776ins3, alpha4S252L, and beta2V287M) displayed an increased ACh sensitivity without pronounced desensitization. In addition, whereas a reduction of calcium permeability was observed for the mutants (alpha4S248F and alpha4L776ins3), no significant modification of ionic selectivity could be detected in the alpha4S252L mutation. Hence increase in ACh sensitivity is the only common characteristic so far observed between the four naturally occurring mutant receptors investigated. Analyses of functional properties of four nAChR mutants associated with ADNFLE indicate that a gain of function of these mutant receptors may be at the origin of the neuronal network dysfunction that causes the epileptic seizures. These data are discussed in the context of our latest knowledge of the pyramidal cell function.
Publisher: Elsevier BV
Date: 05-2015
Publisher: Oxford University Press (OUP)
Date: 02-1995
Abstract: The disorder of autosomal dominant nocturnal frontal lobe epilepsy has recently been identified, and is now delineated in detail. A phenotypically homogeneous group of five families from Australia, Britain and Canada, containing 47 affected in iduals, was studied. The largest family contained 25 affected in iduals spanning six generations. This disorder is characterized by clusters of brief nocturnal motor seizures, with hyperkinetic or tonic manifestations. Subjects often experienced an aura, and remained aware throughout the attacks. Seizures occurred in clusters (mean eight attacks/night) typically as the in idual dozed, or shortly before awakening. The epilepsy usually began in childhood, and persisted through adult life, with considerable intra-family variation in severity. Seizures were often misdiagnosed as benign nocturnal parasomnias, psychiatric and medical disorders. Interictal EEG studies were unhelpful. Ictal video-EEG studies showed that the attacks were partial seizures with frontal lobe seizure semiology. Neuro-imaging was normal. Carbamazepine monotherapy was frequently effective. This disorder showed autosomal dominant inheritance. Recognition of this entity is clinically important for diagnosis, appropriate therapy and genetic counselling. Moreover, this disorder now offers an opportunity to identify a gene for partial epilepsy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-08-2010
Publisher: Elsevier BV
Date: 09-2007
Publisher: Elsevier BV
Date: 09-1994
Publisher: Oxford University Press (OUP)
Date: 29-06-2015
DOI: 10.1093/HMG/DDV245
Abstract: Protocadherin 19 (PCDH19) female limited epilepsy (PCDH19-FE also known as epilepsy and mental retardation limited to females, EFMR MIM300088) is an infantile onset epilepsy syndrome with or without intellectual disability (ID) and autism. We investigated transcriptomes of PCDH19-FE female and control primary skin fibroblasts, which are endowed to metabolize neurosteroid hormones. We identified a set of 94 significantly dysregulated genes in PCDH19-FE females. Intriguingly, 43 of the 94 genes (45.7%) showed gender-biased expression enrichment of such genes was highly significant (P = 2.51E-47, two-tailed Fisher exact test). We further investigated the AKR1C1-3 genes, which encode crucial steroid hormone-metabolizing enzymes whose key products include allopregnanolone and estradiol. Both mRNA and protein levels of AKR1C3 were significantly decreased in PCDH19-FE patients. In agreement with this, the blood levels of allopregnanolone were also (P < 0.01) reduced. In conclusion, we show that the deficiency of neurosteroid allopregnanolone, one of the most potent GABA receptor modulators, may contribute to PCDH19-FE. Overall our findings provide evidence for a role of neurosteroids in epilepsy, ID and autism and create realistic opportunities for targeted therapeutic interventions.
Publisher: Elsevier BV
Date: 11-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-11-2001
Abstract: To characterize seizures in family members of patients with refractory temporal lobe epilepsy (TLE) and hippoc al sclerosis (HS). The authors systematically investigated family history (FH) of seizures in 66 probands with histologically proven HS, and in 51 control subjects. A positive FH was defined as at least one first-to-third-degree relative being affected. The odds ratio (OR) to be affected with seizures was calculated for siblings, parents, and aunts/uncles. An FH of seizures was found in 58% of patients, and in 24% of control subjects (p = 0.02). A variety of seizure types were found. Siblings of patients were more likely to be affected than siblings of control subjects (OR 11.5 95% CI = 1.5 to 86.9 p = 0.003), with febrile convulsions occurring in 5.8% of the siblings of patients. The OR of being affected was 5.7 for parents of patients, and 1.9 for aunts/uncles of patients (p = NS). FH of seizures, particularly febrile convulsions, are a risk factor for TLE with HS. These data suggest that a variety of genes contributing to epilepsy phenotypes in relatives may be involved in the pathogenesis of HS.
Publisher: Wiley
Date: 05-01-2012
DOI: 10.1111/J.1528-1167.2011.03368.X
Abstract: To accurately determine the frequency and nature of the family history of seizures in patients with benign childhood epilepsy with centrotemporal spikes (BECTS). Participants with BECTS were recruited from the electroencephalography (EEG) laboratories of three pediatric centers and by referral. Pedigrees were constructed for up to three degrees of relatedness for each proband. All available affected and unaffected in iduals underwent phenotyping using a validated seizure questionnaire. The proportion of affected relatives according to degree of relatedness was calculated and phenotypic patterns were analyzed. Fifty-three probands with BECTS had a mean age of seizure onset at 7.8 years (range 2-12 years). Thirty-four (64%) of 53 patients were male. For 51 participants, pedigrees were available for three degrees of relatedness. Fifty-seven (2.7%) of 2,085 relatives had a history of seizures: Twenty-one (9.8%) of 214 first-degree, 15 (3%) of 494 second-degree, and 21 (1.5%) of 1,377 third-degree relatives. Febrile seizures were the most frequent phenotype, occurring in 26 of 57 affected relatives. There were 34 relatives with epilepsy: 6.5% (14 of 214) first-degree, 1.8% (9 of 494) second-degree, and 0.8% (11 of 1,377) third-degree relatives. Of 21 affected first-degree relatives: 8 of 21 had febrile seizures (FS), 4 had BECTS, 2 had epilepsy-aphasia spectrum disorder, one had temporal lobe epilepsy with hippoc al sclerosis, 2 had focal epilepsy of unknown cause, 2 had genetic generalized epilepsies, and 3 had miscellaneous. The frequency of epilepsies in relatives and the heterogeneous syndromes observed suggest that BECTS has a genetic component consistent with complex inheritance. Focal epilepsies are the most common seizure disorder observed in relatives, especially BECTS and epilepsy-aphasia spectrum disorder. Additional acquired or environmental factors are likely to be necessary for expression of the seizure disorder.
Publisher: Springer Science and Business Media LLC
Date: 11-1994
DOI: 10.1007/BF00182349
Abstract: Dietary restriction (DR) is a well-known intervention that increases lifespan and resistance to multiple forms of acute stress, including ischemia reperfusion injury. However, the effect of DR on neurological injury after cardiac arrest (CA) remains unknown. The effect of short-term DR (one week of 70% reduced daily diet) on neurological injury was investigated in rats using an asphyxial CA model. The survival curve was obtained using Kaplan-Meier survival analysis. Serum S-100β levels were detected by enzyme linked immunosorbent assay. Cellular apoptosis and neuronal damage were assessed by terminal deoxyribonucleotide transferase dUTP nick end labeling assay and Nissl staining. The oxidative stress was evaluated by immunohistochemical staining of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Mitochondrial biogenesis was examined by electron microscopy and mitochondrial DNA copy number determination. The protein expression was detected by western blot. The reactive oxygen species (ROS) and metabolite levels were measured by corresponding test kits. Short-term DR significantly improved 3-day survival, neurologic deficit scores (NDS) and decreased serum S-100β levels after CA. Short-term DR also significantly attenuated cellular apoptosis, neuronal damage and oxidative stress in the brain after CA. In addition, short-term DR increased mitochondrial biogenesis as well as brain PGC-1α and SIRT1 protein expression after CA. Moreover, short-term DR increased adenosine triphosphate, β-hydroxybutyrate, acetyl-CoA levels and nicotinamide adenine dinucleotide (NAD Reduction of oxidative stress, upregulation of mitochondrial biogenesis and increase of ketone body metabolism may play a crucial role in preserving neuronal function after CA under short-term DR.
Publisher: Elsevier BV
Date: 09-1994
Publisher: Wiley
Date: 13-07-2021
DOI: 10.1002/ANA.26147
Abstract: The MAST family of microtubule‐associated serine–threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in in iduals with a neurodevelopmental disorder, including a mega corpus callosum. Using exome sequencing, we identify MAST3 missense variants in in iduals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP‐16 in HEK293T cells. We identify de novo missense variants in the STK domain in 11 in iduals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 in iduals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug‐resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient‐specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP‐16, compared to wild‐type. These findings suggest the patient‐specific variants may confer MAST3 gain‐of‐function. Moreover, single‐nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. In summary, we describe MAST3 as a novel epilepsy‐associated gene with a potential gain‐of‐function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021 :274–284
Publisher: Oxford University Press (OUP)
Date: 17-02-2016
DOI: 10.1093/BRAIN/AWW019
Abstract: We report on a quantitative analysis of electrocorticography data from a study that acquired continuous ambulatory recordings in humans over extended periods of time. The objectives were to examine patterns of seizures and spontaneous interictal spikes, their relationship to each other, and the nature of periodic variation. The recorded data were originally acquired for the purpose of seizure prediction, and were subsequently analysed in further detail. A detection algorithm identified potential seizure activity and a template matched filter was used to locate spikes. Seizure events were confirmed manually and classified as either clinically correlated, electroencephalographically identical but not clinically correlated, or subclinical. We found that spike rate was significantly altered prior to seizure in 9 out of 15 subjects. Increased pre-ictal spike rate was linked to improved predictability however, spike rate was also shown to decrease before seizure (in 6 out of the 9 subjects). The probability distribution of spikes and seizures were notably similar, i.e. at times of high seizure likelihood the probability of epileptic spiking also increased. Both spikes and seizures showed clear evidence of circadian regulation and, for some subjects, there were also longer term patterns visible over weeks to months. Patterns of spike and seizure occurrence were highly subject-specific. The pre-ictal decrease in spike rate is not consistent with spikes promoting seizures. However, the fact that spikes and seizures demonstrate similar probability distributions suggests they are not wholly independent processes. It is possible spikes actively inhibit seizures, or that a decreased spike rate is a secondary symptom of the brain approaching seizure. If spike rate is modulated by common regulatory factors as seizures then spikes may be useful biomarkers of cortical excitability.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 16-01-1998
DOI: 10.1126/SCIENCE.279.5349.403
Abstract: Benign familial neonatal convulsions (BFNC) is an autosomal dominant epilepsy of infancy, with loci mapped to human chromosomes 20q13.3 and 8q24. By positional cloning, a potassium channel gene ( KCNQ2 ) located on 20q13.3 was isolated and found to be expressed in brain. Expression of KCNQ2 in frog ( Xenopus laevis ) oocytes led to potassium-selective currents that activated slowly with depolarization. In a large pedigree with BFNC, a five–base pair insertion would delete more than 300 amino acids from the KCNQ2 carboxyl terminus. Expression of the mutant channel did not yield measurable currents. Thus, impairment of potassium-dependent repolarization is likely to cause this age-specific epileptic syndrome.
Publisher: Oxford University Press (OUP)
Date: 17-04-2014
DOI: 10.1093/BRAIN/AWU077
Abstract: Epileptic encephalopathies, including Dravet syndrome, are severe treatment-resistant epilepsies with developmental regression. We examined a mouse model based on a human β1 sodium channel subunit (Scn1b) mutation. Homozygous mutant mice shared phenotypic features and pharmaco-sensitivity with Dravet syndrome. Patch-cl analysis showed that mutant subicular and layer 2/3 pyramidal neurons had increased action potential firing rates, presumably as a consequence of their increased input resistance. These changes were not seen in L5 or CA1 pyramidal neurons. This raised the concept of a regional seizure mechanism that was supported by data showing increased spontaneous synaptic activity in the subiculum but not CA1. Importantly, no changes in firing or synaptic properties of gamma-aminobutyric acidergic interneurons from mutant mice were observed, which is in contrast with Scn1a-based models of Dravet syndrome. Morphological analysis of subicular pyramidal neurons revealed reduced dendritic arborization. The antiepileptic drug retigabine, a K+ channel opener that reduces input resistance, d ened action potential firing and protected mutant mice from thermal seizures. These results suggest a novel mechanism of disease genesis in genetic epilepsy and demonstrate an effective mechanism-based treatment of the disease.
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1016/J.EPLEPSYRES.2011.09.011
Abstract: Previous studies have evaluated the inter-session variability of motor thresholds (MT), short intracortical inhibition and intracortical facilitation using paired pulse transcranial magnetic stimulation (TMS) in normal in iduals. Here we evaluate the reproducibility of a range of measures of cortical excitability in patients with epilepsy. Twenty-four drug naïve patients with newly diagnosed epilepsy (13 idiopathic generalised epilepsy [IGE], 11 focal epilepsy) and seventeen non-epilepsy controls were studied. Motor threshold (MT) at rest and recovery curves constructed using paired pulse stimulation at short (2-15 ms) and long (50-400 ms) interstimulus intervals (ISIs) were analysed on two separate occasions, 4-20 weeks apart. The Lin's concordance correlation coefficient test was used to measure agreement between the two sessions. Significant levels of agreement between the two sessions were observed at MT and all the ISIs measured. This was highest in non-epilepsy controls. Cortical excitability measures are repeatable over time in both patients with epilepsy and healthy controls. Increased motor cortex excitability is a stable feature in epilepsy without significant inter-session variability.
Publisher: Elsevier BV
Date: 11-2008
Publisher: Wiley
Date: 02-10-2006
DOI: 10.1111/J.1528-1167.2006.00631.X
Abstract: The diagnosis of paroxysmal events in sleep represents a significant challenge for the clinician, with the distinction of nocturnal epilepsy from nonepileptic sleep disorders often the primary concern. Diagnostic error or uncertainty is not uncommon in this situation, particularly with respect to nocturnal frontal lobe epilepsy (NFLE), which has a variable and often unusual presentation. Such errors can be minimized if the range of nonepileptic disorders with motor activity in sleep is fully appreciated. Here we review these disorders, before discussing the important clinical and electrographic features that allow their accurate differentiation from seizures. Particular emphasis is placed on the differentiation of nocturnal frontal lobe epilepsy from non-rapid eye movement (NREM) arousal disorders and other parasomnias. The value of recording episodes with video EEG polysomnography is discussed.
Publisher: Wiley
Date: 10-2006
DOI: 10.1111/J.1528-1167.2006.00677.X
Abstract: Idiopathic generalized epilepsy (IGE) accounts for approximately 20% of all epilepsies and affects about 0.2% of the general population. The etiology of IGE is genetically determined, but the complex pattern of inheritance suggests an involvement of a large number of susceptibility genes. The objective of the present study was to explore the genetic architecture of common IGE syndromes and to dissect out susceptibility loci predisposing to absence or myoclonic seizures. Genome-wide linkage scans were performed in 126 IGE-multiplex families of European origin ascertained through a proband with idiopathic absence epilepsy or juvenile myoclonic epilepsy. Each family had at least two siblings affected by IGE. To search for seizure type-related susceptibility loci, linkage analyses were carried out in family subgroups segregating either typical absence seizures or myoclonic and generalized tonic-clonic seizures on awakening. Nonparametric linkage scans revealed evidence for complex and heterogeneous genetic architectures involving linkage signals at 5q34, 6p12, 11q13, 13q22-q31, and 19q13. The signal patterns differed in their composition, depending on the predominant seizure type in the families. Our results are consistent with heterogeneous configurations of susceptibility loci associated with different IGE subtypes. Genetic determinants on 11q13 and 13q22-q31 seem to predispose preferentially to absence seizures, whereas loci on 5q34, 6p12, and 19q13 confer susceptibility to myoclonic and generalized tonic-clonic seizures on awakening.
Publisher: Georg Thieme Verlag KG
Date: 04-2010
Publisher: Oxford University Press (OUP)
Date: 2003
DOI: 10.1093/BRAIN/AWG018
Abstract: Although several genes for idiopathic epilepsies from families with simple Mendelian inheritance have been found, genes for the common idiopathic generalized epilepsies, where inheritance is complex, presently are elusive. We studied a large family with epilepsy where the two main phenotypes were childhood absence epilepsy (CAE) and febrile seizures (FS), which offered a special opportunity to identify epilepsy genes. A total of 35 family members had seizures over four generations. The phenotypes comprised typical CAE (eight in iduals) FS alone (15), febrile seizures plus (FS(+)) (three) myoclonic astatic epilepsy (two) generalized epilepsy with tonic-clonic seizures alone (one) partial epilepsy (one) and unclassified epilepsy despite evaluation (two). In three remaining in iduals, no information was available. FS were inherited in an autosomal dominant fashion with 75% penetrance. The inheritance of CAE in this family was not simple Mendelian, but suggestive of complex inheritance with the involvement of at least two genes. A GABA(A) receptor gamma2 subunit gene mutation on chromosome 5 segregated with FS, FS(+) and CAE, and also occurred in in iduals with the other phenotypes. The clinical and molecular data suggest that the GABA(A) receptor subunit mutation alone can account for the FS phenotype. An interaction of this gene with another gene or genes is required for the CAE phenotype in this family. Linkage analysis for a putative second gene contributing to the CAE phenotype suggested possible loci on chromosomes 10, 13, 14 and 15. Examination of these loci in other absence pedigrees is warranted.
Publisher: Wiley
Date: 10-1982
DOI: 10.5694/J.1326-5377.1982.TB132457.X
Abstract: A comatose patient with seizures and focal neurological signs was given vidarabine because herpes simplex encephalitis was a likely diagnosis. Investigations showed that the illness was due to infectious mononucleosis. Although recovery is usual in infectious mononucleosis encephalitis, the complete clinical and neuropsychological recovery documented in this severe case raises the possibility that vidarabine may have exerted a therapeutic effect.
Publisher: Wiley
Date: 04-1998
Abstract: We studied twins to examine the genetics of epilepsy syndromes. We ascertained 358 twin pairs in whom one or both reported seizures. After evaluation, 253 of 358 (71%) had seizure disorders and 105 pairs were false positives. Among the monozygous (MZ) pairs, more were concordant for seizures (48 of 108 casewise concordance = 0.62 +/- 0.05) than among the dizygous (DZ) pairs (14 of 145 casewise concordance = 0.18 +/- 0.04). In 94% of concordant MZ pairs, and 71% of concordant DZ pairs, both twins had the same major epilepsy syndrome. When analyzed according to major epilepsy syndrome, the casewise concordances for generalized epilepsies (MZ = 0.82 DZ = 0.26), both idiopathic (MZ = 0.76 DZ = 0.33) and symptomatic (MZ = 0.83 DZ = 0), were greater than those for partial epilepsies (MZ = 0.36 DZ = 0.05), with intermediate values seen for febrile seizures (MZ = 0.58 DZ = 0.14) and unclassified epilepsies (MZ = 0.53 DZ = 0.18). We conclude that genetic factors are particularly important in the generalized epilepsies but also play a role in the partial epilepsies. The high frequency of concordant MZ pairs with the same major syndrome strongly suggests there are syndrome-specific genetic determinants rather than a broad genetic predisposition to seizures.
Publisher: Wiley
Date: 05-2017
DOI: 10.1002/ANA.24929
Abstract: To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever. We analyzed clinical, electroclinical, and neuroimaging data for 20 patients with MEAK due to recurrent KCNC1 p.R320H mutation. In vitro electrophysiological studies were conducted using whole cell patch-cl to explore biophysical properties of wild-type and mutant K Symptoms began at between 3 and 15 years of age (median = 9.5), with progressively severe myoclonus and rare tonic-clonic seizures. Ataxia was present early, but quickly became overshadowed by myoclonus 10 patients were wheelchair-bound by their late teenage years. Mild cognitive decline occurred in half. Early death was not observed. Electroencephalogram (EEG) showed generalized spike and polyspike wave discharges, with documented photosensitivity in most. Polygraphic EEG-electromyographic studies demonstrated a cortical origin for myoclonus and striking coactivation of agonist and antagonist muscles. Magnetic resonance imaging revealed symmetrical cerebellar atrophy, which appeared progressive, and a prominent corpus callosum. Unexpectedly, transient clinical improvement with fever was noted in 6 patients. To explore this, we performed high-temperature in vitro recordings. At elevated temperatures, there was a robust leftward shift in activation of wild-type K MEAK has a relatively homogeneous presentation, resembling Unverricht-Lundborg disease, despite the genetic and biological basis being quite different. A remarkable improvement with fever may be explained by the temperature-dependent leftward shift in activation of wild-type K
Publisher: Wiley
Date: 1989
Abstract: Ureteric obstruction is a recognised complication of aortic bifurcation grafting where the graft material is in close proximity to the ureter as it crosses the common iliac vessels. We have assessed the value of routine postoperative urography in (1) a retrospective 6-year study of ruptured aortic aneurysm repair (11 patients reviewed) and (2) a prospective 18-month study of all patients receiving intra-abdominal dacron grafts (24 assessable patients) in a district general hospital. Renal function was normal in all cases and only 1 ureter was shown at urography to be minimally dilated but not significantly obstructed out of 32 'at risk' ureters in 18 patients in the 2 studies. This complication is uncommon, and no particular advantage can be demonstrated in positioning the ureters either behind or in front of the graft limbs. There is no place for routine urography which should be reserved for the patient with symptoms of ureteric obstruction.
Publisher: Wiley
Date: 02-0014
DOI: 10.1111/J.1528-1167.2012.03430.X
Abstract: We aimed to assess long-term seizure outcome and risk factors for seizure recurrence in a cohort of patients who have undergone extratemporal resection for management of refractory seizures. Eighty-one patients underwent extratemporal resection at Austin Health, Melbourne, Australia (1991-2004). Seizure recurrence was any postoperative disabling seizure (complex partial seizure [CPS] ± secondary generalization). Multivariate Cox proportional hazards regression models examined potential preoperative and perioperative risk factors and the risk associated with early postoperative seizures (≤ 28 days postsurgery). The change between preoperative and postoperative seizure frequency was also measured. Median follow-up was 10.3 years (range 1-17.7). The probabilities of freedom from disabling seizures (on or off antiepileptic medication) were 40.7% (95% confidence interval [CI] 30-51) at 1 month, 23.5% (95% CI 15-33) at 1 year, and 14.7% (95% CI 8-23) at 5 years postoperative. Reduction of disabling seizures to at least 20% of preoperative frequency was attained by 57% of patients at 5 postoperative years. Of the preoperative erioperative factors, focal cortical dysplasia (FCD) type 1 (hazard ratio [HR] 1.90, 95% CI 1.08-3.34, p = 0.025) and incomplete resection (HR 1.71, 95% CI 1.06-2.76, p = 0.028) were independent recurrence risks. After surgery, an early postoperative seizure was the only factor associated with higher risk (HR 4.28 [2.42-7.57], p = 0.00). Distinction between subtypes of focal cortical dysplasia, which can be made using magnetic resonance imaging (MRI) criteria, may be useful for preoperative prognostication. Early seizures after surgery are not benign and may be markers of factors that contribute to seizure recurrence. Most patients achieve substantial reduction in seizure frequency. Further study of the significance of this reduction in terms of surgical "success" or otherwise is required.
Publisher: Wiley
Date: 07-01-2013
DOI: 10.1111/EPI.12065
Abstract: To characterize the frequency and nature of the family history of seizures in probands with epilepsy falling within the epilepsy-aphasia spectrum (EAS) in order to understand the genetic architecture of this group of disorders. Patients with epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), Landau-Kleffner syndrome (LKS), atypical benign partial epilepsy (ABPE), and intermediate epilepsy-aphasia disorders (IEAD) were recruited. All affected and available unaffected relatives up to three degrees of relatedness underwent phenotyping using a validated seizure questionnaire. Pedigrees were constructed for all families. The proportion of affected relatives according to each degree of relatedness was calculated. The epilepsy phenotypes in close relatives were analyzed. The data were compared to the families of probands with benign childhood epilepsy with centrotemporal spikes (BECTS) using the same methodology. Thirty-one probands, including five ECSWS, three LKS, one ABPE, and 22 IEAD were recruited. The mean age of seizure onset was 3.9 (range 0.5-7) years. A male predominance was seen (68%, 21/31) . Sixteen (51.6%) of 31 had a positive family history of seizures. Among 1,254 relatives, 30 (2.4%) had a history of seizures: 13 (10.2%) of 128 first-degree relatives, 5 (1.7%) of 291 second-degree relatives, and 12 (1.4%) of 835 third-degree relatives. Thirteen had febrile seizures, including two who had both febrile seizures and epilepsy. Of the 19 relatives with epilepsy, 4 had BECTS, 4 epilepsies with focal seizures of unknown cause, 3 IEAD, and 7 unclassified. One had genetic generalized epilepsy. In the families of the BECTS probands, 9.8% of first-degree, 3% of second-degree, and 1.5% of third-degree relatives had seizures, which was not significantly different from the EAS cohort families. The frequencies of seizures in relatives of probands with EAS suggest that the underlying genetic influence of EAS is consistent with complex inheritance and similar to BECTS. The phenotypic pattern observed in the affected relatives comprised predominantly febrile seizures and focal seizures. These findings suggest that a shared genetic predisposition to focal epilepsies underpins the epilepsy-aphasia spectrum.
Publisher: Informa UK Limited
Date: 07-1993
DOI: 10.1080/01688639308402582
Abstract: This study retrospectively investigated the effect of left (LHS) versus right (RHS) hippoc al sclerosis on verbal memory, measured by means of the Paired Associate Learning and Logical Memory subtests of the Wechsler Memory Scale (WMS) administered as part of a routine preoperative assessment. Patients were selected for the presence of unilateral hippoc al sclerosis by means of preoperative magnetic resonance imaging (MRI) and postoperative neuropathology. The LHS patients (n = 20) were significantly worse on paired associate learning than RHS patients (n = 18), the performance of RHS patients being consistent with normative standards. In contrast, no laterality effect was seen on the immediate and delayed recall of passages the evidence suggests that both groups performed at a mildly impaired level. It was suggested that the laterality of verbal memory is conditional upon specific task demands in patients with damage to mesial temporal structures.
Publisher: MDPI AG
Date: 31-07-2023
Abstract: Aicardi Syndrome (AIC) is a rare neurodevelopmental disorder recognized by the classical triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile epileptic spasms syndrome. The diagnostic criteria of AIC were revised in 2005 to include additional phenotypes that are frequently observed in this patient group. AIC has been traditionally considered as X-linked and male lethal because it almost exclusively affects females. Despite numerous genetic and genomic investigations on AIC, a unifying X-linked cause has not been identified. Here, we performed exome and genome sequencing of 10 females with AIC or suspected AIC based on current criteria. We identified a unique de novo variant, each in different genes: KMT2B, SLF1, SMARCB1, SZT2 and WNT8B, in five of these females. Notably, genomic analyses of coding and non-coding single nucleotide variants, short tandem repeats and structural variation highlighted a distinct lack of X-linked candidate genes. We assessed the likely pathogenicity of our candidate autosomal variants using the TOPflash assay for WNT8B and morpholino knockdown in zebrafish (Danio rerio) embryos for other candidates. We show expression of Wnt8b and Slf1 are restricted to clinically relevant cortical tissues during mouse development. Our findings suggest that AIC is genetically heterogeneous with implicated genes converging on molecular pathways central to cortical development.
Publisher: American Medical Association (AMA)
Date: 03-08-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-1999
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1997
DOI: 10.1097/00019052-199704000-00007
Abstract: A minor genetic predisposition to partial epilepsy has been long recognized. Recently, a group of idiopathic partial epilepsies with autosomal dominant inheritance has been identified. The clinical features and molecular genetic findings in these epilepsies are outlined in the present review. The first genetic defect in an idiopathic epilepsy has been found in autosomal dominant nocturnal frontal lobe epilepsy, the archetype of this newly recognized group of inherited partial epilepsies.
Publisher: Wiley
Date: 29-10-2001
DOI: 10.1046/J.1528-1157.2001.02001.X
Abstract: The literature regarding seizure outcome and prognostic factors for outcome after temporal lobectomy is often contradictory. This is problematic, as these data are the basis on which surgical decisions and counseling are founded. We sought to clarify inconsistencies in the literature by critically examining the methods and findings of recent research. A systematic review of the 126 articles concerning temporal lobectomy outcome published from 1991 was conducted. Major methodologic issues in the literature were heterogeneous definitions of seizure outcome, a predominance of cross-sectional analyses (83% of studies), and relatively short follow-up in many studies. The range of seizure freedom was wide (33-93% median, 70%) there was a tendency for better outcome in more recent studies. Of 63 factors analyzed, good outcome appeared to be associated with several factors including preoperative hippoc al sclerosis, anterior temporal localization of interictal epileptiform activity, absence of preoperative generalized seizures, and absence of seizures in the first postoperative week. A number of factors had no association with outcome (e.g., age at onset, preoperative seizure frequency, and extent of lateral resection). Apparently conflicting results in the literature may be explained by the methodologic issues identified here (e.g., s le size, selection criteria and method of analysis). To obtain a better understanding of patterns of long-term outcome, increased emphasis on longitudinal analytic methods is required. The systematic review of possible risk factors for seizure recurrence provides a basis for planning further research.
Publisher: Wiley
Date: 21-07-2004
Publisher: Oxford University Press (OUP)
Date: 05-1999
Abstract: High-resolution MRI can detect dual pathology (an extrahippoc al lesion plus hippoc al atrophy) in about 5-20% of patients with refractory partial epilepsy referred for surgical evaluation. We report the results of 41 surgical interventions in 38 adults (mean age 31 years, range 14-63 years) with dual pathology. Three patients had two operations. The mean postoperative follow-up was 37 months (range 12-180 months). The extrahippoc al lesions were cortical dysgenesis in 15, tumour in 10, contusion/infarct in eight and vascular malformation in five patients. The surgical approach aimed to remove what was considered to be the most epileptogenic lesion, and the 41 operations were classified into lesionectomy (removal of an extrahippoc al lesion) mesial temporal resection (removal of an atrophic hippoc us) and lesionectomy plus mesial temporal resection (removal of both the lesion and the atrophic hippoc us). Lesionectomy plus mesial temporal resection resulted in complete freedom from seizures in 11/15 (73%) patients, while only 2/10 (20%) patients who had mesial temporal resection alone and 2/16 (12.5%) who had a lesionectomy alone were seizure-free (P < 0.001). When classes I and II were considered together results improved to 86, 30 and 31%, respectively. Our findings indicate that in patients with dual pathology removal of both the lesion and the atrophic hippoc us is the best surgical approach and should be considered whenever possible.
Publisher: Wiley
Date: 10-07-2012
DOI: 10.1111/J.1528-1167.2012.03585.X
Abstract: We aimed to refine the phenotypic spectrum and map the causative gene in two families with familial focal epilepsy with variable foci (FFEVF). A new five-generation Australian FFEVF family (A) underwent electroclinical phenotyping, and the original four-generation Australian FFEVF family (B) (Ann Neurol, 44, 1998, 890) was re-analyzed, including new affected in iduals. Mapping studies examined segregation at the chromosome 22q12 FFEVF region. In family B, the original whole genome microsatellite data was reviewed. Five subjects in family A and 10 in family B had FFEVF with predominantly awake attacks and active EEG studies with a different phenotypic picture from other families. In family B, reanalysis excluded the tentative 2q locus reported. Both families mapped to chromosome 22q12. Our results confirm chromosome 22q12 as the solitary locus for FFEVF. Both families show a subtly different phenotype to other published families extending the clinical spectrum of FFEVF.
Publisher: Wiley
Date: 08-04-2010
DOI: 10.1111/J.1528-1167.2010.02572.X
Abstract: Epilepsy due to encephaloceles of the temporal pole may be an under recognized, treatable cause of refractory temporal lobe epilepsy (TLE). We describe three adult patients initially labeled "lesion negative" TLE. In all, video–electroencephalography (EEG) revealed ictal theta in the left temporal region and positron emission tomography (PET) showed temporal lobe hypometabolism, but neuropsychology revealed preserved verbal memory. Close inspection of structural magnetic resonance imaging (MRI) suggested subtle abnormalities at the tip of the left temporal lobe. High resolution computed tomography (CT) confirmed bony defects in the inner table of the skull. 3T MRI with fine coronal and sagittal slices indicated cerebrospinal fluid (CSF) and brain tissue protruding into the defects. All proceeded to resection of the temporal tip and became seizure free. Patients with "lesion negative" TLE should have careful review of images covering the temporal pole. If encephalocele is suspected, further imaging with high-resolution CT and MRI can be helpful. Temporal polar resection, sparing mesial structures, appears to be curative.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-05-2021
DOI: 10.1212/WNL.0000000000011855
Abstract: To identify the causative gene in a large unsolved family with genetic epilepsy with febrile seizures plus (GEFS+), we sequenced the genomes of family members, and then determined the contribution of the identified gene to the pathogenicity of epilepsies by examining sequencing data from 2,772 additional patients. We performed whole genome sequencing of 3 members of a GEFS+ family. Subsequently, whole exome sequencing data from 1,165 patients with epilepsy from the Epi4K dataset and 1,329 Australian patients with epilepsy from the Epi25 dataset were interrogated. Targeted resequencing was performed on 278 patients with febrile seizures or GEFS+ phenotypes. Variants were validated and familial segregation examined by Sanger sequencing. Eight previously unreported missense variants were identified in SLC32A1 , coding for the vesicular inhibitory amino acid cotransporter VGAT. Two variants cosegregated with the phenotype in 2 large GEFS+ families containing 8 and 10 affected in iduals, respectively. Six further variants were identified in smaller families with GEFS+ or idiopathic generalized epilepsy (IGE). Missense variants in SLC32A1 cause GEFS+ and IGE. These variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition. Examination of further epilepsy cohorts will determine the full genotype–phenotype spectrum associated with SLC32A1 variants.
Publisher: SAGE Publications
Date: 23-03-2012
Abstract: Benign neonatal sleep myoclonus is an uncommon, nonepileptic disorder characterized by myoclonic jerks appearing in the neonatal period that occur predominantly during sleep. Although self-limiting, the disorder is frequently confused with epileptic neonatal seizures. A few familial cases have been reported however the genetics has not been studied. We ascertained 3 families with 2 or more affected in iduals and analyzed the pedigrees. We used microsatellite markers to determine if the disorder was possibly linked to KCNQ2 or KCNQ3, the 2 genes that cause most cases of benign familial neonatal seizures, a disorder that it could be easily confused with. The 3 pedigrees, including one with 4 affected in iduals, were suggestive of autosomal dominant inheritance. The loci for KCNQ2 and KCNQ3 were excluded in the 2 larger families. We conclude that benign neonatal sleep myoclonus can show autosomal dominant inheritance and is not allelic with benign familial neonatal seizures.
Publisher: Society for Neuroscience
Date: 09-2000
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-02-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1999
Publisher: Wiley
Date: 07-07-2001
DOI: 10.1046/J.1528-1157.2001.042007837.X
Abstract: Severe myoclonic epilepsy of infancy (SMEI) is an intractable epilepsy of early childhood of unknown etiology. It is often associated with a family history of seizure disorders, but epilepsy phenotypes have not been well described. We sought to characterize the seizure phenotypes of relatives to better understand to the genetic basis of SMEI. Probands with SMEI were identified, and systematic family studies were performed. Epilepsy syndromes were characterized in affected family members. Twelve probands with SMEI were identified. Eleven of the 12 probands with SMEI had a family history of seizures, and the twelfth was the result of a consanguineous marriage. We found that 16.7% of full siblings and 8.3% of parents had definite seizures. A total of 39 affected family members was identified. The most common phenotype was febrile seizures in 14, febrile seizures plus in seven, partial epilepsy in two, and there were single in iduals with SMEI, myoclonic-astatic epilepsy, Lennox-Gastaut syndrome, and 13 cases with unclassified or unconfirmed seizures. The family history of seizures in SMEI is in keeping with the spectrum of seizure phenotypes seen in generalized epilepsy with febrile seizures plus (GEFS+). Our findings suggest that SMEI is the most severe phenotype in the GEFS+ spectrum.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1038/GIM.2017.100
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.NEUROSCIENCE.2007.05.038
Abstract: Two novel mutations (R85C and R85H) on the extracellular immunoglobulin-like domain of the sodium channel beta1 subunit have been identified in in iduals from two families with generalized epilepsy with febrile seizures plus (GEFS+). The functional consequences of these two mutations were determined by co-expression of the human brain NaV1.2 alpha subunit with wild type or mutant beta1 subunits in human embryonic kidney (HEK)-293T cells. Patch cl studies confirmed the regulatory role of beta1 in that relative to NaV1.2 alone the NaV1.2+beta1 currents had right-shifted voltage dependence of activation, fast and slow inactivation and reduced use dependence. In addition, the NaV1.2+beta1 current entered fast inactivation slightly faster than NaV1.2 channels alone. The beta1(R85C) subunit appears to be a complete loss of function in that none of the modulating effects of the wild type beta1 were observed when it was co-expressed with NaV1.2. Interestingly, the beta1(R85H) subunit also failed to modulate fast kinetics, however, it shifted the voltage dependence of steady state slow inactivation in the same way as the wild type beta1 subunit. Immunohistochemical studies revealed cell surface expression of the wild type beta1 subunit and undetectable levels of cell surface expression for both mutants. The functional studies suggest association of the beta1(R85H) subunit with the alpha subunit where its influence is limited to modulating steady state slow inactivation. In summary, the mutant beta1 subunits essentially fail to modulate alpha subunits which could increase neuronal excitability and underlie GEFS+ pathogenesis.
Publisher: Elsevier BV
Date: 12-1996
DOI: 10.1016/S1059-1311(96)80018-5
Abstract: The efficacy and tolerability of vigabatrin as add-on therapy was assessed in patients with uncontrolled partial seizures. Ninety-seven patients entered this seven-centre, double-blind, placebo-crossover study. Vigabatrin (2 g or 3 g) or placebo was administered daily. Vigabatrin was well-tolerated and did not cause clinically significant adverse drug effects when added to established anticonvulsant therapy. No significant differences were observed between dose groups for the overall incidence of adverse events, although drowsiness and visual disturbances (diplopia, ataxia, visual abnormalities) showed a dose-related increase with vigabatrin treatment. The results of this study indicate that vigabatrin, given in a daily dose of either 2 g or 3 g is significantly more effective than placebo in reducing seizure frequency among patients with partial seizures.
Publisher: Oxford University Press (OUP)
Date: 12-12-2006
DOI: 10.1093/HMG/DDL456
Abstract: The expression level for 15,887 transcripts in lymphoblastoid cell lines from 19 monozygotic twin pairs (10 male, 9 female) were analysed for the effects of genotype and sex. On an average, the effect of twin pairs explained 31% of the variance in normalized gene expression levels, consistent with previous broad sense heritability estimates. The effect of sex on gene expression levels was most noticeable on the X chromosome, which contained 15 of the 20 significantly differentially expressed genes. A high concordance was observed between the sex difference test statistics and surveys of genes escaping X chromosome inactivation. Notably, several autosomal genes showed significant differences in gene expression between the sexes despite much of the cellular environment differences being effectively removed in the cell lines. A publicly available gene expression data set from the CEPH families was used to validate the results. The heritability of gene expression levels as estimated from the two data sets showed a highly significant positive correlation, particularly when both estimates were close to one and thus had the smallest standard error. There was a large concordance between the genes significantly differentially expressed between the sexes in the two data sets. Analysis of the variability of probe binding intensities within a probe set indicated that results are robust to the possible presence of polymorphisms in the target sequences.
Publisher: Wiley
Date: 07-2009
DOI: 10.1111/J.1528-1167.2009.02059.X
Abstract: The association between a specific polymorphism (3435C>T) in the ABCB1 gene, coding for the membrane drug transporter P-glycoprotein (PgP), and pharmacoresistance to seizure control is controversial. Studies have been limited by multiple drug use, chronic cohorts with varying definitions, and retrospective clinical data. Herein we examine the relationship of this polymorphism with seizure recurrence in three independent international cohorts of patients newly treated for epilepsy. Data were collected on demographics, medication details, and seizure control after 12 months of treatment. The distribution of ABCB1 3435C>T genotypes was compared between patients with and without recurrent unprovoked seizures. Five hundred forty-two newly treated patients were enrolled (212 from Australia, 285 from Scotland, and 45 from Hong Kong). A total of 38.4% had recurrent unprovoked seizures after starting antiepileptic drug (AED) treatment. Genotype frequencies and ethnicity did not differ between the Scottish and Australian cohorts, but both were significantly different in the Hong Kong cohort. There was no significant relationship between the ABCB1 3435C>T genotype and the rate of recurrence of unprovoked seizures in the three cohorts in idually or combined however the epilepsy syndrome and a greater number of seizures pretreatment was associated with an increased risk of seizure recurrence. The ABCB1 3435C>T genotype does not have a major role in determining the efficacy of seizure control with initial AED therapy. The study highlights issues that arise in combining pharmacogenetic datasets from different ethnic regions and health systems, an approach that is essential to advance this field.
Publisher: Elsevier BV
Date: 08-2006
DOI: 10.1016/J.MOLMED.2006.06.005
Abstract: Febrile seizures, which occur in young children, have long been known to have a major inherited component. Mutations in some genes that encode sodium channel and GABA(A) receptor subunits have been found in a few families affected by febrile seizures. These mutations account only for a minority of cases, and much remains to be learnt about the molecular architecture of febrile seizures. A rare inherited cause--a mutation in the GABA(A) receptor subunit GABRG2 gene--has been recently shown to cause a temperature-dependent intracellular trafficking defect. This is an important step in unravelling the molecular pathogenesis of this common childhood disorder.
Publisher: AMPCo
Date: 09-1996
DOI: 10.5694/J.1326-5377.1996.TB124954.X
Abstract: Given the increase in incidence and mortality from cancer in recent years in Latin America and Peru, it is necessary to identify frailty older adults at higher risk of disability, hospitalizations and mortality. However, its measure is complex and requires time. For this reason, it has been proposed that frailty can be evaluated by a single measure, as gait speed. We aimed to evaluate the role of gait speed as a predictor of mortality in older men with cancer in Peru. A prospective cohort study was carried out that included military veterans (aged 60 years and older) with an oncological diagnosis evaluated at the 922 older men were analyzed from 2013 to 2015, 56.9% (n = 525) of whom were >70 years of age. 41.3% (n = 381) had slow gait speed with a mortality incidence of 22.9% (n = 211) at the end of follow-up. The most frequent types of cancer in the participants who died were of the lung and airways (26.1%), liver and bile ducts (23.2%), and lymphomas and leukemias (16.6%). In the adjusted Cox regression analysis, we found that slow gait speed was a risk factor for mortality in older men with cancer (adjusted hazard ratio = 1.55 95% confidence interval: 1.21-2.23). Slow gait speed was associated with an increased risk of mortality in older men with cancer. Gait speed could represent a simple, useful, inexpensive, rapidly applicable marker of frailty for the identification of older men at higher risk of mortality. Gait speed could be useful in low- and middle-income countries, and in rural areas with limited access to health services.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-12-2021
DOI: 10.1212/WNL.0000000000012946
Abstract: We compared heart rate variability (HRV) in sudden unexpected death in epilepsy (SUDEP) cases and living epilepsy controls. This international, multicenter, retrospective, nested case–control study examined patients admitted for video-EEG monitoring (VEM) between January 1, 2003, and December 31, 2014, and subsequently died of SUDEP. Time domain and frequency domain components were extracted from 5-minute interictal ECG recordings during sleep and wakefulness from SUDEP cases and controls. We identified 31 SUDEP cases and 56 controls. Normalized low-frequency power (LFP) during wakefulness was lower in SUDEP cases (median 42.5, interquartile range [IQR] 32.6–52.6) than epilepsy controls (55.5, IQR 40.7–68.9 p = 0.015, critical value = 0.025). In the multivariable model, normalized LFP was lower in SUDEP cases compared to controls (contrast −11.01, 95% confidence interval [CI] −20.29 to 1.73 p = 0.020, critical value = 0.025). There was a negative correlation between LFP and the latency to SUDEP, where each 1% incremental reduction in normalized LFP conferred a 2.7% decrease in the latency to SUDEP (95% CI 0.95–0.995 p = 0.017, critical value = 0.025). Increased survival duration from VEM to SUDEP was associated with higher normalized high-frequency power (HFP p = 0.002, critical value = 0.025). The survival model with normalized LFP was associated with SUDEP ( c statistic 0.66, 95% CI 0.55–0.77), which nonsignificantly increased with the addition of normalized HFP ( c statistic 0.70, 95% CI 0.59–0.81 p = 0.209). Reduced short-term LFP, which is a validated biomarker for sudden death, was associated with SUDEP. Increased HFP was associated with longer survival and may be cardioprotective in SUDEP. HRV quantification may help stratify in idual SUDEP risk. This study provides Class III evidence that in patients with epilepsy, some measures of HRV are associated with SUDEP.
Publisher: Elsevier BV
Date: 02-1995
DOI: 10.1016/0006-8993(94)01338-I
Abstract: Noradrenergic neurons are thought to be involved in the process of seizure development and long-term central nervous system plasticity associated with kindling and epilepsy. These processes involve actions of noradrenaline at alpha 1-, alpha 2- and beta 1-adrenergic receptors. In this study, quantitative in vitro autoradiography was used to investigate possible changes in the density of brain alpha 1-adrenergic receptors in a kindling model of epilepsy in the rat. Kindling was produced by daily unilateral stimulation of the amygdala. The alpha 1A+alpha 1B subtypes of adrenergic receptors were labelled with the alpha 1-selective antagonist, [3H]prazosin and alpha 1B receptors, detected in the presence of 10 nM WB4101 to selectively occupy alpha 1A receptors, accounted for 50% of total alpha 1 receptors in cerebral cortex. Autoradiographic studies identified significant and long-lasting, ipsilateral increases in specific [3H]prazosin binding throughout layers I-III of the cortex in sham-operated, unstimulated rats, presumably caused by the surgical implantation of the stimulating electrode within the basolateral amygdaloid nucleus. Binding to alpha 1A + alpha 1B receptors and alpha 1B receptors was increased by an average of 35 and 60%, respectively under these conditions. Stimulation-evoked seizures produced dramatic bilateral increases in specific [3H]prazosin binding to alpha 1A + alpha 1B receptors and particularly to alpha 1B receptors in layers I-III of all cortical areas examined. These changes were rapidly induced and the largest increases (range alpha 1A + alpha 1B 80-340% alpha 1B 165-380%) occurred at 0.5-2 h after the last stage 5 kindled seizure. At 1 and 3 days after the last seizure, increases were measured for both alpha 1A + alpha 1B and alpha 1B receptors in layers I-III of particular cortical regions, but not overall (e.g. 60-210% increase in perirhinal cortex at both times, with increases also in retrosplenial, hindlimb, occipital, parietal and temporal cortices). Between 2-8 wk post-stimulation specific receptor binding levels were equivalent to those in sham-operated, unstimulated rats. In contrast to the large and widespread increases in outer cortical [3H]prazosin binding, smaller increases were detected in the inner cortex (layer V-VI) at in idual times (65-75% increase at 30 min), while no significant changes occurred in several other brain regions examined, including thalamus, which contained a high density of alpha 1A and alpha 1B receptors, or hippoc us which has a low density of both alpha 1 receptor subtypes.(ABSTRACT TRUNCATED AT 400 WORDS)
Publisher: Wiley
Date: 30-09-2010
DOI: 10.1111/J.1528-1167.2010.02726.X
Abstract: Paroxysmal exercise-induced dyskinesia (PED) and epilepsy without intellectual disability have recently been recognized as manifestations of deficiency of the glucose transporter GLUT1, due to mutations in the gene SLC2A1. We describe a family with six definitely affected members in two generations. Two had PED, three had epilepsy, and one had both. A missense mutation in SLC2A1 (c.950A>C p.N317T) was detected in five living affected members, but absent in three nonaffected first-degree members and in one subject believed to be a phenocopy. The clinical picture of mild epilepsy with onset in adolescence or early adulthood plus PED should raise a suspicion of GLUT1 deficiency.
Publisher: Cold Spring Harbor Laboratory
Date: 20-04-2021
DOI: 10.1101/2021.04.20.21255696
Abstract: De novo missense variants in KCNQ5 , encoding the voltage-gated K + channel K V 7.5, have been described as a cause of developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease-related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. 1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-cl recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with docking and homology modeling. We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures, two variants were also associated with mild to moderate ID. All three missense variants displayed a strongly decreased current density indicating a loss-of-function (LOF). When mutant channels were co-expressed with wild-type (WT) K V 7.5 or K V 7.5 and K V 7.3 channels, three variants also revealed a significant dominant-negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The p.Arg359Cys variant altered PI(4,5)P 2 - interaction, presumably in the non-conducting preopen-closed state. Our study indicates that specific deleterious KCNQ5 variants are associated with GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant-negative effects through functional, rather than trafficking deficits. LOF of K V 7.5 channels will reduce the M-current, likely resulting in increased excitability of K V 7.5- expressing neurons. Further studies on a network level are necessary to understand which circuits are affected and how the variants induce generalized seizures.
Publisher: Cold Spring Harbor Laboratory
Date: 19-03-2021
DOI: 10.1101/2021.03.19.436102
Abstract: To compare the frequency and impact on channel function of KCNH2 variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss-of-function KCNH2 variants as predictive biomarkers of SUDEP risk. We searched for KCNH2 variants with a minor allele frequency of 5%. Functional analysis in Xenopus laevis oocytes was performed for all KCNH2 variants identified. KCNH2 variants were found in 11.1% (10/90) of SUDEP in iduals compared to 6.0% (20/332) of epilepsy controls ( p = 0.11). Loss-of-function KCNH2 variants, defined as causing 20% reduction in maximal litude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about three-fold enrichment (nominal p = 0.04). KCNH2 variants that did not change channel function occurred at a similar frequency in SUDEP (2.2% 2/90) and epilepsy control (2.7% 9/332) cohorts ( p 0.99). Rare KCNH2 variants ( 1% allele frequency) associated with greater loss of function and an ∼11-fold enrichment in the SUDEP cohort (nominal p = 0.03). In silico tools were unable to predict the impact of a variant on function highlighting the need for electrophysiological analysis. These data show that loss-of-function KCNH2 variants are enriched in SUDEP patients and suggest that cardiac mechanisms contribute to SUDEP risk. We propose that genetic screening in combination with functional analysis can identify loss-of-function KCNH2 variants that could act as biomarkers of an in idual’s SUDEP risk.
Publisher: Wiley
Date: 07-01-2013
DOI: 10.1111/EPI.12076
Abstract: The benign occipital epilepsies of childhood include Panayiotopoulos and Gastaut syndromes a third syndrome, idiopathic photosensitive occipital epilepsy may also begin in childhood or adolescence. We describe siblings with occipital epilepsy characterized by refractory, frequent, brief visual seizures and normal magnetic resonance imaging (MRI). Electroencephalography (EEG) with functional MRI (fMRI) supports localization of interictal epileptiform activity to the occipital lobes. Our hypothesis is that the siblings share a genetic focal epilepsy arising from a localized occipital network. Although they share many features of Gastaut syndrome, their refractory ongoing seizures in adolescence is unusual and likely due to underlying genetic determinants.
Publisher: Wiley
Date: 29-11-2020
DOI: 10.1002/ACN3.51258
Publisher: Wiley
Date: 02-2022
DOI: 10.1002/ALZ.12549
Abstract: Many patients with cognitive and neuropsychiatric symptoms face diagnostic delay and misdiagnosis. We investigated whether cerebrospinal fluid (CSF) neurofilament light (NfL) and total‐tau (t‐tau) could assist in the clinical scenario of differentiating neurodegenerative (ND) from psychiatric disorders (PSY), and rapidly progressive disorders. Biomarkers were examined in patients from specialist services (ND and PSY) and a national Creutzfeldt‐Jakob registry (Creutzfeldt‐Jakob disease [CJD] and rapidly progressive dementias/atypically rapid variants of common ND, RapidND). A total of 498 participants were included: 197 ND, 67 PSY, 161 CJD, 48 RapidND, and 20 controls. NfL was elevated in ND compared to PSY and controls, with highest levels in CJD and RapidND. NfL distinguished ND from PSY with 95%/78% positive/negative predictive value, 92%/87% sensitivity/specificity, 91% accuracy. NfL outperformed t‐tau in most real‐life clinical diagnostic dilemma scenarios, except distinguishing CJD from RapidND. We demonstrated strong generalizable evidence for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2000
DOI: 10.1097/00008480-200012000-00004
Abstract: Recent molecular insights into the human idiopathic epilepsies have suggested the central role of ligand-gated and voltage-gated ion channels in their etiology. So far, genes coding for sodium and potassium channel subunits as well as a nicotinic cholinergic receptor subunit have been identified for Mendelian idiopathic epilepsies. In vitro and in vivo studies of mutations demonstrate functional changes, allowing new insights in mechanisms underlying hyperexcitability. Similarly, spontaneous murine epilepsy models have been associated with calcium channel molecular defects. The major challenge before us in understanding the genetics of the epilepsies is to identify genes for common forms of epilepsy following complex inheritance. Once such genes are discovered, the gene-gene-environmental interactions producing specific epilepsy syndromes can be explored.
Publisher: Wiley
Date: 12-2000
DOI: 10.1111/J.1528-1157.2000.TB01504.X
Abstract: To assess serum prolactin levels in sudden unexpected death in epilepsy (SUDEP) and control groups to test the hypothesis that if seizures occur routinely as a terminal event in SUDEP, then raised prolactin levels may be an indicator of terminal seizure. Blood was taken for measurement of prolactin levels from subjects with SUDEP and three control groups. The control groups were those with epilepsy dying from causes other than epilepsy (e.g., ischemic heart disease or injuries), physiologically stressed in iduals without epilepsy (they were admitted to the hospital after an acute illness and died after several hours to 3 days), and nonepileptic rapid deaths (these people collapsed suddenly and died at the scene). In the SUDEP group, evidence for terminal seizure was considered to be at least one of the following: body found half on, half off the bed, or urinary incontinence at the scene, or bitten lips or tongue at autopsy. There was evidence for terminal seizure at the scene or at autopsy in four of the 10 SUDEP cases. Serum prolactin levels were not significantly increased in the SUDEP group compared with the controls. None of the SUDEP subjects, including those with clinical evidence of a terminal seizure, had high prolactin levels characteristic of those observed after seizures in living subjects. Prolactin levels are not raised in SUDEP, even if there is evidence of terminal seizure. As prolactin takes 15-20 min to peak after a seizure in life, there may be insufficient time for a prolactin increase to occur in SUDEP. Thus prolactin levels cannot be used to determine if a deceased in idual with epilepsy had a seizure or to answer the broad question whether SUDEP is always associated with a terminal seizure.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-01-2005
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-07-2021
DOI: 10.1212/CPJ.0000000000001114
Abstract: To explore the impact of psychiatric comorbidities on all-cause mortality in adults with epilepsy from a cohort of patients admitted for video-EEG monitoring (VEM) over 2 decades. A retrospective medical record audit was conducted on 2,709 adults admitted for VEM and diagnosed with epilepsy at 3 Victorian comprehensive epilepsy programs from 1995 to 2015. A total of 1,805 patients were identified in whom the record of a clinical evaluation by a neuropsychiatrist was available, excluding 27 patients who died of a malignant brain tumor known at the time of VEM admission. Epilepsy and lifetime psychiatric diagnoses were determined from consensus opinion of epileptologists and neuropsychiatrists involved in the care of each patient. Mortality and cause of death were determined by linkage to the Australian National Death Index and National Coronial Information System. Compared with the general population, mortality was higher in people with epilepsy (PWE) with a psychiatric illness (standardized mortality ratio [SMR] 3.6) and without a psychiatric illness (SMR 2.5). PWE with a psychiatric illness had greater mortality compared with PWE without (hazard ratio 1.41, 95% confidence interval 1.02–1.97) after adjusting for age and sex. No single psychiatric disorder by itself conferred increased mortality in PWE. The distribution of causes of death remained similar between PWE with psychiatric comorbidities and those without. The presence of comorbid psychiatric disorders in adults with epilepsy is associated with increased mortality, highlighting the importance of identifying and treating psychiatric comorbidities in these patients.
Publisher: Wiley
Date: 08-2018
Abstract: Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome in which affected in iduals within a family typically have a variety of epilepsy phenotypes, varying from simple febrile seizures and febrile seizures plus with a good outcome to severe epileptic encephalopathies. Here, we review the spectrum of epilepsy phenotypes, the genetic architecture of GEFS+, and the implicated genes. Using an illustrative clinical case study, we describe important steps in managing patients with GEFS+: making the diagnosis of GEFS+, appropriate genetic testing, and counselling.
Publisher: Wiley
Date: 10-02-2023
DOI: 10.1111/EPI.17519
Abstract: Familial adult myoclonus epilepsy/benign adult familial myoclonic epilepsy (FAME/BAFME) has emerged as a specific and recognizable epilepsy syndrome with autosomal dominant inheritance found around the world. Here, we trace the history of this syndrome. Initially, it was likely conflated with other familial myoclonus epilepsies, especially the progressive myoclonus epilepsies. As the progressive myoclonus epilepsies became better understood clinically and genetically, this group began to stand out and was first recognized as such in Japan. Subsequently, families were recognized around the world and there was debate as to whether they represented one or multiple disorders. Clarification came with the identification of pentanucleotide repeats in Japanese families, and FAME/BAFME was quickly shown to be due to pentanucleotide expansions in at least six genes. These have geographic predilections and appear to have been caused by historically ancient initial mutations. Within and between families, there is some variation in the phenotype, explained in large part by expansion size, but whether there are features specific to in idual genes remains uncertain.
Publisher: Wiley
Date: 29-10-2001
DOI: 10.1046/J.1528-1157.2001.23000.X
Abstract: To evaluate the safety, tolerability, efficacy, and impact on quality of life of gabapentin (Neurontin GBP) as adjunctive therapy in patients with refractory partial seizures. AUS-STEPS was an open-label, multicenter, prospective study in patients experiencing partial seizures who were inadequately controlled with one to three concurrent antiepileptic drugs (AEDs). GBP treatment was titrated to a maximum of 4,800 mg/day, over a treatment period of 24 weeks, to achieve an efficacious and tolerable dosage. Efficacy was assessed by seizure-frequency data. Quality of life was evaluated by using the QOLIE-10 questionnaire, and safety was assessed by adverse-event reports and clinical laboratory findings. A total of 176 patients received treatment with GBP, with 174 evaluable for intention-to-treat (ITT) efficacy analysis. A reduction of >50% in overall seizure frequency was observed in 93 patients (53%). There was a small (4.6%) overall improvement in QOLIE-10 score. The most frequent adverse events were dizziness (31%), fatigue (29%), somnolence (27%), headache (21%), and ataxia (20%), with no major increase seen in adverse events necessitating discontinuation as the dose of GBP was titrated upward. This study indicates that patients with partial epilepsy may be effectively treated with GBP at dosages of < or =4,800 mg/day, without altering the safety profile of the drug.
Publisher: Wiley
Date: 2012
DOI: 10.1002/ANA.22644
Abstract: KCNQ2 and KCNQ3 mutations are known to be responsible for benign familial neonatal seizures (BFNS). A few reports on patients with a KCNQ2 mutation with a more severe outcome exist, but a definite relationship has not been established. In this study we investigated whether KCNQ2/3 mutations are a frequent cause of epileptic encephalopathies with an early onset and whether a recognizable phenotype exists. We analyzed 80 patients with unexplained neonatal or early-infantile seizures and associated psychomotor retardation for KCNQ2 and KCNQ3 mutations. Clinical and imaging data were reviewed in detail. We found 7 different heterozygous KCNQ2 mutations in 8 patients (8/80 10%) 6 mutations arose de novo. One parent with a milder phenotype was mosaic for the mutation. No KCNQ3 mutations were found. The 8 patients had onset of intractable seizures in the first week of life with a prominent tonic component. Seizures generally resolved by age 3 years but the children had profound, or less frequently severe, intellectual disability with motor impairment. Electroencephalography (EEG) at onset showed a burst-suppression pattern or multifocal epileptiform activity. Early magnetic resonance imaging (MRI) of the brain showed characteristic hyperintensities in the basal ganglia and thalamus that later resolved. KCNQ2 mutations are found in a substantial proportion of patients with a neonatal epileptic encephalopathy with a potentially recognizable electroclinical and radiological phenotype. This suggests that KCNQ2 screening should be included in the diagnostic workup of refractory neonatal seizures of unknown origin.
Publisher: Research Square Platform LLC
Date: 22-09-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-04-2004
DOI: 10.1212/01.WNL.0000118213.94650.81
Abstract: Background and Objectives: A number of familial temporal lobe epilepsies (TLE) have been recently recognized. Mutations in LGI1 (leucine-rich , glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF). The authors aimed to determine the spectrum of TLE phenotypes with LGI1 mutations, to study the frequency of mutations in ADPEAF, and to examine the role of LGI1 paralogs in ADPEAF without LGI1 mutations. Methods: The authors performed a clinical and molecular analysis on 75 pedigrees comprising 54 with a variety of familial epilepsies associated with TLE and 21 sporadic TLE cases. All were studied for mutations in LGI1 . ADPEAF families negative for LGI1 mutations were screened for mutations in LGI2, LGI3, and LGI4 . Results: Four families had ADPEAF, 22 had mesial TLE, 11 had TLE with febrile seizures, two had TLE with developmental abnormalities, and 15 had various other TLE syndromes. LGI1 mutations were found in two of four ADPEAF families, but in none of the other 50 families nor in the 21 in iduals with sporadic TLE. The mutations were novel missense mutations in exons 1 (c.124T→G C42G) and 8 (c.1418C→T S473L). No mutations in LGI2, LGI3, or LGI4 were found in the other two ADPEAF families. Conclusion: In TLE, mutations in LGI1 are specific for ADPEAF but do not occur in all families. ADPEAF is genetically heterogeneous, but mutations in LGI2, LGI3, or LGI4 did not account for families without LGI1 mutations.
Publisher: Wiley
Date: 09-01-2007
Publisher: Elsevier BV
Date: 09-1998
Publisher: Wiley
Date: 09-1997
DOI: 10.1111/J.1528-1157.1997.TB05202.X
Abstract: Treatment strategies based on the molecular biology of the epilepsies may soon become a reality. Critical steps in this process are identifying molecular genetic defects in specific epilepsies, understanding of the neurobiologic consequences of those defects, and developing methods to correct the molecular defects or their downstream consequences. Identification of molecular defects is easier in single-gene epilepsies than in those with complex inheritance, although the latter are more common. A number of epilepsies have been mapped and, in two cases, specific genes have been identified. Unverricht-Lundborg disease is caused by defects in the cystatin B gene, with absence of the gene product. Autosomal dominant nocturnal frontal lobe epilepsy in some families is caused by mutations in the alpha4-subunit of the nicotinic acetylcholine receptor gene. In vitro studies suggest that the mutations lead to impaired function of the acetylcholine receptor, raising the possibility of cholinergic therapy for this condition. Advances in the molecular biology of the epilepsies are likely to change our understanding radically and to allow opportunities to develop innovative new treatments for epilepsy.
Publisher: Massachusetts Medical Society
Date: 25-05-2017
DOI: 10.1056/NEJME1702205
Publisher: Oxford University Press (OUP)
Date: 19-08-2013
DOI: 10.1093/HMG/DDT403
Publisher: Wiley
Date: 21-05-2021
DOI: 10.1002/ACN3.51374
Abstract: Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of in iduals with drug‐resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. We performed exome sequencing of 1,128 in iduals with non‐familial non‐acquired focal epilepsy (NAFE) (762 non‐responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 in iduals with NAFE (165 non‐responders, 185 responders). We performed gene‐based and gene‐set‐based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. We found no gene or gene set that reached genome‐wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non‐familial NAFE and in association with drug‐resistant NAFE. Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non‐familial NAFE and imply their involvement in drug‐resistant epilepsy. Future large‐scale genetic research studies are needed to substantiate these findings.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Oxford University Press (OUP)
Date: 07-01-2013
DOI: 10.1093/HMG/DDS558
Publisher: SAGE Publications
Date: 07-2015
DOI: 10.5698/1535-7511-15.4.192
Abstract: Genetics should now be part of everyday clinical epilepsy practice. Good data exist to provide empiric risks based on epilepsy syndrome diagnosis. Investigation of the molecular basis of some epilepsies is now a practical clinical task and is of clear value to the patient and family. In some cases, specific therapeutic decisions can now be made based on genetic findings, and this scenario of precision therapy is likely to increase in the coming years.
Publisher: Springer Science and Business Media LLC
Date: 10-12-2018
DOI: 10.1038/S41467-018-07524-Z
Abstract: The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 in iduals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have erse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
Publisher: Oxford University Press (OUP)
Date: 02-1999
DOI: 10.1093/HMG/8.2.345
Abstract: 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 in idual, 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.
Publisher: Elsevier BV
Date: 2010
Publisher: Wiley
Date: 2001
DOI: 10.1002/1531-8249(200101)49:1<45::AID-ANA9>3.0.CO;2-F
Abstract: Whereas some patients with epilepsy have known acquired or genetic causes, in many the cause is unknown. By analyzing monozygotic twins, discordant for epilepsy, subtle etiological factors may be detected. We analyzed 12 monozygotic, discordant twins for factors explaining discordancy. These factors were presence of major clinical risk factors, presence of possibly epileptogenic lesions on brain magnetic resonance imaging (MRI), and quantitative brain volume abnormalities. Major risk factors, with associated acquired lesions were found in 4 of 12 twins. An MRI lesion without a major risk factor was found in a further 4 of 12 twins. Two of these had unilateral malformations of cortical development, 1 had bilateral periventricular heterotopia, and 1 had focal atrophy. Significant twin-twin differences in MRI volumes without obvious MRI lesions or major risk factors were found in 2 of 12 twins. Both had larger volumes than their co-twins, and idiopathic generalized epilepsy. No clinical or MRI findings accounting for discordance for epilepsy were found in 2 of 12 twins. In 10 of 12 pairs a clinical or MR correlate of epilepsy was found some of those were subtle and only apparent by twin-twin comparison. They may be due to occult acquired factors, such as prenatal insults, or to genetic abnormalities resulting from postfertilization genetic processes.
Publisher: Springer Science and Business Media LLC
Date: 17-10-2006
Abstract: Physical activity (PA) is inversely associated with obesity but the effect has been difficult to quantify using questionnaires. In particular, the shape of the association has not yet been well described. Pedometers provide an opportunity to better characterize the association. Residents of households over the age of 25 years in randomly selected census districts in Tasmania were eligible to participate in the AusDiab cross-sectional survey conducted in 1999-2000. 1848 completed the AusDiab survey and 1126 of these (609 women and 517 men) wore a pedometer for 2-weekdays. Questionnaire data on recent PA, TV time and other factors were obtained. The outcomes were waist circumference (in cm) and body mass index (BMI) (kg/m(2)). Increasing daily steps were associated with a decline in the obesity measures. The logarithmic nature of the associations was indicated by a sharper decline for those with lower daily steps. For ex le, an additional 2000 steps for those taking only 2000 steps per day was associated with a reduction of 2.8 (95% confidence interval (CI): 2.1,4.4) cm in waist circumference among men (for women 2.2 (95% CI: 0.6, 3.9 cm)) with a baseline of only 2000, steps compared to a 0.7 (95% CI 0.3, 1.1) cm reduction (for women 0.6 (95% CI: 0.2, 1.0)) for those already walking 10,000 steps daily. In the multivariable analysis, clearer associations were detected for PA and these obesity measures using daily step number rather than PA time by questionnaire. Pedometer measures of activity indicate that the inverse association between recent PA and obesity is logarithmic in form with the greatest impact for a given arithmetic step number increase seen at lower levels of baseline activity. The findings from this study need to be examined in prospective settings.
Publisher: Wiley
Date: 29-01-2010
DOI: 10.1111/J.1528-1167.2009.02254.X
Abstract: Patients taking antiepileptic drugs (AEDs) have an increased incidence of fractures. This study investigated chronic AED use and physical contributors to falls risk using an AED-discordant, twin and sibling matched-pair approach, and assessed clinically relevant subgroups: AED polytherapy longer-duration AED and falls history. Twenty-nine same-sex (mean age 44.9 years, 59% female), ambulatory, community-dwelling twin and sibling pairs, discordant for AED exposure (and AED-indication), were recruited. Validated clinical and laboratory tests of strength, gait, and balance were performed. Relevant AED levels, and fasting serum s les for 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and immunoreactive parathyroid hormone (iPTH) levels were taken. There were significant mean within-pair differences in tests of static and dynamic balance, with the AED user having poorer balance function than the AED nonuser. No difference was seen in lower limb strength or gait measures. Increased duration of AED therapy and AED polytherapy were independent predictors of increased sway. No significant within-pair differences were seen in fasting serum levels of 1,25(OH)(2)D, 25OHD and iPTH after Bonferroni correction. Balance performance is impaired in AED users compared to their matched nonuser siblings. Pairs where the AED users took AED polytherapy, or had a longer duration of AED use, had more impaired balance performance. These balance deficits may contribute to the increased rate of fractures in this population.
Publisher: Cambridge University Press (CUP)
Date: 12-2008
Abstract: Adverse events during the perinatal period have traditionally been thought to contribute to the risk of febrile seizures although an association has not been found in large epidemiological studies. Disease-discordant twins provide a means to assess the role of non-shared environmental factors while matching for confounding factors and avoiding difficulties of epidemiological studies in singletons. This study aimed to examine the association of obstetric events and febrile seizures in a community-based twin study. Twenty-one twin pairs discordant for febrile seizures were ascertained from a community-based twin register. Obstetric events were scored using the McNeil-Sjöström Scale for Obstetric Complications and expressed as a summary score (OC score). The frequency of in idual obstetric events in affected and unaffected twins, the within-pair differences in OC scores and other markers of perinatal risk including birthweight, birth order and Apgar scores were examined. No significant difference was found in the frequency of in idual obstetric events, nor in OC scores between affected and unaffected twins. No differences in birth weight, birth order, 1- or 5-minute Apgar scores were observed. Our results confirm previous findings that obstetric events are not associated with the risk of febrile seizures.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-09-2001
Abstract: Unverricht-Lundborg disease (ULD) is the prototypical form of progressive myoclonus epilepsy, and subjects are usually very photosensitive. ULD is caused by mutations in the cystatin B (CSTB) gene the most common mutation is expansion of a dodecamer repeat near the promoter. The authors studied a five-generation Arab family with ULD lacking photosensitivity. An Arab family from the Galilee region of Israel with progressive myoclonus epilepsy was clinically evaluated. Blood s les were obtained from three living affected and 16 unaffected in iduals. Expansion of dodecamer repeat in the CSTB gene was examined. The three living affected in iduals showed spontaneous and action myoclonus, ataxia, and mild dementia. EEG in two in iduals showed generalized polyspike-wave without photosensitivity. The family structure with large sibships and multiple consanguineous loops allowed the authors to examine the gene over four generations of adults. The three living affected in iduals were homozygous for repeat expansions and 11 of the 16 unaffected family members were heterozygous. Instability was demonstrated by the presence of expansions of different sizes occurring on the same haplotype background in this inbred family. Fragment size variations could be unequivocally detected in two sibships. The expansions were in the 49 to 54 dodecamer repeat range. Changes in one generation were small, 1 to 4 repeat units, consisting of either enlargements or contractions. Instability of the expanded dodecamer repeats in the cystatin B gene is frequent. Almost invariably, a small change is observed in parent-child transmission. The lack of photosensitivity in this family is unexplained.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-08-2012
Publisher: Oxford University Press (OUP)
Date: 06-1997
DOI: 10.1093/HMG/6.6.943
Abstract: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the first, and to date only, idiopathic epilepsy for which a specific mutation has been found. A missense mutation in the critical M2 domain of the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4) has been recently identified in one large Australian pedigree. Here we describe a novel mutation in the M2 domain of the CHRNA4 gene in a Norwegian family. Three nucleotides (GCT) were inserted at nucleotide position 776 into the coding region for the C-terminal end of the M2 domain. Physiological investigations of the receptor reconstituted with the mutated CHRNA4 subunit reveal that this insertion does not prevent the receptor function but increases its apparent affinity for ACh. In addition, this mutant receptor shows a significantly lower calcium permeability that, at the cellular level, may correspond to a loss of function. Comparison of the two mutations identified so far in families with ADNFLE illustrates that different mutations can result in similar phenotypes.
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.YEBEH.2007.06.005
Abstract: The goal of the work described here was to explore the efficacy, safety, and tolerability of adjunctive therapy with levetiracetam and associated changes in health-related quality of life in Australian patients with uncontrolled partial seizures. A phase IV open-label 16-week clinical trial was undertaken. Patients received adjunctive levetiracetam, adjusted according to clinical response to a final daily dose of 1000-3000 mg. Seizure frequency and adverse events were recorded. A quality-of-life questionnaire (QOLIE-10-P) was administered at the start and end of therapy. The intention-to-treat population (N=152) experienced a median reduction in total seizure frequency of 57.7%. The 50% responder rate was 56.6%, and 12.5% of patients were free of seizures throughout the trial. Adverse events were mostly mild or moderate, leading to discontinuation in 9.9%. The most common adverse events were somnolence, fatigue, headache, and dizziness. Behavioral adverse events occurred in approximately one-quarter of patients, including two-thirds of those who withdrew because of adverse events. There was an improvement in the QOLIE-10-P score. Levetiracetam is effective and well tolerated when added to existing therapy in patients with uncontrolled partial seizures.
Publisher: Springer Science and Business Media LLC
Date: 02-1991
DOI: 10.1007/BF00305874
Abstract: Autoantibodies to GAD, an important marker of the autoimmune process in type I or insulin-dependent diabetes mellitus (IDDM), are also found in non-diabetic in iduals with autoimmune polyendocrine syndrome type 1 (APS1), APS2, and stiff man syndrome (SMS). Most IDDM sera contain two distinct GAD antibody specificities, one of which targets an epitope region in the middle-third of GAD65 (IDDM-E1 amino acids 221-359) and one of which targets the carboxy-third of GAD65 (IDDM-E2 amino acids 453-569). Using 11 chimeric GAD65/GAD67 proteins to maintain conformation-dependent epitopes of GAD65, we compared the humoral repertoire of IgG antibodies from an in idual with APS2-like disease (b35, b78, and b96) and MoAbs from an IDDM patient (MICA-2, MICA-3, and MICA-4). Neither the APS2 IgG antibodies nor the IDDM MoAbs bind the amino-terminal third of GAD65, but instead target the carboxy-terminal two-thirds of GAD65. Amino acids 270-359 (IDDM-E1) are targeted by one APS2 IgG antibody and MICA-4, while two other APS2 IgG antibodies, MICA-2 and MICA-3, target amino acids 443-585 (IDDM-E2). Using GAD65/67 chimera that span the IDDM-E2 region, we found that MICA-2 binds amino acids 514-528 of GAD65, but two APS2 IgG antibodies require this region and amino acids 529-570. In contrast, the binding of MICA-3 requires two discontinuous amino acid segments of GAD65 (452-513 and 528-569), but not amino acids 514-528. These results indicate that there are both similarities and differences in the humoral response to GAD65 in APS2 and IDDM.
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1086/319516
Publisher: Wiley
Date: 31-08-2015
DOI: 10.1111/EPI.13127
Abstract: Up to half of patients assessed for suspected new-onset epileptic seizures report previous undiagnosed events. This suggests that delay to timely and expert assessment is a major issue. Very little is known about the degree of delay or nature of the undiagnosed events, impacting on our understanding of new-onset epilepsy. In this study we aimed to examine events that occur before presentation, as well as the extent and risk factors for delay to assessment. Included in this retrospective study were 220 patients diagnosed at the First Seizure Clinic (Austin Health, Australia) between 2003 and 2006 with an epileptic index seizure. Patients with a prior diagnosis of epileptic seizures were excluded. Chart review was undertaken, including detailed interviews conducted by an epileptologist at first assessment. Logistic regression assessed risk factors for delay from first event to presentation, including event characteristics, socioeconomic disadvantage, employment, and distance to medical facility. Forty-one percent (n = 90) of patients had one or more event before their index seizure. Of these, 50% had multiple or more than five prior events and 28% experienced one or more convulsive event before the index seizure. Of the total 220 patients, 36% had delayed presentation >4 weeks, 21% delayed >6 months, and 14% delayed >2 years. First events without convulsions or features likely to disrupt behaviour were strongly associated with delay (p = <0.001). Relative socioeconomic disadvantage was also associated with delay to presentation (p = 0.04). Our findings suggest a gap in early diagnosis and care in a sizable proportion of new-onset cases, despite a "first world" urban environment and the availability of free basic medical care. Delay appears particularly likely when events are nonconvulsive or low-impact, suggesting that these seizure types may be underrepresented in studies of new-onset epilepsy. This has implications for our understanding of the incidence, evolution, impact, and treatment response of new-onset epilepsy.
Publisher: Wiley
Date: 04-08-2023
DOI: 10.1111/EPI.17727
Abstract: Visual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1. Enrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12–60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient , and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1‐weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics. Brain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of .005 for each learning difficulty reported (95% confidence interval [CI] = −.007 to −.002, p = .0003). Each 10‐year increase in age at MRI was associated with a ratio reduction of .006 (95% CI = −.007 to −.005, p .0001). For male participants, the ratio was .011 less than for female participants (95% CI = −.014 to −.007, p .0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities. This study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population.
Publisher: Wiley
Date: 27-10-2004
DOI: 10.1111/J.0013-9580.2004.22904.X
Abstract: Success has been achieved in identifying many mutations in rare monogenic epilepsy syndromes by using linkage analysis, but dissecting the genetic basis of common epilepsy syndromes has proven more difficult. Common epilepsies are genetically complex disorders believed to be influenced by variation in several susceptibility genes. Association studies can theoretically identify these genes, but despite more than 50 association studies in epilepsy, no consistent or convincing susceptibility genes have emerged, leading to scepticism about the association-study approach. We review the results of existing association studies in focal epilepsies, generalized epilepsies, febrile seizures, and epilepsy pharmacogenetics. By using an illustrative ex le, we discuss how methodologic issues of s le size, selection of appropriate controls, population stratification, and significance thresholds can lead to bias and false-positive associations the importance of biologic plausibility also is emphasized. Newer methodologic refinements for association studies, such as use of two control groups, genomic control, haplotyping, and use of two independent datasets, are discussed. A summary of existing guidelines and a checklist for planning and appraising such association studies in epilepsy is presented. We remain cautiously optimistic that with methodologic refinements and multicenter collaborations with large s le sizes, association studies will ultimately be useful in dissecting the genetic basis of common epilepsy syndromes.
Publisher: Proceedings of the National Academy of Sciences
Date: 23-01-2020
Abstract: GABA (γ-aminobutyric acid) is the brain’s predominant inhibitory neurotransmitter and exerts a strong inhibitory influence through extrasynaptic GABA A receptors. This form of neurotransmission is known as tonic inhibition. Tonic inhibition is usually thought to reduce the excitability of all neurons, but here we show that it can selectively modulate the excitability of different types of neurons. Surprisingly, tonic inhibition can increase excitability in a common subtype of interneuron, and modeling results suggest this is achieved through the neuron’s electrophysiological, or functional, properties. These results provide insight into the impact of tonic inhibition upon neural activity and suggest a mechanism through which GABA may modulate the excitability of neurons in a selective manner.
Publisher: BMJ
Date: 09-10-0005
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-11-2006
DOI: 10.1212/01.WNL.0000248189.93630.4F
Abstract: To determine factors predictive of long-term seizure outcome in children with new-onset temporal lobe epilepsy (TLE). A community-based cohort of 77 children with new-onset TLE, including 14 with possible TLE, were followed prospectively with formal review 7 and 14 years following seizure onset. Diagnoses were re-evaluated at each review, and changed when new clinical, EEG, or imaging data were compelling. Sixty-four patients sustained the diagnosis of TLE over time two were lost to follow-up. Age at follow-up was 12 to 29 years (median 20 years). Median follow-up was 13.7 years, 95% being followed for greater than 10 years. Nineteen patients were seizure free (SF) and off treatment, having not had seizures for 5 to 15 years. Duration of active TLE in the SF group was 1 to 8 years, the children being treated with 0 to 3 antiepileptic drugs (AEDs). Forty-three patients were not seizure free (NSF) and had ongoing seizures or had undergone epilepsy surgery. These children were treated with 1 to 10 AEDs. Fifteen NSF patients experienced 22 nonterminal seizure remissions of 1 to 7 years duration. Seventeen children had a significant antecedent to TLE. Lesions were identified on neuroimaging in 28 and included hippoc al sclerosis (HS) in 10, tumor in 8, and dysplasia in 7. All children with lesions on MRI were NSF (p < 0.001). Focal slowing on EEG was also associated with persistent seizures (p = 0.05), although this was correlated with a lesion on MRI. Infantile onset of epilepsy, family history of seizures, initial seizure frequency, antecedents, and early seizure remissions were not predictive of seizure outcome. Seizures spontaneously remit in approximately one third of children with new-onset TLE. A lesion on MRI predicts intractable seizures in TLE and the potential need for epilepsy surgery.
Publisher: Wiley
Date: 28-09-2008
DOI: 10.1002/ANA.21440
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 1999
DOI: 10.1212/WNL.52.2.327
Abstract: To examine the nature and frequency of anterior temporal lobe (AT) abnormalities that occur in intractable temporal lobe epilepsy (TLE). We reviewed the MR scans and clinical histories of 50 consecutive patients with intractable TLE. Histopathology was available in 42 surgically treated cases. MRI demonstrated loss of the gray-white matter differentiation and decreased T1- and increased T2-weighted signal in the ipsilateral AT in 58% of the 50 patients. This appearance was observed in 64% of the 36 patients with hippoc al sclerosis (HS) but was also seen in patients without HS. These changes were associated with temporal lobe atrophy, a higher hippoc al T2 relaxation time, and a history of febrile convulsions. Pathologic examination showed that the MRI appearances were not caused by dysplasia, degenerative abnormalities, or inflammatory change. Histologic quantitation showed increased glial cell nuclei counts in the intractable TLE cases compared with controls. There was no difference in glial cell numbers between cases with AT abnormality and those without this appearance. Presence or absence of changes was not predictive of preoperative neuropsychology, postoperative change in neuropsychology, or seizure outcome after surgery. These frequently seen ipsilateral changes are not caused by gliosis and may reflect a nonspecific increase in water content in the temporal lobe. This may be due to myelin abnormalities or some other as yet unidentified pathologic factor.
Publisher: SAGE Publications
Date: 07-2012
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.EPLEPSYRES.2013.02.011
Abstract: Febrile seizures (FS) are the most common seizure syndrome. A strong genetic component has been well established through family and twin studies however, such studies have not examined the genetics of different FS types (simple, complex, febrile status epilepticus) and sub-syndromes (true FS, febrile seizures plus (FS+), 'FS with later epilepsy'). Here we used a community-based twin s le to analyze genetic factors within different FS subtypes and FS syndromes. Twin pairs were ascertained from the twin database of the Epilepsy Research Centre. A retrospective chart review was conducted and follow-up attempted for all subjects. Casewise concordance values were calculated for the different subgroups and intra-pair variation was analyzed. One hundred and seventy-nine twin pairs with FS were identified. Overall casewise concordance for FS in monozygotic (MZ) twins (0.62) was greater than in dizygotic (DZ) twins (0.16, p<0.0001). A greater concordance amongst MZ pairs than DZ twin pairs was also observed for all FS subtypes and FS sub-syndromes, particularly in twins with FS+. Within concordant MZ pairs, we did not observe the co-occurrence of FS and FS+. These results suggest a strong genetic contribution to different FS subtypes and sub-syndromes. They also support the existence of distinct genetic factors for different FS subtypes and sub-syndromes, especially FS+. This information is important for the strategic planning of next generation sequencing studies of febrile seizures.
Publisher: Wiley
Date: 05-04-2019
DOI: 10.1111/EPI.14698
Publisher: Wiley
Date: 11-1998
DOI: 10.1111/J.1528-1157.1998.TB01308.X
Abstract: In patients with refractory temporal lobe epilepsy, studies have suggested volume deficits measured by MRI of brain structures outside the epileptogenic hippoc us. Hippoc al sclerosis (HS) is a frequent, but not obligate, finding in such patients. The present study examines the influence of the presence of HS on quantitative magnetic resonance imaging (MRI) measurements. We analyzed 47 patients and 30 controls by quantitative MRI, including intracranial volume (ICV), hemicranial volume, hippoc al volume (HCV), and T2 relaxometry. MRI results were compared with histological findings in the resected temporal lobe. Histology documented HS in 35 patients (HS group) and other findings in 12 patients (no-HS group). In both groups, the hemicranial volume ipsilateral to the epileptogenic focus was significantly smaller than on the contralateral side (p < 0.004). The HCV on both sides was smaller in the HS group compared with patients without HS (p < or = 0.004). Unilateral hippoc al atrophy and increased T2 value were found in 71% of patients with HS, and bilaterally normal HCV and T2 value were found in 67% of patients without HS. The smaller hemicranial volume on the focus side, irrespective of the presence or absence of HS suggests a different pathogenic mechanism for the additional hemicranial volume deficit, compared to HS itself. The contralateral HCV deficit depends on the presence of HS, indicating a pathogenic connection between damage to both hippoc i.
Publisher: Oxford University Press (OUP)
Date: 10-2012
DOI: 10.1093/BRAIN/AWS241
Publisher: Wiley
Date: 12-2021
DOI: 10.1002/ALZ.058647
Abstract: Accurate, timely diagnosis of neurodegenerative disorders, in particular distinguishing primary psychiatric from neurological disorders and in younger people, can be challenging. There is a need for biomarkers to reduce the diagnostic odyssey and improve outcomes. Neurofilament light (NfL) has shown promise as a diagnostic biomarker in a wide range of disorders. Our Markers in Neuropsychiatric Disorders (MiND) Study builds on our pilot (Eratne et al, ANZJP, 2020), to explore the diagnostic and broader utility of plasma and cerebrospinal fluid (CSF) NfL and other novel markers such as phosphorylated tau 181 (p‐tau181), in a broad range of psychiatric and neurodegenerative/neurological disorders, with a view of translation into routine clinical practice. We assessed plasma and/or CSF NfL and p‐tau181 concentrations in broad cohorts, including: patients assessed for neurocognitive sychiatric symptoms at Neuropsychiatry and Melbourne Young‐Onset Dementia services and other services, in a wide range of disorders including Alzheimer disease, frontotemporal dementia, schizophrenia, bipolar disorder, depression, Niemann‐Pick Type C, epilepsy, functional neurological disorders. The most recent primary consensus diagnosis informed by established diagnostic criteria was categorised: primary psychiatric disorder (PPD), neurodegenerative/neurological disorder (ND), or healthy controls (HC). Findings from over 500 patients articipants will be presented, which indicate that CSF and plasma NfL levels are significantly elevated in a broad range of ND compared to a broad range of PPD, and HC, and bvFTD progressors from phenocopy syndromes, differentiating with areas under the curve of .90, sensitivity and specificity %. Plasma P‐tau181 levels distinguished Alzheimer disease (mainly younger sporadic), compared to other neurodegenerative disorders, with AUC 0.90, 90% sensitivity and specificity. As recruitment, s le analysis, data collection is ongoing, the most up to date results will be presented. NfL shows great promise as a diagnostic test to assist with the common, challenging diagnostic dilemma of distinguishing neurodegenerative from non‐neurodegenerative and primary psychiatric disorders. Plasma p‐tau181 shows strong diagnostic utility in younger‐onset Alzheimer disease. A significantly elevated NfL in someone with a psychiatric diagnosis should prompt consideration of neurodegenerative differentials. Plasma NfL could dramatically alter clinical care of patients with neuropsychiatric and neurological symptoms, improving outcomes for patients, their families, the healthcare system, and clinical trials.
Publisher: Springer Science and Business Media LLC
Date: 08-1998
DOI: 10.1038/1252
Abstract: Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures. We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant beta1 subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.
Publisher: Wiley
Date: 22-12-2011
DOI: 10.1111/J.1528-1167.2010.02911.X
Abstract: Absence epilepsies are common, with a major genetic contribution to etiology. Certain environmental factors can influence absence occurrence but a complete understanding of absence precipitation is lacking. Herein we investigate if lowering blood glucose increases spike-wave activity in mouse models with varying seizure susceptibility. Three mouse models were used: an absence seizure model based on the knockin of a human GABA(A) γ2(R43Q) mutation (DBA(R43Q)), the spike-wave discharge (SWD)-prone DBA/2J strain, and the seizure resistant C57Bl/6 strain. Electrocorticography (ECoG) studies were recorded to determine SWDs during hypoglycemia induced by insulin or overnight fasting. An insulin-mediated reduction in blood glucose levels to 4 mm (c.a. 40% reduction) was sufficient to double SWD occurrence in the DBA(R43Q) model and in the SWD-prone DBA/2J mouse strain. Larger reductions in blood glucose further increased SWDs in both these models. However, even with large reductions in blood glucose, no discharges were observed in the seizure-resistant C57Bl/6 mouse strain. Injection of glucose reversed the impact of insulin on SWDs in the DBA(R43Q) model, supporting a reduction in blood glucose as the modulating influence. Overnight fasting reduced blood glucose levels to 4.5 mm (c.a. 35% reduction) and, like insulin, caused a doubling in occurrence of SWDs. Low blood glucose can precipitate SWDs in genetically predisposed animal models and should be considered as a potential environmental risk factor in patients with absence epilepsy.
Publisher: Elsevier BV
Date: 2000
Abstract: Sudden unexpected death in epilepsy (SUDEP) refers to sudden unexpected death in patients with epilepsy in whom autopsy fails to reveal an anatomic or toxicological cause of death. The purpose of this study was to examine associated factors and mechanisms relating to SUDEP in Victoria. The study was a retrospective study based on data from questionnaires completed by treating doctors and coronial files including police reports of death, autopsy and toxicology reports. The deaths were of people with epilepsy in Victoria that were referred to the coroner between 1991 and 1997. There were 15,751 coronial autopsies of which 357 had epilepsy and 50 (14%) were SUDEPs. The SUDEP rate was approximately 1 per 3000 epileptics per year. This study suggested the following associations: young age, tonic-clonic seizures, seizure frequency greater than 10/year, duration of epilepsy greater than 10 years, mental retardation, psychiatric disease and alcohol abuse. Antiepileptic drug (AED) compliance was rated by treating doctors as good in 24 cases. One or more postmortem AED drug levels was subtherapeutic in 30 of 50 cases. Only 5 were receiving psychotropic drugs only 1 of these was receiving more than one of these drugs. A history of recent unusually stressful life event was present in only 4 cases. At least 11 showed evidence of terminal seizure, and the majority of events occurred in sleep. These observations support the hypothesis that seizures are the mechanism of many cases of SUDEP. The associations observed were largely in agreement with previous studies. However, seizure frequency was greater and duration of epilepsy greater than most previous studies. The role of factors such as AED compliance, psychotropic drug prescription and recent unusually stressful life event is less clear. This highlights the need for case-control studies of risk factors for SUDEP.
Publisher: Elsevier BV
Date: 09-2014
Publisher: Springer Science and Business Media LLC
Date: 10-1994
DOI: 10.1007/BF00181061
Publisher: Frontiers Media SA
Date: 08-09-2020
Publisher: BMJ
Date: 03-1993
Abstract: Localised neuronal heterotopias are an increasingly recognised cause of intractable focal epilepsies. The aetiology of these circumscribed disorders of neuronal migration is often unknown although in some instances proximity to areas of prenatal infarction suggests that severe ischaemia was responsible. A patient is described with intractable complex partial seizures associated with heterotopic grey matter and cerebral hypoplasia confined to the territory of the left posterior cerebral artery the left hippoc us was spared. Angiography showed a normal left anterior choroidal artery but a hypoplastic left posterior cerebral artery, implicating prenatal ischaemia without frank infarction as the aetiology of the malformation.
Publisher: Elsevier BV
Date: 12-2013
Publisher: Oxford University Press (OUP)
Date: 05-01-2005
DOI: 10.1093/BRAIN/AWH377
Abstract: Progressive myoclonus epilepsy (PME) has a number of causes, of which Unverricht-Lundborg disease (ULD) is the most common. ULD has previously been mapped to a locus on chromosome 21 (EPM1). Subsequently, mutations in the cystatin B gene have been found in most cases. In the present work we identified an inbred Arab family with a clinical pattern compatible with ULD, but mutations in the cystatin B gene were absent. We sought to characterize the clinical and molecular features of the disorder. The family was studied by multiple field trips to their town to clarify details of the complex consanguineous relationships and to personally examine the family. DNA was collected for subsequent molecular analyses from 21 in iduals. A genome-wide screen was performed using 811 microsatellite markers. Homozygosity mapping was used to identify loci of interest. There were eight affected in iduals. Clinical onset was at 7.3 +/- 1.5 years with myoclonic or tonic-clonic seizures. All had myoclonus that progressed in severity over time and seven had tonic-clonic seizures. Ataxia, in addition to myoclonus, occurred in all. Detailed cognitive assessment was not possible, but there was no significant progressive dementia. There was intrafamily variation in severity three required wheelchairs in adult life the others could walk unaided. MRI, muscle and skin biopsies on one in idual were unremarkable. We mapped the family to a 15-megabase region at the pericentromeric region of chromosome 12 with a maximum lod score of 6.32. Although the phenotype of in idual subjects was typical of ULD, the mean age of onset (7.3 years versus 11 years for ULD) was younger. The locus on chromosome 12 does not contain genes for any other form of PME, nor does it have genes known to be related to cystatin B. This represents a new form of PME and we have designated the locus as EPM1B.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2007
Publisher: Wiley
Date: 12-2002
Publisher: Wiley
Date: 15-05-2015
DOI: 10.1111/EPI.13020
Abstract: We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions. Detailed clinical data were collected from 36 families comprising two or more in iduals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci. Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE) 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of in iduals with KCNQ2 mutations later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability a molecular lesion was identified in two the other family remains unsolved. Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE.
Publisher: Wiley
Date: 25-05-2016
DOI: 10.1111/EPI.13381
Abstract: This is the first of a two-part primer on the genetics of the epilepsies within the Genetic Literacy Series of the Genetics Commission of the International League Against Epilepsy. In Part 1, we cover the foundations of epilepsy genetics including genetic epidemiology and the range of genetic variants that can affect the risk for developing epilepsy. We discuss various epidemiologic study designs that have been applied to the genetics of the epilepsies including population studies, which provide compelling evidence for a strong genetic contribution in many epilepsies. We discuss genetic risk factors varying in size, frequency, inheritance pattern, effect size, and phenotypic specificity, and provide ex les of how genetic risk factors within the various categories increase the risk for epilepsy. We end by highlighting trends in epilepsy genetics including the increasing use of massive parallel sequencing technologies.
Publisher: AMPCo
Date: 03-1984
DOI: 10.5694/J.1326-5377.1984.TB108105.X
Abstract: In a series of 1460 consecutive patients admitted to an "acute" stroke unit, 10 patients (0.7%) were found to have a metabolic encephalopathy which mimicked stroke. Of these, three had hypoglycaemia, four had hyperglycaemia, three had hyponatraemia, and one had suffered from hypoxia. Metabolic disorders should be excluded in all patients with a diagnosis of suspected stroke, especially if the presentation is associated with a confusional state or focal seizures. The conventional symptoms and signs of the metabolic disorders may be minimal or absent. The relative rarity of these disorders among patients with suspected stroke is overshadowed by the importance of early recognition and treatment, in order to minimize morbidity and mortality.
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.EPLEPSYRES.2013.02.005
Abstract: We describe the clinical and radiological features of a family with a homozygous mutation in TBC1D24. The phenotype comprised onset of focal seizures at 2 months with prominent eye-blinking, facial and limb jerking with an oral sensory aura. These were controllable with medication but persisted into adult life. Associated features were mild to moderate intellectual disability and cerebellar features. MRI showed subtle cortical thickening with cerebellar atrophy and high signal confined to the ansiform lobule. The disorder is allelic with familial infantile myoclonic epilepsy, where intellect and neurologic examination are normal, highlighting the phenotypic variation with mutations of TBC1D24.
Publisher: Wiley
Date: 27-04-2023
DOI: 10.1111/EPI.17616
Abstract: This study was undertaken to analyze phenotypic features of a cohort of patients with protracted CLN3 disease to improve recognition of the disorder. We analyzed phenotypic data of 10 patients from six families with protracted CLN3 disease. Haplotype analysis was performed in three reportedly unrelated families. Visual impairment was the initial symptom, with onset at 5–9 years, similar to classic CLN3 disease. Mean time from onset of visual impairment to seizures was 12 years (range = 6–41 years). Various seizure types were reported, most commonly generalized tonic–clonic seizures focal seizures were present in four patients. Progressive myoclonus epilepsy was not seen. Interictal electroencephalogram revealed mild background slowing and 2.5–3.5‐Hz spontaneous generalized spike–wave discharges. Additional interictal focal epileptiform discharges were noted in some patients. Age at death for the three deceased patients was 31, 31, and 52 years. Molecular testing revealed five in iduals were homozygous for c.461‐280_677 + 382del966, the "common 1‐kb" CLN3 deletion. The remaining in iduals were compound heterozygous for various combinations of recurrent pathogenic CLN3 variants. Haplotype analysis demonstrated evidence of a common founder for the common 1‐kb deletion. Dating analysis suggested the deletion arose approximately 1500 years ago and thus did not represent cryptic familial relationship in this Australian cohort. We highlight the protracted phenotype of a disease generally associated with death in adolescence, which is a combined focal and generalized epilepsy syndrome with progressive neurological deterioration. The disorder should be suspected in an adolescent or adult patient presenting with generalized or focal seizures preceded by progressive visual loss. The common 1‐kb deletion has been typically associated with classic CLN3 disease, and the protracted phenotype has not previously been reported with this genotype. This suggests that modifying genetic factors may be important in determining this somewhat milder phenotype and identification of these factors should be the subject of future research.
Publisher: Wiley
Date: 18-11-2021
DOI: 10.1111/EPI.16766
Publisher: Wiley
Date: 15-04-2013
DOI: 10.1111/EPI.12168
Abstract: This report is a practical reference guide for genetic testing of SCN1A, the gene encoding the α1 subunit of neuronal voltage-gated sodium channels (protein name: Nav 1.1). Mutations in this gene are frequently found in Dravet syndrome (DS), and are sometimes found in genetic epilepsy with febrile seizures plus (GEFS+), migrating partial seizures of infancy (MPSI), other infantile epileptic encephalopathies, and rarely in infantile spasms. Recommendations for testing: (1) Testing is particularly useful for people with suspected DS and sometimes in other early onset infantile epileptic encephalopathies such as MPSI because genetic confirmation of the clinical diagnosis may allow optimization of antiepileptic therapy with the potential to improve seizure control and developmental outcome. In addition, a molecular diagnosis may prevent the need for unnecessary investigations, as well as inform genetic counseling. (2) SCN1A testing should be considered in people with possible DS where the typical initial presentation is of a developmentally normal infant presenting with recurrent, febrile or afebrile prolonged, hemiclonic seizures or generalized status epilepticus. After age 2, the clinical diagnosis of DS becomes more obvious, with the classical evolution of other seizure types and developmental slowing. (3) In contrast to DS, the clinical utility of SCN1A testing for GEFS+ remains questionable. (4) The test is not recommended for children with phenotypes that are not clearly associated with SCN1A mutations such as those characterized by abnormal development or neurologic deficits apparent at birth or structural abnormalities of the brain. Interpreting test results: (1) Mutational testing of SCN1A involves both conventional DNA sequencing of the coding regions and analyses to detect genomic rearrangements within the relevant chromosomal region: 2q24. Interpretation of the test results must always be done in the context of the electroclinical syndrome and often requires the assistance of a medical geneticist, since many genomic variations are possible and it is essential to differentiate benign polymorphisms from pathogenic mutations. (2) Missense variants may have no apparent effect on the phenotype (benign polymorphisms) or may represent mutations underlying DS, MPSI, GEFS+, and related syndromes and can provide a challenge in interpretation. (3) Conventional methods do not detect variations in introns or promoter or regulatory regions therefore, a negative test does not exclude a pathogenic role of SCN1A in a specific phenotype. (4) It is important to note that a negative test does not rule out the clinical diagnosis of DS or other conditions because genes other than SCN1A may be involved. Obtaining written informed consent and genetic counseling should be considered prior to molecular testing, depending on the clinical situation and local regulations.
Publisher: Elsevier BV
Date: 10-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1998
DOI: 10.1097/00019052-199804000-00009
Abstract: The relationship between febrile seizures and epilepsy has long been debated. We argue that there is some specificity to the types of epilepsy that follow febrile seizures, rather than febrile seizures being a nonspecific marker of a lowered seizure threshold. The relationship between febrile seizures and later epilepsy is frequently genetic. Recent clinical and molecular genetic studies suggest that there are a number of syndrome-specific genes for febrile seizures.
Publisher: Elsevier BV
Date: 2021
Publisher: Wiley
Date: 1988
Abstract: In patients with an acceptable pathological diagnosis of Kufs disease, two major forms have been identified: Type A presenting as progressive myoclonus epilepsy around the age of 30, and Type B presenting in the same age range with dementia as well as cerebellar and/or extra-pyramidal signs. In adolescence, two subgroups of neuronal ceroid-lipofuscinosis (NCL) emerge. The first group consists of patients resembling either type A or B Kufs disease, but with earlier onset (20% of all cases). These must be distinguished from the second group of rare patients with protracted juvenile NCL presenting with early and prominent visual failure. Although Kufs disease is rare, diagnosis during life should now be possible. The advantages, techniques, and pitfalls of biopsy diagnosis are presented by Carpenter et al. [1988]. We believe that delineation of these two clinical syndromes should aid in the identification of other possible cases of Kufs disease, leading to appropriate pathological examinations to confirm the diagnosis. Knowledge of whether this clinical distinction is biologically meaningful must await the discovery of the more fundamental biochemical defects.
Publisher: Wiley
Date: 12-1983
DOI: 10.1111/J.1445-5994.1983.TB02611.X
Abstract: Adrenomyeloneuropathy (AMN) is an X-linked storage disease of very-long-chain fatty acids that presents as primary adrenocortical failure combined with spastic paraparesis and peripheral neuropathy. This disorder was diagnosed in three unrelated adult males. Definitive diagnosis was made by finding elevated very-long-chain fatty acids in plasma and skin biopsy s les. Biochemical characterisation of this disease has elucidated its genetics, clarified its relationship with adrenoleukodystrophy of children and other phenotypic variants, and allowed heterozygote identification, accurate genetic counselling and prenatal diagnosis.
Publisher: Wiley
Date: 1988
Abstract: We have found a group of in iduals with the late infantile, the early juvenile variant, and juvenile neuronal ceroid-lipofuscinosis (NCL) in Newfoundland, an island with a population of 500,000. In the past 25 yr, we have ascertained 44 cases of NCL in 32 sibships: 32 cases of late infantile NCL (LINCL) in 24 sibships, 11 cases of the early juvenile variant in 7 sibships, and one patient with the juvenile form (JNCL). The clinical presentation of the LINCL patients is very characteristic, with onset of seizures at age 2 1/2 to 3 1/2 yr, frequently with drop attacks and myoclonic jerks, followed by mental deterioration, ataxia, visual loss, and death by the end of the first decade. Typical curvilinear profiles are seen on electron microscopy (EM). The second group of patients mainly have the early juvenile variant with onset of seizures at age 5 to 6 yr and fingerprint profiles with occasional curvilinear profiles on EM. However, a child with the juvenile form presenting with blindness was also encountered. In both of these types, death occurs in the second decade of life. There is no overlap of these three clinical forms within sibships, although both late infantile and early juvenile variant types may occur in the same small fishing village. All three forms appear to be inherited as autosomal recessive traits. Although the early juvenile variant has been postulated to represent a double heterozygote between LINCL and JNCL, this cannot be confirmed on the basis of the present study.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Oxford University Press (OUP)
Date: 19-04-2010
DOI: 10.1093/BRAIN/AWQ078
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-06-2019
DOI: 10.1212/NXG.0000000000000340
Abstract: To map functional MRI (fMRI) connectivity within and between the somatosensory cortex, putamen, and ventral thalamus in in iduals from a family with a GABAergic deficit segregating with febrile seizures and genetic generalized epilepsy. We studied 5 adults from a family with early-onset absence epilepsy and/or febrile seizures and a GABA A receptor subunit gamma2 pathogenic variant ( GABRG2[R43Q] ) vs 5 age-matched controls. We infer differences between participants with the GABRG2 pathogenic variant and controls in resting-state fMRI connectivity within and between the somatosensory cortex, putamen, and ventral thalamus. We observed increased fMRI connectivity within the somatosensory cortex and between the putamen and ventral thalamus in all in iduals with the GABRG2 pathogenic variant compared with controls. Post hoc analysis showed less pronounced changes in fMRI connectivity within and between the primary visual cortex and precuneus. Although our s le size was small, this preliminary study suggests that in iduals with a GABRG2 pathogenic variant, raising risk of febrile seizures and generalized epilepsy, display underlying increased functional connectivity both within the somatosensory cortex and in striatothalamic networks. This human network model aligns with rodent research and should be further validated in larger cohorts, including other in iduals with generalized epilepsy with and without known GABA pathogenic variants.
Publisher: Oxford University Press (OUP)
Date: 22-06-2020
Abstract: Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All s les were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.
Publisher: Oxford University Press (OUP)
Date: 12-01-2022
Abstract: Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P & 5 × 10−10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10−4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population s le. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.
Publisher: Wiley
Date: 18-08-2021
DOI: 10.1002/ANA.26191
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-08-2012
Publisher: Cold Spring Harbor Laboratory
Date: 09-09-2022
DOI: 10.1101/2022.09.08.22279663
Abstract: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. We collected longitudinal diagnostic information (mean=36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other), and PSY. We pre-specified NfL pg/mL as indicative of ND/MCI/other. Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-12-2005
DOI: 10.1212/01.WNL.0000195888.51845.80
Abstract: To analyze seizure control and treatment in pregnant women with epilepsy. Seizure control and treatment were recorded prospectively in 1,956 pregnancies of 1,882 women with epilepsy participating in EURAP, an international antiepileptic drugs (AEDs) and pregnancy registry. Of all cases, 58.3% were seizure-free throughout pregnancy. Occurrence of any seizures was associated with localization-related epilepsy (OR: 2.5 1.7 to 3.9) and polytherapy (OR: 9.0 5.6 to 14.8) and for tonic-clonic seizures, with oxcarbazepine monotherapy (OR: 5.4 1.6 to 17.1). Using first trimester as reference, seizure control remained unchanged throughout pregnancy in 63.6%, 92.7% of whom were seizure-free during the entire pregnancy. For those with a change in seizure frequency, 17.3% had an increase and 15.9% a decrease. Seizures occurred during delivery in 60 pregnancies (3.5%), more commonly in women with seizures during pregnancy (OR: 4.8 2.3 to 10.0). There were 36 cases of status epilepticus (12 convulsive), which resulted in stillbirth in one case but no cases of miscarriage or maternal mortality. AED treatment remained unchanged in 62.7% of the pregnancies. The number or dosage of AEDs were more often increased in pregnancies with seizures (OR: 3.6 2.8 to 4.7) and with monotherapy with lamotrigine (OR: 3.8 2.1 to 6.9) or oxcarbazepine (OR: 3.7 1.1 to 12.9). The majority of patients with epilepsy maintain seizure control during pregnancy. The apparently higher risk of seizures among women treated with oxcarbazepine and the more frequent increases in drug load in the oxcarbazepine and lamotrigine cohorts prompts further studies on relationships with pharmacokinetic changes. Risks associated with status epilepticus appear to be lower than previously reported.
Publisher: Wiley
Date: 12-1999
DOI: 10.1111/J.1528-1157.1999.TB01600.X
Abstract: (a) To compare postmortem antiepileptic drug (AED) levels in patients with sudden unexpected death in epilepsy (SUDEP) with those in a control group of subjects with epilepsy. If SUDEP patients more frequently had undetectable or subtherapeutic AED levels, this would suggest that compliance with AED treatment is poorer in this group and that poor compliance is a risk factor for SUDEP. (b) To determine whether a particular AED was detected more commonly in the SUDEP group, suggesting that this AED is associated with a higher risk of SUDEP. A retrospective study of coronial cases was performed. Postmortem AED levels in 44 SUDEP cases and 44 control cases were compared. The control group consisted of epileptics who died of causes other than epilepsy, including natural disease (e.g., ischemic heart disease, accidents, and suicide). The AEDs measured included carbamazepine (CBZ), phenytoin, (PHT), valproate (VPA), phenobarbitone (PB), lamotrigine (LTG), clonazepam (CZP), and clobazam (CLB). The number of SUDEP and control cases in which CBZ only was detected were compared, as were the number in which PHT only was detected. Compared with the controls, the SUDEP group showed no difference in the number with no detectable AEDs (13 vs. 11), the number with subtherapeutic AEDs (10 vs. 13), and the number with therapeutic levels (21 in both groups). CBZ only was detected in 11 SUDEPs and 11 controls, and PHT only in five SUDEPs and 10 controls. Our study suggests the SUDEP group were no less compliant with AED treatment than the control group. This study does not support the hypothesis that poor compliance with AED treatment is a risk factor for SUDEP. There was no evidence that PHT or CBZ is associated with a higher risk of SUDEP.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-08-2005
DOI: 10.1212/01.WNL.0000172920.34994.63
Abstract: Objective: To examine the genetic relationships among epilepsies with different seizure types—myoclonic, absence, and generalized tonic-clonic—within the idiopathic generalized epilepsies (IGEs). Background: Careful phenotype definition in the epilepsies may allow ision into groups that share susceptibility genes. Examination of seizure type, a phenotypic characteristic less complex than IGE syndrome, may help to define more homogeneous subgroups. Methods: Using the approach that found evidence of distinct genetic effects on myoclonic vs absence seizures in families from the Epilepsy Family Study of Columbia University, the authors examined an independent s le of families from Australia and Israel. They also examined the familial clustering of generalized tonic-clonic seizures (GTCs) within the IGEs in two combined data sets. Families were defined as concordant if all affected members had the same type of seizure or IGE syndrome, as appropriate for the analysis performed. Results: The proportion of families concordant for myoclonic vs absence seizures was greater than expected by chance in the Australian families. In addition, GTCs clustered in families with IGEs to a degree greater than expected by chance. Conclusions: These results provide additional evidence for distinct genetic effects on myoclonic vs absence seizures in an independent set of families and suggest that there is a genetic influence on the occurrence of generalized tonic-clonic seizures within the idiopathic generalized epilepsies.
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.CELREP.2018.11.029
Abstract: The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with the structural brain malformation periventricular nodular heterotopia (PH). De novo coding variants were observed in excess in genes defining a transcriptomic signature of basal radial glia, a cell type linked to brain evolution. In addition, we located two variants in human isoforms of two genes that have no ortholog in mice. Modulating the levels of one of these isoforms for the gene PLEKHG6 demonstrated its role in regulating neuroprogenitor differentiation and neuronal migration via RhoA, with phenotypic recapitulation of PH in human cerebral organoids. This suggests that this PLEKHG6 isoform is an ex le of a primate-specific genomic element supporting brain development.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-12-2003
Publisher: Elsevier BV
Date: 04-1995
DOI: 10.1016/0887-8994(95)00022-8
Abstract: The relationship between hippoc al sclerosis, febrile seizures, and complex partial seizures in temporal lobe epilepsy continues to be the subject of great debate in the literature. Hippoc al sclerosis is reported infrequently in young children with temporal lobe epilepsy, a factor that has supported the theory that hippoc al sclerosis develops in later life during the course of recurrent complex partial seizures. In a blinded review of magnetic resonance imaging in 53 children, aged 2-17 years (mean: 10 years) with temporal lobe epilepsy, hippoc al sclerosis was diagnosed in 30 children (57%), concordant with ictal electroencephalographic lateralization in 93% and pathologic diagnosis in all children who had undergone surgery and had hippoc al tissue available for histologic examination. Fourteen of the children (47%) with hippoc al sclerosis were younger than 10 years of age, the youngest being 2 years. Thirty-four children (64%) had histories of neurologic insults prior to the onset of complex partial seizures, including idiopathic febrile seizures in 22. Hippoc al sclerosis was associated with a history of a neurologic insult prior to the onset of complex partial seizures (P < .001) and was not associated with age at onset of temporal lobe epilepsy, age at magnetic resonance imaging, duration of epilepsy, or presence of secondarily generalized seizures. These findings suggest that hippoc al sclerosis is underdiagnosed in children and is the cause and not the consequence of temporal lobe epilepsy.
Publisher: Elsevier BV
Date: 10-2013
Publisher: Wiley
Date: 04-2021
DOI: 10.1111/EPI.16854
Abstract: We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy. We enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene‐level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion‐deletion (indel) variants, and copy number variants present in leukocyte‐derived DNA. Across the cohort of 86 in iduals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2 , including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome‐wide threshold of significance in the gene‐level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2 , we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62 , all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy‐associated and neurodevelopmental disease‐associated genes ( SCN2A in two in iduals, GRIA3 , CACNA1C ) and a 597‐kb deletion at 15q25, a neurodevelopmental disease susceptibility locus. This study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio‐based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for SCN2A , GRIA3 , CACNA1C , and 15q25 deletion in polymicrogyria, each already associated with epilepsy or other neurodevelopmental conditions without brain malformations. The role of these genes in polymicrogyria will be further understood as more patients with polymicrogyria undergo genetic evaluation.
Publisher: Elsevier BV
Date: 06-2012
Publisher: Elsevier BV
Date: 06-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-02-2003
DOI: 10.1212/WNL.60.3.405
Abstract: Objective: To correlate the clinical phenotype with hippoc al volumes (HcVs) and signal changes in patients with familial mesial temporal lobe epilepsy (FMTLE). Methods: FMTLE was defined when at least two first-degree relatives in a family had a clinical-EEG diagnosis of MTLE. Hippoc al formation measurements were performed using 1- to 3-mm coronal T1-weighted MRIs. The presence of hyperintense T2 signal was evaluated by visual analysis. For statistical analyses, analysis of variance, χ 2 test, and regression analysis were used. Results: A total of 142 patients from 45 unrelated families were studied: 113 in iduals with MTLE (80 with good seizure control) and 29 family members with other seizure types. There were 99 patients (69.7%) with hippoc al atrophy (HA). Sixty-seven of the 99 patients with HA also had a hyperintense T2 signal. Hyperintense T2 signal was associated with more severe HA ( p = 0.04). Patients with refractory FMTLE had more frequent HA ( p = 0.03) and hyperintense T2 signal ( p = 0.004) and more severe atrophy ( p 0.0001). Duration of epilepsy correlated with HcV asymmetry index ( r 2 = 0.12, p = 0.00008) and with the more atrophic hippoc i but not with contralateral hippoc i. Conclusion: In familial mesial temporal lobe epilepsy, seizure severity is variable in affected in iduals. Hippoc al atrophy was present in 70% of these patients and 69% of these had an associated hyperintense T2 signal. Although hippoc al atrophy associated with abnormal T2 signal was more frequent and more severe in patients with poor seizure control, it was also frequent in affected in iduals across families. These observations suggest that one or more genes resulting in familial mesial temporal lobe epilepsy predisposes both to the clinical features of mesial temporal lobe epilepsy and to the development of hippoc al sclerosis.
Publisher: American Society for Clinical Investigation
Date: 02-08-2010
DOI: 10.1172/JCI42219
Publisher: Springer Science and Business Media LLC
Date: 21-10-2012
DOI: 10.1038/NG.2440
Abstract: We performed genomic mapping of a family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and intellectual and psychiatric problems, identifying a disease-associated region on chromosome 9q34.3. Whole-exome sequencing identified a mutation in KCNT1, encoding a sodium-gated potassium channel subunit. KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features. These findings implicate the sodium-gated potassium channel complex in ADNFLE and, more broadly, in the pathogenesis of focal epilepsies.
Publisher: Wiley
Date: 23-10-2020
DOI: 10.1111/EPI.16732
Publisher: BMJ
Date: 20-09-2019
Abstract: Psychosis of epilepsy (POE) occurs more frequently in temporal lobe epilepsy, raising the question as to whether abnormalities of the hippoc us are aetiologically important. Despite decades of investigation, it is unclear whether hippoc al volume is reduced in POE, perhaps due to small s le sizes and methodological limitations of past research. In this study, we examined the volume of the total hippoc us, and the hippoc al head, body and tail, in a large cohort of patients with POE and patients with epilepsy without psychosis (EC). One hundred adults participated: 50 with POE and 50 EC. Total and subregional hippoc al volumes were manually traced and compared between (1) POE and EC (2) POE with temporal lobe epilepsy, extratemporal lobe epilepsy and generalised epilepsy and (3) patients with POE with postictal psychosis (PIP) and interictal psychosis (IP). Compared with EC the POE group had smaller total left hippoc us volume (13.5% decrease, p .001), and smaller left hippoc al body (13.3% decrease, p=0.002), and left (41.5% decrease, p .001) and right (36.4% decrease, p .001) hippoc al tail volumes. Hippoc al head volumes did not differ between groups. Posterior hippoc al volumes are bilaterally reduced in POE. Volume loss was observed on a posteroanterior gradient, with severe decreases in the tail and moderate volume decreases in the body, with no difference in the hippoc al head. Posterior hippoc al atrophy is evident to a similar degree in PIP and IP. Our findings converge with those reported for the paradigmatic psychotic disorder, schizophrenia, and suggest that posterior hippoc al atrophy may serve as a biomarker of the risk for psychosis, including in patients with epilepsy.
Publisher: Elsevier BV
Date: 09-2006
DOI: 10.1016/J.NEUROIMAGE.2006.05.059
Abstract: Understanding the consequences of newly discovered single gene mutations causing human epilepsy has the potential to yield new insights into the underlying mechanisms of this disorder. A mutation of the gamma2 subunit of the GABA(A) receptor, which substitutes glutamine for arginine at position 43 (R43Q) has been found in a familial generalized epilepsy. We tested the hypothesis that in iduals affected by the GABRG2(R43Q) mutation have reduced binding to the GABA(A) receptor complex using positron emission tomography (PET) and the benzodiazepine receptor ligand [(11)C]-flumazenil. Fourteen subjects with the GABRG2(R43Q) mutation and 20 controls were studied. Benzodiazepine receptor binding was reduced in subjects with the mutation (mean whole brain binding potential for [(11)C]-flumazenil: GABA(A) mutation 0.66+/-0.1 controls 0.89+/-0.1 P<0.003). The greatest change in benzodiazepine binding occurred anteriorly, with peak differences in insular and anterior cingulate cortices revealed by statistical parametric mapping. Our findings provide in vivo evidence of reduced benzodiazepine receptor binding in subjects with the mutation. As synaptic inhibition in the human brain is largely mediated by the GABA(A) receptor, these findings are likely to represent an important clue to the mechanisms linking this gene defect and the epilepsy phenotype.
Publisher: Springer Science and Business Media LLC
Date: 30-05-2022
DOI: 10.1038/S42003-022-03454-1
Abstract: In SCN2A- related disorders, there is an urgent demand to establish efficient methods for determining the gain- (GoF) or loss-of-function (LoF) character of variants, to identify suitable candidates for precision therapies. Here we classify clinical phenotypes of 179 in iduals with 38 recurrent SCN2A variants as early-infantile or later-onset epilepsy, or intellectual disability/autism spectrum disorder (ID/ASD) and assess the functional impact of 13 variants using dynamic action potential cl (DAPC) and voltage cl . Results show that 36/38 variants are associated with only one phenotypic group (30 early-infantile, 5 later-onset, 1 ID/ASD). Unexpectedly, we revealed major differences in outcome severity between in iduals with the same variant for 40% of early-infantile variants studied. DAPC was superior to voltage cl in predicting the impact of mutations on neuronal excitability and confirmed GoF produces early-infantile phenotypes and LoF later-onset phenotypes. For one early-infantile variant, the co-expression of the α 1 and β 2 subunits of the Na v 1.2 channel was needed to unveil functional impact, confirming the prediction of 3D molecular modeling. Neither DAPC nor voltage cl reliably predicted phenotypic severity of early-infantile variants. Genotype, phenotypic group and DAPC are accurate predictors of the biophysical impact of SCN2A variants, but other approaches are needed to predict severity.
Publisher: Oxford University Press (OUP)
Date: 06-09-2013
DOI: 10.1093/BRAIN/AWT233
Publisher: BMJ
Date: 11-2002
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-10-2000
Abstract: The authors studied six patients with refractory temporal lobe epilepsy and postictal psychosis using quantitative MRI and histopathology, and compared the results with 45 patients with temporal lobe epilepsy without postictal psychosis. Total hippoc al volumes were not different between the two groups. However, patients with postictal psychosis had a relatively preserved anterior hippoc us, and temporal lobe dysplasia was more frequent (p = 0.006, chi-square test). These findings may be associated with the clinical symptoms.
Publisher: Wiley
Date: 03-1995
Publisher: American Medical Association (AMA)
Date: 14-12-2022
Publisher: Wiley
Date: 07-10-2013
DOI: 10.1111/EPI.12395
Abstract: Lennox-Gastaut syndrome (LGS) is a devastating childhood-onset epilepsy syndrome. The cause is unknown in 25% of cases. Little has been described about the specific clinical or electroencephalography (EEG) features of LGS of unknown or genetic cause (LGS(u)). The Epilepsy Phenome/Genome Project (EPGP) aims to characterize LGS(u) by phenotypic analysis of patients with LGS(u) and their parents. One hundred thirty-five patients with LGS with no known etiology and their parents were enrolled from 19 EPGP centers in the United States and Australia. Clinical data from medical records, standardized questionnaires, imaging, and EEG were collected with use of online informatics systems developed for EPGP. LGS(u) in the EPGP cohort had a broad range of onset of epilepsy from 1 to 13 years, was male predominant (p < 0.0002), and was associated with normal development prior to seizure onset in 59.2% of patients. Despite the diagnosis, almost half of the adult patients with LGS(u) completed secondary school. Parents were cognitively normal. All subjects had EEG recordings with generalized epileptiform abnormalities with a spike wave frequency range of 1-5 Hz (median 2 Hz), whereas 8.1% of subjects had EEG studies with a normal posterior dominant rhythm. Almost 12% of patients evolved from West syndrome. LGS(u) has distinctive characteristics including a broad age range of onset, male predominance, and often normal development prior to the onset of seizures. Cognitive achievements such as completion of secondary school were possible in half of adult patients. Our phenotypic description of LGS(u) coupled with future genetic studies will advance our understanding of this epilepsy syndrome.
Publisher: American Medical Association (AMA)
Date: 10-2009
DOI: 10.1001/ARCHNEUROL.2009.219
Abstract: To use computer simulation to perform a "genetic sensitivity" analysis to predict which genes are best positioned to increase risk as well as to predict functionally how variants in these genes might increase network excitability. A previously published, biophysically realistic model of the dentate gyrus that included mossy fiber sprouting between granule cells was used to model putative environmental changes associated with temporal lobe epilepsy. Properties of voltage-gated ion channels, either 1 at a time or in combinations, were varied systematically to determine their effect on network excitability. We found that the network is most sensitive to changes in steady-state voltage dependence of activation and relatively insensitive to changes in inactivation. Changes in sodium channels had the greatest effect on excitability, followed by changes in fast-delayed rectifier potassium channels and then N-type calcium channels. We also investigated the effects of simultaneous small changes in several ion channels, modeling a complex genetic background expected for common epilepsies. A combination of 2 or 3 simultaneous voltage shifts in steady-state activation as small as 2 mV could produce large changes in network excitability. Statistical power calculations indicate that changes this small are effectively undetectable with current experimental practices, thus posing new challenges for the functional analysis and validation of epilepsy genes.
Publisher: BMJ
Date: 07-1995
DOI: 10.1136/JNNP.59.1.26
Abstract: The yield of ictal, postictal, and interictal SPECT was compared in the localisation of seizure foci in 177 patients with partial epilepsy. In 119 patients with known unilateral temporal lobe epilepsy ictal SPECT (97% correct localisation) was superior to postictal SPECT (71% correct), which was better than interictal studies (48% correct). Similarly, in cases of known or suspected extratemporal epilepsy the yield of ictal SPECT studies was high (92%). By contrast, the yield of postictal studies was much lower (46%) and usually only very early postictal studies were diagnostic. Interictal SPECT was of little value. The accuracy of ictal SPECT in localising temporal lobe seizures is now well established. Extratemporal seizures are often brief and difficult to localise. This report shows that ictal SPECT also has a high diagnostic yield in a wide range of extratemporal epilepsies. The brevity of many extratemporal seizures means that true ictal SPECT examinations can be difficult to achieve, but the high diagnostic yield justifies the special organisational effort needed to obtain such studies.
Publisher: Hindawi Limited
Date: 2011
DOI: 10.1155/2011/917565
Abstract: Sixty cases of febrile seizures from a Chinese cohort had previously been reported with a strong association between variants in the seizure-related ( SEZ ) 6 gene and febrile seizures. They found a striking lack of genetic variation in their controls. We found genetic variation in SEZ6 at similar levels at the same DNA sequence positions in our 94 febrile seizure cases as in our 96 unaffected controls. Two of our febrile seizure cases carried rare variants predicted to have damaging consequences. Combined with some of the variants from the Chinese cohort, these data are compatible with a role for SEZ6 as a susceptibility gene for febrile seizures. However, the polygenic determinants underlying most cases of febrile seizures with complex inheritance remain to be determined.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2002
DOI: 10.1097/00004691-200208000-00004
Abstract: Transcranial magnetic stimulation has been used to study generalized and focal epilepsies for more than a decade. The technique appears safe and has yielded important information about the mechanisms underlying epilepsy. Transcranial magnetic stimulation findings differ depending on the epilepsy syndrome, lending support to the concept that there are distinct pathophysiologies underlying each condition. In most studies of generalized epilepsies, transcranial magnetic stimulation has indicated a state of relative hyperexcitability of excitatory cortical interneurons and possibly inhibitory interneurons as well, which can be reversed through the actions of anticonvulsant medications. Transcranial magnetic stimulation studies in patients with a seizure focus in the motor cortex indicate increased cortical excitability and reduced inhibition, but in patients with seizure foci located elsewhere the findings are similar to those in generalized epilepsies. Transcranial magnetic stimulation has also been used to study the mode of action of anticonvulsants and may prove to be a useful means of testing the potential for new drugs to act as anticonvulsants. Repetitive transcranial magnetic stimulation may prove to have a therapeutic role by producing long-lasting cortical inhibition after a train of impulses.
Publisher: American Medical Association (AMA)
Date: 2009
DOI: 10.1001/ARCHNEUROL.2008.532
Abstract: To investigate the developmental time frame of epilepsy onset on adult personality traits of neuroticism and extraversion and to consider their role in adjustment to intractable epilepsy. Prospective, preoperative and postoperative survey of the psychological and psychosocial effects of intractable epilepsy and its surgical treatment. Data from the preoperative phase are reported. Comprehensive Epilepsy Program (CEP), Austin Health. Sixty adult patients with focal epilepsy undergoing inpatient monitoring. Groups of patients with epilepsy onset in different developmental periods were empirically derived and compared with each other and with normative personality data from 1571 cases. Scores on the Eysenck Personality Questionnaire Revised-Short Form the Beck Depression Inventory-II the State-Trait Anxiety Inventory (state form) and the Austin CEP Interview, a semistructured interview providing in-depth psychosocial assessment. Patients with onset of epilepsy during the self-defining period of adolescence had higher neuroticism scores relative to normative data (95% confidence interval, 0.16 to 3.57) and other patients (-0.46 to -5.63). High neuroticism, particularly when accompanied by lower extraversion, predisposed to poor adjustment to intractable epilepsy as reflected by impaired mood (P < .01) and difficulties with family functioning (48% of patients). These data provide initial evidence that onset of chronic neurologic illness in adolescence influences the development of adult personality traits. We also found a relationship between personality and adjustment to chronic epilepsy. The findings are relevant to the provision of psychologically informed neurologic care.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-08-2000
DOI: 10.1212/WNL.55.3.435
Abstract: The authors analyzed the association between APOE epsilon4 genotype and clinical and MRI findings in 43 refractory temporal lobe epilepsy patients. The distribution of the alleles were normal. Ten patients (23%) had an APOE epsilon 4 allele and had an earlier onset of habitual seizures (with epsilon4 5 +/- 5 years without epsilon4 15 +/- 10 years). Quantitative MRI findings were not influenced by the APOE epsilon4 genotype. APOE epsilon4 may shorten the latency between an initial injury and seizure onset.
Publisher: American Medical Association (AMA)
Date: 08-2007
Publisher: Oxford University Press (OUP)
Date: 20-09-2013
DOI: 10.1093/BRAIN/AWT249
Abstract: Periventricular nodular heterotopia is caused by defective neuronal migration that results in heterotopic neuronal nodules lining the lateral ventricles. Mutations in filamin A (FLNA) or ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) cause periventricular nodular heterotopia, but most patients with this malformation do not have a known aetiology. Using comparative genomic hybridization, we identified 12 patients with developmental brain abnormalities, variably combining periventricular nodular heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia and polymicrogyria, harbouring a common 1.2 Mb minimal critical deletion in 6q27. These anatomic features were mainly associated with epilepsy, ataxia and cognitive impairment. Using whole exome sequencing in 14 patients with isolated periventricular nodular heterotopia but no copy number variants, we identified one patient with periventricular nodular heterotopia, developmental delay and epilepsy and a de novo missense mutation in the chromosome 6 open reading frame 70 (C6orf70) gene, mapping in the minimal critical deleted region. Using immunohistochemistry and western blots, we demonstrated that in human cell lines, C6orf70 shows primarily a cytoplasmic vesicular puncta-like distribution and that the mutation affects its stability and subcellular distribution. We also performed in utero silencing of C6orf70 and of Phf10 and Dll1, the two additional genes mapping in the 6q27 minimal critical deleted region that are expressed in human and rodent brain. Silencing of C6orf70 in the developing rat neocortex produced periventricular nodular heterotopia that was rescued by concomitant expression of wild-type human C6orf70 protein. Silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration but not periventricular nodular heterotopia. The complex brain phenotype observed in the 6q terminal deletion syndrome likely results from the combined haploinsufficiency of contiguous genes mapping to a small 1.2 Mb region. Our data suggest that, of the genes within this minimal critical region, C6orf70 plays a major role in the control of neuronal migration and its haploinsufficiency or mutation causes periventricular nodular heterotopia.
Publisher: Oxford University Press (OUP)
Date: 1988
Abstract: A review of 118 cases published as Kufs' disease revealed only 50 cases, including 2 patients described herein, that fulfilled our criteria for this diagnosis. Of the other 68 cases, 16 had inadequate data for analysis, 21 had evidence of a storage disease other than Kufs' disease, 10 did not have clear evidence of any neuronal storage, and 21 had atypical clinical features considered outside the spectrum of Kufs' disease. The 50 cases accepted as Kufs' disease comprised two clinical phenotypes progressive myoclonus epilepsy (Type A) and dementia with motor disturbances (Type B). Marked photosensitivity was a striking feature of some Type A cases, and facial dyskinesias were common amongst Type B patients. Onset was typically at around the age of 30 years. A few cases began in adolescence these differ from the protracted juvenile form of neuronal ceroid-lipofuscinosis by the absence of visual failure. Demonstration of fingerprint profiles or granular osmiophilic deposits by electron microscopy is mandatory for definitive diagnosis. Urinary sediment dolichol levels were markedly elevated in our 2 cases. This biochemical finding confirms the relationship of Kufs' disease to the early forms of neuronal ceroid-lipofuscinosis and is consistent with our hypothesis that these diseases are due to defects in the intracellular processing of lysosomal and related membranes.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Informa UK Limited
Date: 22-09-2021
DOI: 10.1080/14737175.2021.1981288
Abstract: Mosaic variants arising in brain tissue are increasingly being recognized as a hidden cause of focal epilepsy. This knowledge gain has been driven by new, highly sensitive genetic technologies and genome-wide analysis of brain tissue from surgical resection or autopsy in a small proportion of patients with focal epilepsy. Recently reported novel strategies to detect mosaic variants limited to brain have exploited trace brain DNA obtained from cerebrospinal fluid liquid biopsies or stereo-electroencephalography electrodes. The authors review the data on these innovative approaches published in PubMed before 12 June 2021, discuss the challenges associated with their application, and describe how they are likely to improve detection of mosaic variants to provide new molecular diagnoses and therapeutic targets for focal epilepsy, with potential utility in other nonmalignant neurological disorders. These cutting-edge approaches may reveal the hidden genetic etiology of focal epilepsies and provide guidance for precision medicine.
Publisher: SAGE Publications
Date: 17-11-2022
DOI: 10.1177/00048674211058684
Abstract: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of erse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for ex le with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias. This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine ( We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2] parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman's Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.
Publisher: Elsevier BV
Date: 10-2009
Publisher: Oxford University Press (OUP)
Date: 08-2001
Abstract: Periventricular heterotopia (PH) is a human neuronal migration disorder in which many neurons destined for the cerebral cortex fail to migrate. Previous analysis showed heterozygous mutations in the X-linked gene filamin 1 (FLN1), but examined only the first six (of 48) coding exons of the gene and hence did not assess the incidence and functional consequences of FLN1 mutations. Here we perform single-strand conformation polymorphism (SSCP) analysis of FLN1 throughout its entire coding region in six PH pedigrees, 31 sporadic female PH patients and 24 sporadic male PH patients. We detected FLN1 mutations by SSCP in 83% of PH pedigrees and 19% of sporadic females with PH. Moreover, no PH females (0/7 tested) with atypical radiographic features showed FLN1 mutations, suggesting that other genes may cause atypical PH. Surprisingly, 2/24 males analyzed with PH (9%) also carried FLN1 mutations. Whereas FLN1 mutations in PH pedigrees caused severe predicted loss of FLN1 protein function, both male FLN1 mutations were consistent with partial loss of function of the protein. Moreover, sporadic female FLN1 mutations associated with PH appear to cause either severe or partial loss of function. Neither male could be shown to be mosaic for the FLN1 mutation in peripheral blood lymphocytes, suggesting that some neurons in the intact cortex of PH males may be mutant for FLN1 but migrate adequately. These results demonstrate the sensitivity and specificity of DNA testing for FLN1 mutations and have important functional implications for models of FLN1 protein function in neuronal migration.
Publisher: Proceedings of the National Academy of Sciences
Date: 11-2002
Abstract: The γ-aminobutyric acid type A (GABA A ) receptor mediates fast inhibitory synaptic transmission in the CNS. Dysfunction of the GABA A receptor would be expected to cause neuronal hyperexcitability, a phenomenon linked with epileptogenesis. We have investigated the functional consequences of an arginine-to-glutamine mutation at position 43 within the GABA A γ 2 -subunit found in a family with childhood absence epilepsy and febrile seizures. Rapid-application experiments performed on receptors expressed in HEK-293 cells demonstrated that the mutation slows GABA A receptor deactivation and increases the rate of desensitization, resulting in an accumulation of desensitized receptors during repeated, short applications. In Xenopus laevis oocytes, two-electrode voltage-cl analysis of steady-state currents obtained from α 1 β 2 γ 2 or α 1 β 2 γ 2 (R43Q) receptors did not reveal any differences in GABA sensitivity. However, differences in the benzodiazepine pharmacology of mutant receptors were apparent. Mutant receptors expressed in oocytes displayed reduced sensitivity to diazepam and flunitrazepam but not the imidazopyridine zolpidem. These results provide evidence of impaired GABA A receptor function that could decrease the efficacy of transmission at inhibitory synapses, possibly generating a hyperexcitable neuronal state in thalamocortical networks of epileptic patients possessing the mutant subunit.
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.YEBEH.2010.01.168
Abstract: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a nonlesional condition associated with mutation of the gene coding for the alpha4 nicotinic acetylcholine receptor (nAChR). The nAChR modulates aspects of memory and attention. We examined the neuropsychological phenotype of ADNFLE, with a particular emphasis on understanding the impact on frontal lobe functions. We used standard clinical tests as well as focused measures of frontal lobe function in a well-defined group of patients with ADNFLE. Their performance was compared with that of a group of age-, sex-, and education-matched control participants. Patients with ADNFLE showed impairments on tasks requiring cognitive flexibility against a background of well-preserved intellectual abilities. In accord with existing research, verbal memory impairments were identified in the patient group the level of impairment on these tasks correlated with disease-related factors. In our study of ADNFLE associated with one mutation, cognitive flexibility appears to be the core cognitive deficit.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-01-2022
DOI: 10.1212/NXG.0000000000000652
Abstract: The 2-hit model of genetic disease is well established in cancer, yet has only recently been reported to cause brain malformations associated with epilepsy. Pathogenic germline and somatic variants in genes in the mechanistic target of rapamycin (mTOR) pathway have been implicated in several malformations of cortical development. We investigated the 2-hit model by performing genetic analysis and searching for germline and somatic variants in genes in the mTOR and related pathways. We searched for germline and somatic pathogenic variants in 2 brothers with drug-resistant focal epilepsy and surgically resected focal cortical dysplasia (FCD) type IIA. Exome sequencing was performed on blood- and brain-derived DNA to identify pathogenic variants, which were validated by droplet digital PCR. In vitro functional assays of a somatic variant were performed. Exome analysis revealed a novel, maternally inherited, germline pathogenic truncation variant (c.48delG p.Ser17Alafs*70) in NPRL3 in both brothers. NPRL3 is a known FCD gene that encodes a negative regulator of the mTOR pathway. Somatic variant calling in brain-derived DNA from both brothers revealed a low allele fraction somatic variant (c.338C T p.Ala113Val) in the WNT2 gene in 1 brother, confirmed by droplet digital PCR. In vitro functional studies suggested a loss of WNT2 function as a consequence of this variant. A second somatic variant has not yet been found in the other brother. We identify a pathogenic germline mTOR pathway variant ( NPRL3 ) and a somatic variant ( WNT2 ) in the intersecting WNT signaling pathway, potentially implicating the WNT2 gene in FCD and supporting a dual-pathway 2-hit model. If confirmed in other cases, this would extend the 2-hit model to pathogenic variants in different genes in critical, intersecting pathways in a malformation of cortical development. Detection of low allele fraction somatic second hits is challenging but promises to unravel the molecular architecture of FCDs.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2020
Abstract: We used actuarial methods to study outcome after temporal lobectomy in 135 consecutive patients classified into subgroups according to preoperative MRI findings. Sixty months after surgery, 69% of patients with foreign tissue lesions, 50% with hippoc al sclerosis, and 21% with normal MRIs had no postoperative seizures. An eventual seizure-free state of 2 years or more, whether the patient was seizure-free since surgery or not, was achieved by 80% of patients with foreign tissue lesions, 62% of those with hippoc al sclerosis, and 36% of those with normal MRIs. Outcome was worse in those with normal MRIs than in the other two groups. Early postoperative seizures with later remission (the "running down" phenomenon) occurred in all groups. Late seizure recurrence was present only in the hippoc al sclerosis group. These data show that preoperative MRI is a useful predictor of outcome and that actuarial analysis provides insight into different longitudinal patterns of outcome in MRI subgroups. This information can now be used in preoperative counseling.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-09-2010
Publisher: Springer Science and Business Media LLC
Date: 11-2018
Publisher: Elsevier BV
Date: 09-1994
DOI: 10.1016/S0010-9452(13)80342-5
Abstract: Mild language production difficulties, particularly in confrontation naming, have been documented previously in patients with left temporal lobe epilepsy (LTLE). These difficulties, however, do not seem to be reflected in the conversational speech of these patients. In order to compare speech fluency in patients with left and right temporal lobe epilepsy (RTLE) experimentally, we studied global pause-to-speech ratios in patients with unilateral temporal lobe epilepsy, using cases with primary generalized epilepsy (PGE) as controls. We hypothesized that left-sides cases would exhibit longer pause durations than right-sided cases. Speech s les were elicited by asking subjects to describe five different New Yorker cartoons, with three repetitions of each description. Phonation was converted to graphic output, and pauses between 200 ms and 4000 ms were summated and ided by total phonation time. This measure did not discriminate significantly between the groups, although the LTLE group tended to pause longer than the RTLE or PGE groups. Increased variability in pause duration in the LTLE group during cycle 1 suggested that some in iduals with LTLE are vulnerable to disruption when planning demands are high. A post hoc correlational analysis showed that variation in fluency was primarily explained by orthographically-based lexical retrieval, suggesting that in idual differences in fluency are related to limitations in a high-level capacity relevant to the production of speech. It is unlikely that such limitations are specific to LTLE.
Publisher: Wiley
Date: 17-08-2010
DOI: 10.1111/J.1528-1167.2010.02694.X
Abstract: Lennox-Gastaut syndrome (LGS) has numerous causes,but only rarely has familial recurrence been observed. We studied a family in which three male members had severe epilepsy and intellectual disability. The proband had seizure onset at 7 years of age with atonic, myoclonic, atypical absence, and tonic seizures with slow spike-wave on electroencephalography (EEG). One living sibling had a similar clinical pattern. One deceased sibling was known to have had seizures with intellectual disability. Neuroimaging revealed anterior predominant pachygyria. DNA sequencing of the gene doublecortin (DCX) on the X chromosome revealed a novel missense mutation in the two living affected male siblings. The occurrence of three affected male family members with proven or suspected LGS in this family was puzzling and only solved by a combination of magnetic resonance (MR) and molecular genetics evaluations. This finding provided essential information for genetic counseling.
Publisher: Springer Science and Business Media LLC
Date: 1998
DOI: 10.2165/00007256-199825020-00005
Abstract: Concussive convulsions (CC) are nonepileptic phenomena which are an immediate sequelae of concussive brain injury. Although uncommon, occurring with an approximate incidence of 1 case per 70 concussions, these episodes are often confused with post-traumatic epilepsy which may occur with more severe structural brain injury. The pathophysiological mechanism of CC remains speculative, but may involve a transient traumatic functional decerebration with loss of cortical inhibition and release of brainstem activity. The phenomenology of the CC is somewhat akin to convulsive syncope, with an initial tonic phase occurring within 2 seconds of impact, followed by a clonic or myoclonic phase which may last several minutes. Lateralising features are common during the convulsions. There is no evidence of structural or permanent brain injury on clinical assessment, neuropsychological testing or neuroimaging studies. Long term outcome is universally good with no evidence of long term epilepsy and athletes are usually able to return to sport within 2 weeks. The correct management of these episodes centres on the appropriate management of the associated concussive injury and the exclusion of other cerebral injury by medical assessment. The CC requires no specific management beyond immediate onfield first aid measures such as protection of the airway. Antiepileptic therapy is not indicated and prolonged absence from sport is unwarranted. These episodes, although dramatic, are relatively straightforward to manage and all team physicians and those involved in athlete care need to be aware of this condition.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-1992
DOI: 10.1212/WNL.42.2.371
Abstract: We analyzed the lateralizing value of ictal dystonia and head-turning in temporal lobe epilepsy, and sought the biologic basis of these clinical signs by studying the regional changes in perfusion with ictal single-photon emission computed tomography (SPECT). We identified unilateral temporal lobe epilepsy in 40 of 42 patients undergoing evaluation for temporal lobe surgery, and with ictal SPECT all 40 showed striking hyperperfusion of the epileptogenic temporal lobe. Twenty-five of the 40 patients showed unilateral or predominantly unilateral upper limb dystonia, which was opposite the epileptic temporal lobe in all cases. Analysis of regional count ratios in cases with ictal dystonia, compared with those without, showed significant changes only in the basal ganglia. Specifically, we found that ictal dystonia was associated with a relative increase in perfusion of the basal ganglia opposite the dystonic limb. Although we found 26 cases with head-turning, the sign was of no lateralizing value, even when only those with major or “tonic” versions (n = 11) were analyzed. Slight increases in cortical blood flow on the side opposite the direction of version were associated with head-turning, irrespective of the side of seizure focus. In clinical practice, ictal SPECT is a highly accurate aid in the lateralization of temporal lobe foci, in addition to providing a new method to investigate the pathophysiology of clinical signs in focal seizures.
Publisher: Elsevier BV
Date: 08-2006
Publisher: Wiley
Date: 09-2013
DOI: 10.1002/ANA.23934
Publisher: BMJ
Date: 10-1999
Publisher: Wiley
Date: 04-02-2019
DOI: 10.1111/EPI.14657
Abstract: Juvenile myoclonic epilepsy (JME) is a common syndrome of genetic generalized epilepsies (GGEs). Linkage and association studies suggest that the gene encoding the bromodomain-containing protein 2 (BRD2) may increase risk of JME. The present methylation and association study followed up a recent report highlighting that the BRD2 promoter CpG island (CpG76) is differentially hypermethylated in lymphoblastoid cells from Caucasian patients with JME compared to patients with other GGE subtypes and unaffected relatives. In contrast, we found a uniform low average percentage of methylation (<4.5%) for 13 CpG76-CpGs in whole blood cells from 782 unrelated European Caucasians, including 116 JME patients, 196 patients with genetic absence epilepsies, and 470 control subjects. We also failed to confirm an allelic association of the BRD2 promoter single nucleotide polymorphism (SNP) rs3918149 with JME (Armitage trend test, P = 0.98), and we did not detect a substantial impact of SNP rs3918149 on CpG76 methylation in either 116 JME patients (methylation quantitative trait loci [meQTL], P = 0.29) or 470 German control subjects (meQTL, P = 0.55). Our results do not support the previous observation that a high DNA methylation level of the BRD2 promoter CpG76 island is a prevalent epigenetic motif associated with JME in Caucasians.
Publisher: Wiley
Date: 07-1994
DOI: 10.1111/J.1528-1157.1994.TB02513.X
Abstract: A multicenter, double-blind, randomized, placebo-controlled study evaluated the efficacy and safety of gabapentin (Neurontin, GBP) as add-on therapy in 272 patients with refractory partial seizures who were receiving one to two standard antiepileptic drugs (AEDs). Efficacy assessments compared the frequency of partial seizures during the 12-week treatment phase (T) and the 12-week baseline period (B). The primary analysis compared data for patients receiving GBP 900 mg/day with placebo the GBP 1,200-mg/day group provided dose-response data. Efficacy criteria were percentage of change in seizure frequency (PCH), responder rate (percentage of patients with > or = 50% reduction in seizure frequency), and response ratio, where RRatio = (T-B)/(T + B). Median PCH was -21.8% in the 900-mg/day group and -17.8% in the 1,200-mg/day group as compared with -0.3% in the placebo group. Responder rate was 22.9% in the 900-mg/day group and 10.1% in the placebo group (p = 0.020, Fisher's exact test). Adjusted mean RRatio was -0.136 in the 900-mg/day group and -0.025 in the placebo group (p = 0.0046, analysis of variance ANOVA). Results showed slightly greater improvement for the 1,200-mg/day than for the 900-mg/day group (RRatio = -0.157, responder rate 28.0%). Adverse events (AE) occurred in 69% of patients in the 900-mg/day group and in 64% in the 1,200-mg/day group as compared with 52% in patients receiving placebo as add-on therapy. The most frequent AE among patients treated with GBP were somnolence, dizziness, and fatigue. Clinical laboratory evaluations showed no clinically important trends and no evidence of hepatic or hematopoietic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Wiley
Date: 18-05-2021
DOI: 10.1002/ACN3.51381
Abstract: To compare the frequency and impact on the channel function of KCNH2 variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss‐of‐function KCNH2 variants as predictive biomarkers of SUDEP risk. We searched for KCNH2 variants with a minor allele frequency of %. Functional analysis in Xenopus laevis oocytes was performed for all KCNH2 variants identified. KCNH2 variants were found in 11.1% (10/90) of SUDEP in iduals compared to 6.0% (20/332) of epilepsy controls ( p = 0.11). Loss‐of‐function KCNH2 variants, defined as causing % reduction in maximal litude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about threefold enrichment (nominal p = 0.04). KCNH2 variants that did not change channel function occurred at a similar frequency in SUDEP (2.2% 2/90) and epilepsy control (2.7% 9/332) cohorts ( p 0.99). Rare KCNH2 variants ( % allele frequency) associated with greater loss of function and an ~11‐fold enrichment in the SUDEP cohort (nominal p = 0.03). In silico tools were unable to predict the impact of a variant on function highlighting the need for electrophysiological analysis. These data show that loss‐of‐function KCNH2 variants are enriched in SUDEP patients when compared to an epilepsy population older than 50 years, suggesting that cardiac mechanisms contribute to SUDEP risk. We propose that genetic screening in combination with functional analysis can identify loss‐of‐function KCNH2 variants that could act as biomarkers of an in idual’s SUDEP risk.
Publisher: Wiley
Date: 11-2012
DOI: 10.1002/ANA.23702
Abstract: We examined whether glucose transporter 1 (GLUT1) deficiency causes common idiopathic generalized epilepsies (IGEs). The IGEs are common, heritable epilepsies that usually follow complex inheritance currently little is known about their genetic architecture. Previously considered rare, GLUT1 deficiency, due to mutations in SLC2A1, leads to failure of glucose transport across the blood-brain barrier and inadequate glucose for brain metabolism. GLUT1 deficiency was first associated with an encephalopathy and more recently found in rare dominant families with epilepsy and paroxysmal exertional dyskinesia (PED). Five hundred four probands with IGEs and 470 controls underwent SLC2A1 sequencing. Glucose transport was assayed following expression of SLC2A1 variants in Xenopus oocytes. All available relatives were phenotyped, and SLC2A1 was sequenced. Functionally validated mutations in SLC2A1 were present in 7 of 504 (1.4%) probands and 0 of 470 controls. PED, undiagnosed prior to study, occurred in 1 proband and 3 of 13 relatives with mutations. The IGEs in probands and relatives were indistinguishable from typical IGE. Three cases (0.6%) had mutations of large functional effect and showed autosomal dominant inheritance or were de novo. Four (0.8%) cases had a subtle functional effect 2 showed possible dominant inheritance, and 2 did not. These alleles leading to subtle functional impairment may contribute to complex, polygenic inheritance of IGE. SLC2A1 mutations contribute to approximately 1% of IGE both as a dominant gene and as a susceptibility allele in complex inheritance. Diagnosis of GLUT1 deficiency has important treatment (ketogenic diet) and genetic counseling implications. The mechanism of restricted glucose delivery differs from the current focus on IGEs as ion channel disorders.
Publisher: Oxford University Press (OUP)
Date: 04-2003
DOI: 10.1093/BRAIN/AWG080
Abstract: Occipital epilepsies often elude diagnosis as they frequently masquerade as other seizure syndromes. Visual hallucinations are the key clinical symptoms indicating an occipital focus, but may be difficult to elicit on history, especially from children, and are not always present. When visual symptoms are not prominent, the seizure semiology and scalp EEG may lead the clinician away from considering an occipital focus, as they often reflect seizure propagation rather than seizure origin. Clinical and neuroimaging advances have led to the recognition of many new occipital epilepsy syndromes, which generally present in childhood or adolescence. Major groups include malformations of cortical development [focal cortical dysplasia, periventricular heterotopia (PVH), subcortical band heterotopia (SBH), polymicrogyria], vascular (including epilepsy with bilateral occipital calcifications often associated with coeliac disease), metabolic and the emerging idiopathic occipital epilepsies. The idiopathic occipital epilepsies now comprise three identifiable electroclinical syndromes of childhood and adolescence, the biological inter-relationships and overlap with idiopathic generalized epilepsies of which are discussed here. We emphasize the clues to recognition of specific occipital epilepsies, some of which now have specific treatments. Where medical therapy is ineffective, occipital corticectomy should be considered. Emerging evidence suggests that some syndromes have a good surgical outcome, and the consequences to visual function may be less severe than anticipated.
Publisher: Therapeutic Guidelines Limited
Date: 1995
Publisher: BMJ
Date: 02-1983
Abstract: Dissection of the basilar artery caused sudden coma and death in a 40-year-old man. Atypical clinical features were explained at necropsy. A ventral dissection of the artery within its outer layers resulted in destruction of the pontine tegmentum with sparing of the basis pontis. An unsuspected defect in the internal elastic lamina in the left internal carotid artery was also found suggesting a more generalised disorder of arterial walls. Basilar artery dissection should be considered in the diagnosis of coma in young people.
Publisher: Wiley
Date: 10-2022
Abstract: Epilepsy genetics is a rapidly developing field, in which novel disease‐associated genes, novel mechanisms associated with epilepsy, and precision medicine approaches are continuously being identified. In the past decade, advances in genomic knowledge and analysis platforms have begun to make clinical genetic testing accessible for, in principle, people of all ages with epilepsy. For this reason, the Genetics Commission of the International League Against Epilepsy (ILAE) presents this update on clinical genetic testing practice, including current techniques, indications, yield of genetic testing, recommendations for pre‐ and post‐test counseling, and follow‐up after genetic testing is completed. We acknowledge that the resources vary across different settings but highlight that genetic diagnostic testing for epilepsy should be prioritized when the likelihood of an informative finding is high. Results of genetic testing, in particular the identification of causative genetic variants, are likely to improve in idual care. We emphasize the importance of genetic testing for in iduals with epilepsy as we enter the era of precision therapy.
Publisher: Oxford University Press (OUP)
Date: 16-06-2014
DOI: 10.1093/HMG/DDU306
Abstract: Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected in iduals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.
Publisher: Annual Reviews
Date: 31-08-2020
DOI: 10.1146/ANNUREV-GENOM-120219-074937
Abstract: Epilepsy encompasses a group of heterogeneous brain diseases that affect more than 50 million people worldwide. Epilepsy may have discernible structural, infectious, metabolic, and immune etiologies however, in most people with epilepsy, no obvious cause is identifiable. Based initially on family studies and later on advances in gene sequencing technologies and computational approaches, as well as the establishment of large collaborative initiatives, we now know that genetics plays a much greater role in epilepsy than was previously appreciated. Here, we review the progress in the field of epilepsy genetics and highlight molecular discoveries in the most important epilepsy groups, including those that have been long considered to have a nongenetic cause. We discuss where the field of epilepsy genetics is moving as it enters a new era in which the genetic architecture of common epilepsies is starting to be unraveled.
Publisher: Elsevier BV
Date: 07-1995
DOI: 10.1016/S0967-5868(95)80009-3
Abstract: At the Austin Hospital, Melbourne, Australia, 200 consecutive temporal lobectomies were performed for refractorycomplex partial seizures between 1969 and 1991 as part of its Comprehensive Epilepsy Program. The complications of this retrospective series are reported. There were no 30-day postoperative deaths but there were 6 late deaths. Complications are ided into 'major' if permanent and/or severe or 'minor' if temporary or not severe. Complications included hemiparesis (2% major, 1% minor), visual field defect (3% major, 18. 5% minor), dysphasia (96 dominant resections - 0% major, 5. 5% minor), memory impairment (1 % major, 9. 5% minor) intracranial infection (2% major, 0% minor), and miscellaneous (11 % minor). The mechanisms of the complications are discussed. Temporal lobectomy for the treatment of epilepsy can be performed with a low morbidity.
Publisher: Wiley
Date: 10-1998
Publisher: Wiley
Date: 04-10-2019
DOI: 10.1002/MDS.27828
Publisher: Wiley
Date: 09-2001
DOI: 10.1046/J.1528-1157.2001.0420S5016.X
Abstract: Recent molecular insights into the human idiopathic epilepsies have suggested the central role of ligand-gated and voltage-gated ion channels in their etiology. So far, genes coding for sodium and potassium channel subunits as well as a nicotinic cholinergic receptor subunit have been identified for mendelian idiopathic epilepsies. In vitro and in vivo studies of mutations demonstrate functional changes, allowing new insights into mechanisms underlying hyperexcitability. Similarly, spontaneous murine epilepsy models have been associated with calcium channel molecular defects. The major challenge before us in understanding the genetics of the epilepsies is to identify genes for common forms of epilepsy following complex inheritance. Once such genes are discovered, the gene-gene-environmental interactions producing specific epilepsy syndromes can be explored.
Publisher: Elsevier BV
Date: 10-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-1990
Abstract: Two independent blinded observers reported the preoperative MRIs in a series of 81 consecutive patients with intractable temporal lobe epilepsy who were undergoing temporal lobectomy. We then compared the nature and lateralization of the MRI abnormalities with the pathologic diagnosis and the side of lobectomy. The MRI criteria of hippoc al sclerosis were an increased T2-weighted signal and the signal's confinement to a unilaterally small hippoc us. Imaging was performed in coronal and axial planes, specially orientated along and perpendicular to the long axis of the hippoc al body. We found diagnostic MRI abnormalities in 25 of the 27 cases with pathologically proven hippoc al sclerosis (sensitivity 93%, specificity 86%). In addition, we detected all 13 foreign tissue lesions on MRI. Overall, we detected lateralized lesions on MRI that correctly predicted the side of the epileptogenic temporal lobe in 72 cases (89%), with 2 possible errors. A learning effect in appreciating the relatively subtle MRI changes of hippoc al sclerosis was apparent in our later cases, as shown by an improved correlation between the 2 observers. This study demonstrates that hippoc al sclerosis can be identified on MRI with a high degree of sensitivity and specificity.
Publisher: Elsevier BV
Date: 04-2010
Publisher: Elsevier BV
Date: 04-2010
Publisher: Elsevier BV
Date: 05-2000
Publisher: Elsevier BV
Date: 10-2010
Publisher: Oxford University Press (OUP)
Date: 12-2009
Publisher: Wiley
Date: 12-1993
Abstract: We measured the peak voltage induced in a sensing loop by a Magstim 200 magnetic stimulator. Coil output varied little for repeated stimulation at the same intensity over a wide range of coil output. In contrast, the first stimulus immediately after a change in intensity was of larger litude and showed greater variability than subsequent stimuli. The effect was seen for changes in intensity of 5% and 60% and was greater for reductions than for increases in stimulation intensity. Stimulation immediately after a reduction in intensity from 100% to 40% resulted in peak induced voltages as high as those recorded for repeated stimulation at 43% of maximum coil output. Increased coil output following changes in stimulation intensity may affect measurement of the threshold old for motor cortical stimulation. The effect of a change in intensity could be minimized by delaying stimulation for at least 30 s or discarding the first stimulus after the change.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-07-2020
DOI: 10.1212/WNL.0000000000009855
Abstract: To investigate the hypothesis that patients diagnosed with psychogenic nonepileptic seizures (PNES) on video-EEG monitoring (VEM) have increased mortality by comparison to the general population. This retrospective cohort study included patients evaluated in VEM units of 3 tertiary hospitals in Melbourne, Australia, between January 1, 1995, and December 31, 2015. Diagnosis was based on consensus opinion of experienced epileptologists and neuropsychiatrists at each hospital. Mortality was determined in patients diagnosed with PNES, epilepsy, or both conditions by linkage to the Australian National Death Index. Lifetime history of psychiatric disorders in PNES was determined from formal neuropsychiatric reports. A total of 5,508 patients underwent VEM. A total of 674 (12.2%) were diagnosed with PNES, 3064 (55.6%) with epilepsy, 175 (3.2%) with both conditions, and 1,595 (29.0%) received other diagnoses or had no diagnosis made. The standardized mortality ratio (SMR) of patients diagnosed with PNES was 2.5 (95% confidence interval [CI] 2.0–3.3). Those younger than 30 had an 8-fold higher risk of death (95% CI 3.4–19.8). Direct comparison revealed no significant difference in mortality rate between diagnostic groups. Among deaths in patients diagnosed with PNES (n = 55), external causes contributed 18%, with 20% of deaths in those younger than 50 years attributed to suicide, and “epilepsy” was recorded as the cause of death in 24%. Patients diagnosed with PNES have a SMR 2.5 times above the general population, dying at a rate comparable to those with drug-resistant epilepsy. This emphasizes the importance of prompt diagnosis, identification of risk factors, and implementation of appropriate strategies to prevent potential avoidable deaths.
Publisher: BMJ
Date: 04-1996
DOI: 10.1136/JMG.33.4.308
Abstract: Febrile convulsions affect 2 to 5% of all children under the age of 5 years. These convulsions probably have a variety of causes, but a genetic component has long been recognised. A large and remarkable family is described in which febrile convulsions appear to result from autosomal dominant inheritance at a single major locus. A gene for febrile convulsions was excluded from regions of previously mapped epilepsy genes and extension of exclusion mapping, using microsatellite markers, to the entire genome implied that a locus on chromosome 8q13-21 may be involved. Linkage analysis of markers on chromosome 8 gave a multipoint lod score of 3.40, maximised over different values of penetrance and phenocopy rate, for linkage between the gene for febrile convulsions and the region flanked by markers D8S553 and D8S279. This lod score was calculated assuming the disease has a penetrance of 60% and a phenocopy rate of 3%. Although there was no indication of linkage other than to markers on chromosome 8, linkage remains suggestive rather than significant because of the maximisation procedure applied. The support for linkage involving a major gene, as opposed to an alternative hypothesis of a complex inheritance pattern, relied upon the assumption of low penetrance.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-06-2000
Abstract: Objective: To evaluate the safety and efficacy of oxcarbazepine (OXC) as adjunctive therapy in children with inadequately controlled partial seizures on one or two concomitant antiepileptic drugs (AEDs). Background: OXC has shown antiepileptic activity in several comparative monotherapy trials in newly diagnosed patients with epilepsy, and in a placebo-controlled monotherapy trial in hospitalized patients evaluated for epilepsy surgery. Design: A total of 267 patients were evaluated in a multicenter, randomized, placebo-controlled trial consisting of three phases: 1) a 56-day baseline phase (patients maintained on their current AEDs) 2) a 112-day double-blind treatment phase (patients received either OXC 30–46 mg/kg/day orally or placebo) and 3) an open-label extension phase. Data are reported only from the double-blind treatment phase the open-label extension phase is ongoing. Methods: Children (3 to 17 years old) with inadequately controlled partial seizures (simple, complex, and partial seizures evolving to secondarily generalized seizures) were enrolled. Results: Patients treated with OXC experienced a significantly greater median percent reduction from baseline in partial seizure frequency than patients treated with placebo ( p = 0.0001 35% versus 9%, respectively). Forty-one percent of patients treated with OXC experienced a ≥50% reduction from baseline in partial seizure frequency per 28 days compared with 22% of patients treated with placebo ( p = 0.0005). Ninety-one percent of the group treated with OXC and 82% of the group treated with placebo reported ≥1 adverse event vomiting, somnolence, dizziness, and nausea occurred more frequently (twofold or greater) in the group treated with OXC. Conclusion: OXC adjunctive therapy administered in a dose range of 6 to 51 mg/kg/day (median 31.4 mg/kg/day) is safe, effective, and well tolerated in children with partial seizures.
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.SEIZURE.2022.02.004
Abstract: Between 16-77% of patients with newly diagnosed epilepsy report seizures before diagnosis but little is known about the risk factors for diagnostic delay. Here, we examined the association between prior seizures and neuroimaging findings in newly diagnosed focal epilepsy. Adults diagnosed with focal epilepsy at First Seizure Clinics (FSC) at the Royal Melbourne Hospital or Austin Health, Melbourne, Australia, between 2000 and 2010 were included. Medical records were audited for seizure history accrued from the detailed FSC interview. Potentially epileptogenic brain abnormality type, location and extent was determined from neuroimaging. Statistical analysis comprised multivariate logistic regression. Of 735 patients, 44% reported seizure/s before the index seizure. Among the 260 in iduals with a potentially epileptogenic brain imaging abnormality, 34% reported prior seizures. Of 475 in iduals with no abnormality, 50% reported prior seizures (p 50 years had lower odds compared to those 18-30 years (OR 0.5, p = 0.01). A history of prior seizures is less common in patients with newly diagnosed focal epilepsy associated with antecedent stroke or high-grade tumor than in those without a lesion, and is also less common in older in iduals. These findings may be related to age, biological mechanisms or aspects of diagnosis and assessment of these events.
Publisher: Wiley
Date: 25-10-2012
DOI: 10.1111/EPI.12007
Abstract: Glucose transporter 1 (GLUT1) deficiency caused by mutations of SLC2A1 is an increasingly recognized cause of genetic generalized epilepsy. We previously reported that >10% (4 of 34) of a cohort with early onset absence epilepsy (EOAE) had GLUT1 deficiency. This study uses a new cohort of 55 patients with EOAE to confirm that finding. Patients with typical absence seizures beginning before 4 years of age were screened for solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) mutations or deletions. All had generalized spike-waves on electroencephalography (EEG). Those with tonic and/or atonic seizures were excluded. Mutations were found in 7 (13%) of 55 cases, including five missense mutations, an in-frame deletion leading to loss of a single amino acid, and a deletion spanning two exons. Over both studies, 11 (12%) of 89 probands with EOAE have GLUT1 deficiency. Given the major treatment and genetic counseling implications, this study confirms that SLC2A1 mutational analysis should be strongly considered in EOAE.
Publisher: Elsevier BV
Date: 12-2015
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 20-12-2018
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.MITO.2013.03.003
Abstract: Multiple Symmetrical Lipomatosis (MSL) is an unusual disorder characterized by the development of axial lipomas in adulthood. The pathoetiology of lipoma tissue in MSL remains unresolved. Seven patients with MSL were followed for a mean period of 12 years (8-20 years). All patients had cervical lipomas ranging from subtle lesions to disfiguring masses six patients had peripheral neuropathy and five had proximal myopathy. Myoclonus, cerebellar ataxia and additional lipomas were variably present. All patients showed clinical progression. Muscle histopathology was consistent with mitochondrial disease. Five patients were positive for mtDNA point mutation m.8344A>G, three of whom underwent lipoma resection--all s les were positive for uncoupling protein-1 mRNA (unique to brown fat). Lipoma from one case stained positive for adipocyte fatty-acid protein-2 (unique to brown fat and immature adipocytes). This long-term study hallmarks the phenotypic heterogeneity of MSL's associated clinical features. The clinical, genetic and molecular findings substantiate the hypothesis that lipomas in MSL are due to a mitochondrial disorder of brown fat.
Publisher: Wiley
Date: 22-11-2002
DOI: 10.1002/ANA.10408
Publisher: Oxford University Press (OUP)
Date: 28-02-2013
DOI: 10.1093/BRAIN/AWT021
Abstract: We previously identified a homozygous mutation in the Golgi SNAP receptor complex 2 gene (GOSR2) in six patients with progressive myoclonus epilepsy. To define the syndrome better we analysed the clinical and electrophysiological phenotype in 12 patients with GOSR2 mutations, including six new unrelated subjects. Clinical presentation was remarkably similar with early onset ataxia (average 2 years of age), followed by myoclonic seizures at the average age of 6.5 years. Patients developed multiple seizure types, including generalized tonic clonic seizures, absence seizures and drop attacks. All patients developed scoliosis by adolescence, making this an important diagnostic clue. Additional skeletal deformities were present, including pes cavus in four patients and syndactyly in two patients. All patients had elevated serum creatine kinase levels (median 734 IU) in the context of normal muscle biopsies. Electroencephalography revealed pronounced generalized spike and wave discharges with a posterior predominance and photosensitivity in all patients, with focal EEG features seen in seven patients. The disease course showed a relentless decline patients uniformly became wheelchair bound (mean age 13 years) and four had died during their third or early fourth decade. All 12 cases had the same variant (c.430G>T, G144W) and haplotype analyses confirmed a founder effect. The cases all came from countries bounding the North Sea, extending to the coastal region of Northern Norway. 'North Sea' progressive myoclonus epilepsy has a homogeneous clinical presentation and relentless disease course allowing ready identification from the other progressive myoclonus epilepsies.
Publisher: American Diabetes Association
Date: 07-2007
DOI: 10.2337/DB06-1491
Abstract: Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in high-fat–fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet–induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.
Publisher: Wiley
Date: 23-10-2020
DOI: 10.1111/EPI.16729
Publisher: Wiley
Date: 1999
DOI: 10.1002/1531-8249(199901)45:1<75::AID-ART13>3.0.CO;2-W
Abstract: We examined the phenotypic variation and clinical genetics in nine families with generalized epilepsy with febrile seizures plus (GEFS+). This genetic epilepsy syndrome with heterogeneous phenotypes was hitherto described in only one family. We obtained genealogical information on 799 in iduals and conducted detailed evaluation of 272 in iduals. Ninety-one in iduals had a history of seizures and 63 had epilepsy consistent with the GEFS+ syndrome. Epilepsy phenotypes were febrile seizures (FS) in 31, febrile seizures plus (FS+) in 15, FS+ with other seizure types (atonic, myoclonic, absence, or complex partial) in 8, and myoclonic-astatic epilepsy in 9 in iduals. Inheritance was autosomal dominant with approximately 60% penetrance. This study confirms and expands the spectrum of GEFS+ and provides new insights into the phenotypic relationships and genetics of FS and the generalized epilepsies of childhood. Moreover, the ability to identify large families with this newly recognized common, childhood-onset, generalized genetic epilepsy syndrome suggests that it should be a prime target for attempts to identify genes relevant to FS and generalized epilepsy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-05-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-08-2014
Publisher: Wiley
Date: 06-2000
DOI: 10.1002/1531-8249(200006)47:6<840::AID-ANA28>3.0.CO;2-V
Publisher: No publisher found
Date: 2001
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-08-2014
Publisher: Elsevier BV
Date: 06-2021
Publisher: Wiley
Date: 04-1991
Abstract: Phosphorus magnetic resonance spectroscopy allows noninvasive measurement of the intracellular phosphate-containing metabolites and intracellular pH in localized volumes of human muscle and brain in vivo. This technique was used to study 8 patients with a mitochondrial cytopathy (myoclonus epilepsy with ragged red fibers). Phosphorus magnetic resonance spectroscopy of resting gastrocnemius muscle demonstrated significantly increased relative intracellular inorganic phosphate concentrations (p less than 0.0005) and decreased phosphocreatine to inorganic phosphate concentration ratios (p less than 0.01) in the patients, although only 3 had myopathic signs or symptoms. We propose, therefore, that phosphorus magnetic resonance spectroscopy of resting skeletal muscle is a useful clinical test in evaluation of progressive myoclonus epilepsy. In contrast to results from muscle, however, the relative phosphate metabolite concentrations and intracellular pH in central volumes of the brains of these patients were normal, despite evidence from our previous positron emission tomography studies suggesting that there is diffuse impairment of cerebral oxidative metabolism.
Publisher: Elsevier BV
Date: 11-1992
DOI: 10.1016/0022-510X(92)90260-R
Abstract: An almost invariable association with HLA-DR2 and DQw1 has previously been reported in Japanese and caucasian narcoleptics. We performed HLA typing in 18 Australian narcoleptics using serological techniques and sequence specific oligonucleotide probes. HLA-DQw1 was present in 15 patients and DR2 in 12 3 patients with cataplectic narcolepsy were DR2-negative. The serological haplotype most strongly associated with narcolepsy was DRw15 (a subtype of DR2), DQw1. DRw15-positive patients were positive for the alleles DRB1*1501 and DQB1*0602 defined with oligonucleotide probes. We conclude that the association of narcolepsy with DR2 and DQw1 is not as strong as previously reported and the absence of DR2 or DQw1 does not preclude the diagnosis of classical narcolepsy, at least in caucasians. Secondly, DR2-positive narcoleptics possess characteristic serological subtypes and alleles defined with oligonucleotide probes that are also found in normals. Thirdly, the occurrence of DR2-negative cataplectic narcoleptics points to the existence of more than one narcolepsy susceptibility gene.
Publisher: Springer Science and Business Media LLC
Date: 16-03-2202
Publisher: Springer Science and Business Media LLC
Date: 20-07-2023
DOI: 10.1038/S41467-023-39539-6
Abstract: Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 in iduals with seizure disorders, 16,109 in iduals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 in iduals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of in iduals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between in idual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2001
Publisher: Elsevier
Date: 2003
Publisher: BMJ
Date: 18-01-1997
Abstract: To study the ictal phenomenology, aetiology, and outcome of convulsions occurring within seconds of impact in violent collision sport. Retrospective identification of convulsions associated with concussive brain injury from case records from medical officers of football clubs over a 15 year period. Elite Australian rules and rugby league footballers. Neuroimaging studies, electroencephalography, neuropsychological test data, and statistics on performance in matches to determine presence of structural or functional brain injury. Clinical follow up and electroencephalography for evidence of epilepsy. Twenty two cases of concussive convulsions were identified with four events documented on television videotape. Convulsions began within 2 seconds of impact and comprised an initial period of tonic stiffening followed by myoclonic jerks of all limbs lasting up to 150 seconds. Some asymmetry in the convulsive manifestations was common, and recovery of consciousness was rapid. No structural or permanent brain injury was present on clinical assessment, neuropsychological testing, or neuroimaging studies. All players returned to elite competition within two weeks of the incident. Epilepsy did not develop in any player over a mean (range) follow up of 3.5 (1-13) years. These concussive or impact convulsions are probably a non-epileptic phenomenon, somewhat akin to convulsive syncope. The mechanism may be a transient traumatic functional decerebration. In concussive convulsions the outcome is universally good, antiepileptic treatment is not indicated, and prolonged absence from sport is unwarranted.
Publisher: Wiley
Date: 02-1997
Publisher: Wiley
Date: 19-11-2019
DOI: 10.1002/ANA.25619
Publisher: Elsevier BV
Date: 09-2015
Publisher: CSIRO Publishing
Date: 2010
DOI: 10.1071/HE10099
Abstract: There are moves to ban smoking in outdoor areas of pubs, restaurants and cafes. Some argue that this is unnecessary as exposure to second hand smoke (SHS) is minimal. The aim of this study was to determine potential exposure of patrons to SHS in outdoor areas of eating and drinking venues. Concentrations of fine particulate matter (PM2.5) were measured in the alfresco areas of 28 cafes and pubs. Data were collected on the number of smokers present during s ling and factors that could influence PM2.5concentrations. PM2.5concentrations for periods with and without smokers were compared using paired and independent s le tests. PM2.5 concentrations were significantly increased when there was at least one smoker compared to periods with no smoking (14.25 microg/m3 and 3.98 g/m3, respectively). There was evidence of a dose response increase with mean concentrations for none, one and two or more smokers of 3.98, 10.59and 17.00microg/m3, respectively. The differences remained significant after controlling for other factors. When two or more people were smoking, average PM2.5reached levels the US Environmental Protection Agency warns may put particularly sensitive people at risk of respiratory symptoms. Smoking increases PM2.5concentrations in outdoor areas to levels that are potentially hazardous to health.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-1997
Abstract: Progressive myoclonus epilepsy (PME) may develop in adult life. We present two patients with PME appearing around the age of 30 years in whom the disorder represented a manifestation of Alzheimer's disease. This diagnosis must be considered in addition to possible Kufs' disease or myoclonic epilepsy with ragged red fibers (MERRF) when PME develops in young adults.
Publisher: Wiley
Date: 04-07-2023
DOI: 10.1002/EPD2.20090
Abstract: A 24‐year‐old man with non‐lesional bitemporal lobe epilepsy since age 16 years was found dead in bed around midday. He was last seen the previous night when he was witnessed to have a tonic–clonic seizure. Before his death, he was experiencing weekly focal impaired awareness seizures and up to two focal‐to‐bilateral tonic–clonic seizures each year. He had trialed several antiseizure medications and was on levetiracetam 1500 mg/day, lamotrigine 400 mg/day, and clobazam 10 mg/day at the time of death. Other than epilepsy, his medical history was unremarkable. Of note, he had an older brother with a history of febrile seizures and a paternal first cousin with epilepsy. No cause of death was identified following a comprehensive postmortem investigation. The coroner classified the death as “sudden unexpected death in epilepsy” (SUDEP), and it would qualify as “definite SUDEP” using the current definitions. 1 This left the family with many questions unanswered in particular, they wish to know what caused the death and whether it could happen to other family members. Could postmortem genetic testing identify a cause of death, provide closure to the family, and facilitate cascade genetic testing of first‐degree family members who may be at risk of sudden death? While grieving family members struggle with uncertainty about the cause of death, we as clinicians also face similar uncertainties about genetic contributions to SUDEP, especially when the literature is sparse, and the utility of genetic testing is still being worked out. We aim to shed some light on this topic, highlighting areas where data is emerging but also areas where uncertainty remains, keeping our case in mind as we examine this clinically important area.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-02-2009
DOI: 10.1212/01.WNL.0000341942.29513.BD
Abstract: Genome-wide association studies are utilized for gene discovery in common diseases. Genotypes of large groups of unrelated patients are compared to controls. This has become feasible due to the recent technical advances in genomics and convincing positive results are now regularly being published. This review is an accessible introduction to the genetic and technical knowledge needed to interpret such studies. Genome-wide association studies are being applied to many neurologic diseases. Here we use idiopathic generalized epilepsy as an ex le to highlight the phenotyping, s le size, and statistical issues that must be addressed in such studies. These studies are likely to transform our understanding of complex neurologic diseases in the next few years.
Publisher: Wiley
Date: 09-1987
Abstract: A retrospective single-blind study assessing the value of magnetic resonance imaging (MRI) in 48 patients treated surgically for temporal lobe epilepsy was carried out. The imaging findings were correlated with the surgical findings in all cases. Abnormal MRI signals were detected in 34 of 48 (71%) epileptic patients and in 3 of 48 (6.2%) normal or disease control subjects. Twelve patients had structural foreign-tissue lesions, all detected by MRI. Of 14 patients with severe gliosis of the neocortex and/or mesial temporal structures, 11 had abnormal MRI scans. In patients with mild or moderate gliosis of mesial temporal structures, 6 of 12 had abnormal MRI scans. These results indicate that MRI is a sensitive technique for localizing foreign-tissue lesions, mesial temporal sclerosis, and gliosis in patients with intractable temporal lobe seizures.
Publisher: Wiley
Date: 18-01-2017
DOI: 10.1111/EPI.13666
Abstract: Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling-mediated neuronal proliferation, migration and differentiation. Mutations in the X-linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy-aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike-waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X-linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X-linked EAS because of the specific genetic counseling implications.
Publisher: AMPCo
Date: 2011
Publisher: Wiley
Date: 18-11-2019
DOI: 10.1002/ANA.25625
Publisher: Wiley
Date: 21-01-2021
DOI: 10.1111/EPI.16810
Abstract: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. A population‐based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. Seventy‐three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS‐like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS‐like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe–profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe–profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS‐like," or "unifocal epilepsy" had severe–profound delay, and only two of 64 (3%) were deceased. Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-1997
DOI: 10.1212/WNL.48.2.418
Abstract: Chronic encephalitis and epilepsy (Rasmussen's encephalitis) is a rare progressive disorder of uncertain etiology that usually occurs in children, producing focal epilepsy, hemiparesis, and intellectual deterioration. We identified 13 patients in whom seizures developed in adolescence or adulthood with a pathologic picture of chronic encephalitis. The clinical characteristics were more variable than those occurring in children, with the patients falling into three groups: five patients developed seizures in adulthood, but otherwise showed many resemblances to the childhood form five developed seizures in adolescence, with similar presentation but rather more benign course than in the younger patients and three presented with clinical features initially suggestive of a tumor. Occipital onset to the seizures appeared to be more common than in the childhood form, and bilateral disease also occurred.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-03-2016
Publisher: Wiley
Date: 12-1998
Abstract: Familial partial epilepsy with variable foci (FPEVF) joins the recently recognized group of inherited partial epilepsies. We describe an Australian family with 10 in iduals with partial seizures over four generations. Detailed electroclinical studies were performed on all affected and 17 clinically unaffected family members. The striking finding was that the clinical features of the seizures and interictal electroencephalographic foci differed among family members and included frontal, temporal, occipital, and centroparietal seizures. Mean age of seizure onset was 13 years (range, 0.75-43 years). Two in iduals without seizures had epileptiform abnormalities on electroencephalographic studies. Penetrance of seizures was 62%. A genome-wide search failed to demonstrate definitive linkage, but a suggestion of linkage was found on chromosome 2q with a LOD score of 2.74 at recombination fraction of zero with the marker D2S133. FPEVF differs from the other inherited partial epilepsies where partial seizures in different family members are clinically similar. The inherited nature of this new syndrome may be overlooked because of relatively low penetrance and because of the variability in age at onset and electroclinical features between affected family members.
Publisher: Elsevier BV
Date: 10-2007
Publisher: Wiley
Date: 19-01-2010
Publisher: Elsevier BV
Date: 11-2001
DOI: 10.1016/S0387-7604(01)00272-8
Abstract: The majority of severe epileptic encephalopathies of early childhood are symptomatic where a clear etiology is apparent. There is a small subgroup, however, where no etiology is found on imaging and metabolic studies, and genetic factors are important. Myoclonic-astatic epilepsy (MAE) and severe myoclonic epilepsy in infancy (SMEI), also known as Dravet syndrome, are epileptic encephalopathies where multiple seizure types begin in the first few years of life associated with developmental slowing. Clinical and molecular genetic studies of the families of probands with MAE and SMEI suggest a genetic basis. MAE was originally identified as part of the genetic epilepsy syndrome generalized epilepsy with febrile seizures plus (GEFS(+)). Recent clinical genetic studies suggest that SMEI forms the most severe end of the spectrum of the GEFS(+). GEFS(+) has now been associated with molecular defects in three sodium channel subunit genes and a GABA subunit gene. Molecular defects of these genes have been identified in patients with MAE and SMEI. Interestingly, the molecular defects in MAE have been found in the setting of large GEFS(+) pedigrees, whereas, more severe truncation mutations arising de novo have been identified in patients with SMEI. It is likely that future molecular studies will shed light on the interaction of a number of genes, possibly related to the same or different ion channels, which result in a severe phenotype such as MAE and SMEI.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-07-2007
Publisher: Cold Spring Harbor Laboratory
Date: 14-10-2021
DOI: 10.1101/MCS.A006133
Abstract: Nevus sebaceous syndrome (NSS) is a rare, multisystem neurocutaneous disorder, characterized by a congenital nevus, and may include brain malformations such as hemimegalencephaly or focal cortical dysplasia, ocular, and skeletal features. It has been associated with several eponyms including Schimmelpenning and Jadassohn. The isolated skin lesion, nevus sebaceous, is associated with postzygotic variants in HRAS or KRAS in all in iduals studied. The RAS proteins encode a family of GTPases that form part of the RAS/MAPK signaling pathway, which is critical for cell cycle regulation and differentiation during development. We studied an in idual with nevus sebaceous syndrome with an extensive nevus sebaceous, epilepsy, intellectual disability, and hippoc al sclerosis without pathological evidence of a brain malformation. We used high-depth gene panel sequencing and droplet digital polymerase chain reaction (PCR) to detect and quantify RAS/MAPK gene variants in nevus sebaceous and temporal lobe tissue collected during plastic and epilepsy surgery, respectively. A mosaic KRAS c.34G T p.(Gly12Cys) variant, also known as G12C, was detected in nevus sebaceous tissue at 25% variant allele fraction (VAF), at the residue most commonly substituted in KRAS . Targeted droplet digital PCR validated the variant and quantified the mosaicism in other tissues. The variant was detected at 33% in temporal lobe tissue but was absent from blood and healthy skin. We provide molecular confirmation of the clinical diagnosis of NSS. Our data extends the histopathological spectrum of KRAS G12C mosaicism beyond nevus sebaceous to involve brain tissue and, more specifically, hippoc al sclerosis.
Publisher: Springer Science and Business Media LLC
Date: 26-05-2013
DOI: 10.1038/NG.2646
Publisher: Georg Thieme Verlag KG
Date: 12-1998
Abstract: The etiology and relationships between different forms of malformations of cortical development are poorly understood. Schizencephaly is generally regarded as unrelated to arachnoid cysts. As part of a systematic study of epilepsy in twins we observed a monozygotic twin pair discordant for temporal lobe epilepsy where the twin with epilepsy had unilateral temporal schizencephaly and periventricular heterotopia. The twin without epilepsy had an arachnoid cyst in the same temporal lobe. Although an incidental association is possible, this observation, together with occasional reports of schizencephaly and arachnoid cysts within one in idual, suggests a shared pathogenic mechanism. Schizencephaly can be caused by both genetic and acquired factors. We propose that our observations in this twin pair are best explained by a genetic factor present in both twins, with an additional environmental insult resulting in schizencephaly in only one of the pair.
Publisher: S. Karger AG
Date: 26-04-2013
DOI: 10.1159/000350737
Abstract: b i Background/Aims: /i /b Renin processing and storage is believed to occur in lysosome-like structures in the afferent arteriole. SCARB2/Limp-2 is a transmembrane lysosomal protein responsible for the intracellular trafficking of β-glucocerebrosidase. This study aimed to confirm the expression of SCARB2/Limp-2 in renin secretory granules, and explore its role in renin processing and secretion. b i Methods: /i /b Co-localisation studies of (pro)renin with lysosomal membrane proteins, SCARB2/Limp-2, LAMP-1 and LAMP-2, were performed in mouse and human kidney sections. Intrarenal expression and secretion of (pro)renin in wild-type (WT) and Limp-2 sup -/- /sup mice were compared with and without stimulation. b i Results: /i /b SCARB2/Limp-2, LAMP-1 and LAMP-2 co-localised with (pro)- renin in mouse and human kidney. Plasma renin concentration was increased in Limp-2 sup -/- /sup mice when compared to WT littermates. No change in (pro)renin expression, however, was observed in Limp-2 sup -/- /sup mouse kidney cortex by immunofluorescence microscopy, Western blotting, quantitative RT-PCR or the ultrastructural appearance of renin secretory granules. Acute stimulation of renin release by isoprenaline or hydralazine was similar in WT and Limp-2 sup -/- /sup mice. Following chronic salt restriction, however, immunofluorescence microscopy showed less (pro)renin expressed in Limp-2 sup -/- /sup compared with WT mouse kidneys, and there was significantly less prorenin but not renin by Western blotting in Limp-2 sup -/- /sup mouse kidney cortex, despite no difference in circulating renin levels. b i Conclusion: /i /b Renin secretory granules possess integral lysosomal proteins, confirming that they are indeed modified lysosomes. Limp-2 deficiency leads to a minor increase in circulating renin. Limp-2, however, is not required for acute or chronic stimulation of renin release.
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.YEBEH.2022.108960
Abstract: People with epilepsy have a higher prevalence of medical and psychiatric comorbidities compared to the general population. Comorbidities are associated with poor epilepsy outcomes, and there have been recommendations for screening and early identification to improve clinical management. Data from 'First Seizure Clinics' (FSCs) with expert epileptological review can inform about disorders already present at the point of diagnosis of epilepsy or unprovoked seizures. Here, we aimed to describe pre-existing conditions with a focus on psychiatric, substance use, cardiac, neurological, and cancer health domains. We included 1383 adults who received a new diagnosis of epilepsy or unprovoked seizures at Austin Hospital (AH) or Royal Melbourne Hospital (RMH) (Australia) FSCs from 2000 to 2010. Data were audited from FSC records, primarily detailed interviews undertaken by epileptologists. Logistic regression examined age distribution and other risk factors. The median age at FSC presentation was 37 years (IQR 26-53, range 18-94). Pre-existing conditions were reported by 40 % from 32 % in the youngest group (18-30 years) to 53 % in the oldest (65+ years). Psychiatric (18 %) and substance use (16 %) disorders were most common, with higher prevalence among patients 18 to 65 years of age compared to those older than 65 years (p < 0.001). Cardiac, neurological, or cancer conditions were reported by 3-6 %, most often amongst those older than 65 years (p 1 health domain. The commonest combination was a psychiatric condition with substance use disorder. Of the sixty-two patients reporting this combination, 61 were ≤65 years of age. Pre-existing health conditions are present in a substantial proportion of patients diagnosed with epilepsy or unprovoked seizures. Disorders are highest amongst elders, but one-third of younger adults also reported positive histories. These are predominantly psychiatric and/or substance use disorders, conditions strongly associated with poor outcomes in the general population. These findings inform post-diagnosis planning and management, as well as research examining post-diagnostic outcomes and associations between comorbidities and epilepsy.
Publisher: American Physiological Society
Date: 06-2011
DOI: 10.1152/AJPRENAL.00015.2011
Abstract: Deficiency of the intrinsic lysosomal protein human scavenger receptor class B, member 2 (SCARB2 Limp-2 in mice) causes collapsing focal and segmental glomerular sclerosis (FSGS) and myoclonic epilepsy in humans, but patients with no apparent kidney damage have recently been described. We now demonstrate that these patients can develop tubular proteinuria. To determine the mechanism, mice deficient in Limp-2, the murine homolog of SCARB2, were studied. Most low-molecular-weight proteins filtered by the glomerulus are removed in the proximal convoluted tubule (PCT) by megalin/cubilin-dependent receptor-mediated endocytosis. Expression of megalin and cubilin was unchanged in Limp-2 −/− mice, however, and the initial uptake of injected Alexa Fluor 555-conjugated bovine serum albumin (Alexa-BSA) was similar to wild-type mice, indicating that megalin/cubilin-dependent, receptor-mediated endocytosis was unaffected. There was a defect in proteolysis of reabsorbed proteins in the Limp-2 −/− mice, demonstrated by the persistence of Alexa-BSA in the PCT compared with controls. This was associated with the failure of the lysosomal protease cathepsin B to colocalize with Alexa-BSA and endogenous retinol-binding protein in kidneys from Limp-2 −/− mice. The data suggest that tubular proteinuria in Limp-2 −/− mice is due to failure of endosomes containing reabsorbed proteins to fuse with lysosomes in the proximal tubule of the kidney. Failure of proteolysis is a novel mechanism for tubular proteinuria.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-11-2005
DOI: 10.1212/01.WNL.0000180910.72487.18
Abstract: Long-term antiepileptic drug (AED) use has been associated with bone disease, but many previous studies have been limited by inadequate control subjects. We used a cotwin affected sib-pair model to investigate this issue. The authors studied 31 female twin (15 monozygous and 16 dizygous) and four sibling pairs ( 12 months of AED treatment. Areal bone mineral density (ABMD, g/cm2) was measured at the lumbar spine (LS), total hip (TH), femoral neck (FN), and total forearm (FA). Three primary a priori defined subgroups were analyzed: a) use for > 2 years, b) use of enzyme-inducing AEDs, or c) age older than 40 years. For all pairs (n = 35), there were no significant within-pair differences in any ABMD measure. However, in Subgroup a (n = 27), there was a within-pair difference at the FA (0.513 vs 0.534, -3.9%, p = 0.016). In Subgroup b (n = 29), there was also a within-pair difference at the FA for AED user vs nonuser (0.508 vs 0.529, -3.8%, p = 0.010). In Subgroup c (n = 15), there were within-pair differences at the FA (0.492 vs 0.524, -6.1%, p = 0.017) and the LS (0.884 vs 0.980, -9.8%, p = 0.036). Patients using AEDs for > 2 years, in particular those taking enzyme-inducing AEDs and those older than 40 years, have significantly lower bone mineral density at clinically relevant fracture risk sites.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-11-2021
DOI: 10.1212/NXG.0000000000000641
Abstract: To assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort. Of 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: “Unverricht-Lundborg disease-like PME,” “late-onset PME,” “PME plus developmental delay,” and “PME plus dementia.” Sixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS , CACNA2D2 , STUB1 , AFG3L2 , CLN6 , NAXE , and CHD2 . Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories. The application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield %, PME is one of the best genetically defined epilepsy syndromes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2014
Publisher: Oxford University Press (OUP)
Date: 15-12-2019
DOI: 10.1093/BRAIN/AWY297
Abstract: Kufs disease is the major adult form of neuronal ceroid lipofuscinosis, but is rare and difficult to diagnose. Diagnosis was traditionally dependent on the demonstration of characteristic storage material, but distinction from normal age-related accumulation of lipofuscin can be challenging. Mutation of CLN6 has emerged as the most important cause of recessive Kufs disease but, remarkably, is also responsible for variant late infantile ceroid lipofuscinosis. Here we provide a detailed description of Kufs disease due to CLN6 pathogenic variants. We studied 20 cases of Kufs disease with CLN6 pathogenic variants from 13 unrelated families. Mean age of onset was 28 years (range 12-51) with bimodal peaks in teenage and early adult life. The typical presentation was of progressive myoclonus epilepsy with debilitating myoclonic seizures and relatively infrequent tonic-clonic seizures. Patients became wheelchair-bound with a mean 12 years post-onset. Ataxia was the most prominent motor feature. Dementia appeared to be an invariable accompaniment, although it could take a number of years to manifest and occasionally cognitive impairment preceded myoclonic seizures. Patients were usually highly photosensitive on EEG. MRI showed progressive cerebral and cerebellar atrophy. The median survival time was 26 years from disease onset. Ultrastructural examination of the pathology revealed fingerprint profiles as the characteristic inclusions, but they were not reliably seen in tissues other than brain. Curvilinear profiles, which are seen in the late infantile form, were not a feature. Of the 13 unrelated families we observed homozygous CLN6 pathogenic variants in four and compound heterozygous variants in nine. Compared to the variant late infantile form, there was a lower proportion of variants that predicted protein truncation. Certain heterozygous missense variants in the same amino acid position were found in both variant late infantile and Kufs disease. There was a predominance of cases from Italy and surrounding regions this was partially explained by the discovery of three founder pathogenic variants. Clinical distinction of type A (progressive myoclonus epilepsy) and type B (dementia with motor disturbance) Kufs disease was supported by molecular diagnoses. Type A is usually caused by recessive pathogenic variants in CLN6 or dominant variants in DNAJC5. Type B Kufs is usually associated with recessive CTSF pathogenic variants. The diagnosis of Kufs remains challenging but, with the availability of genetic diagnosis, this will largely supersede the use of diagnostic biopsies, particularly as biopsies of peripheral tissues has unsatisfactory sensitivity and specificity.
Publisher: Cold Spring Harbor Laboratory
Date: 14-06-2022
DOI: 10.1101/2022.06.08.22276120
Abstract: Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here, we report a trans-ethnic GWAS including 29,944 cases, stratified into three broad- and seven sub-types of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants substantially close the missing heritability gap for GGE. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analysis of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current anti-seizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.
Publisher: Elsevier BV
Date: 05-2007
Publisher: Wiley
Date: 13-03-2007
DOI: 10.1111/J.1528-1167.2007.01004.X
Abstract: We observed three apparently unrelated and geographically separate Arab families with Lafora disease in Israel and the Palestinian territories. We clinically evaluated the families and analyzed their DNA for EPM2A mutations. Of seven in iduals with Lafora disease, the clinical onset varied from 13 to 20 years. All three families shared the same novel homozygous deletion in EPM2A. Haplotype analysis around the deletion showed that the families shared a common homozygous haplotype. The boundaries of this haplotype varied between families and even within one family. We conclude that considerable variability in the age at onset of Lafora disease can occur within families. Identical mutations can be associated with the classic adolescent presentation, as well as late-onset cases. Haplotype analysis suggests that this EPM2A mutation arose many generations previously, so it may be of importance for cases distributed more widely in the Middle East.
Publisher: Wiley
Date: 30-10-2019
DOI: 10.1111/JON.12673
Publisher: BMJ
Date: 05-1993
Abstract: The results of a multicentre, randomised, double-blind, placebo controlled, crossover trial of lamotrigine as add-on therapy in patients with partial seizures poorly controlled by established antiepileptic drugs (AEDs) are presented. The study consisted of two 12 week treatment periods each followed by a four week washout period. During the lamotrigine treatment phase, patients received 150 mg or 300 mg daily dose depending on their concomitant AEDs to achieve concentrations in the range 1-3 mg/L. Forty one patients were entered at four centres and all patients entered completed the study. There was a highly significant (p < 0.001) decrease in total seizure counts on lamotrigine compared with placebo. Overall, 22% of patients experienced at least a 50% reduction in the total numbers of all seizures types on lamotrigine, compared with none on placebo. When the total numbers of partial seizures (simple and complex partial) were analysed there was also a significant (p < 0.05) reduction in seizure counts on lamotrigine compared with placebo. When total numbers of secondarily generalised seizures were compared the trend for a reduction in this seizure type did not achieve significance (0.05 < p < 0.1). Concomitant AED plasma concentrations were virtually unchanged. It is concluded that lamotrigine is an effective AED in the treatment of therapy-resistant partial seizures.
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.YEBEH.2012.01.016
Abstract: We aimed to examine post-operative auras/simple partial seizures and the associated risk of seizure recurrence after temporal lobectomy. Included were 159 patients who underwent anterior temporal lobectomy (1995-2006) at Austin Health, Australia. Initial analyses used Cox regression. Post-hoc, exploratory analyses of aura and seizure patterns were undertaken. Initial analyses indicated that post-operative auras were not associated with subsequent disabling seizures (HR 0.65, 95%CI 0.4-1.1 p=0.08). However, post-hoc examination found data patterns that suggest that post-operative auras may have been under-reported when medical contact between these events was absent. These findings are relevant to current research, as similar methodology is commonly employed in post-operative outcome studies. Important implications include potential underestimation of seizure risk associated with auras. Carefully planned prospective studies are required to assess the risk associated with post-operative auras.
Publisher: American Medical Association (AMA)
Date: 08-07-2022
DOI: 10.1001/JAMANETWORKOPEN.2022.20189
Abstract: Cannabidiol has shown efficacy in randomized clinical trials for drug-resistant epilepsy in specific syndromes that predominantly affect children. However, high-level evidence for the efficacy and safety of cannabidiol in the most common form of drug-resistant epilepsy in adults, focal epilepsy, is lacking. To investigate the efficacy, safety, and tolerability of transdermally administered cannabidiol in adults with drug-resistant focal epilepsy. A randomized, double-blind, placebo-controlled, multicenter clinical trial at 14 epilepsy trial centers in Australia and New Zealand. Participants were adults with drug-resistant focal epilepsy receiving a stable regimen of up to 3 antiseizure medications. Data were analyzed from July 2017 to November 2018. Eligible participants were randomized (1:1:1) to 195-mg or 390-mg transdermal cannabidiol or placebo twice daily for 12 weeks, after which they could enroll in an open-label extension study for up to 2 years. Seizure frequency was self-reported using a daily diary. The primary efficacy end point was the least squares mean difference in the log-transformed total seizure frequency per 28-day period, adjusted to a common baseline log seizure rate, during the 12-week treatment period. A total of 188 patients (45% male [85 patients] and 54.8% female [103 patients]) with a mean (SD) age of 39.2 (12.78) years were randomized, treated, and analyzed (195-mg cannabidiol, 63 participants 390-mg cannabidiol, 62 participants placebo, 63 participants). At week 12 of the double-blind period, there was no difference in seizure frequency between placebo (mean [SD] 2.49 [1.31] seizures per 28 days) and 195-mg cannabidiol (mean [SD] 2.51 [1.15] seizures per 28 days least squares mean difference, 0.014 95% CI, −0.175 to 0.203 P = .89) or 390-mg cannabidiol (mean [SD] 2.59 [1.12] seizures per 28 days least squares mean difference, 0.096 95% CI, −0.093 to 0.285 P = .32). By month 6 of the open-label extension, 115 patients (60.8%) achieved a seizure reduction of at least 50%. Treatment-emergent adverse events occurred in 50.4% (63 of 125 participants) of the cannabidiol group vs 41.3% (26 of 63 participants) in the placebo group, with a treatment difference of 9.1% (95% CI, −6.0% to 23.6%), and occurred at similar rates in the cannabidiol groups. Few participants discontinued (7% [14 of 188 participants]), and most (98% [171 of 174 participants]) continued into the open-label extension. Both doses of transdermal cannabidiol were well tolerated and safe. No significant difference in efficacy was observed between cannabidiol and placebo during the double-blind treatment period. The open-label extension demonstrated the long-term safety, tolerability, and acceptability of transdermal cannabidiol delivery. ACTRN12616000510448 (double-blind) ACTRN12616001455459 (open-label).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-1998
DOI: 10.1212/WNL.51.1.78
Abstract: To test both the genetic and acquired hypotheses for the etiology of hippoc al sclerosis (HS) by studying with optimized and quantitative MRI three monozygous (MZ) twin pairs in which the index twin had temporal lobe epilepsy and HS. There is conflicting evidence in the literature regarding whether HS is genetic or acquired prenatally, perinatally, or as a consequence of prolonged childhood seizures. We compared three MZ pairs with 30 age-matched control subjects who had no history of a neurologic disorder we also used the twins as matched s les to assess subtle differences between the affected and the unaffected twins. All of the affected twins had prolonged seizures with fever in early childhood, which stood out as the unique factor common to all affected twins and was absent in all the unaffected twins. HS was present in all affected twins but was absent in the unaffected twin on visual, volumetric, and T2 relaxometry criteria. Comparison of the affected twin with the co-twin revealed that intracranial volume ipsilateral to the HS was relatively small in two of three affected twins. The absence of HS in the unaffected twin is strong evidence against a genetic hypothesis for HS. Neither perinatal problems nor birth order were factors in determining the presence of HS. This twin study supports the notion of HS as an acquired lesion secondary to prolonged seizures in early childhood and suggests that regional abnormalities of intracranial volume are associated with HS.
Publisher: Elsevier BV
Date: 11-1995
DOI: 10.1016/0920-1211(95)00049-6
Abstract: Familial frontal epilepsy has been recently described in six pedigrees. All families reported show autosomal dominant inheritance with incomplete penetrance. Affected in iduals develop predominantly nocturnal seizures with frontal lobe semiology. In 1959, a genetic mouse model for partial epilepsy, the El mouse, was reported. In the El mouse, a major seizure susceptibility gene, El-1, segregates in an autosomal dominant fashion and has been localized to a region distal to the centromere of mouse ch 9. Comparative genetic maps between man and mouse have been used to predict the location of several human disease genes. The El-1 locus in the mouse is homologous to human chromosomes 3p23-p21.2, 3p11.2-q11.2, 3q21-q25.3, 6p12-q12 and 15q24. Polymorphic microsatellite markers covering these candidate regions were used for genotyping in iduals in the three larger families ascertained, one of which is French-Canadian and two are Australian. Significant negative two-point and multipoint lod scores were obtained separately for each family, thus excluding linkage with the candidate regions on chromosomes 3, 6 and 15.
Publisher: Cold Spring Harbor Laboratory
Date: 07-06-2021
DOI: 10.1101/2021.06.01.21257500
Abstract: The vacuolar H + -ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in ATP6V0A1 , the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four in iduals. Here we identified 17 in iduals from 14 unrelated families with both with new and previously characterised variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 in iduals carried de novo missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in C. elegans . Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of ATP6V0A1 -related conditions.
Publisher: Wiley
Date: 1997
DOI: 10.1111/J.1528-1157.1997.TB01080.X
Abstract: The pathophysiologic basis for the [18F]fluorodeoxyglucose positron-emission tomography (FDG-PET) temporal lobe hypometabolism in patients with hippoc al sclerosis (HS) is uncertain. We tested the hypothesis that hippoc al atrophy, which is strongly correlated with hippoc al cell loss, is largely responsible for the regional hypometabolism in HS. Regions of interest (ROIs) on FDG-PET scanning were determined in the medial, lateral, and posterior temporal lobe, thalamus, and basal ganglia. A right/left asymmetry index for each ROI was calculated. These results were correlated with hippoc al magnetic resonance imaging (MRI) volume ratios. There was no correlation between the magnitudes of the FDG-PET asymmetry index and the MRI volume ratio for the mesial or lateral temporal regions (r = -0.09, r = -0.04). When the right/left asymmetry index was compared with the right/left hippoc al volume ratio, correlations for the mesial temporal ROI (r = 0.79, p < 0.0001) and lateral temporal ROI (r = 0.57, p < 0.0005) were found. These, however, simply indicated that both tests accurately reflect the side of the epileptogenic region. The concordance of the side of relative hypometabolism of the FDG-PET with the side of the hippoc al atrophy was higher for the mesial temporal region (100%) than for the lateral (77.5%). The lack of correlation between the magnitudes of the ratios argues against hippoc al atrophy and cell loss having a central role in the FDG-PET temporal hypometabolism.
Publisher: Elsevier BV
Date: 11-2013
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.EPLEPSYRES.2015.04.014
Abstract: To describe clinical and EEG phenotypes of a family with an unusual familial epilepsy syndrome characterized by myoclonus and dystonia. Family members underwent electroclinical phenotyping including review of EEGs and MRI. DNA from family members was genotyped using Illumina OmniExpress genotyping arrays. Parametric and nonparametric linkage analyses were performed using MERLIN. The disorder followed autosomal dominant (AD) inheritance and affected seven in iduals over two generations. Seizures began at a mean of 14.5 years. Six in iduals had spontaneous myoclonic seizures, of which five also had photic-induced myoclonus and four had photic-induced occipital seizures. Six in iduals had convulsive seizures generalized in two and focal in four. Photosensitivity was prominent with generalized spike wave and polyspike wave in four in iduals of which two also had occipital spikes. MRI scans were normal in the four in iduals tested. Extensive metabolic investigation was normal. Juvenile myoclonic epilepsy (JME) occurred in two and JME overlapping with idiopathic photosensitive epilepsy (IPOE) in four in iduals. All three affected males had a more severe disorder than the four affected females. Two males had a progressive neurological disorder with progressive myoclonus epilepsy and deterioration in their early 30s. They developed episodes of paroxysmal cervical dystonia with cognitive decline during periods of poor seizure control. One plateaued after years of poor seizure control but remained intractable with periods of deterioration. The other deteriorated with episodes of status dystonicus and status epilepticus, ataxia and a progressive ophthalmoplegia before succumbing at 38 years. Parametric linkage analysis identified three peaks achieving a maximum LOD score of 1.21. Nonparametric analysis identified eight peaks achieving LOD scores above 0.80. These were not statistically significant. This is a novel autosomal dominant familial epilepsy syndrome. "Myoclonic occipital photosensitive epilepsy with dystonia" (MOPED) involves a spectrum of phenotypes from JME, sometimes with an IPOE overlap, to progressive myoclonus epilepsy with paroxysmal dystonia.
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier BV
Date: 1995
DOI: 10.1016/0730-725X(95)02021-K
Abstract: MRI, PET, and SPECT are all used to image abnormalities in the epileptic brain. Comparison of the techniques is difficult because they measure different aspects of the epileptic process--structure, metabolism, and perfusion. SPECT is the only one that can be systematically applied during seizures, while all three are used to image interictal abnormalities. Literature review suggests that of interictal techniques, PET has the highest diagnostic sensitivity in temporal lobe epilepsy (TLE) (84% vs. 66% for SPECT, 55% for qualitative MRI, 71% for quantitative MRI) while SPECT has the highest sensitivity in extratemporal epilepsy (ETE) (60% vs. 43% for MRI and 33% for PET). The highest diagnostic sensitivity and specificity were achieved by ictal imaging with SPECT (90% in TLE, 81% in ETE). The techniques, however, were not always redundant. One reason for the wide discrepancy of results in TLE and ETE might be the differing pathologic substrates. A literature review of imaging findings associated with mesial temporal sclerosis (MTS), developmental lesion or tumor as the underlying abnormality associated with epilepsy supports this explanation. PET and MRI are much more sensitive to MTS than SPECT (100%, 95% vs. 70%). On the other hand, in developmental lesions the three techniques are equally sensitive (88-92%) and in tumors, MRI was most sensitive (96%) and SPECT least (82%). A study at NIH explains the differing sensitivities: using PET to measure both blood flow and metabolism revealed discrepant findings in the same patients. Preliminary evidence also indicates that the distribution of hyperperfusion on ictal SPECT can differentiate subtypes of TLE. Combining the results of refined imaging techniques holds great promise in epilepsy localization and diagnosis.
Publisher: Cold Spring Harbor Laboratory
Date: 15-01-2022
DOI: 10.1101/2022.01.14.22269323
Abstract: Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non-neurodegenerative ‘non-progressor’, ‘phenocopy’ mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay. Cerebrospinal fluid (CSF) NfL, amyloid beta 1-42 (AB42), total and phosphorylated tau (T-tau, P-tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow up information, patients were categorised as Progressors. Non-Progressors were subtyped in to Phenocopy Non-Progressors (non-neurological/neurodegenerative final diagnosis), and Static Non-Progressors (static deficits, not fully explained by non-neurological/neurodegenerative causes). Forty-three patients were included: 20 Progressors, 23 Non-Progressors (15 Phenocopy, 8 Static), 20 controls. NfL concentrations were lower in Non-Progressors (Non-Progressors Mean, M=554pg/mL, 95%CI:[461, 675], Phenocopy Non-Progressors M=459pg/mL, 95%CI:[385, 539], Static Non-Progressors M=730pg/mL, 95%CI:[516, 940]), compared to bvFTD Progressors (M=2397pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non-Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Static Non-Progressors tended to have higher T-tau and P-tau levels compared to Phenocopy Non-Progressors. This study demonstrated strong diagnostic utility of CSF NfL to distinguish bvFTD from phenocopy non-progressor variants, at baseline, with high accuracy, in a real-world clinical setting. This has important clinical implications, to improve outcomes for patients and clinicians facing this challenging clinical dilemma, as well as for healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non-progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1038/S41467-019-12763-9
Abstract: Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same in idual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.
Publisher: The Japan Epilepsy Society
Date: 30-06-2019
DOI: 10.3805/JJES.37.6
Publisher: Wiley
Date: 05-1991
Abstract: Multiple symmetrical lipomatosis is a striking clinical finding associated with a variety of peripheral and central nervous system abnormalities. We describe 4 unrelated patients with evidence of mitochondrial dysfunction in skeletal muscle. Multiple symmetrical lipomatosis is an additional, albeit unusual, manifestation of the expanding clinical spectrum of mitochondrial diseases.
Publisher: SAGE Publications
Date: 10-1994
DOI: 10.1177/0883073894009001121
Abstract: Single-photon emission computed tomography (SPECT) is being used increasingly in the investigation of children with intractable partial seizures. SPECT imaging of regional cerebral blood flow with 99mTc-hexamethylpropylene amine oxime, iodinated radiopharmaceuticals, and 133Xe typically reveals decreased cortical perfusion interictally and increased cortical perfusion ictally in the region of the epileptic focus. Studies in both adults and children indicate significantly greater sensitivity and specificity with ictal injection of radiopharmaceutical, with interictal SPECT not infrequently revealing nonlocalizing or falsely localizing information. Recent SPECT studies employing iodinated neuroreceptor ligands report altered receptor binding in the region of the epileptic focus, providing insight into the underlying neuropharmacology of partial epilepsy. SPECT has an established role in the presurgical localization of seizure foci in children with intractable partial seizures and may be a useful modality to study the functional anatomy and clinical semiology of partial seizures in childhood. (J Child Neurol 1994 (Suppl):S71-S81).
Publisher: Cold Spring Harbor Laboratory
Date: 13-10-2023
Publisher: Springer Science and Business Media LLC
Date: 05-1995
DOI: 10.1038/NG0595-117
Abstract: The epilepsies comprise a group of syndromes that are ided into generalized and partial (focal) types. Familial occurrence has long been recognized but progress in mapping epilepsy genes has been slow except for rare cases where the inheritance is easily determined from classical genetic studies. Linkage is established for three generalized syndromes: the EBN1 and EBN2 genes for benign familial neonatal convulsions (BFNC) map to chromosomes 20q and 8q (refs 2-5), the EPM1 gene for Unverricht-Lundborg disease maps to 21q (ref. 6) and the gene for the northern epilepsy syndrome maps to 8p (ref. 7). A claim for linkage of the EJM1 gene for the common generalized syndrome of juvenile myoclonic epilepsy to 6p is currently in dispute. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was recently described in five families. We now report the chromosomal assignment, to 20q13.2, for the gene for ADNFLE in one large Australian kindred with 27 affected in iduals spanning six generations.
Publisher: Oxford University Press (OUP)
Date: 27-04-2005
DOI: 10.1093/BRAIN/AWH520
Abstract: To determine the effect of an established mutation of the beta1 subunit of Na(+) channels on nerve excitability, studies were undertaken in patients diagnosed with generalized epilepsy with febrile seizures plus (GEFS+). Multiple nerve excitability measurements were used to investigate the membrane properties of sensory and motor axons in five patients (aged 18-55 years) who were currently experiencing no seizures and were not on anticonvulsants. There was no history of paraesthesiae, fasciculation or cr s to suggest hyperexcitability of peripheral nerve axons. The median nerve was stimulated at the wrist, and compound muscle action potentials (CMAPs) were recorded from abductor pollicis brevis and the antidromic compound sensory nerve action potential (CSAPs) from digit 2. Stimulus-response behaviour, strength-duration time constant, threshold electrotonus, current-threshold relationship and the recovery of excitability following a supramaximal conditioning stimulus were recorded using threshold tracking. Compared with normal controls (n = 29), the axons of patients were of higher threshold. CMAPs and CSAPs were relatively small, although in idual values remained within the normal ranges. Refractoriness and relative refractory period (markers of transient Na(+) channel function) were significantly reduced in GEFS+ patients with established mutations in SCN1B (P < 0.05), and strength-duration time constants (dependent on persistent Na(+) conductances) were reduced. It is suggested that, in peripheral nerve axons, the mutation underlying GEFS+ reduces the number of functioning Na(+) channels at the node of Ranvier and that this rather than any change in gating of in idual channels dominates axonal excitability in these patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-02-2015
Publisher: Springer Science and Business Media LLC
Date: 25-01-2011
DOI: 10.1038/NRNEUROL.2010.212
Abstract: Benign mesial temporal lobe epilepsy (bMTLE), which is defined as at least 24 months of seizure freedom with or without antiepileptic medication, has probably been under-recognized because of a literature bias toward refractory epilepsy cases. Seizure onset in bMTLE tends to be in adolescence or adulthood, and patients frequently have a family history of febrile seizures and epilepsy. Long-term seizure freedom is observed with or without antiepileptic medication. On brain MRI, nearly 40% of patients with long-standing bMTLE show evidence of hippoc al sclerosis, a feature usually associated with refractory temporal lobe epilepsy. Prospective studies are needed to determine the features that allow prediction of a benign course, and to clarify the significance of hippoc al MRI changes.
Publisher: AMPCo
Date: 09-2003
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-06-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-10-2006
Publisher: Wiley
Date: 17-01-2019
DOI: 10.1002/ANA.25405
Abstract: We investigated the relationship between the interictal metabolic patterns, the extent of resection of Eighty-two patients with hippoc al sclerosis or normal magnetic resonance imaging (MRI) findings, concordant Striking differences in metabolic patterns were observed depending on the lateralization of the epileptogenic TL. The extent of the ipsilateral TLH was significantly greater in left MTLE patients (p < 0.001), whereas right MTLE patients had significantly higher rates of contralateral (CTL) TLH (p = 0.016). In right MTLE patients, CTL hypometabolism was the strongest predictor of an unfavorable seizure outcome, associated with a 5-fold increase in the likelihood of seizure recurrence (odds ratio [OR] = 4.90, 95% confidence interval [CI] = 1.07-22.39, p = 0.04). In left MTLE patients, greater extent of resection of ipsilateral TLH was associated with lower rates of seizure recurrence (p = 0.004) in univariate analysis however, its predictive value did not reach statistical significance (OR = 0.96, 95% CI = 0.90-1.02, p = 0.19). The difference in metabolic patterns depending on the lateralization of MTLE may represent distinct epileptic networks in patients with right versus left MTLE, and can guide preoperative counseling and surgical planning. Ann Neurol 2019 1-10 ANN NEUROL 2019 :241-250.
Publisher: Wiley
Date: 14-08-2007
DOI: 10.1002/ANA.21169
Abstract: The relationship between genetic variation in the T-type calcium channel gene CACNA1H and childhood absence epilepsy is well established. The purpose of this study was to investigate the range of epilepsy syndromes for which CACNA1H variants may contribute to the genetic susceptibility architecture and determine the electrophysiological effects of these variants in relation to proposed mechanisms underlying seizures. Exons 3 to 35 of CACNA1H were screened for variants in 240 epilepsy patients (167 unrelated) and 95 control subjects by single-stranded conformation analysis followed by direct sequencing. Cascade testing of families was done by sequencing or single-stranded conformation analysis. Selected variants were introduced into the CACNA1H protein by site-directed mutagenesis. Constructs were transiently transfected into human embryo kidney cells, and electrophysiological data were acquired. More than 100 variants were detected, including 19 novel variants leading to amino acid changes in subjects with phenotypes including childhood absence, juvenile absence, juvenile myoclonic and myoclonic astatic epilepsies, as well as febrile seizures and temporal lobe epilepsy. Electrophysiological analysis of 11 variants showed that 9 altered channel properties, generally in ways that would be predicted to increase calcium current. Variants in CACNA1H that alter channel properties are present in patients with various generalized epilepsy syndromes. We propose that these variants contribute to an in idual's susceptibility to epilepsy but are not sufficient to cause epilepsy on their own. The genetic architecture is dominated by rare functional variants therefore, CACNA1H would not be easily identified as a susceptibility gene by a genome-wide case-control study seeking a statistical association.
Publisher: Wiley
Date: 23-11-2009
DOI: 10.1111/J.1528-1167.2009.02103.X
Abstract: Lesion-negative refractory partial epilepsy is a major challenge in the assessment of patients for potential surgery. Finding a potential epileptogenic lesion simplifies assessment and is associated with good outcome. Here we describe imaging features of subtle parahippoc al dysplasia in five cases that were initially assessed as having imaging-negative frontal or temporal lobe epilepsy. We analyzed the clinical and imaging features of five patients with seizures from the parahippoc al region. Five patients had subtle but distinctive magnetic resonance imaging (MRI) abnormalities in the parahippoc al gyrus. This was a unilateral signal abnormality in the parahippoc al white matter extending into gray matter on heavily T(1)- and T(2)-weighted images with relative preservation of the gray-white matter boundary on T(1)-weighted volume sequences. Only one of these patients had typical electroclinical unilateral temporal lobe epilepsy (TLE) one mimicked frontal lobe epilepsy, two showed bitemporal seizures, and one had unlocalized partial seizures. All have had surgery four are seizure-free (one has occasional auras only, follow-up 6 months to 10 years), and one has a >50% seizure reduction. Histopathologic evaluation suggested dysplastic features in the surgical specimens in all. In patients with lesion-negative partial epilepsy with frontal or temporal semiology, or in cases with apparent bitemporal seizures, subtle parahippoc al abnormalities should be carefully excluded. Recognizing the MRI findings of an abnormal parahippoc al gyrus can lead to successful surgery without invasive monitoring, despite apparently incongruent electroclinical features.
Publisher: Wiley
Date: 23-05-2007
DOI: 10.1111/J.1528-1167.2007.01138.X
Abstract: Photosensitive epilepsy is less frequent among males than females. Red is the most epileptogenic color. The X-linked red pigment gene contains the polymorphism Ser180Ala the Ser180 allele increases red sensitivity. We hypothesized that the paucity of males with photosensitive epilepsy is explained by the distribution of this sex-linked allele, and predicted photosensitive males would have a low frequency of this allele. We genotyped 35 males with photosensitive epilepsy and 84 male controls. Allele frequencies did not differ between these groups. The hypothesis was not supported, so alternate reasons for the sex bias in photosensitive epilepsy must be sought.
Publisher: Oxford University Press (OUP)
Date: 27-02-2009
DOI: 10.1093/BRAIN/AWP017
Abstract: In this study, transcranial magnetic stimulation was used to investigate motor cortical excitability changes in the peri-ictal period, in drug-naive new-onset epilepsy patients. Eighty-seven studies were performed on 58 patients (23 with idiopathic generalized epilepsy and 35 with focal epilepsy) within 72 h before or after a seizure. Fifty studies in 35 patients were within 24 h of a seizure. In all 58 patients, an interictal baseline study was performed, at least 14 days from a seizure. Motor threshold and paired pulse recovery curve results obtained at short (2-15 ms) and long (50-400 ms) interstimulus intervals in each hemisphere (at <24 h pre- or post-seizure and 24-72 h pre- and post-seizure) were compared against the interictal results and normal control values obtained from 32 subjects. The nature of the seizure (generalized, focal or focal with secondary generalization) was also recorded. Increased motor cortex excitability, measured by decreased motor threshold, increased intracortical facilitation and decreased intracortical inhibition at short and long interstimulus intervals was seen in the 24 h before a seizure. Conversely, decreased excitability occurred in the 24 h after a seizure. These effects were bilateral in tonic-clonic seizures in idiopathic generalized epilepsy and also in secondarily generalized seizures in patients with focal epilepsy. Similar changes were seen in the hemisphere ipsilateral to the seizure focus in focal seizures that did not secondarily generalize, accompanied by complex excitability changes in the contralateral hemisphere. These effects were not apparent in the 24-72 h window. These results show that there are major and prolonged changes in motor cortex excitability in the pre and the postictal 24 h. Increased excitation precedes the seizure by hours and there is a similar period of decreased excitability following a seizure.
Publisher: Wiley
Date: 08-11-2013
DOI: 10.1111/EPI.12433
Abstract: Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand currently being investigated for the treatment of epilepsy. The purpose of this phase III study was to evaluate the efficacy and safety/tolerability of adjunctive BRV in adults with uncontrolled partial-onset (focal) seizures. This was a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose trial (N01253 NCT00464269). Adults aged 16-70 years with well-characterized partial epilepsy not fully controlled despite treatment with one or two antiepileptic drugs (AEDs) were enrolled. Patients who experienced eight or more partial-onset seizures, whether or not secondarily generalized, during the 8-week prospective baseline period were randomized (1:1:1:1) to receive twice-daily placebo (PBO) or BRV (5, 20, or 50 mg/day) without titration. The primary efficacy endpoint was percent reduction over PBO in baseline-adjusted partial-onset seizure frequency/week during the 12-week treatment period. Comparison of BRV with PBO was sequential (50, 20 mg/day, then 5 mg/day). Secondary endpoints included ≥50% responder rate and median percent reduction from baseline in partial-onset seizure frequency/week. Post hoc analyses included the primary efficacy endpoint evaluated over 28 days and exploratory subanalyses of efficacy by seizure subtype. Safety and tolerability assessments included treatment-emergent adverse events (TEAEs), laboratory tests, electrocardiography, vital signs, and physical and neurologic examinations. Of 400 patients randomized, 396 were included in the intent-to-treat (ITT) population (PBO n = 98, BRV 5 mg/day n = 97, BRV 20 mg/day n = 100, BRV 50 mg/day n = 101) and 392 comprised the modified ITT (mITT) population. A total of 361 (91.2%) of 396 patients completed the study. Most patients (78.3%) were receiving two concomitant AEDs. Percent reduction in partial-onset seizure frequency/week over PBO was -0.9% (p = 0.885) for BRV 5 mg/day, 4.1% (p = 0.492) for BRV 20 mg/day, and 12.8% (p = 0.025) for BRV 50 mg/day (mITT population). Statistical significance was also achieved for the percent reduction over PBO in baseline-adjusted partial-onset seizure frequency/28 days for BRV 50 mg/day (22.0% p = 0.004) but not for the other BRV dose groups. In the BRV 50 mg/day group, statistical significance was also seen for the ≥50% responder rate (BRV 32.7% vs. PBO 16.7% p = 0.008) and median percent reduction from baseline in partial-onset seizure frequency/week (BRV 30.5% vs. PBO 17.8% p = 0.003). In the exploratory subanalysis by seizure subtype, median percent reduction from baseline in seizure frequency/week and ≥50% responder rate were numerically greater than PBO in the BRV 20 and 50 mg/day groups for simple partial, complex partial, and secondarily generalized seizures. BRV was generally well tolerated, with the majority of TEAEs being mild-to-moderate in intensity. Of the TEAEs reported by ≥5% patients, those with a frequency >3% higher than PBO for any dose of BRV compared with PBO were somnolence, dizziness, fatigue, influenza, insomnia, nasopharyngitis, vomiting, diarrhea, urinary tract infection, and nausea. Adjunctive BRV at a daily dose of 50 mg was associated with statistically significant reductions in seizure frequency compared with PBO. All doses of BRV showed good tolerability throughout the study.
Publisher: Springer US
Date: 1994
Publisher: Elsevier BV
Date: 03-2008
Publisher: Wiley
Date: 13-01-2017
DOI: 10.1111/EPI.13649
Abstract: Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by heterogeneous phenotypes ranging from mild disorders such as febrile seizures to epileptic encephalopathies (EEs) such as Dravet syndrome (DS). Although DS often occurs with de novo SCN1A pathogenic variants, milder GEFS+ spectrum phenotypes are associated with inherited pathogenic variants. We identified seven cases with non-EE GEFS+ phenotypes and de novo SCN1A pathogenic variants, including a monozygotic twin pair. Febrile seizures plus (FS+) occurred in six patients, five of whom had additional seizure types. The remaining case had childhood-onset temporal lobe epilepsy without known febrile seizures. Although early development was normal in all in iduals, three later had learning difficulties, and the twin girls had language impairment and working memory deficits. All cases had SCN1A missense pathogenic variants that were not found in either parent. One pathogenic variant had been reported previously in a case of DS, and the remainder were novel. Our finding of de novo pathogenic variants in mild phenotypes within the GEFS+ spectrum shows that mild GEFS+ is not always inherited. SCN1A screening should be considered in patients with GEFS+ phenotypes because identification of pathogenic variants will influence antiepileptic therapy, and prognostic and genetic counseling.
Publisher: Elsevier BV
Date: 06-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-10-2012
Publisher: American Medical Association (AMA)
Date: 07-1993
DOI: 10.1001/ARCHNEUR.1993.00540070015007
Abstract: Neuronal migration disorders are usually, but not necessarily, demonstrated by magnetic resonance imaging. Preoperative suspicion of these anomalies in the presence of normal magnetic resonance studies has important practical implications. This study delineates some clinical features that permit early suspicion of focal cortical dysplasia localized in the central and precentral regions. In a retrospective case series, we studied the clinical presentation of four consecutive patients with normal preoperative magnetic resonance images in whom focal cortical dysplasia was found in the surgical specimen. Patients were seen in three referral centers specializing in epilepsy surgery. Four patients (three female), between the ages of 4 and 21 years, had intractable partial seizures leading to resective brain surgery. Three patients had corticectomies in the central (two patients) or frontal (one patient) regions. One underwent an en bloc resection of the central area after two unsuccessful corticectomies and cortical transection. Three patients presented with life-threatening focal motor status epilepticus necessitating intubation, and one had epilepsia partialis continua. All had had seizures previously, and the attacks progressed to intractability after 1 1/2 to 3 years. Surgery led to control of the seizures, but only two patients became seizure free (mean follow-up, 15.7 months). All but one developed a postoperative deficit, which eventually improved. Focal cortical dysplasia should be suspected when life-threatening focal motor status epilepticus or epilepsia partialis continua occur in children or young persons without another obvious cause. Normal magnetic resonance studies do not exclude neuronal migration disorders.
Publisher: American Medical Association (AMA)
Date: 06-2023
DOI: 10.1001/JAMANEUROL.2023.0473
Abstract: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. To test the association between pathogenic somatic variants in the hippoc us and MTLE. This case-control genetic association study analyzed the DNA derived from hippoc al tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy–associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. Drug-resistant MTLE. Presence and abundance of pathogenic somatic variants in the hippoc us vs the unaffected temporal neocortex. Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippoc us relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9] P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11 , SOS1 , KRAS , BRAF , and NF1 , all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippoc al tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Hippoc al somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.
Publisher: Elsevier
Date: 2005
Publisher: Springer Science and Business Media LLC
Date: 11-08-2013
DOI: 10.1038/NG.2727
Publisher: Wiley
Date: 20-08-2012
DOI: 10.1111/J.1528-1167.2012.03631.X
Abstract: Voltage-gated sodium channels (VGSCs) are integral membrane proteins. They are essential for normal neurologic function and are, currently, the most common recognized cause of genetic epilepsy. This review summarizes the neurobiology of VGSCs, their association with different epilepsy syndromes, and the ways in which we can experimentally interrogate their function. The most important sodium channel subunit of relevance to epilepsy is SCN1A, in which over 650 genetic variants have been discovered. SCN1A mutations are associated with a variety of epilepsy syndromes the more severe syndromes are associated with truncation or complete loss of function of the protein. SCN2A is another important subtype associated with epilepsy syndromes, across a range of severe and less severe epilepsies. This subtype is localized primarily to excitatory neurons, and mutations have a range of functional effects on the channel. SCN8A is the other main adult subtype found in the brain and has recently emerged as an epilepsy gene, with the first human mutation discovered in a severe epilepsy syndrome. Mutations in the accessory β subunits, thought to modulate trafficking and function of the α subunits, have also been associated with epilepsy. Genome sequencing is continuing to become more affordable, and as such, the amount of incoming genetic data is continuing to increase. Current experimental approaches have struggled to keep pace with functional analysis of these mutations, and it has proved difficult to build associations between disease severity and the precise effect on channel function. These mutations have been interrogated with a range of experimental approaches, from in vitro, in vivo, to in silico. In vitro techniques will prove useful to scan mutations on a larger scale, particularly with the advance of high-throughput automated patch-cl techniques. In vivo models enable investigation of mutation in the context of whole brains with connected networks and more closely model the human condition. In silico models can help us incorporate the impact of multiple genetic factors and investigate epistatic interactions and beyond.
Publisher: Elsevier BV
Date: 02-2003
DOI: 10.1016/S0028-3908(02)00369-6
Abstract: Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) is associated in some kindreds with mutations in the genes encoding the alpha 4 or beta 2 subunits of the neuronal nicotinic acetylcholine receptor (nAChR). Functional characterisation of the described ADNFLE mutations in oocyte preparations has produced conflicting results, with some studies suggesting hypofunction but others showing increased ligand sensitivity or delayed desensitisation. Knockout mice were studied to investigate extreme hypofunction of alpha 4 nAChRs in vivo. Mutant (Mt) and control mice underwent epidural electroencephalographic (EEG) recording for 2 h in the untreated state and for 1 h following administration of the gamma-amino butyric acid (GABA) antagonist, pentylenetetrazole (PTZ, 80 mg/kg). No spontaneous seizures occurred and no EEG differences were observed between the genotypes in drug naïve mice. Following PTZ, however, Mt mice showed markedly increased mortality compared to controls (85 vs 30%, P<0.001). Mts also had a greater number of generalised clonic seizures in the first 40 min following injection. In the same period, the EEGs of Mt mice showed an excess of spikes (P=0.033), multi-spike complexes (P=0.002) and continuous fast activity (P=0.017) compared to controls. These findings demonstrate that intact alpha 4 nAChR subunits provide significant in vivo protection against the proconvulsant effects of GABA antagonism.
Publisher: Oxford University Press (OUP)
Date: 23-02-2006
DOI: 10.1093/HMG/DDL035
Abstract: The rolandic and sylvian fissures ide the human cerebral hemispheres and the adjacent areas participate in speech processing. The relationship of rolandic (sylvian) seizure disorders with speech and cognitive impairments is well known, albeit poorly understood. We have identified the Xq22 gene SRPX2 as being responsible for rolandic seizures (RSs) associated with oral and speech dyspraxia and mental retardation (MR). SRPX2 is a secreted sushi-repeat containing protein expressed in neurons of the human adult brain, including the rolandic area. The disease-causing mutation (N327S) resulted in gain-of-glycosylation of the secreted mutant protein. A second mutation (Y72S) was identified within the first sushi domain of SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his female relatives with mild MR or unaffected carrier status. In cultured cells, both mutations were associated with altered patterns of intracellular processing, suggesting protein misfolding. In the murine brain, Srpx2 protein expression appeared in neurons at birth. The involvement of SRPX2 in these disorders suggests an important role for SRPX2 in the perisylvian region critical for language and cognitive development.
Publisher: Elsevier BV
Date: 03-2008
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-03-2015
Publisher: Elsevier BV
Date: 09-2004
Publisher: Wiley
Date: 24-08-2004
Publisher: Springer Science and Business Media LLC
Date: 04-2007
DOI: 10.1016/J.NURT.2007.01.009
Abstract: Approximately 70% of all patients with epilepsy lack an obvious extraneous cause and are presumed to have a predominantly genetic basis. Both familial and de novo mutations in neuronal voltage-gated and ligand-gated ion channel subunit genes have been identified in autosomal dominant epilepsies. However, patients with dominant familial mutations are rare and the majority of idiopathic epilepsy is likely to be the result of polygenic susceptibility alleles (complex epilepsy). Data on the identity of the genes involved in complex epilepsy is currently sparse but again points to neuronal ion channels. The number of genes and gene families associated with epilepsy is rapidly increasing and this increase is likely to escalate over the coming years with advances in mutation detection technologies. The genetic heterogeneity underlying idiopathic epilepsy presents challenges for the rational selection of therapies targeting particular ion channels. Too little is currently known about the genetic architecture of the epilepsies, and genetic testing for the known epilepsy genes remains costly. Pharmacogenetic studies have yet to explain why 30% of patients do not respond to the usual antiepileptic drugs. Despite this, the recognition that the idiopathic epilepsies are a group of channelopathies has, to a limited extent, explained the therapeutic action of the common antiepileptic drugs and has assisted clinical diagnosis of some epilepsy syndromes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1999
DOI: 10.1097/00019052-199904000-00008
Abstract: Epilepsies, like other common diseases, have complex inheritance, and molecular genetic studies in such conditions are difficult. There has been recent success in identifying the molecular basis of certain epilepsies, particularly in those syndromes with autosomal dominant inheritance. All four genes discovered to date for idiopathic epilepsies code for ion channel subunits, either ligand-gated or voltage-gated. The idiopathic epilepsies thus appear, at least in part, to be a family of channelopathies.
Publisher: Elsevier BV
Date: 03-1984
DOI: 10.1016/S0140-6736(84)91013-4
Abstract: Niemann-Pick disease is caused by reduced level of the lysosomal enzyme acid sphingomyelinase. Children can survive between 2 and 12 years based on the disease type. Two main types are well known: type A and B. Niemann-Pick disease type A is characterized by severe central nervous system deterioration and hepatosplenomegaly while type B is a progressive hypersplenism accompanied with gradual deterioration of pulmonary function. We describe an 11-month-old Palestinian baby boy with hepatosplenomegaly, hypotonia, delayed motor development, laryngomalacia, bilateral cherry-red spots, and failure to thrive. Metabolic screening, blood count, differential tests, immunology screen, infectious disease screen, urine, biochemical tests as well as molecular diagnosis were performed. The molecular diagnosis was done by lifying the whole sphingomyelin phosphodiesterase 1 (SMPD1) gene, followed by deep sequencing. The obtained sequences were aligned, de novo assembled and compared to human reference gene (GenBank GeneID: NG_011780.1, Ensembl version ENSG00000166311 and protein identified as UniProtKB - P17405). Two known mutations were identified in our patient: the pathogenic frameshift mutation NM_000543.4(SMPD1):c.573delT (p.Ser192Alafs) and the benign polymorphism NM_000543.4(SMPD1):c.107T>C (p.Val36Ala). The enzyme study showed a very low level of enzymatic activity of acidic sphingomyelinase (0.1 nmol/ml per hour). Correlations between clinical findings, laboratory data, and sequence analysis are presented. In conclusion, this is the first report about a heterozygote frameshift p.Ser192AlafsX65 in a Palestinian patient with Niemann-Pick disease type A, emphasizing the importance of deep sequencing in genetic diagnosis of this rare inherited disease.
Publisher: Wiley
Date: 23-04-2009
DOI: 10.1111/J.1471-0528.2009.02141.X
Abstract: While most women with epilepsy can expect a normal pregnancy outcome, epilepsy remains a significant contributor to both maternal and perinatal morbidity. Pre-pregnancy planning must address reliable contraception and optimisation of antiepileptic drug (AED) regimens to minimise teratogenic risk while maintaining seizure control. The most recent data from the AED registries regarding malformations is presented in this review, as is the limited data on the newer AEDs and studies linking neurocognitive outcomes to AED exposure. During pregnancy, important considerations include therapeutic drug monitoring, surveillance for obstetric complications and vigilance for seizures during the intrapartum and postpartum period.
Publisher: American Medical Association (AMA)
Date: 05-1988
DOI: 10.1001/ARCHNEUR.1988.00520290048013
Abstract: One hundred consecutive cases of clinically diagnosed, acute forebrain infarction were studied using computerized tomography (CT) and electroencephalography (EEG). Computed tomography confirmed brain infarction in 91 patients and was normal in the remaining nine. Each EEG was read independently by two experienced electroencephalographers without knowledge of CT or clinical details and their findings were compared with those of CT. Lateralized theta and/or delta activity predicted ipsilateral cortical infarction with a sensitivity of 76% and specificity of 82%. In contrast, cerebral hemisphere lacunae produced similar EEG abnormalities in only a few cases (9%). Electroencephalography is particularly useful following stroke if the initial CT excludes hemorrhage but does not detect infarction. In conjunction with clinical details, the EEG can then be used to indicate the likelihood of cortical involvement and thus suggest the likely pathophysiologic mechanism of infarction.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-03-2012
Publisher: Elsevier BV
Date: 03-2008
Publisher: Elsevier BV
Date: 12-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-09-2003
DOI: 10.1212/01.WNL.0000086379.71183.78
Abstract: Mutations in SCN1A, the gene encoding the alpha1 subunit of the sodium channel, have been found in severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). Mutations in SMEI include missense, nonsense, and frameshift mutations more commonly arising de novo in affected patients. This finding is difficult to reconcile with the family history of GEFS+ in a significant proportion of patients with SMEI. Infantile spasms (IS), or West syndrome, is a severe epileptic encephalopathy that is usually symptomatic. In some cases, no etiology is found and there is a family history of epilepsy. The authors screened SCN1A in 24 patients with SMEI and 23 with IS. Mutations were found in 8 of 24 (33%) SMEI patients, a frequency much lower than initial reports from Europe and Japan. One mutation near the carboxy terminus was identified in an IS patient. A family history of seizures was found in 17 of 24 patients with SMEI. The rate of SCN1A mutations in this cohort of SMEI patients suggests that other factors may be important in SMEI. Less severe mutations associated with GEFS+ could interact with other loci to cause SMEI in cases with a family history of GEFS+. This study extends the phenotypic heterogeneity of mutations in SCN1A to include IS.
Publisher: Elsevier BV
Date: 06-2011
Publisher: Public Library of Science (PLoS)
Date: 29-11-2017
Publisher: Wiley
Date: 12-12-2020
DOI: 10.1002/ANA.25650
Abstract: Febrile seizures may follow vaccination. Common variants in the sodium channel gene, SCN1A, are associated with febrile seizures, and rare pathogenic variants in SCN1A cause the severe developmental and epileptic encephalopathy Dravet syndrome. Following vaccination, febrile seizures may raise the specter of poor outcome and inappropriately implicate vaccination as the cause. We aimed to determine the prevalence of SCN1A variants in children having their first febrile seizure either proximal to vaccination or unrelated to vaccination compared to controls. We performed SCN1A sequencing, blind to clinical category, in a prospective cohort of children presenting with their first febrile seizure as vaccine proximate (n = 69) or as non-vaccine proximate (n = 75), and children with no history of seizures (n = 90) recruited in Australian pediatric hospitals. We detected 2 pathogenic variants in vaccine-proximate cases (p.R568X and p.W932R), both of whom developed Dravet syndrome, and 1 in a non-vaccine-proximate case (p.V947L) who had febrile seizures plus from 9 months. All had generalized tonic-clonic seizures lasting >15 minutes. We also found enrichment of a reported risk allele, rs6432860-T, in children with febrile seizures compared to controls (odds ratio = 1.91, 95% confidence interval = 1.31-2.81). Pathogenic SCN1A variants may be identified in infants with vaccine-proximate febrile seizures. As early diagnosis of Dravet syndrome is essential for optimal management and outcome, SCN1A sequencing in infants with prolonged febrile seizures, proximate to vaccination, should become routine. ANN NEUROL 2020 :281-288.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-10-2021
DOI: 10.1212/WNL.0000000000012773
Abstract: Hypothalamic hamartomas (HH) are rare, basilar developmental lesions with widespread comorbidities often associated with refractory epilepsy and encephalopathy. Imaging advances allow for early, even prenatal, detection. Genetic studies suggest mutations in GLI3 and other patterning genes are involved in HH pathogenesis. About 50%–80% of children with HH have severe rage and aggression and a majority of patients exhibit externalizing disorders. Behavioral disruption and intellectual disability may predate epilepsy. Neuropsychological, sleep, and endocrine disorders are typical. The purpose of this article is to provide a summary of the current understanding of HH and to highlight opportunities for future research.
Publisher: Cold Spring Harbor Laboratory
Date: 26-12-2022
Publisher: Wiley
Date: 04-07-2018
DOI: 10.1111/EPI.14506
Abstract: The clinical genetics of genetic generalized epilepsy suggests complex inheritance large pedigrees, with multiple affected in iduals, are rare exceptions. We studied a large consanguineous family from Turkey where extensive electroclinical phenotyping revealed a familial phenotype most closely resembling juvenile myoclonic epilepsy. For a subject to be considered affected (n = 14), a diagnostic electroencephalogram was required. Seizure onset ranged between 6 and 19 years (mean = 12 years). Thirteen of 14 experienced myoclonic jerks in 11, this was associated with eyelid blinking, and in 10 it was interspersed with absences. Generalized tonic-clonic seizures were seen in 11. One in idual had generalized tonic-clonic seizures alone. Electroencephalograms demonstrated generalized polyspike and wave discharges that were not associated with photoparoxysmal response. Intellect was normal. Nineteen family members were subsequently chosen for nonparametric multipoint linkage analyses, which identified a 39.5 Mb region on chromosome 5 (P < 0.0001). Iterative analysis, including discovery of a subtly affected in idual, narrowed the critical region to 15.4 Mb and possibly to 5.5 Mb. Homozygous versus heterozygous state of the refined 5p13.2-q11.1 haplotype was not associated with phenotypic severity or onset age, suggesting that one versus two pathogenic variants may result in similar phenotypes. Whole exome sequencing (n = 3) failed to detect any rare, protein-coding variants within the highly significant linkage region that includes HCN1 as a promising candidate.
Publisher: Wiley
Date: 17-05-2013
DOI: 10.1002/AJMG.A.35946
Publisher: Springer Science and Business Media LLC
Date: 05-2001
DOI: 10.1038/88259
Publisher: Hindawi Limited
Date: 06-09-2022
DOI: 10.1002/HUMU.24454
Abstract: Tuberous sclerosis complex (TSC) is a multi-system genetic disorder. Most patients have germline mutations in TSC1 or TSC2 but, 10%-15% patients do not have TSC1/TSC2 mutations detected on routine clinical genetic testing. We investigated the contribution of low-level mosaic TSC1/TSC2 mutations in unsolved sporadic patients and families with TSC. Thirty-one sporadic TSC patients negative on routine testing and eight families with suspected parental mosaicism were sequenced using deep panel sequencing followed by droplet digital polymerase chain reaction. Pathogenic variants were found in 22/31 (71%) unsolved sporadic patients, 16 were mosaic (median variant allele fraction [VAF] 6.8% in blood) and 6 had missed germline mutations. Parental mosaicism was detected in 5/8 families (median VAF 1% in blood). Clinical testing laboratories typically only report pathogenic variants with allele fractions above 10%. Our findings highlight the critical need to change laboratory practice by implementing higher sensitivity assays to improve diagnostic yield, inform patient management and guide reproductive counseling.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.EJMG.2019.103799
Abstract: Mutations in ATP6V1B2, which encodes the B2 subunit of the vacuolar H + ATPase have previously been associated with Zimmermann-Laband syndrome 2 (ZLS2) and deafness-onychodystrophy (DDOD) syndrome. Recently epilepsy has also been described as a potentially associated phenotype. Here we further uncover the role of ATP61VB2 in epilepsy and report autosomal dominant inheritance of a novel missense variant in ATP6V1B2 in a large Polish family with relatively mild gingival and nail problems, no phalangeal hypoplasia and with generalized epilepsy. In light of our findings and review of the literature, we propose that the ATP6V1B2 gene should be considered in families with autosomal dominant epilepsy both with or without intellectual disability, and that presence of subtle gingival and nail problems may be another characteristic calling card of affected in iduals with ATP6V1B2 mutations.
Publisher: Springer Science and Business Media LLC
Date: 22-10-2010
Publisher: Oxford University Press (OUP)
Date: 11-2002
DOI: 10.1093/BRAIN/AWF248
Abstract: Subcortical band heterotopia (SBH) or double cortex syndrome is a neuronal migration disorder, which occurs very rarely in males: to date, at least 110 females but only 11 in males have been reported. The syndrome is usually associated with mutations in the doublecortin (DCX) (Xq22.3-q23) gene, and much less frequently in the LIS1 (17p13.3) gene. To determine whether the phenotypic spectrum, the genetic basis and genotype-phenotype correlations of SBH in males are similar to those in females, we compared the clinical, imaging and molecular features in 30 personally evaluated males and 60 previously reported females with SBH. Based on the MRI findings, we defined the following band subtypes: partial, involving one or two cerebral lobes intermediate, involving two lobes and a portion of a third diffuse, with substantial involvement of three or more lobes and pachygyria-SBH, in which posterior SBH merges with anterior pachygyria. Karyo typing and mutation analysis of DCX and/or LIS1 were performed in 23 and 24 patients, respectively. The range of clinical phenotypes in males with SBH greatly overlapped that in females. MRI studies revealed that some anatomical subtypes of SBH, such as partial and intermediate posterior, pachygyria-SBH and diffuse bands with posterior predominance, were more frequently or exclusively present in males. Conversely, classical diffuse SBH and diffuse bands with anterior predominance were more frequent in females. Males had either mild or the most severe band subtypes, and these correlated with the over-representation of normal/borderline intelligence and severe mental retardation, respectively. Conversely, females who had predominantly diffuse bands exhibited mostly mild or moderate mental retardation. Seven patients (29%) had missense mutations in DCX in four, these were germline mutations, whereas in three there was evidence for somatic mosaicism. A germline missense mutation of LIS1 and a partial trisomy of chromosome 9p were identified in one patient (4%) each. One male each had a possible pathogenic intronic base change in both DCX and LIS1 genes. Our study shows that SBH in males is a clinically heterogeneous syndrome, mostly occurring sporadically. The clinical spectrum is similar to that of females with SBH. However, the greater cognitive and neuroradiological heterogeneity and the small number of mutations identified to date in the coding sequences of the DCX and LIS1 genes in males differ from the findings in females. This suggests other genetic mechanisms such as mutations in the non-coding regions of the DCX or LIS1 genes, gonadal or somatic mosaicism, and finally mutations of other genes.
Publisher: Springer Berlin Heidelberg
Date: 2009
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.EPLEPSYRES.2019.106154
Abstract: To describe the characteristics of a patient group who, after temporal lobectomy for predominantly diurnal seizures, experience a postoperative conversion from diurnal to predominantly nocturnal seizures, and compare this group to those who continue to have a diurnal seizure pattern postoperatively. From a cohort of 470 surgical cases with long-term follow-up, we retrospectively identified 16 patients with a predominantly nocturnal seizure pattern, including five with nocturnal seizures only (median follow-up 21 years) and compared them with 20 predominantly diurnal seizure patients. Sustained postoperative improvement in seizure frequency was observed in 14/16 cases. Seizure recurrence after surgery occurred within the first postoperative year in 13/16 cases. In all but 3 cases the seizures were all predominantly nocturnal from the time of recurrence, whereas in 3 there was a period of diurnal seizures during the early postoperative years. One patient lapsed back to diurnal seizures after 16 years of predominantly nocturnal seizures. Compared to the predominantly diurnal group, these patients had a significantly later age at seizure onset and were older at the time of surgery. Patients with predominantly nocturnal seizures comprise a small but distinct post-operative outcome category. Although not formally assessed, this outcome appears associated with improved quality of life, such as with eligibility to drive, with 50% of the s le confirmed as driving. This finding may help with providing prognostic information and counseling to these patients when they are identified postoperatively.
Publisher: Research Square Platform LLC
Date: 28-10-2020
DOI: 10.21203/RS.3.RS-96773/V1
Abstract: Background : CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2), or Late-Infantile Neuronal Ceroid Lipofuscinosis (LINCL), is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. These guidelines provide robust evidence-based, expert-agreed recommendations on the risks/benefits of disease-modifying treatments and the medical interventions used to manage this condition. Methods : An expert mapping tool process was developed ranking multidisciplinary professionals, with knowledge of CLN2 disease, diagnostic or management experience of CLN2 disease, or family support professionals. In iduals were sequentially approached to identify two chairs, ensuring that the process was transparent and unbiased. A systematic literature review of published evidence using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidance was independently and simultaneously conducted to develop key statements based upon the strength of the publications. Clinical care statements formed the basis of an international modified Delphi consensus determination process using the virtual meeting (Within3) online platform which requested experts to agree or disagree with any changes. Statements reaching the consensus mark became the guiding statements within this manuscript, which were subsequently assessed against the Appraisal of Guidelines for Research and Evaluation (AGREEII) criteria. Results: Twenty-one international experts from 7 different specialities, including a patient advocate, were identified. Fifty-three guideline statements were developed covering 13 domains: General Description and Statements, Diagnostics, Clinical Recommendations and Management, Assessments, Interventions and Treatment, Additional Care Considerations, Social Care Considerations, Pain Management, Epilepsy / Seizures, Nutritional Care Interventions, Respiratory Health, Sleep and Rest, and End of Life Care. Consensus was reached after a single round of voting, with one exception which was revised, and agreed by 100% of the SC and achieved 80% consensus in the second voting round. The overall AGREE II assessment score obtained for the development of the guidelines was 5.7 (where 1 represents the lowest quality, and 7 represents the highest quality). Conclusion: This program provides robust evidence- and consensus-driven guidelines that can be used by all healthcare professionals involved in the management of patients with CLN2 disease. This addresses the clinical need to complement other information available.
Publisher: Springer Science and Business Media LLC
Date: 26-10-2000
Abstract: The filamin-1 (FLN-1) gene is responsible for periventricular nodular heterotopia (PNH), which is an X-linked dominant neuronal migration disorder. To review the clinical and imaging findings in a series of patients with documented filamin-1 mutations. A retrospective review of the medical records and MR studies of a series of patients with PNH and confirmed FLN-1 mutations was done. There were 16 female patients (age range: .67-71 years mean = 28.6) with filamin-1 gene mutations. In six of the patients the same mutation was inherited in four generations in one pedigree. In a second pedigree, a distinct mutation was found in two patients in two generations. In a third pedigree, a third mutation was found in four patients in two generations. The remaining four patients had sporadic de novo mutations that were not present in the parents. Ten patients had seizures, and all patients had normal intelligence. In all 16 patients MR demonstrated bilateral near-continuous PNH. There were no consistent radiographic or clinical differences between patients carrying different mutations. Patients with confirmed FLN-1 gene mutations are usually female and have a distinctive MR pattern of PNH. Other female patients with this same MR pattern probably harbor FLN-1 mutations and risk transmission to their progeny. This information is important for genetic counseling.
Publisher: Wiley
Date: 02-1991
Abstract: The value of magnetic resonance imaging in the detection of hippoc al sclerosis has been controversial. We studied 10 patients aged 22.5 +/- 6.0 years with intractable temporal lobe epilepsy selected because of a history of a prolonged childhood convulsion, which is characteristic of a group of patients in whom hippoc al sclerosis is a constant finding. All 10 patients showed reduction in size of one hippoc us associated with increased signal intensity on T2-weighted magnetic resonance images. These changes were reliably detected on coronal spin-echo images, perpendicular to the long axis of the hippoc us. Appreciation of the normal imaging anatomy of the hippoc us allowed correct interpretation of the relative changes in signal intensities of the hippoc us and adjacent temporal horn on sequential echo images. The side of the abnormal hippoc us on magnetic resonance imaging accorded with the electroencephalographic localization in all 10 patients, and with the lateralization of the early convulsions in all 6 patients where this was known. Temporal lobectomy was performed in all 10 patients. Hippoc al sclerosis was confirmed in the 3 patients in whom hippoc al tissue was available for histological examination. The value of this technique was reinforced by the excellent postoperative results, with 80% being seizure free at a mean follow-up time of 33 +/- 4 months.
Publisher: Wiley
Date: 12-1999
DOI: 10.1111/J.1528-1157.1999.TB01604.X
Abstract: We analyzed a large group of patients investigated for suspected seizures to test whether gender or side are important factors in the origins of hippoc al sclerosis (HS). We studied 996 consecutive patients (48% men, 52% women) by using standard hippoc al T2-relaxometry methods. HS was associated with a highly abnormal T2 time (< or =113 ms). Categoric analysis showed that hippoc al T2 time was independent of gender and side. T2 time was bilaterally normal in 81% of men and in 79% of women it was unilaterally abnormal in 15% of both men and women and bilaterally abnormal in 4% of men and in 6% of women. Highly abnormal T2 relaxometry, suggesting HS, occurred with equal frequency in men and women and on the right and left sides. Quantitative analysis of hippoc al T2 times showed values not differing significantly between men and women or between the right and left hemispheres. There was no significant interaction between gender and side. In patients with seizure disorders, hippoc al T2 relaxometry is not different in adult men and women and in the right and left hemispheres.
Publisher: Frontiers Media SA
Date: 18-03-2022
DOI: 10.3389/FNEUR.2022.858333
Abstract: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Although lots of effort has been made in identifying clinical risk factors for SUDEP in the literature, there are few validated methods to predict in idual SUDEP risk. Prolonged postictal EEG suppression (PGES) is a potential SUDEP biomarker, but its occurrence is infrequent and requires epilepsy monitoring unit admission. We use machine learning methods to examine SUDEP risk using interictal EEG and ECG recordings from SUDEP cases and matched living epilepsy controls. This multicenter, retrospective, cohort study examined interictal EEG and ECG recordings from 30 SUDEP cases and 58 age-matched living epilepsy patient controls. We trained machine learning models with interictal EEG and ECG features to predict the retrospective SUDEP risk for each patient. We assessed cross-validated classification accuracy and the area under the receiver operating characteristic (AUC) curve. The logistic regression (LR) classifier produced the overall best performance, outperforming the support vector machine (SVM), random forest (RF), and convolutional neural network (CNN). Among the 30 patients with SUDEP [14 females mean age (SD), 31 (8.47) years] and 58 living epilepsy controls [26 females (43%) mean age (SD) 31 (8.5) years], the LR model achieved the median AUC of 0.77 [interquartile range (IQR), 0.73–0.80] in five-fold cross-validation using interictal alpha and low gamma power ratio of the EEG and heart rate variability (HRV) features extracted from the ECG. The LR model achieved the mean AUC of 0.79 in leave-one-center-out prediction. Our results support that machine learning-driven models may quantify SUDEP risk for epilepsy patients, future refinements in our model may help predict in idualized SUDEP risk and help clinicians correlate predictive scores with the clinical data. Low-cost and noninvasive interictal biomarkers of SUDEP risk may help clinicians to identify high-risk patients and initiate preventive strategies.
Publisher: Wiley
Date: 06-02-2014
DOI: 10.1111/EPI.12533
Abstract: Focal cortical dysplasia is a common cortical malformation and an important cause of epilepsy. There is evidence for shared molecular mechanisms underlying cortical dysplasia, ganglioglioma, hemimegalencephaly, and dysembryoplastic neuroepithelial tumor. However, there are no familial reports of typical cortical dysplasia or co-occurrence of cortical dysplasia and related lesions within the same pedigree. We report the clinical, imaging, and histologic features of six pedigrees with familial cortical dysplasia and related lesions. Twelve patients from six pedigrees were ascertained from pediatric and adult epilepsy centers, eleven of whom underwent epilepsy surgery. Pedigree data, clinical information, neuroimaging findings, and histopathologic features are presented. The families comprise brothers with focal cortical dysplasia, a male and his sister with focal cortical dysplasia, a female with focal cortical dysplasia and her brother with hemimegalencephaly, a female with focal cortical dysplasia and her female first cousin with ganglioglioma, a female with focal cortical dysplasia and her male cousin with dysembryoplastic neuroepithelial tumor, and a female and her nephew with focal cortical dysplasia. This series shows that focal cortical dysplasia can be familial and provides clinical evidence suggesting that cortical dysplasia, hemimegalencephaly, ganglioglioma, and dysembryoplastic neuroepithelial tumors may share common genetic determinants.
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.GIM.2022.08.020
Abstract: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20. Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed. We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type β-propeller domain of the KLHL20 protein, which shapes the substrate binding surface. Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity.
Publisher: Wiley
Date: 13-03-2012
DOI: 10.1002/J.1532-2149.2012.00130.X
Abstract: Growing pains (GP) is a prevalent familial childhood disorder of unknown aetiology. Familial occurrence of GP, and in idual and familial association of GP with restless legs syndrome (RLS) has been reported. We applied a twin family design to search for evidence of genetic susceptibility to GP, and for a genetic relationship between GP and RLS. The parents of 1843 twin pairs aged 3-16 years were administered a questionnaire, which identified 88 pairs with at least one twin in idual fulfilling criteria for GP. Standard questionnaires for history of GP and RLS were completed for these twin pairs, their siblings and parents. Twenty-five of 34 monozygotic (MZ) pairs were concordant for GP, compared with 12 of the 54 dizygotic (DZ) pairs. The casewise concordance was 0.85 and 0.36 for MZ and DZ pairs, respectively (p < 0.001). The lifetime GP prevalence for relatives of twins with GP was 51% for non-twin siblings, 47% for parents. Twenty-three percent of twin in iduals with GP met RLS criteria compared with 8% of twin in iduals without GP (p = 0.03). Of the twins with GP concordance, 19% met RLS criteria compared with 2% of twins with GP discordance (p = 0.01). In two MZ pairs, one had GP and the other RLS. The lifetime prevalence of RLS was 40% for mothers, and 24% for fathers and 18% for non-twin siblings. This first twin family study of GP provides evidence for a genetic aetiology and for a genetic relationship to RLS.
Publisher: Elsevier BV
Date: 1994
DOI: 10.1016/0967-5868(94)90008-6
Abstract: 11 patients with foreign tissue lesions (FTL) in the temporal lobe associated with complex partial seizures (CPS) were studied. All had lesions clearly definable on magnetic resonance imaging (MRI) but not seen on computerised tomographic (CT) scans. All cases showed seizure reduction following temporal lobectomy with 10 becoming seizure free. Pathology showed 9 tumours, 1 hamartoma and 1 cavernous angioma. Hippoc us was available for examination in 7 cases, showing abnormalities in 6. Our findings suggest MRI be mandatory in screening patients with CPS and that following surgery, outcome should be excellent.
Publisher: Wiley
Date: 10-1995
Abstract: We describe a family of 9 affected in iduals in three generations with nocturnal oro-facio-brachial partial seizures, secondarily generalized partial seizures, and centro-temporal epileptiform discharges, associated with oral and speech dyspraxia and cognitive impairment. The speech disorder was prominent, but differed from that of Landau-Kleffner syndrome and of epilepsy with continuous spike and wave during slow-wave sleep. The electroclinical features of this new syndrome of autosomal dominant rolandic epilepsy resemble those of benign rolandic epilepsy, a common inherited epilepsy of childhood. This family shows clinical anticipation of the seizure disorder, the oral and speech dyspraxia, and cognitive dysfunction, suggesting that the genetic mechanism could be expansion of an unstable triplet repeat. Molecular studies on this syndrome, where the inheritance pattern is clear, could also be relevant to identifying a gene for benign rolandic epilepsy where anticipation does not occur and the mode of inheritance is uncertain.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-06-2016
Publisher: Wiley
Date: 05-11-2021
DOI: 10.1002/ANA.25941
Abstract: Exome sequencing was performed in 2 unrelated families with progressive myoclonus epilepsy. Affected in iduals from both families shared a rare, homozygous c.191A G variant affecting a splice site in SLC7A6OS . Analysis of cDNA from lymphoblastoid cells demonstrated partial splice site abolition and the creation of an abnormal isoform. Quantitative reverse transcriptase polymerase chain reaction and Western blot showed a marked reduction of protein expression. Haplotype analysis identified a ~0.85cM shared genomic region on chromosome 16q encompassing the c.191A G variant, consistent with a distant ancestor common to both families. Our results suggest that biallelic loss‐of‐function variants in SLC7A6OS are a novel genetic cause of progressive myoclonus epilepsy. ANN NEUROL 2021 :402–407
Publisher: Wiley
Date: 22-12-2011
DOI: 10.1111/J.1528-1167.2011.03350.X
Abstract: Febrile infection-related epilepsy syndrome (FIRES) is an increasingly recognized epileptic syndrome that presents with multifocal refractory status epilepticus in previously normal children and evolves into a chronic, refractory, focal epilepsy with associated cognitive and behavioral difficulties. Herein we describe the features of the chronic epilepsy and critically review evidence for the etiology of this syndrome. Seven patients with FIRES were studied. The duration of follow-up in six survivors was 5-17 years. Clinical, electroencephalography (EEG), neuroimaging, and other investigative findings during the acute and chronic phases were reviewed. These previously normal children presented with a febrile illness and status epilepticus that was refractory to antiepileptic medications in all children, to immunotherapies (including immunoglobulin, corticosteroids, plasma exchange, and rituximab) in four, and to acute vagus nerve stimulation in one. Markers of cerebral inflammation were few and response to antiepileptic and immunomodulatory therapies was poor. Evolution to chronic epilepsy occurred without a silent period. Seizure characteristics in the chronic phase were strikingly stereotyped and similar to the acute phase, with head and eye version, unilateral facial jerking, asymmetric tonic posturing, and unilateral limb jerking in all patients. Electrographic ictal onset was lateralized in all recorded seizures, unilateral in one patient, and independent bilateral in three. Seizures were refractory to multiple antiepileptic medications in all patients and partly responsive to chronic vagus nerve stimulation in two patients. Moderate to severe intellectual impairment was noted in four patients, and borderline intellectual abilities were noted in two. Magnetic resonance imaging (MRI) in the chronic phase was normal in three patients and showed mild diffuse cortical atrophy and/or mild hippoc al atrophy or sclerosis in three. The similar perirolandic and perisylvian features of acute and chronic seizures, the lack of a silent period, the absence of evidence of cerebral inflammation, and the poor response to immunotherapies suggest FIRES is best conceptualized as a chronic epilepsy with explosive onset, not a remote-symptomatic epilepsy with an acute inflammatory antecedent.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-04-2003
DOI: 10.1212/01.WNL.0000055898.00349.02
Abstract: Familial periventricular heterotopia (PH) represents a disorder of neuronal migration resulting in multiple gray matter nodules along the lateral ventricular walls. Prior studies have shown that mutations in the filamin A (FLNA) gene can cause PH through an X-linked dominant inheritance pattern. To classify cortical malformation syndromes associated with PH. Analyses using microsatellite markers directed toward genomic regions of FLNA and to a highly homologous autosomal gene, FLNB, were performed on two pedigrees to evaluate for linkage with either filamin gene. Two consanguineous pedigrees with PH that suggest an autosomal recessive inheritance pattern are reported. MRI of the brain revealed periventricular nodules of cerebral gray matter intensity, typical for PH. Seizures or developmental delay appeared to be a common presenting feature. Microsatellite analysis suggested no linkage to FLNA or FLNB. Autosomal recessive PH is another syndromic migrational disorder, distinct from X-linked dominant PH. Further classification of these different syndromes will provide an approach for genetic evaluation.
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.EPLEPSYRES.2019.106161
Abstract: Over the past decade there has been a substantial increase in genetic studies of brain malformations, fueled by the availability of improved technologies to study surgical tissue to address the hypothesis that focal lesions arise from focal, post-zygotic genetic disruptions. Traditional genetic studies of patients with malformations utilized leukocyte-derived DNA to search for germline variants, which are inherited or arise de novo in parental gametes. Recent studies have demonstrated somatic variants that arise post-zygotically also underlie brain malformations, and that somatic mutation explains a larger proportion of focal malformations than previously thought. We now know from studies of non-diseased in iduals that somatic variation occurs routinely during cell ision, including during early brain development when the rapid proliferation of neuronal precursor cells provides the ideal environment for somatic mutation to occur and somatic variants to accumulate. When confined to brain, pathogenic variants contribute to the "hidden genetics" of neurological diseases. With burgeoning novel high-throughput genetic technologies, somatic genetic variations are increasingly being recognized. Here we discuss accumulating evidence for the presence of somatic variants in normal brain tissue, review our current understanding of somatic variants in brain malformations associated with lesional epilepsy, and provide strategies to identify the potential contribution of somatic mutation to non-lesional epilepsies. We also discuss technologies that may improve detection of somatic variants in the future in these and other neurological conditions.
Publisher: Cold Spring Harbor Laboratory
Date: 20-03-2023
DOI: 10.1101/2023.03.16.23287290
Abstract: Diffusion MRI has provided insight into the widespread structural connectivity changes that characterise the epilepsies. Although syndrome-specific white matter abnormalities have been demonstrated, studies have predominantly relied on statistical comparisons between patient and control groups. For diffusion MRI techniques to be of clinical value, they should be able to detect white matter microstructural changes in in idual patients. In this study, we apply an in idualised approach to a novel technique known as fixel-based analysis, to examine fibre-tract-specific abnormalities in in iduals with epilepsy. We explore the potential clinical value of this in idualised fixel-based approach in epilepsy patients with differing syndromic diagnoses. Diffusion MRI data from 90 neurologically healthy control participants and 10 patients with epilepsy (temporal lobe epilepsy, Progressive Myoclonus Epilepsy, Dravet Syndrome, malformations of cortical development) were included in this study. Measures of fibre density and cross-section were extracted for all participants across brain white matter fixels, and mean values computed within select tracts-of-interest. Scanner harmonised and normalised data were then used to compute Z-scores for in idual patients with epilepsy. Microstructural white matter abnormalities were observed in distinct patterns in in idual patients with epilepsy, both at the tract and fixel level. For patients with specific epilepsy syndromes, the detected white matter abnormalities were largely in line with expected syndrome-specific clinical phenotypes. In patients with lesional epilepsies (e.g., hippoc al sclerosis, periventricular nodular heterotopia, bottom-of-sulcus dysplasia), microstructural abnormalities were concordant with lesion location. This study demonstrates the clinical potential of translating advanced diffusion MRI methodology to in idual patient-level use in epilepsy. This technique could be useful both in aiding diagnosis of specific epilepsy syndromes, and in localising structural abnormalities, and is readily amenable to other neurological disorders. We have included code and data for this study, so that in idualised white matter changes can be explored robustly in larger cohorts in future work.
Publisher: Wiley
Date: 24-01-2005
DOI: 10.1002/ANA.20372
Abstract: Patients are understandably anxious if seizures occur immediately after temporal lobectomy. Such "neighborhood" seizures are commonly regarded as irrelevant to seizure outcome and discounted in outcome measurement. We conducted an in-depth examination of early postoperative seizures (<28 days) and outcome. The risk of recurrence at one postoperative year was calculated using Poisson regression, and statistical adjustments were made for preoperative pathology. Of 321 patients, 69 (22%) experienced early postoperative seizures. These early seizures were associated with subsequent seizure recurrence (rate ratio [RR] 5.9 95% confidence interval [CI], 4.1-8.4). Among patients with early seizures, the only significant factor was the presence of seizure precipitants, which was associated with a lower recurrence risk. However, when compared with patients with no early seizures, those with precipitants to early seizures had a higher risk of recurrence (RR, 3.0 95% CI, 1.8-5.2). The risk was higher again for patients without precipitants to early seizures (RR, 7.6 95% CI, 5.0-11.5). Early seizures and other seizure recurrences in the first postoperative year did not differ in their effect on subsequent outcome (X(2) [3] = 3.4, p = 0.33). We conclude that early postoperative seizures are associated with subsequent seizure recurrence. These findings have implications for patient counseling and the measurement of outcome.
Publisher: Wiley
Date: 26-08-2016
DOI: 10.1111/EPI.13505
Abstract: There is considerable difficulty in diagnosing hippoc al malrotation (HIMAL), with different criteria of variable reliability. Here we assess qualitative and quantitative criteria in HIMAL diagnosis and explore the role of HIMAL in magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE). We studied the MRI of 155 adult patients with MRI-negative TLE and 103 healthy volunteers, and we asked (1) what are the qualitative and quantitative features that allow a reliable diagnosis of HIMAL, (2) how common is HIMAL in a normal control population, and (3) is HIMAL congruent with the epileptogenic side in MRI-negative TLE. We found that the features that are most correlated with the expert diagnosis of HIMAL are hippoc al shape change with hippoc al diameter ratio > 0.8, lack of normal lateral convex margin, and a deep dominant inferior temporal sulcus (DITS) with DITS height ratio > 0.6. In a blinded analysis, a consensus diagnosis of unilateral or bilateral HIMAL was made in 25 of 103 controls (24.3% of people, 14.6% of hippoc i-14 left, six right, 10 bilateral) that did not differ from 155 lesion-negative TLE patients where 25 had HIMAL (16.1% of patients, 11.6% of hippoc i-12 left, two right, 11 bilateral). Of the 12 with left HIMAL only, 9 had seizures arising from the left temporal lobe, whereas 3 had right-sided seizures. Of the two with right HIMAL only, both had seizures arising from the left temporal lobe. HIMAL is an anatomic variant commonly found in controls. HIMAL is also an incidental nonpathologic finding in adult MRI-negative TLE and should not influence surgical decision making.
Publisher: Wiley
Date: 27-04-2005
DOI: 10.1111/J.1528-1167.2005.49004.X
Abstract: gamma-Aminobutyric acid (GABA)-receptor genes are prime candidates for a role in seizure susceptibility. An association between the c.1465G-->A variant in the GABA(B) receptor 1 gene (GABBR1) and susceptibility to temporal lobe epilepsy (TLE) has been reported in an Italian cohort. We sought to replicate this association in an independent Australian cohort. The 234 patients with TLE and 164 healthy controls were genotyped for the c.1465G-->A variant, by using inclusion criteria identical to those of the first study. The c.1465G-->A variant was found in one TLE patient and one control subject. Genotype and allele frequencies did not differ between groups. We did not replicate the reported associations between the c.1465G-->A variant and susceptibility to TLE. We suggest that the initial positive association may be due to undetected population stratification the importance of genomic control is emphasized. Population-specific effects also may play a role, and we highlight the need to demonstrate an in vitro functional effect to give biologic meaning to any proposed association.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Oxford University Press (OUP)
Date: 1991
Abstract: A novel event-related potential (ERP) elicited by a visuospatial recognition memory task was recorded in 20 patients with temporal lobe epilepsy using depth electrodes sited in the temporal lobes. The ERPs comprised two components, an N400 and a P600, and were similar in morphology to the previously reported ERP to verbal recognition memory tasks. The two ERP components in both verbal and visuospatial tasks were dependent on stimulus type and our data suggest that they do not simply represent delayed P300 ERP responses. In 17/20 patients robust, reliable bilaterally present ERPs were elicited by both verbal and visuospatial memory tasks. N400 litude was larger in response to novel stimuli, whereas P600 litude was larger to repeated stimuli. P600 litude was larger in the right temporal lobe to both visuospatial and verbal stimulus material. N400 and P600 latencies did not vary with task, stimulus type or side of recording. In 3/20 patients, no ERPs were elicited by either memory task. In all 3 cases, unilateral temporal white matter abnormalities were demonstrated by magnetic resonance imaging. Behavioural measures, expressed in the form of standardized accuracy scores, did not differ from those of a normal control group, and hence are unlikely to account for the abnormalities in ERPs. These results are discussed with reference to the primate visual recognition memory pathway and suggest that ERPs to recognition memory tasks are generated by an interaction between the two homologous inferotemporal recognition memory pathways.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-08-2002
DOI: 10.1212/WNL.59.3.348
Abstract: To describe a new syndrome of X-linked myoclonic epilepsy with generalized spasticity and intellectual disability (XMESID) and identify the gene defect underlying this disorder. The authors studied a family in which six boys over two generations had intractable seizures using a validated seizure questionnaire, clinical examination, and EEG studies. Previous records and investigations were obtained. Information on seizure disorders was obtained on 271 members of the extended family. Molecular genetic analysis included linkage studies and mutational analysis using a positional candidate gene approach. All six affected boys had myoclonic seizures and TCS two had infantile spasms, but only one had hypsarrhythmia. EEG studies show diffuse background slowing with slow generalized spike wave activity. All affected boys had moderate to profound intellectual disability. Hyperreflexia was observed in obligate carrier women. A late-onset progressive spastic ataxia in the matriarch raises the possibility of late clinical manifestations in obligate carriers. The disorder was mapped to Xp11.2-22.2 with a maximum lod score of 1.8. As recently reported, a missense mutation (1058C>T/P353L) was identified within the homeodomain of the novel human Aristaless related homeobox gene (ARX). XMESID is a rare X-linked recessive myoclonic epilepsy with spasticity and intellectual disability in boys. Hyperreflexia is found in carrier women. XMESID is associated with a missense mutation in ARX. This disorder is allelic with X-linked infantile spasms (ISSX MIM 308350) where polyalanine tract expansions are the commonly observed molecular defect. Mutations of ARX are associated with a wide range of phenotypes functional studies in the future may lend insights to the neurobiology of myoclonic seizures and infantile spasms.
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.YEBEH.2006.12.008
Abstract: This study aimed to characterize the process of psychosocial adjustment following a newly diagnosed seizure. Eighty-five adult patients were assessed 1 and 3 months after a first seizure presentation with a purpose-developed semistructured interview, the NEWQOL, and the COPE. Among a broad range of patient concerns, psychological issues were paramount, representing a process of losing and restoring perceived control. Two psychological adjustment trajectories were identified, which hinged on the experience of a limited (n=37) or pervasive (n=48) loss of control. These adjustment trajectories were predicted by demographic and clinical factors. The pervasive group described a more extensive process of reevaluation, leading to an improved sense of self at 3 months. Pervasive loss of control, anxiety, and depression predicted subsequent seizure recurrence. Overall, a first seizure can trigger a complex adjustment process, which might require therapeutic management in some patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1997
DOI: 10.1212/WNL.49.4.969
Abstract: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a newly recognized autosomal dominant partial epilepsy. We studied seizure localization and intrafamilial variation using video-EEG monitoring (VEM) and functional neuroimaging in two pairs of subjects from unrelated families. The clinical features of seizures were similar from seizure to seizure in each in idual, but varied between in iduals. As is often found in frontal lobe epilepsies, ictal EEG localization was imprecise in three of four cases. One patient showed a consistent left fronto-polar onset that was corroborated by congruent focal hypometabolism on interictal PET and focal hyperperfusion on ictal single photon emission computed tomography (SPECT). A second case studied with ictal SPECT showed a right parasagittal, midfrontal focus. We conclude that this autosomal dominant epilepsy syndrome, which in one of the two families was due to a known neuronal nicotinic acetylcholine receptor mutation, causes frontal lobe foci that are unilateral and in variable locations in different in iduals.
Publisher: BMJ
Date: 02-2003
Abstract: To study the clinical features and genetics of idiopathic generalised epilepsy (IGE) beginning in adult life. Consecutive patients with IGE, defined as generalised seizures with spike or polyspike and wave on EEG, were studied in the setting of a first seizure clinic where an early postictal EEG record is part of the protocol. Patients were ided into two groups: "classical IGE" with onset before 20 years and inclusive of all the IGE subsyndromes recognised by the international classification and "adult onset IGE", when seizure onset was at age 20 years or later. Seizure patterns, clinical features, and genetics of the adult onset group were examined. Of 121 patients with an electro-clinical diagnosis of IGE, 34 (28%) were diagnosed as adult onset IGE. The seizure patterns in these 34 cases were tonic-clonic seizures + absences (3), tonic-clonic seizures + myoclonus (6), and tonic-clonic seizures alone (25). Tonic-clonic seizures were often precipitated by alcohol or sleep deprivation. The proportion of affected first and second degree relatives did not differ between the classical and adult onset IGE groups. Twenty adult onset cases were treated with sodium valproate, four with other antiepileptic drugs, and 10 were untreated. Follow up of 32 of the 34 cases (for 31 (22) months (mean (SD)) showed that tonic-clonic seizures recurred in eight patients: five with identified provocative factors and three without. Adult onset IGE is a relatively frequent and benign disorder. Seizures are usually provoked and are easy to control. Patients in this age group may often be misdiagnosed as having non-lesional partial epilepsy. Early postictal EEG and sleep deprivation studies may improve the detection of these patients. Pedigree analysis suggests that adult onset IGE, like classical IGE, has a genetic aetiology.
Publisher: Wiley
Date: 06-1995
Abstract: We retrospectively compared ictal technetium 99m hexamethylpropyleneamineoxime single-photon emission computed tomography (SPECT) and interictal 18F-fluorodeoxyglucose positron emission tomography (PET) in 35 patients with well-lateralized temporal lobe epilepsy (TLE). Based on SPECT scans the two observers correctly lateralized seizure foci with certainty in 89% of patients interobserver agreement was excellent. Both observers incorrectly lateralized the seizure focus on two SPECT scans one error was explained by rapid electroencephalographic spread to the contralateral side and for the other patient, isotope was injected during a brief aura. Based on PET scans, observers correctly lateralized the foci with certainty in 63% and with lesser confidence in 83% four incorrect lateralizations were made by one observer and none by the other. PET interobserver disagreement was explained by differences between observers in weighting the relative hypometabolism in medial and lateral temporal regions. The detection rate for PET was lower in the absence of structural imaging abnormalities (60 vs 87%). PET yielded correct lateralizations in the 2 patients for whom SPECT interpretation was difficult. We conclude that both ictal SPECT and interictal PET are sensitive methods for the lateralization of TLE, but SPECT can be interpreted with greater certainty and is more sensitive when magnetic resonance imaging findings are negative. False lateralization is rare with ictal SPECT and can be explained when interpreted in conjunction with electroclinical data. Both investigations have complementary roles when localization is difficult.
Publisher: Hindawi Limited
Date: 13-11-2017
DOI: 10.1002/HUMU.23357
Abstract: Genetic generalized epilepsy (GGE) is a common epilepsy syndrome that encompasses seizure disorders characterized by spike-and-wave discharges (SWDs). Pacemaker hyperpolarization-activated cyclic nucleotide-gated channels (HCN) are considered integral to SWD genesis, making them an ideal gene candidate for GGE. We identified HCN2 missense variants from a large cohort of 585 GGE patients, recruited by the Epilepsy Phenome-Genome Project (EPGP), and performed functional analysis using two-electrode voltage cl recordings from Xenopus oocytes. The p.S632W variant was identified in a patient with idiopathic photosensitive occipital epilepsy and segregated in the family. This variant was also independently identified in an unrelated patient with childhood absence seizures from a European cohort of 238 familial GGE cases. The p.V246M variant was identified in a patient with photo-sensitive GGE and his father diagnosed with juvenile myoclonic epilepsy. Functional studies revealed that both p.S632W and p.V246M had an identical functional impact including a depolarizing shift in the voltage dependence of activation that is consistent with a gain-of-function. In contrast, no biophysical changes resulted from the introduction of common population variants, p.E280K and p.A705T, and the p.R756C variant from EPGP that did not segregate with disease. Our data suggest that HCN2 variants can confer susceptibility to GGE via a gain-of-function mechanism.
Publisher: Elsevier BV
Date: 11-2017
Publisher: Elsevier
Date: 2009
Publisher: Oxford University Press (OUP)
Date: 16-02-2010
DOI: 10.1093/BRAIN/AWQ016
Publisher: Elsevier BV
Date: 06-1993
DOI: 10.1016/0006-8993(93)90902-Y
Abstract: This study was designed to evaluate the functional significance of angiotensin II (Ang II) receptors identified by previous receptor autoradiography studies to be located presynaptically on terminals of dopaminergic neurones projecting to the striatum. Microdialysis was performed in the striatum of conscious freely moving rats and dopamine and serotonin metabolites measured by HPLC with electrochemical detection. During perfusion with artificial CSF, the major extracellular dopamine metabolite identified was DOPAC with smaller concentrations of HVA. When Ang II (1 microM) was introduced into the dialysis perfusion medium, DOPAC output increased markedly, peaking at 219%, and returned to control with vehicle perfusion during the recovery period. This increase in DOPAC output with Ang II was completely blocked by co-administration of the AT1 selective antagonist, Losartan (1 microM). Administration of Losartan alone led to a significant (16%) depression of DOPAC output relative to vehicle, suggesting that dopamine release is under a tonic facilitatory influence of Ang II via the AT1 receptor subtype. Parallel, but smaller changes were seen with HVA outputs. During Ang II perfusion the output of HVA was elevated 34-79% of that in vehicle-treated rats and this effect was completely abolished by concomitant administration of Losartan. As was observed with DOPAC output, administration of Losartan alone led to a 13-24% depression of HVA output compared to vehicle perfusion. When nomifensine (10 microM) was included in the infusion fluid, dopamine was clearly measurable. Ang II perfusion increased the levels of dopamine to 225%. Values returned towards baseline during the recovery period. Ang II administration also increased (by 15% and 55%) the levels of the major serotonin metabolite, 5HIAA.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Oxford University Press (OUP)
Date: 03-2022
Publisher: Wiley
Date: 29-05-2012
Publisher: Wiley
Date: 22-03-2004
DOI: 10.1002/ANA.20028
Publisher: BMJ
Date: 07-2019
DOI: 10.1136/JNNP-2019-ANZAN.9
Abstract: Mutations in SCN1A encoding the Na v 1.1 subunit of the neuronal sodium channel underlie the devastating epilepsy of Dravet’s syndrome. 1 The mechanism by which Na v 1.1 dysfunction causes seizures is not clear. In vitro and in silico channel evaluation can support mutation pathogenicity but cannot define the in vivo impact of channel dysfunction. Axonal excitability studies can show the pattern of single-channel dysfunction in disorders where the channel is peripherally expressed. 2 This study was undertaken to determine whether axonal excitability studies could detect changes in Dravet’s patients related to the condition or due to medication effect. Patients with Dravet’s syndrome were recruited from clinics in Sydney and Melbourne and axonal excitability studies were performed. Excitability results were analysed in 3 age groups and compared to age-matched normal controls. Twenty six patients (ages 2–46) were studied. Findings were most pronounced in patients aged 20–46 (n=7) with 6.9% greater increase in threshold during hyperpolarization(p=0.1), 7.6% greater threshold decrease on depolarization(p=0.005) and, in the recovery cycle, 19.7% reduction in superexcitability(p=0.002) and 26% reduction in subexcitability(p=0.03). Axonal excitability studies resembled previously published changes seen in patients with sodium channel blockade caused by acute tetrodotoxin poisoning. 3 Changes in excitability of axonal membrane in Dravet’s syndrome are consistent with a decrease in sodium channel function. As the affected channel in Dravet’s syndrome is not peripherally expressed, the effect seen is likely due to the heavy anticonvulsant regime required to control epilepsy, combined with a progressive loss of sodium channel function that occurs with age. Meisler MH, O’Brien JE, Sharkey LM. Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects. J Physiol 2010 :1841–1848. Tomlinson SE, Howells J, Burke D. In vivo assessment of neurological channelopathies: Application of peripheral nerve excitability studies. Neuropharmacology . 2018 Apr :98–107. Kiernan MC, Isbister GK, Lin CS, Burke D, Bostock H. Acute tetrodotoxin-induced neurotoxicity after ingestion of puffer fish. Ann Neurol 2005 :339–48.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1989
Abstract: We assessed the value of valproate in the prevention of recurrent attacks of absence status in 25 patients. Eighteen patients had primary generalized epilepsy with a mean frequency of attacks of absence status of 5.7 per year. After a mean follow-up period of 4.4 years, the attack frequency was reduced to 0.6 per year (p less than 0.0005) 14 patients had no recurrence, 3 had rare attacks with noncompliance, and 1 had an incomplete response probably due to gastrointestinal intolerance. Patients with evidence of generalized cerebral damage (n = 2) or with EEG evidence of focalization (n = 5) did not respond as favorably. Valproate is the drug of choice for the prevention of recurrence of absence status. Moreover, the response can be predicted on the basis of the electroclinical subtype of absence status.
Publisher: Wiley
Date: 04-2010
DOI: 10.1111/J.1528-1167.2009.02423.X
Abstract: We have created the Epilepsy Genetic Association Database (epiGAD, www.epigad.org, an online database of epilepsy genetic association studies. A systematic search using several search engines identified 165 studies. Herein we analyze the types of studies available, the s le sizes used, and the strength of the findings. Common questions examined were susceptibility to idiopathic generalized epilepsy, focal epilepsy, or febrile seizures, and pharmacogenomic approaches to drug-resistant epilepsy. S le sizes were generally small 80% of studies had 200 or fewer cases, although more recent studies published from 2005-2008 incorporated slightly larger s le sizes. No association was judged as "strong" using current criteria for assessing genetic associations--this is probably due to inadequate s le sizes. S le sizes need to increase, either by research collaboration or via systematic reviews and meta-analyses. We believe epiGAD will facilitate future meta-analyses.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-11-2006
DOI: 10.1212/01.WNL.0000242735.24539.33
Abstract: We studied outcome subsequent to the initial post-temporal lobectomy seizure recurrence (n = 202) or remission. Two years after recurrence, there was 74% (95% CI 67% to 79%) probability of further seizures. Two years after a 2-year seizure remission, there was 68% (95% CI 52% to 79%) probability of remaining seizure-free (n = 50). Remission after seizures had a significantly poorer outcome than an equivalent period of complete seizure freedom after surgery. Implications for outcome classification are discussed.
Publisher: Proceedings of the National Academy of Sciences
Date: 29-05-2018
Abstract: SCN2A , encoding the voltage-gated sodium channel Na v 1.2, has emerged as a major gene implicated in neonatal-, infantile-, and even childhood-onset epilepsies. Many of these epilepsies are also associated with cognitive and behavioral impairments that range in type and severity. The biophysical, neurophysiological, and clinical impacts of SCN2A mutations are poorly understood. Here, we use clinical evaluation and biophysical analyses to explore the mechanisms underpinning distinctive phenotypes produced by SCN2A variants associated with mild familial or severe de novo forms of epilepsy. We show that dynamic cl analysis provides clear benefits over conventional voltage cl for a rapid and definitive prediction of neuron-scale phenotypic consequences, and is well positioned to impact diagnosis and drug discovery in genetic epilepsy.
Publisher: Wiley
Date: 04-1996
DOI: 10.1111/J.1445-5994.1996.TB00877.X
Abstract: Exposure to airborne particulate matter (PM) may affect neurodevelopmental outcomes in children. The mechanisms underlying these relationships are not currently known. We aim to assess whether PM affects the developing brains of schoolchildren in Poland, a country characterized by high levels of PM pollution. Children aged from 10 to 13 years (
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1997
DOI: 10.1212/WNL.49.4.960
Abstract: Sixty-three children with new-onset temporal lobe epilepsy (TLE) underwent extensive clinical, EEG, and neuroimaging investigation as part of a prospective, community-based cohort study of the natural history of TLE in childhood. Complex partial seizures occurred in 94% of the children, and tonic-clonic seizures occurred in 14%. Developmental, behavioral, or learning problems were present in 38%. Eighteen children (29%) had a significant illness/event prior to the onset of TLE, including febrile status epilepticus in seven, meningitis in four, respiratory arrest in two, and head injury in one. Magnetic resonance imaging or computed tomography revealed structural abnormalities of the temporal lobe in 24 children (38%), including hippoc al sclerosis (HS) in 13 and tumor in eight. There was a strong association between HS and a history of significant illness/event prior to the onset of TLE ( p 0.001). Analysis of past history and neuroimaging findings led us to propose three etiologically defined subgroups of TLE developmental TLE (10 children with long-standing, nonprogressive temporal lobe tumors and malformations), TLE with HS/significant antecedents (18 children with HS or a history of a significant illness/event), and cryptogenic TLE (34 children with normal neuroimaging findings and no significant past history). Etiologic differences between children with new-onset TLE may confer prognostic information that will be useful for counselling families and planning treatment.
Publisher: Oxford University Press (OUP)
Date: 10-1994
Publisher: Elsevier BV
Date: 12-1998
Publisher: Elsevier BV
Date: 08-1991
Publisher: Elsevier BV
Date: 10-2007
Publisher: Elsevier BV
Date: 09-1997
DOI: 10.1016/S0140-6736(05)63516-7
Abstract: In recent years, many vaccines have been developed for the prevention of a variety of diseases. Although the primary objective of vaccination is to prevent disease, vaccination can also reduce the severity of disease in those in iduals who develop breakthrough disease. Observations of apparent mitigation of breakthrough disease in vaccine recipients have been reported for a number of vaccine-preventable diseases such as Herpes Zoster, Influenza, Rotavirus, and Pertussis. The burden-of-illness (BOI) score was developed to incorporate the incidence of disease as well as the severity and duration of disease. A severity-of-illness score S > 0 is assigned to in iduals who develop disease and a score of 0 is assigned to uninfected in iduals. In this article, we derive the vaccine efficacy statistic (which is the standard statistic for presenting efficacy outcomes in vaccine clinical trials) based on BOI scores, and we extend the method to adjust for baseline covariates. Also, we illustrate it with data from a clinical trial in which the efficacy of a Herpes Zoster vaccine was evaluated.
Publisher: Elsevier BV
Date: 02-1997
DOI: 10.1016/S0022-510X(96)00241-9
Abstract: Heteroplasmic populations of mtDNA, consisting of normal mtDNA and mtDNA with large deletions, are found in the skeletal muscle and other tissues of certain patients with mitochondrial respiratory chain deficiencies, particularly in those with the CPEO (chronic progressive external ophthalmoplegia) phenotype. To study the developmental genetics of this mitochondrial disorder, the distribution of the deleted mtDNA in a wide range of tissues of different embryonic origins (total 34 s les from 27 tissues obtained at autopsy) was investigated in a patient with the CPEO syndrome. Three species of partially deleted mtDNA were observed, with deletions of 2.3 kb, 5.0 kb and 6.4 kb. Their tissue distribution suggests that the mtDNA deletions have occurred very early during embryonic development, prior to the differentiation events that lead to the formation of the three primary embryonic germ layers, and that the partially deleted mtDNA species were segregated during development mainly to the skeletal muscle and to tissues of the central nervous system.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.SEIZURE.2015.03.020
Abstract: To determine clinical phenotypes, evolution and genetic background of a large family with a combination of two unusual forms of reflex epilepsies. Phenotyping was performed in eighteen family members (10 F, 8 M) including standardized EEG recordings with intermittent photic stimulation (IPS). Genetic analyses (linkage scans, Whole Exome Sequencing (WES) and Functional studies) were performed using photoparoxysmal EEG responses (PPRs) as affection status. The proband suffered from speaking induced jaw-jerks and increasing limb jerks evoked by flickering sunlight since about 50 years of age. Three of her family members had the same phenotype. Generalized PPRs were found in seven members (six above 50 years of age) with myoclonus during the PPR. Evolution was typical: Sensitivity to lights with migraine-like complaints around adolescence, followed by jerks evoked by lights and spontaneously with dropping of objects, and strong increase of light sensitivity and onset of talking induced jaw jerks around 50 years. Linkage analysis showed suggestive evidence for linkage to four genomic regions. All photosensitive family members shared a heterozygous R129C mutation in the SCNM1 gene that regulates splicing of voltage gated ion channels. Mutation screening of 134 unrelated PPR patients and 95 healthy controls, did not replicate these findings. This family presents a combination of two rare reflex epilepsies. Genetic analysis favors four genomic regions and points to a shared SCNM1 mutation that was not replicated in a general cohort of photosensitive subjects. Further genetic studies in families with similar combination of features are warranted.
Publisher: Wiley
Date: 21-03-2004
DOI: 10.1002/ANA.20029
Abstract: We recently reported mutations in the sodium channel gene SCN2A in two families with benign familial neonatal-infantile seizures (BFNISs). Here, we aimed to refine the molecular-clinical correlation of SCN2A mutations in early childhood epilepsies. SCN2A was analyzed in 2 families with probable BFNIS, 9 with possible BFNIS, 10 with benign familial infantile seizures, and in 93 additional families with various early childhood epilepsies. Mutations effecting changes in conserved amino acids were found in two of two probable BFNIS families, in four of nine possible BFNIS families, and in none of the others. Our eight families had six different SCN2A mutations one mutation (R1319Q) occurred in three families. BFNIS is an autosomal dominant disorder presenting between day 2 and 7 months (mean, 11.2 +/- 9.2 weeks) with afebrile secondarily generalized partial seizures neonatal seizures were not seen in all families. The frequency of seizures varied some in iduals had only a few attacks without treatment and others had clusters of many per day. Febrile seizures were rare. All cases remitted by 12 months. Ictal recordings in four subjects showed onset in the posterior quadrants. SCN2A mutations appear specific for BFNIS the disorder can now be strongly suspected clinically and the families can be given an excellent prognosis.
Publisher: Hindawi Limited
Date: 15-06-2021
DOI: 10.1002/HUMU.24237
Abstract: PCDH19 is a nonclustered protocadherin molecule involved in axon bundling, synapse function, and transcriptional coregulation. Pathogenic variants in PCDH19 cause infantile-onset epilepsy known as PCDH19-clustering epilepsy or PCDH19-CE. Recent advances in DNA-sequencing technologies have led to a significant increase in the number of reported PCDH19-CE variants, many of uncertain significance. We aimed to determine the best approaches for assessing the disease relevance of missense variants in PCDH19. The application of the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines was only 50% accurate. Using a training set of 322 known benign or pathogenic missense variants, we identified MutPred2, MutationAssessor, and GPP as the best performing in silico tools. We generated a protein structural model of the extracellular domain and assessed 24 missense variants. We also assessed 24 variants using an in vitro reporter assay. A combination of these tools was 93% accurate in assessing known pathogenic and benign PCDH19 variants. We increased the accuracy of the ACMG-AMP classification of 45 PCDH19 variants from 50% to 94%, using these tools. In summary, we have developed a robust toolbox for the assessment of PCDH19 variant pathogenicity to improve the accuracy of PCDH19-CE variant classification.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2014
Abstract: Understanding the aetiology of epilepsy is essential both for clinical management of patients and for conducting neurobiological research that will direct future therapies. The aetiology of epilepsy was formerly regarded as unknown in about three-quarters of patients however, massively parallel gene-sequencing studies, conducted in a framework of international collaboration, have yielded a bounty of discoveries that highlight the importance of gene mutations in the aetiology of epilepsy. These data, coupled with clinical genetic studies, suggest a new paradigm for use in the clinic: many forms of epilepsy are likely to have a genetic basis. Enquiry about a genetic cause of epilepsy is readily overlooked in the clinic for a number of understandable but remediable reasons, not least an incomplete understanding of its genetic architecture. In addition, the importance of de novo mutagenesis is often underappreciated, particularly in the epileptic encephalopathies. Other genomic surprises are worth emphasizing, such as the emerging evidence of a genetic contribution to focal epilepsies-long regarded as acquired conditions-and the complex role of copy number variation. The importance of improved understanding of the genetics of the epilepsies is confirmed by the positive outcomes, in terms of treatment selection and counselling, of receiving a genetic diagnosis.
Publisher: Elsevier BV
Date: 2002
DOI: 10.1016/S0028-3932(01)00092-6
Abstract: Medial temporal lobe (MTL) structures are implicated in forming conjunctions between events in order to form enduring relational memories these memories are not evident using direct measures with varieties of amnesic subjects. Extratemporal brain structures are thought to be responsible for preserved memories, which are sometimes detectable using indirect measures. The present study tests this theory of multiple memory systems by examining whether preserved learning can be demonstrated for relational material in MTL-disordered subjects using an indirect measure which minimises conscious mediation of performance. The subjects had undergone anterior temporal lobectomy for relief of temporal lobe epilepsy: left-sided (LATL) cases had a mild verbal amnesia and right-sided (RATL) cases had better verbal memory, forming a comparison group. A direct measure of verbal relational memory was provided by successive trials of cued recall in a specially-constructed paired associate learning task with arbitrarily paired words pairs consisted of either concrete or abstract words. LATL subjects performed worse than RATL subjects, and particularly so with abstract words. Following direct testing, memory for the pairings was measured indirectly using a masked recognition priming technique. RATL subjects showed savings in RT, demonstrating that masked priming can reveal evidence of the formation of conjunctions. Critically, LATL subjects showed no evidence of preserved learning with priming. Thus when MTL structures are damaged, relational memory appears to be affected without exception, consistent with the tenets of multiple memory systems theory.
Publisher: Wiley
Date: 29-04-2014
DOI: 10.1111/EPI.12632
Abstract: We detail the phenotype of a novel form of neuronal ceroid lipofuscinosis due to a homozygous progranulin gene mutation (c.813_816del CLN11 MIM #614706). The symptoms appeared in two young adult siblings, and included progressive retinopathy, recurrent generalized seizures, moderate ataxia, and subtle cognitive dysfunction. Long-lasting episodes of palinopsia were a recurring symptom and associated with polyphasic visual-evoked potential waveform that suggested hyperexcitability of the occipital cortex. Electroencephalography showed rare spike-wave paroxysms, and magnetic resonance imaging revealed selective cerebellar atrophy. Skin biopsy revealed fingerprint storage and the absence of progranulin protein. Electron microscopy of peripheral blood leukocytes showed fingerprint profiles in 1/100 lymphocytes. These findings define a novel phenotype and provide clues for better understanding of progranulin function. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Publisher: Wiley
Date: 24-02-2005
DOI: 10.1002/ANA.20398
Publisher: Wiley
Date: 28-06-2004
DOI: 10.1002/ANA.20153
Abstract: Benign rolandic epilepsy (BRE) is considered to be a genetically determined idiopathic partial epilepsy. We studied twins with BRE and compared the concordance with a twin s le of idiopathic generalized epilepsy (IGE). All eight BRE pairs (six monozygous [MZ], two dizygous [DZ]) were discordant. MZ pairwise concordance was 0 (95% confidence interval [CI], 0-0.4) for BRE compared with 0.7 (95% CI, 0.5-0.9) for 26 IGE MZ pairs. Our data suggest that conventional genetic influences in BRE are considerably less than for IGE, and other mechanisms need to be explored.
Publisher: Wiley
Date: 15-04-2020
DOI: 10.1002/ANA.25724
Publisher: Wiley
Date: 04-2000
DOI: 10.1111/J.1528-1157.2000.TB00190.X
Abstract: To compare the localizing value of ictal single photon emission computed tomography (SPECT) and interictal fluorodeoxyglucose-positron emission tomography (FDG-PET) in refractory occipital lobe epilepsy. Six patients who underwent surgery for refractory epilepsy associated with pathology in the occipital lobe were retrospectively selected from records of the Austin & Repatriation Centre Comprehensive Epilepsy Programme. Interictal SPECT and PET and ictal SPECT were obtained by standard methods. All studies were read by a nuclear medicine expert blinded to clinical data except the diagnosis of epilepsy. Ictal SPECT showed unilateral occipital hyperperfusion in five of six cases often accompanied by temporal lobe hyperperfusion. These patterns were seen in cases with or without magnetic resonance imaging (MRI) abnormality. Interictal SPECT was not localizing in any case, in contrast to PET, which showed occipital hypometabolism in three of five studies. Ictal SPECT can provide novel localizing data in MRI-negative occipital lobe epilepsy. Interictal PET can provide useful localizing information, but its role in providing novel information was not demonstrated. Interictal SPECT is useful only as a baseline to aid in interpretation of ictal studies.
Publisher: SAGE Publications
Date: 07-2013
Abstract: Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype–genotype study designed to gather and analyze detailed phenotypic information and DNA s les on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy. EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants. EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.
Publisher: Wiley
Date: 24-02-2005
DOI: 10.1002/ANA.20399
Publisher: Wiley
Date: 04-1988
Abstract: Focal cortical myoclonus is rare. Obvious causes include tumor or atrophy involving the motor strip, but in some cases no cause is apparent. We present 4 patients who started to have focal myoclonus in childhood. All had focal motor seizures as well, and one had recurrent focal motor status epilepticus. All 4 had a mild progressive hemiparesis. Electrographic investigations showed focal epileptic discharges in the contralateral rolandic areas. Radiological studies were unrevealing, but magnetic resonance showed rolandic lesions in 3 patients. At surgery, abnormally wide gyri were found in the distribution demonstrated by magnetic resonance. The pathological substrate was focal cortical dysplasia. All patients have improved considerably following surgery. These findings suggest that focal myoclonus may be due to a rolandic neuronal migration disorder. Visualization of these lesions by magnetic resonance permits development of a surgical strategy leading to optimal treatment of these medically intractable epileptic disorders.
Publisher: Elsevier BV
Date: 12-1998
DOI: 10.1016/S0896-6273(00)80651-0
Abstract: Long-range, directed migration is particularly dramatic in the cerebral cortex, where postmitotic neurons generated deep in the brain migrate to form layers with distinct form and function. In the X-linked dominant human disorder periventricular heterotopia (PH), many neurons fail to migrate and persist as nodules lining the ventricular surface. Females with PH present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy, while hemizygous males die embryonically. We have identified the PH gene as filamin 1 (FLN1), which encodes an actin-cross-linking phosphoprotein that transduces ligand-receptor binding into actin reorganization, and which is required for locomotion of many cell types. FLN1 shows previously unrecognized, high-level expression in the developing cortex, is required for neuronal migration to the cortex, and is essential for embryogenesis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-1994
Abstract: We studied clinical and ictal single-photon emission computed tomography (SPECT) features in 14 patients with parietal lobe epilepsy, nine of whom had structural parietal lobe lesions. Thirteen patients had simple partial seizures of somatosensory (eight), psychic (four), and motor (nine) types. Complex partial seizures (CPS) occurred in seven patients six were psychoparetic (prominent staring, relative immobility) and one had hyperkinetic activity. Seizures lasted 7 to 110 seconds 99mTc-HMPAO (hexamethylpropylene amine oxime) was injected ictally, 7 to 89 seconds from seizure onset and 0 to 74 seconds (mean, 21.0 +/- 24.4 seconds) before seizure termination. Ictal SPECT demonstrated focal areas of parietal hyperperfusion in all 14 cases and corresponded with sites of the structural lesions. Parietal hyperperfusion was anterior in eight, posterior in four, and diffuse in two. Quantitative analysis revealed increases in parietal side-to-side perfusion ratios on ictal compared with interictal scans of 11 to 51% (mean, 25.5 +/- 14.4%). Ictal SPECT localization correlated with two main clinical seizure patterns: an anterior syndrome characterized by sensorimotor manifestations and a posterior syndrome characterized by CPS of the psychoparetic type. Ictal SPECT is helpful for localization of parietal seizures. Parietal hyperperfusion is discrete and short-lived, demanding true ictal injections for diagnostic studies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 1996
DOI: 10.1212/WNL.46.1.242
Abstract: Article abstract-Rasmussen's encephalitis (RE) is a progressive childhood disorder characterized by intractable focal seizures, hemiplegia, dementia, and inflammatory histopathology. The process is typically limited to one cerebral hemisphere. We report four patients with pathologically confirmed RE who were treated with repeated plasmapheresis. Three patients exhibited repeated, dramatic, transient responses to plasmapheresis, manifested by reduced seizure frequency and improved neurologic function. One patient exhibited marginal improvement after treatment with plasmapheresis. These observations indicate that circulating factors, likely autoantibodies, are pathogenic in at least some patients with RE and suggest that RE is an autoimmune disease. Plasmapheresis may be a useful adjunctive therapy in RE, specifically for treatment of patients with acute deteriorations such as status epilepticus, and can also aid in assessment of residual function in the diseased hemisphere before surgical resection. NEUROLOGY 1996 : 242-246
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 10-2015
Publisher: Elsevier BV
Date: 10-2021
Publisher: Wiley
Date: 19-03-2002
DOI: 10.1002/ANA.10133
Abstract: We explored the hypothesis that components of verbal memory are subserved by separate temporal lobe structures in patients with temporal lobe structures in patients with temporal lobe epilepsy [correction]. Uptake of 18F-fluorodeoxyglucose (FDG) measured by positron emission tomography, hippoc al volume, and memory for arbitrarily and semantically related verbal paired associates were examined in 27 patients with left temporary lobe epilepsy. Scores from memory tests performed outside the scanner were regressed against normalized resting FDG uptake at each voxel. Significant regression was seen in the left perirhinal cortex (Talaraich coordinates x, y, z: -29, 10, -34 p < 0.05) for arbitrarily related word pairs. For semantically related paired associates, significant regression was present in the left inferior temporal gyrus (x, y, z: -48, -18, -24 p < 0.05). In subsequent analyses, mean FDG uptake within a spherical region of interest centered on the perirhinal peak predicted performance on both tasks. Mean FDG uptake in a region of interest centered on the inferior temporal peak made an additional, independent contribution to memory for semantically related pairs. Hippoc al volumes did not explain any additional variance in memory scores. Our findings indicate that heterogeneity in the left temporal lobe structures mediating verbal memory function, and support the view that the perirhinal cortex is an important mnemonic substrate.
Publisher: Oxford University Press (OUP)
Date: 16-06-2004
DOI: 10.1093/BRAIN/AWH211
Publisher: Wiley
Date: 26-03-2007
DOI: 10.1111/J.1528-1167.2007.01049.X
Abstract: Mutations of the sodium channel subunit gene SCN2A have been described in families with benign familial neonatal-infantile seizure (BFNIS). We describe two large families with BFNIS and novel SCN2A mutations. The families had 12 and 9 affected in iduals, respectively, with phenotypes consistent with BFNIS. Two mutations were discovered in SCN2A (E430Q I1596S). Both families had in iduals with neonatal onset but the typical age of onset was in the early infantile period (mean 3.0 months). One mutation positive in idual, with an otherwise typical clinical pattern, had seizures beginning at 13 months. Two in iduals with SCN2A mutations were identified with seizures in later life. In each family a single in idual with infantile seizures was mutation negative and thus represented phenocopies. This study extends the age range of presentation of BFNIS, confirms that neonatal and early infantile onsets are characteristic, and emphasizes the role of molecular diagnosis to confirm the etiology.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-07-2016
Publisher: Springer Science and Business Media LLC
Date: 05-2001
DOI: 10.1038/NG0501-49
Publisher: Wiley
Date: 09-1993
DOI: 10.1111/J.1528-1157.1993.TB02110.X
Abstract: We reviewed the outcome of corpus callosal section in 64 adult and pediatric patients to identify factors associated with a good outcome: 48% of patients had a favorable outcome for overall seizure frequency. Improvement was noted in several seizure types and was most likely for drop attacks, particularly in the setting of a unilateral focal cerebral lesion or a true generalized epilepsy of Lennox-Gastaut type. Poor outcomes for drop attacks were more likely if there was associated severe intellectual handicap or bilateral independent spikes on interictal EEG. Complex partial seizures (CPS), most commonly of frontal lobe origin, also responded favorably. The complications of callosal section were usually mild and transient. New focal seizures occurred in only 2 patients and were not as frequent or disabling as preoperative seizures types. A worthwhile improvement in seizure outcome was achieved by completion of the callosotomy in 6 of 10 patients with unsatisfactory results from anterior callosotomy.
Publisher: Wiley
Date: 23-03-2017
DOI: 10.1002/ACN3.401
Publisher: Elsevier BV
Date: 02-2021
Publisher: Frontiers Media SA
Date: 27-06-2014
Publisher: BMJ
Date: 1990
DOI: 10.1136/JNNP.53.1.89
Abstract: Microsomes, isolated from rat liver homogenate in 0.88 M sucrose, have been fractionated by differential centrifugation. The 2nd microsomal fraction, sedimented between 60 minutes at 105,000 g and 3 hours at 145,000 g, consists mainly of smooth vesicles, free ribosomes, and ferritin. By utilizing the differences in density existing between the membranes and the granular elements it has been possible to separate the smooth membranes from the free ribosomes and ferritin. The procedure is to resuspend the 2nd microsomal fraction in a sucrose solution of 1.21 or 1.25 density and centrifuge it at 145,000 g for 20 or 40 hours. A centripetal migration of membranes and a centrifugal sedimentation of granular elements are obtained. Phospholipids, as well as the enzymatic activities DPNH-cytochrome c reductase, glucose-6-phosphatase and esterase are localized in the membranes. The free ribosomes have been purified by washing. A concentration of 200 microg RNA per mg nitrogen has been reached. RNA is also present in the membranes. These results are discussed in relation to current views on microsomal structure and chemistry.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.EPLEPSYRES.2017.01.012
Abstract: Amongst autosomal dominant genetic epilepsy with febrile seizures plus (GEFS+) families, SCN1A variants are the most common genetic cause. Initially regarded as a generalized form of epilepsy, the GEFS+ spectrum is now known to include some focal epilepsies, but it is generally not conceptualized as extending to the self-limited focal epilepsies of childhood, such as Panayiotopoulos syndrome. There are, however, three reports of SCN1A variants in Panayiotopoulos syndrome. We describe the variable clinical phenotypes that include the self-limited focal epilepsies of childhood, present in a large GEFS+ family, segregating a heterozygous SCN1A missense variant. Electro-clinical details on all putatively affected family members were sought and blood s les were taken for genetic analysis. Two in iduals were chosen for SCN1A testing. All 26 exons and exon-intron junctions were lified, sequenced and analyzed. This was followed by pedigree segregation analysis of the variant identified. A pathogenic heterozygous SCN1A (c.2624C>A p.Thr875Lys) variant was identified. Sixteen of the 18 variant positive family members were affected (88% penetrance): 8 with febrile seizures, 2 febrile seizures plus, 1 unclassified seizures and 5 with self-limited focal epilepsy of childhood. Of these, one was diagnosed with atypical childhood epilepsy with centrotemporal spikes and four with Panayiotopoulos syndrome. By characterizing the heterogeneous clinical phenotypes in a large, SCN1A mutation positive GEFS+ family, we conclude that the GEFS+ spectrum can extend to the self-limited focal epilepsies of childhood, including Panayiotopoulos syndrome, and in turn highlight the complex genotype-phenotype correlations associated with SCN1A-related epilepsies.
Publisher: Wiley
Date: 18-11-2015
DOI: 10.1002/ANA.24520
Publisher: Wiley
Date: 02-11-2011
DOI: 10.1111/J.1528-1167.2011.03307.X
Abstract: Mutations of the SCARB2 gene cause action myoclonus renal failure syndrome (AMRF), a rare condition that combines progressive myoclonus epilepsy (PME) with severe renal dysfunction. We describe the clinical and neurophysiologic features of PME associated with SCARB2 mutations without renal impairment. Clinical and neurophysiologic investigations, including wakefulness and sleep electroencephalography (EEG), polygraphic recording (with jerk-locked back-averaging and analysis of the EEG-EMG (electromyography) relationship by coherence spectra and phase calculation), multimodal evoked potentials, and electromyography were performed on five Italian patients with SCARB2 mutations. The main clinical features were adolescent-young adulthood onset, progressive action myoclonus, ataxia, absence of cognitive deterioration and, in most cases, epilepsy. The severity of the epilepsy could vary from uncontrolled seizures and status epilepticus in patients with adolescent onset to absent or rare seizures in patients with adult onset. Relevant neurophysiologic findings were a pronounced photosensitivity and massive action myoclonus associated with rhythmic myoclonic jerks at a frequency of 12-20 Hz, clinically resembling a postural tremor. The cortical origin of rhythmic myoclonus was demonstrated mainly by coherence and phase analysis of EEG-EMG signals indicating a significant EEG-EMG coupling and a direct corticospinal transfer. Our patients with SCARB2 mutations showed the clinical and neurophysiologic phenotype of PME, in which epilepsy could be extremely severe, extending the spectrum reported in the typical AMRF syndrome. Patients with PME of unknown origin of adolescent or young adult onset, with these neurophysiologic features, should be tested for SCARB2 mutations, even in the absence of renal impairment.
Publisher: Wiley
Date: 05-2004
Publisher: Oxford University Press (OUP)
Date: 02-08-2004
DOI: 10.1093/BRAIN/AWH221
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.SEIZURE.2022.09.006
Abstract: To explore the cortical morphological associations of the psychoses of epilepsy. Psychosis of epilepsy (POE) has two main subtypes - postictal psychosis and interictal psychosis. We used automated surface-based analysis of magnetic resonance images to compare cortical thickness, area, and volume across the whole brain between: (i) all patients with POE (n = 23) relative to epilepsy-without psychosis controls (EC n = 23), (ii) patients with interictal psychosis (n = 10) or postictal psychosis (n = 13) relative to EC, and (iii) patients with postictal psychosis (n = 13) relative to patients with interictal psychosis (n = 10). POE is characterised by cortical thickening relative to EC, occurring primarily in nodes of the cognitive control network (rostral anterior cingulate, caudal anterior cingulate, middle frontal gyrus), and the default mode network (posterior cingulate, medial paracentral gyrus, and precuneus). Patients with interictal psychosis displayed cortical thickening in the left hemisphere in occipital and temporal regions relative to EC (lateral occipital cortex, lingual, fusiform, and inferior temporal gyri), which was evident to a lesser extent in postictal psychosis patients. There were no significant differences in cortical thickness, area, or volume between the postictal psychosis and EC groups, or between the postictal psychosis and interictal psychosis groups. However, prior to correction for multiple comparisons, both the interictal psychosis and postictal psychosis groups displayed cortical thickening relative to EC in highly similar regions to those identified in the POE group overall. The results show cortical thickening in POE overall, primarily in nodes of the cognitive control and default mode networks, compared to patients with epilepsy without psychosis. Additional thickening in temporal and occipital neocortex implicated in the dorsal and ventral visual pathways may differentiate interictal psychosis from postictal psychosis. A novel mechanism for cortical thickening in POE is proposed whereby normal synaptic pruning processes are interrupted by seizure onset.
Publisher: American Society of Neuroradiology (ASNR)
Date: 24-01-2013
DOI: 10.3174/AJNR.A3427
Publisher: BMJ
Date: 10-2003
Publisher: Wiley
Date: 02-2003
DOI: 10.1046/J.1528-1157.2003.26402.X
Abstract: It remains controversial whether adult-onset idiopathic generalized epilepsy (IGE) is a distinct syndrome or a continuum among IGE syndromes. EEG is the only known biologic marker of IGE and helps differentiate many of its classic subsyndromes. In this study, we looked for the differences in the EEG findings of IGE of classic adolescent onset versus adult onset that may suggest syndromic heterogeneity. Seventy-six patients (47 adolescent-onset IGE, 29 adult-onset IGE) with a clinical and EEG diagnosis of IGE were included. We defined IGE with age at onset of 11-20 years as adolescent-onset IGE and age at onset of 20 years or after as adult-onset IGE. Patients with first-decade onset of seizures, delayed EEGs, and no EEG available for review were excluded. The first EEG was performed within 24 h of the seizure, and if negative, a sleep-deprived EEG was done. All EEGs were reviewed in detail with respect to the background activity and the generalized spike-wave (GSW) characteristic. EEGs (87 56 adolescent-onset IGE, 31 adult-onset IGE) were systematically reviewed. Background was normal in all patients. The morphology, litude, duration, frequency, occurrence, or activation of the GSW pattern did not differ between these two groups. No differences of EEG features were found between the classic adolescent-onset and the adult-onset IGE. This supports the hypothesis that they share common biologic determinants and exist along a life-long age spectrum of classic IGE.
Publisher: American Medical Association (AMA)
Date: 08-1986
DOI: 10.1001/ARCHNEUR.1986.00520080083031
Abstract: The association of monoclonal paraproteinemia, neuropathy, and dermato-endocrine disturbances is well recognized in Japan, and it also occurs in white patients. Neuropathy in such patients is classically distal and sensorimotor, and the paraprotein almost always contains lambda light chains. A 58-year-old white man presented with severe progressive proximal motor neuropathy, dermato-endocrine changes, and an IgG kappa paraprotein. Over a 2 1/2-year period, treatment with melphalan and prednisolone produced improvement in the neuropathy and resolution of dermato-endocrine features with a corresponding decline in the serum paraprotein concentration. Subsequent reappearance of the paraprotein, despite treatment, was associated with clinical relapse.
Publisher: Elsevier
Date: 2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-08-2001
DOI: 10.1212/WNL.57.4.706
Abstract: Transcranial magnetic stimulation (TMS) produces a cortical silent period (CSP) during a voluntary contraction. The duration of the CSP was used to assess the level of intracortical inhibition in patients with untreated idiopathic generalized epilepsy (IGE). Mean CSP duration was assessed at three TMS stimuli in 21 patients with IGE compared with 19 normal control subjects. Mean CSP duration was increased at all stimulus intensities, indicating that intracortical inhibition is increased in patients with IGE.
Publisher: Oxford University Press (OUP)
Date: 17-03-2015
DOI: 10.1093/BRAIN/AWV052
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.PNEUROBIO.2008.09.016
Abstract: It is just over a decade since the discovery of the first human epilepsy associated ion channel gene mutation. Since then mutations in at least 25 different genes have been described, although the strength of the evidence for these genes having a pathogenic role in epilepsy varies. These discoveries are allowing us to gradually begin to unravel the molecular basis of this complex disease. In the epilepsies, virtually all the established genes code for ion channel subunits. This has led to the concept that the idiopathic epilepsies are a family of channelopathies. This review first introduces the epilepsy syndromes linked to mutations in the various genes. Next it collates the genetic and functional analysis of these genes. This part of the review is ided into voltage-gated channels (Na+, K+, Ca2+, Cl(-) and HCN), ligand-gated channels (nicotinic acetylcholine and GABA(A) receptors) and miscellaneous proteins. In some cases significant advances have been made in our understanding of the molecular and cellular deficits caused by mutations. However, the link between molecular deficit and clinical phenotype is still unknown. Piecing together this puzzle should allow us to understand the underlying pathology of epilepsy ultimately providing novel therapeutic strategies to complete the clinic-bench-clinic cycle.
Publisher: Oxford University Press (OUP)
Date: 12-2004
Abstract: Presentation of patients with recurrent stupor associated with apparently elevated levels of an endogenous benzodiazepine-like agent, endozepine-4, has been reported from several centers, and a new syndrome, endozepine stupor has been proposed. We recently reported a case with typical features of this syndrome, which proved to be an ex le of surreptitious administration of exogenous benzodiazepine. This and other ex les of clandestine drug use, together with uncertainties about the validity of tests used to distinguish exogenous and endogenous benzodiazepines, prompted us to undertake a reappraisal of this clinical syndrome.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2003
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1986
Abstract: Adoption of hospital information systems offers distinctive advantages in healthcare delivery. First, implementation of consolidated hospital information system in Seoul National University Hospital led to significant improvements in quality of healthcare and efficiency of hospital management. THE HOSPITAL INFORMATION SYSTEM IN SEOUL NATIONAL UNIVERSITY HOSPITAL CONSISTS OF COMPONENT APPLICATIONS: clinical information systems, clinical research support systems, administrative information systems, management information systems, education support systems, and referral systems that operate to generate utmost performance when delivering healthcare services. Clinical information systems, which consist of such applications as electronic medical records, picture archiving and communication systems, primarily support clinical activities. Clinical research support system provides valuable resources supporting various aspects of clinical activities, ranging from management of clinical laboratory tests to establishing care-giving procedures. Seoul National University Hospital strives to move its hospital information system to a whole new level, which enables customized healthcare service and fulfills in idual requirements. The current information strategy is being formulated as an initial step of development, promoting the establishment of next-generation hospital information system.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-1990
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-01-2018
DOI: 10.1212/WNL.0000000000004999
Abstract: The progressive myoclonic epilepsies (PME) are a heterogeneous group of disorders in which a specific diagnosis cannot be made in a subset of patients, despite exhaustive investigation. C9orf72 repeat expansions are emerging as an important causal factor in several adult-onset neurodegenerative disorders, in particular frontotemporal lobar degeneration and amyotrophic lateral sclerosis. An association with PME has not been reported previously. To identify the causative mutation in a Belgian family where the proband had genetically unexplained PME. We report a 33-year old woman who had epilepsy since the age of 15 and then developed progressive cognitive deterioration and multifocal myoclonus at the age of 18. The family history suggested autosomal dominant inheritance of psychiatric disorders, epilepsy, and dementia. Thorough workup for PME including whole exome sequencing did not reveal an underlying cause, but a C9orf72 repeat expansion was found in our patient and affected relatives. Brain biopsy confirmed the presence of characteristic p62-positive neuronal cytoplasmic inclusions. C9orf72 mutation analysis should be considered in patients with PME and psychiatric disorders or dementia, even when the onset is in late childhood or adolescence.
Publisher: Elsevier BV
Date: 10-2023
Publisher: Hindawi Limited
Date: 06-2005
DOI: 10.1002/HUMU.20178
Abstract: SCN1A is part of the SCN1A-SCN2A-SCN3A gene cluster on chromosome 2q24 that encodes for alpha pore forming subunits of sodium channels. The 26 exons of SCN1A are spread over 100 kb of genomic DNA. Genetic defects in the coding sequence lead to generalized epilepsy with febrile seizures plus (GEFS+) and a range of childhood epileptic encephalopathies of varied severity (e.g., SMEI). All published mutations are collated. More than 100 novel mutations are spread throughout the gene with the more debilitating usually de novo. Some clustering of mutations is observed in the C-terminus and the loops between segments 5 and 6 of the first three domains of the protein. Functional studies so far show no consistent relationship between changes to channel properties and clinical phenotype. Of all the known epilepsy genes SCN1A is currently the most clinically relevant, with the largest number of epilepsy related mutations so far characterized.
Publisher: Wiley
Date: 02-04-2010
DOI: 10.1111/J.1528-1167.2010.02557.X
Abstract: We used transcranial magnetic stimulation (TMS) to investigate whether there were any characteristic cortical excitability changes in progressive myoclonic epilepsy (PME) compared to juvenile myoclonic epilepsy (JME). Six patients with PME were studied. Motor threshold (MT) at rest and recovery curve analysis using paired-pulse stimulation at a number of interstimulus intervals (ISIs) was determined. Results were compared to those of 9 patients with chronic refractory JME and 10 with chronic well-controlled JME. PME showed a marked increase in cortical excitability at all the long ISIs (p < 0.01), compared to refractory JME (effect sizes ranging from 1.4 to 1.9) and well-controlled JME (effect sizes ranging from 2.0 to 2.4). Significant differences at the short ISIs 2-5 ms were seen only on comparison with the well-controlled group (p < 0.05, effect size 0.6, 0.7). There were no significant differences in MTs of PME compared to either JME groups. Our findings demonstrate specific differences in cortical excitability using TMS between PME and those with JME, particularly at long latencies in the paired-pulse paradigm, implicating a role for γ-aminobutyric acid (GABA)(B) -mediated networks.
Publisher: Oxford University Press (OUP)
Date: 05-07-2007
Abstract: A missense mutation of the gamma2 subunit of the gamma-aminobutyric acid A (GABA(A)) receptor has been linked to an inherited human generalized epilepsy. As synaptic inhibition in the human brain is largely mediated by the GABA(A) receptor, we tested the hypothesis that the GABRG2(R43Q) mutation alters cortical excitability. Fourteen subjects affected by the GABRG2(R43Q) mutation (5 males, mean age: 44 +/- 15 years) and 24 controls (11 males, mean age: 38 +/- 11 years) were studied with transcranial magnetic stimulation (TMS). To assess the specificity of the effect of the mutation, 4 additional family members unaffected by the GABRG2(R43Q) mutation (2 males, mean age: 41 +/- 16 years) were included. Subjects affected by the GABRG2(R43Q) mutation demonstrated reduced net short-interval intracortical inhibition and increased intracortical facilitation assessed with paired-pulse stimulation. Subjects with the mutation had similar motor thresholds to controls both at rest and with weak voluntary activation. No significant differences were noted between groups in the cortical silent period. Our findings provide in vivo evidence for increased intracortical excitability in subjects affected by the GABRG2(R43Q) mutation. These findings are also likely to represent an important clue to the mechanisms linking this gene defect and the epilepsy phenotype.
Publisher: Wiley
Date: 09-1993
DOI: 10.1111/J.1528-1157.1993.TB02104.X
Abstract: Seventeen ictal 99mTc-HMPAO single photon emission computed tomography (SPECT) studies were performed in 15 children with temporal lobe epilepsy (TLE) aged 7-14 years (mean 10.3 years). Ictal SPECT was informative in 16 of 17 (94%) studies in 14 of 15 (93%) children, showing unilateral temporal lobe hyperperfusion. In all 16 informative ictal SPECT studies, lateralization was concordant with ictal EEG, magnetic resonance imaging (MRI), and pathology. In 4 children, ictal SPECT provided additional localizing information that was not apparent from concurrent ictal EEG recording. Blinded interpretation of ictal SPECT studies by two independent investigators showed correct lateralization of the epileptic focus in every child. Results of visual analysis of ictal SPECT images were corroborated by quantitative analysis. Although interictal SPECT studies showed a degree of temporal lobe hypoperfusion in all children, in 9 of 15 hypoperfusion was either minimal, bilateral, contralateral, or associated with extratemporal hypoperfusion. In children with TLE, ictal SPECT provides reliable lateralizing information to corroborate or supplement that obtained from surface EEG and MRI.
Publisher: Wiley
Date: 02-2000
Publisher: Elsevier BV
Date: 02-2021
DOI: 10.1016/J.EPLEPSYRES.2020.106537
Abstract: We investigated the possible significance of rare genetic variants to response to valproic acid (VPA) and ethosuximide (ETX) in patients with absence epilepsy. Our primary hypothesis was that rare CACNA1H variants are more frequent in ETX-non-responsive patients compared to ETX-responsive. Our secondary hypothesis was that rare variants in GABA-receptor genes are more frequent in VPA-non-responsive patients compared to VPA-responsive. We recruited patients with absence epilepsy treated with both VPA and ETX, and performed whole exome sequencing in order to investigate the potential role of rare variants in CACNA1H, other voltage-gated calcium channel (VGCC) genes, or GABA-receptor genes in predicting response to ETX or VPA. Sixty-two patients were included 12 were ETX-responsive, 14 VPA-responsive, and 36 did not have a clear positive response to either medication. We did not find significant enrichment inCACNA1H rare variants in ETX-responsive patients (odds ratio 3.43 0.43-27.65 p = 0.20), nor was there enrichment for other VGCC genes. No significant enrichment of GABA-receptor gene rare variants was seen for VPA-non-responsive patients versus VPA-responsive. We found enrichment of rare GABA-receptor variants in our absence cohort compared to controls (odds ratio 3.82 1.68-8.69). There was no difference in frequency of CACNA1H rs61734410 and CACNA1I rs3747178 polymorphisms between ETX-responsive and ETX-non-responsive groups these polymorphisms have previously been reported to predict lack of response to ETX in absence epilepsy. We conclude that if CACNA1H rare variants predict lack of response to ETX, a larger s le is necessary to test this with sufficient power. Increased GABA-receptor gene rare variant frequency in absence epilepsy patients who fail initial anti-seizure therapy suggests subtle GABA receptor dysfunction may contribute to the underlying pathophysiology.
Publisher: Wiley
Date: 12-2005
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-1995
Abstract: Juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures (GTCS) on awakening are the three syndromes of idiopathic generalized epilepsy of adolescent onset currently included in the classification of epilepsy syndromes of the International League Against Epilepsy (ILAE). Although they differ in their predominant seizure types, the syndromes share several clinical features, thus giving rise to questions of phenotypic overlap and purity. We studied the clinical features of 101 patients with idiopathic generalized epilepsy beginning in adolescence. A standardized interview was used to elucidate seizure phenomenology, precipitants, frequency, and response to treatment. Groups defined by seizure type were compared and their similarities examined. The group with myoclonic but not absence seizures (21 patients) corresponded to the ILAE syndrome of juvenile myoclonic epilepsy, whereas those with absences but not myoclonus (37 patients) resembled juvenile absence epilepsy. Twenty-six patients shared the features of juvenile myoclonic epilepsy and juvenile absence epilepsy. Epilepsy with GTCS on awakening was not a specific syndromic entity 10 patients had this seizure type alone. Seven patients were without a syndromic diagnosis. In these patients only GTCS occurred, but neither on awakening nor in the evening period of relaxation. We conclude that whilst syndromes of idiopathic generalized epilepsy of adolescence can be recognized, the current classification does not include all patients. In addition, the boundaries between the syndromes are indistinct, suggesting underlying neurobiological, possibly genetic, relationships.
Publisher: Springer Science and Business Media LLC
Date: 31-08-2023
DOI: 10.1038/S41588-023-01485-W
Abstract: Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.
Publisher: Wiley
Date: 12-2018
Publisher: Wiley
Date: 05-1988
Abstract: Detailed study of 4 patients and review of the literature allowed us to delineate further the epileptic syndrome associated with hypothalamic hamartomas, which characteristically begins in infancy with laughing seizures. Because early childhood psychomotor development is usually normal, the condition appears benign and may not even be recognized. The episodes of laughter are brief, frequent, and mechanical in nature. These features distinguish it from other forms of epileptic laughter, particularly that which occurs in temporal lobe epilepsy. Subsequently, the seizures become longer, other seizure types appear, and between the ages of 4 and 10 years, the clinical and electroencephalographic features of secondary generalized epilepsy develop. Cognitive deterioration occurs and severe behavior problems are frequent. Prognosis for seizure control and social adjustment is poor. Cortical abnormality occurs in association with the hypothalamic hamartoma. The lesions are best detected by magnetic resonance imaging but may be difficult to identify by computed tomographic scanning.
Publisher: Massachusetts Medical Society
Date: 18-04-2019
DOI: 10.1056/NEJMC1805100
Publisher: BMJ
Date: 03-2004
Publisher: Wiley
Date: 08-03-2017
DOI: 10.1111/EPI.13709
Publisher: Wiley
Date: 12-1995
Abstract: We report the development of intractable epilepsy in 3 patients treated with irradiation to "strawberry" scalp nevi in infancy. Low-dose radiation was used (12 and 13 Gy in 2 of the patients). The clinical evolution suggested a recognizable and distinctive postradiation syndrome. There was concordance between the site of radiation as shown by localized alopecia, the clinical features of the partial seizures, and electrographic abnormalities. The clinical picture was unlike delayed cerebral radiation necrosis of adulthood, which is not thought to occur at doses below 50 Gy, in 2-Gy fractions. Neurological deficits were not progressive and in 2 patients there was no evidence of parenchymal injury on cranial magnetic resonance imaging scanning. These differences suggest pathogenetic differences to cerebral radiation injury of adulthood, probably relating to the interaction between nervous system development, in idual susceptibility, and the low doses of radiation employed.
Publisher: Springer Science and Business Media LLC
Date: 10-1995
DOI: 10.1038/NG1095-201
Abstract: Epilepsy affects at least 2% of the population at some time in their lives. The epilepsies are a heterogeneous group of disorders, many with an inherited component. Although specific genes have been identified in a few rare diseases causing seizures as part of a more diffuse brain disorder, the molecular pathology of the common idiopathic epilepsies is still unknown. Linkage has been reported for some generalised epilepsy syndromes, but only very recently for familial partial epilepsy syndromes. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a partial epilepsy causing frequent, violent, brief seizures at night, usually beginning in childhood. The gene for ADNFLE maps to chromosome 20q13.2-q13.3 in one large Australian kindred. The neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) maps to the same region of 20q (ref. 12) and the gene is expressed in all layers of the frontal cortex. We screened affected family members for mutations within CHRNA4 and found a missense mutation that replaces serine with phenylalanine at codon 248, a strongly conserved amino acid residue in the second transmembrane domain. The mutation is present in all 21 available affected family members and in four obligate carriers, but not in 333 healthy control subjects.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-06-2013
Publisher: Wiley
Date: 10-11-2001
DOI: 10.1046/J.1528-1157.2001.03201.X
Abstract: Genetic factors are the only identified cause of idiopathic generalized epilepsies (IGEs), but the majority of cases do not have affected first-degree relatives. Here we investigate whether subjects with sporadic and familial IGE differ in terms of antecedent events and clinical and EEG features. Differences would support the hypothesis of a different etiology for sporadic cases, which has implications for choice of subjects for genetic association studies. We analyzed 98 patients with IGE, diagnosed on clinical and EEG criteria. All patients and, if possible, one relative were interviewed, with special emphasis on potential antecedent events and family history. Patients with first-degree relatives affected with epileptic seizures were regarded as "familial," and the other patients were regarded as "sporadic." Of the 98 IGE patients, 32 (33%) patients were familial. The risk for seizures was 13.2% for siblings, and 7.7% for parents. The distribution of the IGE subsyndromes, the presence of antecedent events, and other electroclinical features did not differ between familial and sporadic IGE groups. No differences were found between familial and sporadic IGE patients. This does not the support the hypothesis that sporadic and familial IGE cases have separate etiologies.
Publisher: Elsevier BV
Date: 2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-1991
Abstract: The MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) can be difficult to identify. We report MRI abnormalities that we believe are specific to this disorder in three patients with complete or partial MELAS syndrome. The patients all showed an unusual pattern on T2-weighted MRI with multifocal areas of hyperintense signal confined to the cortex of the cerebrum, cerebellum, and adjacent white matter. Some images suggested selective cortical involvement of deeper layers only. Deep white matter was relatively spared, distinguishing this from usual cerebrovascular disease or the edema after status epilepticus. Specificity of these findings is further suggested by a good correlation of these findings with the previously described unique postmortem brain pathology of MELAS.
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.EPLEPSYRES.2012.04.007
Abstract: Levetiracetam, a broad spectrum antiepileptic drug, binds to membrane protein SV2A. The protein coding region of SV2A was sequenced in 158 patients with focal or generalized epilepsies ided into three groups based on their response to levetiracetam: responders (>75% decrease), exacerbators (50% increase) and non-responders. Nonsynonymous coding variation within SV2A was extremely rare, suggesting that rare variation is not likely to account for the in idual differences in response to levetiracetam.
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.EPLEPSYRES.2010.01.013
Abstract: Photoparoxysmal response (PPR) is considered to be a risk factor for idiopathic generalised epilepsy (IGE) and it has a strong genetic basis. Two genome-wide linkage studies have been published before and they identified loci for PPR at 6p21, 7q32, 13q13, 13q31 and 16p13. Here we combine these studies, augmented with additional families, in a mega-analysis of 100 families. Non-parametric linkage analysis identified three suggestive peaks for photosensitivity, two of which are novel (5q35.3 and 8q21.13) and one has been found before (16p13.3). We found no evidence for linkage at four previously detected loci (6p21, 7q32, 13q13 and 13q31). Our results suggest that the different family data sets are not linked to a shared locus. Detailed analysis showed that the peak at 16p13 was mainly supported by a single subset of families, while the peaks at 5q35 and 8q21 had weak support from multiple subsets. Family studies clearly support the role of PPR as a risk factor for IGE. This mega-analysis shows that distinct loci seem to be linked to subsets of PPR-positive families that may differ in subtle clinical phenotypes or geographic origin. Further linkage studies of PPR should therefore include in-depth phenotyping to make appropriate subsets and increase genetic homogeneity.
Publisher: Elsevier BV
Date: 11-2009
Publisher: Elsevier BV
Date: 10-2017
Publisher: Elsevier BV
Date: 08-2016
Publisher: Oxford University Press (OUP)
Date: 04-1997
DOI: 10.1093/HMG/6.4.555
Abstract: While disorders of neuronal migration are associated with as much as 25% of recurrent childhood seizures, few of the genes required to establish neuronal position in cerebral cortex are known. Subcortical band heterotopia (SBH) and lissencephaly (LIS), two distinct neuronal migration disorders producing epilepsy and variable cognitive impairment, can be inherited alone or together in a single pedigree. Here we report a new genetic locus, XLIS, mapped by linkage analysis of five families and physical mapping of a balanced X translocation in a girl with LIS. Linkage places the critical region in Xq21-q24, containing the breakpoint that maps to Xq22.3-q23 by high-resolution chromosome analysis. Markers used for somatic cell hybrid and fluorescence in situ hybridization analyses place the XLIS region within a 1 cM interval. These data suggest that SBH and X-linked lissencephaly are caused by mutation of a single gene, XLIS, that the milder SBH phenotype in females results from random X-inactivation (Lyonization), and that cloning of genes from the breakpoint region on X will yield XLIS.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-05-2002
Abstract: Generalized epilepsy with febrile seizures plus (GEFS(+)) is an important childhood genetic epilepsy syndrome with heterogeneous phenotypes, including febrile seizures (FS) and generalized epilepsies of variable severity. Forty unrelated GEFS(+) and FS patients were screened for mutations in the sodium channel beta-subunits SCN1B and SCN2B, and the second GEFS(+) family with an SCN1B mutation is described here. The family had 19 affected in iduals: 16 with typical GEFS(+) phenotypes and three with other epilepsy phenotypes. Site-specific mutation within SCN1B remains a rare cause of GEFS(+), and the authors found no evidence to implicate SCN2B in this syndrome.
Publisher: Oxford University Press (OUP)
Date: 02-04-2007
DOI: 10.1093/BRAIN/AWM013
Abstract: Some patients considered for left temporal lobectomy for epilepsy present with normal verbal learning and no MRI evidence of hippoc al pathology. In order to preserve learning function, the surgical approach in these cases often aims at sparing the hippoc us. Parahippoc al structures, including the left perirhinal region, however, also appear to contribute to some forms of verbal learning. We studied aspects of verbal learning in four patients with left temporal lobe resections that preserved the hippoc us, but which included perirhinal/entorhinal cortices in two cases. Pre- and postoperative T1-weighted MRI scans were spatially normalized and residual mesial temporal structures identified. The two patients whose resection included perirhinal and entorhinal cortices exhibited a marked decrement in the ability to acquire arbitrarily related word pairs that persisted at 12-month follow-up. Word list learning showed an early postoperative impairment, but recovered to normal levels within 12 months. In two patients, resection encompassed anterolateral and inferior temporal neocortex but spared the perirhinal and entorhinal cortices, amygdala and hippoc us. No postoperative change in verbal learning was evident. We concluded that hippoc al-sparing left temporal lobe resections result in task-specific verbal learning deficits when perirhinal/entorhinal tissue is included in the resection.
Publisher: Wiley
Date: 14-08-2014
DOI: 10.1111/EPI.12745
Abstract: Chronic treatment with valproate (VPA) is commonly associated with weight gain, which potentially has important health implications, in particular increased central fat distribution. We utilized a VPA-discordant same-sex, twin and matched sibling pair study design to primarily examine for differences in fat distribution between patients with epilepsy treated with VPA compared to their matched twin or sibling control. Weight, blood pressure, and leptin levels were assessed. Height, weight, waist and hip measurements, exercise, blood pressure (BP), and serum leptin levels were measured. Body composition was measured using dual-energy x-ray absorptiometry (DXA). Abdominal fat was expressed as a percentage of the abdominal region (AFat%) and of whole body fat (WBF) (AFat%WBF). Mean within-pair differences were assessed (VPA-user and nonuser). Restricted maximum likelihood (REML) linear mixed model analysis was fitted to examine associations of anthropometrics, zygosity, gender, menopausal status, VPA dose and duration, with weight and AFat%. We studied 19 pairs of VPA-discordant, gender-matched (five male, 14 female) twins and siblings. Mean (standard deviation, SD) duration of therapy for VPA users was 11.0 (7.4) years. There were no statistically significant within-pair differences in age, height, weight, body mass index (BMI), BP, leptin level, WBF, AFat%, or AFat%WBF. For pairs in which VPA-user was treated for >11 years there were statistically significant mean within-pair differences in AFat%, (+7.1%, p = 0.03, n = 10 pairs), mean BP (+11.0 mm Hg, p = 0.006, n = 8 pairs) but not in AFat%WBF. VPA duration was positively associated with weight (estimate +0.98 kg er year of VPA, p = 0.03) VPA treatment duration and dose were not significantly associated with AFat%. This study demonstrated a relationship between long-term VPA use and abdominal adiposity (AFat%), which could have significant health implications. We recommend ongoing monitoring of weight, BMI, and blood pressure for patients taking VPA.
Publisher: Elsevier BV
Date: 02-1994
DOI: 10.1016/S0140-6736(94)91463-X
Abstract: We describe a distinctive epilepsy syndrome in six families, which is the first partial epilepsy syndrome to follow single gene inheritance. The predominant seizure pattern had frontal lobe seizure semiology with clusters of brief motor attacks occurring in sleep. Onset was usually in childhood, often persisting through adult life. Misdiagnosis as night terrors, nightmares, hysteria, or paroxysmal nocturnal dystonia was common, and the inheritance pattern was often not appreciated. This autosomal dominant epilepsy syndrome is ideal for identification of partial epilepsy genes.
Publisher: World Scientific Pub Co Pte Lt
Date: 30-12-2012
DOI: 10.1142/S012906571250030X
Abstract: Transcranial magnetic stimulation was used to study the effect of recurrent seizures on cortical excitability over time in epilepsy. 77 patients with firm diagnoses of idiopathic generalized epilepsy (IGE) or focal epilepsy were repeatedly evaluated over three years. At onset, all groups had increased cortical excitability. At the end of follow-up the refractory group was associated with a broad increase in cortical excitability. Conversely, cortical excitability decreased in all seizure free groups after introduction of an effective medication.
Publisher: Oxford University Press (OUP)
Date: 10-2021
DOI: 10.1093/BRAINCOMMS/FCAB245
Abstract: The vacuolar H+-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in ATP6V0A1, the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four in iduals. Here, we identified 17 in iduals from 14 unrelated families with both with new and previously characterized variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 in iduals carried de novo missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in Caenorhabditis elegans. Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of ATP6V0A1-related conditions.
Publisher: Wiley
Date: 12-08-2003
DOI: 10.1046/J.1528-1157.2003.07303.X
Abstract: Little is known about offspring of parents who both have idiopathic generalized epilepsy (IGE). This is of importance for understanding the complex genetic architecture of IGE. Families in whom both parents had proven IGE were ascertained through a multiplex families database. Clinical information including EEG recordings and detailed pedigrees was obtained. In family I, the mother had juvenile myoclonic epilepsy (JME), and the father had IGE. One daughter had Lennox-Gastaut syndrome, and the other had unclassified epilepsy. In family II, the mother had JME, and the father had IGE. Two of three sons had an identical clinical picture of clinical picture of childhood absence epilepsy (CAE), but with fast polyspike-wave discharges on EEG. The clinical phenotype of affected offspring suggested that their epilepsy could be due to the combination of a putative "double dose" of genes from both sides of the family. In such families, as epilepsy genes could be inherited from both parents, a high risk of epilepsy in the offspring could be expected.
Publisher: Wiley
Date: 21-06-2011
DOI: 10.1111/J.1528-1167.2011.03134.X
Abstract: Cases of severe childhood epilepsies in temporal association with vaccination have great impact on the acceptance of vaccination programs by parents and health care providers. However, little is known about the type and frequency of seizures and epilepsy syndromes following vaccination. This study aims to describe the clinical features of children presenting with seizures after vaccination using a register-based cohort. We surveyed the national German database of adverse events following immunization (AEFI) for reported seizures and epilepsies in children aged 0-6 years. All cases reported in 2006-2008 were analyzed retrospectively available clinical information was reevaluated and classified by seizure type and epilepsy syndrome. In total, 328 cases reported between 2006 and 2008 were included. Data supportive of seizures or epilepsy were present in 247 (75.3%) of 328 patients with a mean interval between the vaccination and the epileptic event of 24 h and 7.5 days for inactivated and attenuated vaccines, respectively. Fifty-one (15.5%) of 328 patients presented with syncope, hypotonic-hyporesponsive episodes, or other nonepileptic events. Information was insufficient for classification into epileptic versus nonepileptic events in 30 (11.3%) of 328 patients. For cases with confirmed seizures, febrile seizures were present in 121 (49%) of 247 cases, and 38 (15.4%) of 247 patients had single afebrile seizures. Status epilepticus was described in 21 (8.5%) of 247 patients. Thirty-one (12.6%) of 247 patients presented with various pediatric epilepsy syndromes. Severe childhood epilepsies (Dravet syndrome, West syndrome, Lennox-Gastaut syndrome, or Doose syndrome) were diagnosed in 29 (11.7%) of 247 patients, with the vaccination-associated event being the first documented seizure in 15 (51.7%) of 29 patients. Vaccination-associated seizures present in the setting of various epilepsy syndromes, including severe childhood epilepsies in >10% of cases. Early diagnosis of the corresponding epilepsy syndromes and confirmation of an underlying etiology is important for treatment decisions, genetic counseling, and public health evaluation of vaccine safety.
Publisher: Elsevier BV
Date: 10-1998
DOI: 10.1086/302047
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-10-1999
Abstract: Congenital brain lesions producing focal seizures may be accompanied by reorganization of the areas responsible for motor and sensory functions within the brain due to a phenomenon that has been termed "neuronal plasticity." This can be studied using functional MRI (fMRI) and transcranial magnetic stimulation (TMS). Using either method, the motor cortex can be localized noninvasively, but to date there have been few studies correlating the level of agreement between the two techniques. We used fMRI and TMS to localize the motor cortex in a young woman with intractable focal seizures, congenital left arm weakness, and a dysplastic right hemisphere on MRI. There was excellent agreement in the localization of motor representation for each hand. Both were predominantly located in the left hemisphere. fMRI also showed an area of posterior activation in the right hemisphere, but there was no evidence of descending corticospinal projections from this site using TMS, direct cortical stimulation, and Wada testing. Functional MRI (fMRI) and transcranial magnetic stimulation (TMS) were successfully used to localize cortical motor function before epilepsy surgery. Each technique demonstrated migration of motor function for the left hand to the left motor cortex. After resection of the dysplastic right precentral gyrus there was no permanent increase in weakness or disability. The two techniques are complementary fMRI indicates all cortical areas activated by the motor task, whereas TMS identifies only those areas giving rise to corticospinal projections.
Publisher: American Medical Association (AMA)
Date: 11-1987
DOI: 10.1001/ARCHNEUR.1987.00520230064016
Abstract: Three unrelated patients, aged 4, 18, and 47 years, had generalized dystonia associated with bilateral striatal hypodensities on computed tomography. Mitochondrial encephalopathy was considered to be the most likely diagnosis, but this could not be proved. These patients confirm previous reports linking acquired generalized dystonia with bilateral putaminal lesions and they highlight the problem in differential diagnosis of this clinicoradiologic syndrome.
Publisher: American Medical Association (AMA)
Date: 09-2011
DOI: 10.1001/ARCHNEUROL.2011.102
Abstract: To determine if a significant proportion of patients with myoclonic-astatic epilepsy (MAE) have glucose transporter 1 (GLUT1) deficiency. Genetic analysis. Ambulatory and hospitalized care. Eighty-four unrelated probands with MAE were phenotyped and SLC2A1 was sequenced and analyzed by multiplex ligation-dependent probe lification. Any identified mutations were then screened in controls. Any SLC2A1 mutations. Four of 84 probands with MAE had a mutation of SLC2A1 on sequencing. Multiplex ligation-dependent probe lification analysis did not reveal any genomic rearrangements in 75 of the remaining cases 5 could not be tested. Two patients with MAE with SLC2A1 mutations also developed paroxysmal exertional dyskinesia in childhood. Five percent of our patients with MAE had SLC2A1 mutations, suggesting that patients with MAE should be tested for GLUT1 deficiency. Diagnosis of GLUT1 deficiency is a strong indication for early use of the ketogenic diet, which may substantially improve outcome of this severe disorder.
Publisher: Wiley
Date: 17-06-2019
DOI: 10.1002/ACN3.50815
Publisher: Wiley
Date: 08-1996
Abstract: We describe a new syndrome of familial temporal lobe epilepsy in 38 in iduals from 13 unrelated white families. The disorder was first identified in 5 concordant monozygotic twin pairs as part of a large-scale twin study of epilepsy. When idiopathic partial epilepsy syndromes were excluded, the 5 pairs accounted for 23% of monozygotic pairs with partial epilepsies, and 38% of monozygotic pairs with partial epilepsy and no known etiology. Seizure onset for twin and nontwin subjects usually occurred during adolescence or early adult life. Seizure types were simple partial seizures with psychic or autonomic symptoms, infrequent complex partial seizures, and rare secondarily generalized seizures. Electroencephalograms revealed sparse focal temporal interictal epileptiform discharges in 22% of subjects. Magnetic resonance images appeared normal. Nine affected family members (24%) had not been diagnosed prior to the study. Pedigree analysis suggested autosomal dominant inheritance with age-dependent penetrance. The estimated segregation ratio was 0.3, indicating an overall penetrance of 60% assuming autosomal dominant inheritance. The mild and often subtle nature of the symptoms in some family members may account for lack of prior recognition of this common familial partial epilepsy. This disorder has similarities to the El mouse, a genetic model of temporal lobe epilepsy with a major gene on mouse chromosome 9, which is homologous with a region on human chromosome 3.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.NEULET.2009.02.038
Abstract: Rare GABA(A) receptor gamma2 and alpha1 subunit mutations of pathogenic effect have been described segregating in families with "monogenic" epilepsies. We now report globally on the genetic variation contained within all 16 neuronal GABA(A) receptor subunit genes from the one patient cohort. The cohort consists of GEFS(+), FS, and IGE subgroups as either sporadic cases or index cases from small families, with one index case from one large IGE family. The rarity of mutations and coding variation in general across all of the subunits suggests a low tolerance for mutations affecting GABA mediated neuronal inhibition. Characterization of the broader channelopathy load associated with susceptibility to these common epilepsies mostly with complex genetics will need to be expanded beyond the family of GABA(A) receptor subunits to all families of neuronal ion channels and their interacting molecules by systematic mutation detection associated with functional investigation of their naturally occurring genetic variations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-06-2010
Publisher: Wiley
Date: 28-11-2017
DOI: 10.1111/BPH.13658
Publisher: BMJ
Date: 02-2002
Publisher: Wiley
Date: 11-1997
DOI: 10.1111/J.1528-1157.1997.TB01226.X
Abstract: Quality assessment in health care is a process of planned activities with the ultimate goal of achieving a continuous improvement of medical care through the evaluation of structure, process, and outcome measures. Physicians and health care specialists involved with quality issues are faced with an enormous and nearly always increasing amount of literature to read and integrate. Nevertheless, the novelty and quality of these articles (in terms of evidence-based medicine) has not been systematically assessed and described. The objective of this study was to test the hypothesis that the number of high-evidence journal articles (according to the pyramid of evidence), such as randomized control trials, systematic reviews, and ultimately, practice guidelines, increases over time, relative to lower-evidence journal articles, such as editorials, reviews, and letters to the editors. We used PubMed database to retrieve relevant articles published during the 31-year period between January 1, 1989, and December 31, 2021. The search was conducted in April 2022. We used the keywords "quality care," "quality management," "quality indicators," and "quality improvement" and limited the search fields to title and abstract in order to limit our search results to articles nearly exclusively related to health care quality. During this 31-year evaluation period, there was a significant cubic increase in the total number of publications, reviews, clinical trials (peaking in 2017, with a sharp decline until 2021), controlled trials (peaking in 2016, with a sharp drop until 2021), randomized controlled trials (peaking in 2017, with a sharp drop until 2021), systematic reviews (nearly nonexistent in the 1980s through 1990s to a peak of 222 in 2021), and meta-analyses (from nearly none in the 1980s through 1990s to a peak of approximately 40 per year in 2020). There was a linear increase in practice guidelines from none during 1989-1991 to approximately 25 per year during 2019-2021, including a cubic increase in editorials, peaking in 2021 at 125 per year, and in letters to the editor, peaking at 50-78 per year in the last 4 years (ie, 2018-2021). Over the past 31 years, the field of quality in health care has seen a significant yearly increase of published original studies with a relative stagnation since 2015. We suggest that contributors to this dynamic field of research should focus on producing more evidence-based publications and guidelines.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-02-2013
Publisher: Wiley
Date: 06-09-2023
DOI: 10.1002/EPD2.20152
Abstract: Progressive Myoclonus Epilepsy (PME) is a rare epilepsy syndrome characterised by the development of progressively worsening myoclonus, ataxia and seizures. A molecular diagnosis can now be established in approximately 80% of in iduals with PME. Almost fifty genetic causes of PME have now been established, although some remain extremely rare. Herein we provide a review of clinical phenotypes and genotypes of the more commonly encountered PMEs. Using an illustrative case ex le, we describe appropriate clinical investigation and therapeutic strategies to guide the management of this often relentlessly progressive and devastating epilepsy syndrome.
Publisher: Wiley
Date: 07-11-2012
DOI: 10.1111/CGE.12020
Abstract: We sought to identify the molecular basis of the autosomal dominant form of Kufs disease, an adult onset form of neuronal ceroid lipofuscinosis. We used a combination of classic linkage analysis and Next Generation Sequencing to map and identify mutations in DNAJC5 in a total of three families. We analyzed the clinical manifestations in 20 in iduals with mutation in DNAJC5. We report here the mapping and the identification of a p.L116del mutation in DNAJC5 segregating with the disease in two distinct American families, as well as a p.L115R mutation in an additional family. The age of onset and clinical manifestations were very homogeneous among mutation positive in iduals, including generalized tonic-clonic seizures, myoclonus, ataxia, speech deterioration, dementia, and premature death. A few in iduals also exhibited parkinsonism. DNAJC5, which encodes the cysteine string protein (CSPα), a presynaptic protein implicated in neurodegeneration, causes autosomal dominant Kufs disease. The leucine residues at positions 115 and 116 are hotspots for mutations and result in a homogeneous phenotype of progressive myoclonus epilepsy with onset around 30 years old.
Publisher: Oxford University Press (OUP)
Date: 2021
DOI: 10.1093/BRAINCOMMS/FCAA235
Abstract: Brain somatic mutations are an increasingly recognized cause of epilepsy, brain malformations and autism spectrum disorders and may be a hidden cause of other neurodevelopmental and neurodegenerative disorders. At present, brain mosaicism can be detected only in the rare situations of autopsy or brain biopsy. Liquid biopsy using cell-free DNA derived from cerebrospinal fluid has detected somatic mutations in malignant brain tumours. Here, we asked if cerebrospinal fluid liquid biopsy can be used to detect somatic mosaicism in non-malignant brain diseases. First, we reliably quantified cerebrospinal fluid cell-free DNA in 28 patients with focal epilepsy and 28 controls using droplet digital PCR. Then, in three patients we identified somatic mutations in cerebrospinal fluid: in one patient with subcortical band heterotopia the LIS1 p. Lys64* variant at 9.4% frequency in a second patient with focal cortical dysplasia the TSC1 p. Phe581His*6 variant at 7.8% frequency and in a third patient with ganglioglioma the BRAF p. Val600Glu variant at 3.2% frequency. To determine if cerebrospinal fluid cell-free DNA was brain-derived, whole-genome bisulphite sequencing was performed and brain-specific DNA methylation patterns were found to be significantly enriched (P = 0.03). Our proof of principle study shows that cerebrospinal fluid liquid biopsy is valuable in investigating mosaic neurological disorders where brain tissue is unavailable.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-09-2006
DOI: 10.1212/01.WNL.0000237392.64230.F7
Abstract: To use transcranial magnetic stimulation (TMS) to investigate the hypothesis that sleep deprivation increases cortical excitability in people with epilepsy. We performed paired pulse TMS stimulation, using a number of interstimulus intervals (ISIs) on each hemisphere of 30 patients with untreated newly diagnosed epilepsy (15 idiopathic generalized epilepsy [IGE] and 15 focal epilepsy) and on the dominant hemisphere of 13 healthy control subjects, before and after sleep deprivation. Both hemispheres in patients with IGE and the hemisphere ipsilateral to the EEG seizure focus in those with focal epilepsy showed an increase in cortical excitability following sleep deprivation at a number of ISIs. This change in excitability was most prominent in the patients with IGE. Although there were minor changes after sleep deprivation in control subjects and the contralateral hemisphere in the focal epilepsy group seen at the 250-millisecond ISI, it was less than in the other groups. Sleep deprivation increases cortical excitability in epilepsy the pattern of change is syndrome dependent.
Publisher: Elsevier BV
Date: 02-2002
DOI: 10.1086/338710
Publisher: Elsevier BV
Date: 12-2021
Publisher: MDPI AG
Date: 31-08-2020
DOI: 10.3390/IJMS21176333
Abstract: The CACNA1G gene encodes the low-voltage-activated Cav3.1 channel, which is expressed in various areas of the CNS, including the cerebellum. We studied two missense CACNA1G variants, p.L208P and p.L909F, and evaluated the relationships between the severity of Cav3.1 dysfunction and the clinical phenotype. The presentation was of a developmental and epileptic encephalopathy without evident cerebellar atrophy. Both patients exhibited axial hypotonia, developmental delay, and severe to profound cognitive impairment. The patient with the L909F mutation had initially refractory seizures and cerebellar ataxia, whereas the L208P patient had seizures only transiently but was overall more severely affected. In transfected mammalian cells, we determined the biophysical characteristics of L208P and L909F variants, relative to the wild-type channel and a previously reported gain-of-function Cav3.1 variant. The L208P mutation shifted the activation and inactivation curves to the hyperpolarized direction, slowed the kinetics of inactivation and deactivation, and reduced the availability of Ca2+ current during repetitive stimuli. The L909F mutation impacted channel function less severely, resulting in a hyperpolarizing shift of the activation curve and slower deactivation. These data suggest that L909F results in gain-of-function, whereas L208P exhibits mixed gain-of-function and loss-of-function effects due to opposing changes in the biophysical properties. Our study expands the clinical spectrum associated with CACNA1G mutations, corroborating further the causal association with distinct complex phenotypes.
Publisher: Oxford University Press (OUP)
Date: 24-06-2008
DOI: 10.1093/BRAIN/AWN113
Publisher: Wiley
Date: 1997
Publisher: Massachusetts Medical Society
Date: 31-07-1986
DOI: 10.1056/NEJM198607313150506
Abstract: A new genus and species of scorpion belonging to the family Pseudochactidaeare described based on four specimens collected in the Tien Son cave at the Phong Nha - Ke Bang National Park, Quang Binh Province, Vietnam. The new species represents a true troglobitic element, the first one known for the family Pseudochactidae. This represents the third known record of a pseudochactid, and the first from Vietnam.
Publisher: Elsevier BV
Date: 12-2010
Publisher: Elsevier BV
Date: 09-2000
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1038/GIM.2017.15
Abstract: Sudden death in the young is a devastating complication of inherited heart disorders. Finding the precise cause of death is important, but it is often unresolved after postmortem investigation. The addition of postmortem genetic testing, i.e., the molecular autopsy, can identify additional causes of death. We evaluated DNA extracted from formalin-fixed paraffin-embedded postmortem tissue for exome sequencing-based molecular autopsy after sudden death in the young. We collected clinical and postmortem information from patients with sudden death. Exome sequencing was performed on DNA extracted from fixed postmortem tissue. Variants relevant to the cause of death were sought. Five patients with genetically unresolved sudden death were recruited. DNA extracted from fixed postmortem tissue was degraded. Exome sequencing achieved 20-fold coverage of at least 82% of coding regions. A threefold excess of singleton variants was found in the exome sequencing data of one patient. We found a de novo SCN1A frameshift variant in a patient with sudden unexpected death in epilepsy and a LMNA nonsense variant in a patient with dilated cardiomyopathy. DNA extracted from fixed postmortem tissue is applicable to exome sequencing-based molecular autopsy. Fixed postmortem tissues are an untapped resource for exome-based studies of rare causes of sudden death.Genet Med advance online publication 23 March 2017.
Publisher: Wiley
Date: 12-1982
DOI: 10.1111/J.1445-5994.1982.TB02650.X
Abstract: Repetitive focal seizures were associated with hyperglycemia in three patients, and with hypoxia in another patient. Autopsy in one case and computed tomography (CT) scans in two patients failed to reveal relevant focal cerebral disease. Awareness of the occurrence of focal seizures in metabolic disorders, especially non-ketotic hyperglycemia, should be increased as early recognition is vital for successful treatment. Metabolic encephalopathies can cause focal seizures with or without underlying focal cerebral pathology.
Publisher: Elsevier BV
Date: 10-2022
Publisher: Elsevier BV
Date: 2020
Publisher: Wiley
Date: 22-06-2023
DOI: 10.1002/EPD2.20026
Abstract: The self‐limited (familial) epilepsies with onset in neonates or infants, formerly called benign familial neonatal and/or infantile epilepsies, are autosomal dominant disorders characterized by neonatal‐ or infantile‐onset focal motor seizures and the absence of neurodevelopmental complications. Seizures tend to remit during infancy or early childhood and are therefore called “self‐limited”. A positive family history for epilepsy usually suggests the genetic etiology, but incomplete penetrance and de novo inheritance occur. Here, we review the phenotypic spectrum and the genetic architecture of self‐limited (familial) epilepsies with onset in neonates or infants. Using an illustrative case study, we describe important clues in recognition of these syndromes, diagnostic steps including genetic testing, management, and genetic counseling.
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.BBRC.2014.12.111
Abstract: The lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) has been identified as a receptor for enterovirus 71 uptake and mannose-6-phosphate-independent lysosomal trafficking of the acid hydrolase β-glucocerebrosidase. Here we show that LIMP-2 undergoes proteolytic cleavage mediated by lysosomal cysteine proteases. Heterologous expression and in vitro studies suggest that cathepsin-F is mainly responsible for the lysosomal processing of wild-type LIMP-2. Furthermore, examination of purified lysosomes revealed that LIMP-2 undergoes proteolysis in vivo. Mutations in the gene encoding cathepsin-F (CTSF) have recently been associated with type-B-Kufs-disease, an adult form of neuronal ceroid-lipofuscinosis. In this study we show that disease-causing cathepsin-F mutants fail to cleave LIMP-2. Our findings provide evidence that LIMP-2 represents an in vivo substrate of cathepsin-F with relevance for understanding the pathophysiology of type-B-Kufs-disease.
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1016/J.TINS.2006.05.009
Abstract: Epilepsies, once regarded as due to demoniacal possession, can have both genetic and acquired causes, with interaction of these factors in many cases. To date, nearly all the genes discovered to be involved in human epilepsies encode subunits of ion channels, both voltage-gated and ligand-gated. Established acquired causes include serious brain trauma, stroke, tumours and infective lesions. Thus, in terms of exploring the neurobiology of "nature and nurture" in disease, the epilepsies are an excellent paradigm. Here, we review the evidence and discuss the possibility that ion channels are a common biological substrate for both genetic and acquired epilepsies. This review is part of the INMED/TINS special issue "Nature and nurture in brain development and neurological disorders", based on presentations at the annual INMED/TINS symposium (inmednet.com/).
Publisher: Springer Science and Business Media LLC
Date: 11-08-2013
DOI: 10.1038/NATURE12439
Publisher: BMJ
Date: 06-03-2013
DOI: 10.1136/JMEDGENET-2012-101448
Abstract: Recent advances in molecular genetics have translated into the increasing utilisation of genetic testing in the routine clinical practice of neurologists. There has been a steady, incremental increase in understanding the genetic variation associated with epilepsies. Genetic testing in the epilepsies is not yet widely practiced, but the advent of new screening technologies promises to exponentially expand both knowledge and clinical utility. To maximise the value of this new genetic insight we need to rapidly extrapolate genetic findings to inform patients of their diagnosis, prognosis, recurrence risk and the clinical management options available for their specific genetic condition. Comprehensive, highly specific and sensitive genetic test results improve the management of patients by neurologists and clinical geneticists. Here we discuss the latest developments in clinical genetic testing for epilepsy and describe new molecular genetics platforms that will transform both genetic screening and novel gene discovery.
Publisher: The Endocrine Society
Date: 02-2008
DOI: 10.1210/JC.2007-1611
Abstract: Pulsatile GH secretion from the anterior pituitary is a key mediator of human growth regulation and is affected by a number of genetic and environmental factors. Activation of neuronal nicotinic acetylcholine (nACh) receptors promotes GH release, but the role of these receptors in growth regulation is unknown. Our aim was to assess the effect of a mutation in the alpha4 subunit of the nACh receptor on cholinergic-mediated GH release. Forty-one healthy volunteers (24 male, age 36.2 +/- 12.2 yr, mean +/- sd) and 13 subjects with the alpha4-Ser248Phe mutation (four male, age 43.2 +/- 16.8 yr) were studied. Serum levels of GH, LH, FSH, prolactin, TSH, free T(4), and cortisol were measured at baseline and at regular intervals after infusion of physostigmine. Height and weight were recorded in all participants as well as from additional family members with (n = 11, four male) and without (n = 16, seven male) the mutation. Subjects with the mutation were shorter (1.62 +/- 0.08 vs. 1.72 +/- 0.09 m, P < 0.05) and had a greater body mass index (31 +/- 6 vs. 24 +/- 3 kg/m(2), P 0.2 vs. control). These findings suggest a role of the nACh receptor in human growth regulation.
Publisher: Elsevier BV
Date: 02-1992
Publisher: Wiley
Date: 11-09-2012
DOI: 10.1111/J.1528-1167.2012.03658.X
Abstract: Underdiagnosed depression and anxiety are well-recognized issues in chronic epilepsy, but the evolution of these symptoms after diagnosis is not well understood. We aimed to identify mood trajectories after a first seizure, and to examine factors impacting these trajectories. Seventy-four patients were evaluated at 1, 3, and 12 months with (1) the Hospital Anxiety and Depression Scale, and (2) a semistructured interview assessing patients' initial psychological reaction to the seizure at 1 month (limited vs. pervasive loss of control). The SAS Institute's TRAJ data modelling procedure was employed to delineate trajectories. Two depression and three anxiety trajectories were identified, with significant overlap. The majority of patients (≈ 74%) followed a trajectory with low depression throughout the study, and either low or moderate anxiety. A minority followed trajectories with high depression and anxiety from diagnosis (≈ 16%). Patients with high levels of distress were adversely affected by seizure recurrence and antiepileptic drugs (AEDs), whereas those with low levels were not. Trajectories were predicted by the patient's sense of loss of control early after diagnosis and were weakly related to demographic and medical variables (age, gender, education, relationship status, psychiatric history, and prior epileptic events). Methods that account for heterogeneity in patient responses are critical for developing a clinically relevant understanding of adjustment after a newly diagnosed seizure. Most patients appear to be resilient in the face of early seizures, whereas those at risk of longer-term psychological difficulties may be evident from diagnosis. Early screening for depression and anxiety is warranted.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.EPLEPSYRES.2017.02.001
Abstract: Driven by advances in genomic technology and reduction in costs, next-generation sequencing (NGS) is venturing into routine clinical care. The 'real-world' clinical utility of NGS remains to be determined in focal epilepsies, which account for 60% of all epilepsies and for which the importance of genetic factors is just beginning to emerge. We investigated the diagnostic yield and management implications of whole exome sequencing (WES)-based screening of selected genes in the routine care of common focal epilepsies suspected to have a genetic basis. We performed WES, followed by targeted analysis of 64 epilepsy genes, on 40 consecutive children and adults enrolled prospectively from routine clinical practice who had MRI-negative focal epilepsy and a family history of febrile seizures or any type of epilepsy in at least one first- or second-degree relative. Exclusion criteria were previous genetic testing, severe intellectual disability and benign focal epilepsies of childhood. 5/40 (12.5%) patients had a pathogenic or likely pathogenic variant, detected in SCN1A, DEPDC5, PCDH19, GABRG2 or NPRL2. Identifying a pathogenic SCN1A variant in a patient with drug-resistant epilepsy prompted to halt presurgical investigations due to concern of unfavorable post-surgical outcome. It also led in the same patient to discontinue long-standing carbamazepine therapy (a potentially aggravating drug in epilepsies due to SCN1A mutations), resulting in complete seizure control. Patients with pathogenic or likely pathogenic variants had a younger median age of seizure onset (range) compared to those without [18 months (8 months-18 years) vs 18 years (18 months-70 years), p=0.02]. Our data demonstrate that WES with targeted gene analysis is an effective diagnostic tool for patients with common focal epilepsies in whom a genetic etiology is suspected. It can also influence clinical decision-making, including antiepileptic drug selection and consideration of epilepsy surgery, hence supporting its incorporation in the routine clinical care of this patient group.
Publisher: Public Library of Science (PLoS)
Date: 19-01-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-04-2004
DOI: 10.1212/01.WNL.0000118201.89498.48
Abstract: Objective: To classify the Lennox twin pairs according to modern epilepsy classifications, use the classic twin model to identify which epilepsy syndromes have an inherited component, search for evidence of syndrome-specific genes, and compare concordances from Lennox’s series with a contemporary Australian series. Methods: Following review of Lennox’s original files describing twins with seizures from 1934 through 1958, the International League Against Epilepsy classifications of seizures and epileptic syndromes were applied to 169 pairs. Monozygous (MZ) and dizygous (DZ) pairs were sub ided into epilepsy syndromes and casewise concordances estimated. Results: The authors excluded 26 pairs, with 71 MZ and 72 DZ pairs remaining. Seizure analysis demonstrated strong parallels between contemporary seizure classification and Lennox’s terminology. Epilepsy syndrome diagnoses were made in 75%. The MZ and DZ casewise concordance estimates gave strong evidence for a major genetic influence in idiopathic generalized epilepsies (0.80 versus 0.00 n = 23). High MZ casewise concordances also supported a genetic etiology in symptomatic generalized epilepsies and febrile seizures. The pairs who were concordant for seizures usually had the same syndromic diagnoses in both twins (86% in MZ, 60% in DZ), suggesting syndrome-specific genes. Apart from partial epilepsies, the MZ casewise concordances were similar to those derived from Australian twin data. Conclusions: The authors were able to apply contemporary classifications to Lennox’s twins. The data confirm genetic bases for common generalized epilepsies as well as febrile seizures and provide further support for syndrome-specific genes. Finally, comparable results to our Australian series were obtained, verifying the value of twin studies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2017
DOI: 10.1212/WNL.0000000000004769
Abstract: To evaluate quinidine as a precision therapy for severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1 . A single-center, inpatient, order-randomized, blinded, placebo-controlled, crossover trial of oral quinidine included 6 patients with severe autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) due to KCNT1 mutation. Order was block randomized and blinded. Four-day treatment blocks were used with a 2-day washout between. Dose started at 900 mg over 3 ided doses then, in subsequent participants, was reduced to 600 mg, then 300 mg. Primary outcome was seizure frequency measured on continuous video-EEG in those completing the trial. Prolonged QT interval occurred in the first 2 patients at doses of 900 and 600 mg quinidine per day, respectively, despite serum quinidine levels well below the therapeutic range (0.61 and 0.51 μg/mL, reference range 1.3–5.0 μg/mL). Four patients completed treatment with 300 mg/d without adverse events. Patients completing the trial had very frequent seizures (mean 14 per day, SD 7, median 13, interquartile range 10–18). Seizures per day were nonsignificantly increased by quinidine (median 2, 95% confidence interval −1.5 to +5, p = 0.15) and no patient had a 50% seizure reduction. Quinidine did not show efficacy in adults and teenagers with ADNFLE. Dose-limiting cardiac side effects were observed even in the presence of low measured serum quinidine levels. Although small, this trial suggests use of quinidine in ADNFLE is likely to be ineffective coupled with considerable cardiac risks. Australian Therapeutic Goods Administration Clinical Trial Registry (trial number 2015/0151). This study provides Class II evidence that for persons with severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1 , quinidine does not significantly reduce seizure frequency.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2005
DOI: 10.1007/S00259-005-1844-6
Abstract: We performed a retrospective analysis of the results of FDG PET scans in children with refractory epilepsy referred to our centre over an 8-year period, with a view to ascertaining the impact of FDG PET on subsequent patient management. A questionnaire was used to assess the impact of FDG PET scan on diagnosis, management and clinical decision-making processes for epilepsy surgery from the managing clinician's perspective. FDG PET scan results were also compared with MRI, EEG and SPECT results and coded according to whether the FDG PET scan provided independent information and localisation of epileptogenic regions. A total of 118 eligible patients under the age of 14 years were identified, with questionnaires being completed on 113 evaluable patients (96%). The pre-PET management plan consisted of consideration for surgery in 92 patients (81%) and medical therapy for the remaining 21 patients (19%). Managing physicians rated FDG PET as providing information additional to that obtained with other investigations regarding epileptogenic sites in 88 patients (77%). FDG PET had either a minor or a major impact on clinical management in 58 patients (51%), principally with regard to surgical candidacy. FDG PET has a definite role in the assessment of paediatric patients with refractory epilepsy who are being considered for surgery. In the future, analysis of FDG PET data in specific subpopulations of children with refractory epilepsy may lead to novel insights regarding aetiology.
Publisher: Wiley
Date: 07-2019
DOI: 10.1002/ACN3.50822
Publisher: Wiley
Date: 30-04-2002
DOI: 10.1002/ANA.10171
Abstract: This longitudinal quantitative magnetic resonance imaging study of 24 patients with mild temporal lobe epilepsy shows an ipsilateral hippoc al volume decrease of 9% (range, -30 to +0.5% p = 0.002, paired t test) over a period of 3.5 +/- 0.7 years. The hippoc al volume loss was correlated to the number of generalized seizures between the scans (p = 0.0007, r = 0.6), suggesting seizure-associated hippoc al damage.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2001
DOI: 10.1097/00006123-200101000-00019
Abstract: Hypothalamic hamartomas (HHs) are associated with precocious puberty and gelastic epilepsy the seizures are often refractory to antiepileptic medications and associated with delayed development and disturbed behavior. The current opinion is that surgery to treat intrahypothalamic lesions is formidable and that complete excision is not technically achievable. We report our experience with a transcallosal approach to the resection of HHs. Five children (age, 4–13 yr) with intractable epilepsy and HHs underwent preoperative clinical, electroencephalographic, and imaging evaluations. Two patients experienced only gelastic seizures, and three patients experienced mixed seizure disorders with drop attacks all experienced multiple daily seizures. Patients were evaluated with respect to seizures, cognition, behavior, and endocrine status 9 to 37 months (mean, 24 mo) after surgery. The HHs were approached via a transcallosal-interforniceal route to the third ventricle and were resected using a microsurgical technique and frameless stereotaxy. Complete or nearly complete (& %) excision of the HHs was achieved for all patients, with no adverse neurological, psychological, or visual sequelae. Two patients experienced mild transient diabetes insipidus after surgery. Two patients developed appetite stimulation, but no other significant endocrinological sequelae were observed. Three patients are seizure-free and two patients have experienced only occasional, brief, mild gelastic seizures after surgery, all with reduced antiepileptic medications. On the basis of parental reports and our own subjective observations, the children also exhibited marked improvements in behavior, school performance, and quality of life. Complete or nearly complete resection of HHs can be safely achieved via a transcallosal approach, with the possibility of seizure freedom and neurobehavioral improvements.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-1983
Abstract: Metabolic syndrome involves a set of metabolic risk factors that directly increases the risk of atherosclerotic cardiovascular disease. Physical inactivity due to driving can increase the risk of metabolic syndrome. It is also known that sleep disorders (sleep apnea) can result in MetS. Driving in Iran is considered a very popular but risky occupation, so paying attention to this profession is of special importance. Therefore, the researchers aimed to investigate the association between sleep disorders and metabolic syndrome in drivers in Shahroud city in 2018. This cross-sectional study was carried out on 948 drivers from Shahroud city in 2018. After obtaining consent from participants, 3 questionnaires including demographic, Epworth Sleepiness Scale and STOP-BANG were completed. Clinical and anthropometric measurements were assessed, including blood pressure, waist circumference, hip circumference, weight, height, and body mass index. In addition, blood was drawn to measure High Density Lipoprotein, Low Density Lipoprotein, Triglyceride, cholesterol, and Fasting Blood Sugar levels. The relationship between metabolic syndrome and sleep disorders was then studied. In this study, statistical analyses were performed using SPSS software version 23 at a significance level of 0.05. Mean age of drivers was 44.15 ± 11.66 (years). The mean waist circumference and mean hip circumference in subjects with a Class 1 Driver's License (a certificate for trucks and buses) were higher than those with a Class 2 Driver's License (a certificate for motorcars, minibuses, vans, etc. (seating< 20)) (P = 0.01 and P = 0.003, respectively). Moreover, the BMI in subjects with a Class 1 Driver's License was higher compared to subjects with a Class 2 Driver's License. The correlation between metabolic syndrome with sleep apnea based on STOP-BANG questionnaire was significant (p < 0.001) irrespective of definition (ATP and IDF). According to the results of this study, there was a bi-directional association between sleep disorders and Mets, so this group should pass periodic medical examinations and training courses. Moreover, their families should be informed of prevention and treatment of this syndrome.
Publisher: Elsevier BV
Date: 06-2011
Publisher: Cambridge University Press (CUP)
Date: 04-2003
Publisher: American Medical Association (AMA)
Date: 11-1994
DOI: 10.1001/ARCHNEUR.1994.00540230063014
Abstract: To determine whether the syndrome of benign familial neonatal convulsions in a large family was linked to markers on chromosome 20q and to study the seizure patterns in affected in iduals. A clinical and molecular biologic study of a single large family in which the probands were identical twins with benign familial neonatal convulsions. Thirteen living affected family members and 27 living unaffected family members were evaluated. Multipoint linkage analysis with use of the chromosome 20q markers CMM6 and RMR6 gave a maximum lod score of 3.13 at theta = 0.063, indicating linkage in this family. Of the 13 affected members, 10 had known neonatal seizures. Four subjects had febrile seizures, of whom only two had known neonatal seizures. Two members had afebrile seizures later, one of whom had not previously suffered neonatal or febrile seizures. The phenotypic heterogeneity in this family, with an epilepsy syndrome determined by a single gene, was striking. This suggests that molecular genetic approaches to the common forms of idiopathic epilepsy, involving patients with clinically similar phenotypes from unrelated families, may be inappropriate.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-11-2008
Publisher: Wiley
Date: 20-05-2019
DOI: 10.1002/ANA.25499
Publisher: Cambridge University Press (CUP)
Date: 1999
DOI: 10.1017/S1355617799511090
Abstract: Left-to-right reorganization of verbal memory following early left hemisphere damage has been reported in patients whose expressive language is governed by the right hemisphere. We present a case in which verbal memory performance was intact, despite severe left mesial temporal damage, and despite aphasia on left internal carotid sodium amytal ablation. The distribution and degree of left mesial temporal damage was assessed visually and quantitatively on MRI. These findings raise the possibility that verbal memory may shift to the language-nondominant hemisphere as a result of early left mesial temporal damage. ( JINS , 1999, 5 , 69–74.)
Publisher: Springer Science and Business Media LLC
Date: 16-01-2022
Publisher: Wiley
Date: 04-2010
DOI: 10.1111/J.1528-1167.2010.02522.X
Abstract: The International League Against Epilepsy (ILAE) Commission on Classification and Terminology has revised concepts, terminology, and approaches for classifying seizures and forms of epilepsy. Generalized and focal are redefined for seizures as occurring in and rapidly engaging bilaterally distributed networks (generalized) and within networks limited to one hemisphere and either discretely localized or more widely distributed (focal). Classification of generalized seizures is simplified. No natural classification for focal seizures exists focal seizures should be described according to their manifestations (e.g., dyscognitive, focal motor). The concepts of generalized and focal do not apply to electroclinical syndromes. Genetic, structural-metabolic, and unknown represent modified concepts to replace idiopathic, symptomatic, and cryptogenic. Not all epilepsies are recognized as electroclinical syndromes. Organization of forms of epilepsy is first by specificity: electroclinical syndromes, nonsyndromic epilepsies with structural-metabolic causes, and epilepsies of unknown cause. Further organization within these isions can be accomplished in a flexible manner depending on purpose. Natural classes (e.g., specific underlying cause, age at onset, associated seizure type), or pragmatic groupings (e.g., epileptic encephalopathies, self-limited electroclinical syndromes) may serve as the basis for organizing knowledge about recognized forms of epilepsy and facilitate identification of new forms.
Publisher: Wiley
Date: 08-1993
DOI: 10.1111/J.1528-1167.1993.TB06256.X
Abstract: The progressive myoclonus epilepsies (PMEs) are a group of rare genetic disorders previously shrouded in nosological confusion. Recent advances have clarified the features of these disorders and provided a rational approach to diagnosis. The major causes of PME are now known to be Unverricht-Lundborg disease, myoclonus epilepsy ragged-red fiber (MERRF) syndrome, Lafora disease, neuronal ceroid lipofuscinoses, and sialidoses. Over the past 3 years, a series of molecular genetic findings have further refined the understanding of the PMEs. The specific mutation responsible for many cases of MERRF has been identified, and the genes for Unverricht-Lundborg disease and for juvenile neuronal ceroid lipofuscinosis have been linked to chromosomes 21 and 16, respectively. Although the PMEs are among the rarest of the inherited epilepsies, because of molecular genetic discoveries they may soon be the best understood at the neurobiologic level.
Publisher: Wiley
Date: 10-2000
Publisher: Oxford University Press (OUP)
Date: 1989
Abstract: Thirteen patients, including 6 from one family, with the syndrome of myoclonus epilepsy and ragged-red fibres (MERRF) were studied. There was considerable heterogeneity in the age of onset, severity and associated clinical features. Postmortem studies in 3 patients from the one family showed a particular system degeneration. In addition, the youngest and most severely affected family member showed the pathological changes of Leigh's syndrome. Cortical dysfunction is a prominent clinical feature in MERRF, but postmortem examination failed to reveal cortical abnormalities. Positron emission tomographic studies, however, showed decreased cortical metabolic rates for glucose and oxygen utilization, with normal cortical blood flow and cerebral pH. Analyses of kinetic rate constants for uptake and phosphorylation of the glucose analogue, fluorodeoxyglucose showed decreased hexokinase-mediated phosphorylation: normal K1 and k2 values but reduced k3. Phosphorus magnetic resonance spectroscopy studies suggested a normal cerebral intracellular pH. Biochemical studies on muscle homogenates in 6 patients showed partial deficiencies of the activities of certain mitochondrial enzymes in 4 cases, whereas in 2 patients no abnormality was found. Our data, combined with previous reports, show that MERRF is biochemically and genetically heterogeneous. Our experience, and analysis of the literature, suggests that many cases previously described as the Ramsay Hunt syndrome, as well as other hitherto unclassified system degenerations associated with myoclonus epilepsy, are ex les of MERRF. These data permit the formulation of a hypothesis to explain the clinical, biochemical and genetic heterogeneity of MERRF, and its overlap with Leigh's syndrome. We suggest that different biochemical defects of the mitochondrial respiratory chain may cause similar cerebral metabolic effects, as measured by positron emission tomography, resulting in similar phenotypes. Reduced activity of one enzyme, however, may result in different phenotypes, depending on the severity of the defect and its tissue distribution. Moreover, the phenotypic expression of certain biochemical defects may be influenced by randomly occurring factors such as fever, which may increase metabolic demand and result in more deleterious cellular metabolic effects.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-1991
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-11-2009
Publisher: Wiley
Date: 02-01-2023
DOI: 10.1002/ANA.26581
Abstract: Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug‐resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippoc al sclerosis and ≥2‐year postsurgical follow‐up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. Nine centers from 3 continents contributed 206 patients operated for drug‐resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss‐of‐function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9–3.5, p = 1.3E‐09) and in genes encoding voltage‐gated cation channels (OR = 2.4, 95% CI = 1.4–3.8, p = 2.7E‐04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between‐group differences. Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision‐making and counseling. ANN NEUROL 2023 :752–761
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-1991
Abstract: We used single-photon emission computed tomography (SPECT) to study postictal cerebral blood flow (CBF) in 51 patients with temporal lobe epilepsy. There were 78 seizures studied, 77 by early postictal injection of Tc-99m HMPAO (delay from seizure onset = 4.3 +/- 4.5 min) and one by ictal injection. Increased focal temporal lobe uptake, predominantly confined to the anteromesial region, was present in 83% and declined rapidly over 5 minutes. Reduced activity in the lateral temporal lobe accompanied the mesial increase in 80% of studies, extending over much of the ipsilateral hemisphere and closely associated with the degree and extent of postictal EEG slow waves. These patterns enabled correct seizure localization by blinded analysis in 69% (31/45) of the patients with a unilateral EEG focus. The remainder showed bilateral or no changes. One of six patients with bitemporal EEG foci had unilateral perfusion changes. The positive predictive value for the correct localization of a unilateral focus by postictal SPECT was 97% (31/32). Postictal CBF imaging with SPECT can be used to support noninvasive electrographic localization and may decrease the need for invasive electrode studies.
Publisher: Cold Spring Harbor Laboratory
Date: 20-11-2020
DOI: 10.1101/2020.11.18.20233916
Abstract: Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental, and developmental factors. While usually benign, in a minority of cases, febrile seizures precede later development of epilepsy. Here, we conducted a genome-wide association study of febrile seizures with 7,635 cases and 93,966 controls identifying and replicating seven new loci, all with P 5 × 10 −10 . Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10 , and four other loci harbored genes ( BSN, ERC2, GABRG2, HERC1 ) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. GABRG2 is a well-established epilepsy gene comprising variants associated with febrile seizures, and overall we found positive genetic correlations with epilepsies ( r g = 0.39, P = 1.68 × 10 −4 ). Finally, a polygenic risk score based on all genome-wide significant loci was associated within patients with number of hospital admissions with febrile seizures and age at first admission, suggesting potential clinical utility of improved genetic understanding of febrile seizure genesis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-04-2002
Publisher: Wiley
Date: 10-1997
Publisher: Wiley
Date: 11-1997
Publisher: Wiley
Date: 29-01-2010
DOI: 10.1111/J.1528-1167.2009.02317.X
Abstract: We identified a patient with electrophysiologically verified neonatal long QT syndrome (LQTS) and neonatal seizures in the presence of a controlled cardiac rhythm. To find a cause for this unusual combination of phenotypes, we tested the patient for mutations in seven ion channel genes associated with either LQTS or benign familial neonatal seizures (BFNS). Comparative genome hybridization (CGH) was done to exclude the possibility of a contiguous gene syndrome. No mutations were found in the genes (KCNQ2, KCNQ3) associated with BFNS, and CGH was negative. A previously described mutation and a known rare variant were found in the LQTS-associated genes SCN5A and KCNE2. Both are expressed in the brain, and although mutations have not been associated with epilepsy, we propose a pathophysiologic mechanism by which the combination of molecular changes may cause seizures.
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1038/S41467-019-12671-Y
Abstract: Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7 . The ATTTC expansions segregate in 158/158 in iduals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved.
Publisher: Oxford University Press (OUP)
Date: 07-05-2015
DOI: 10.1093/HMG/DDV171
Publisher: Elsevier BV
Date: 2001
DOI: 10.1086/316946
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-1984
Abstract: A specific form of deep cerebral hemisphere infarction was identified in 11 of 1,600 stroke register patients. Despite the CT finding of a deep striatocapsular lesion, these patients showed evidence of both cortical and capsular abnormalities. Angiography showed significant proximal carotid artery lesions as well as evidence of occlusive or obstructive lesions in the region of the T junction of the internal carotid artery. The combination of these pathologic entities would explain this particular clinical picture.
Publisher: Public Library of Science (PLoS)
Date: 15-10-2021
DOI: 10.1371/JOURNAL.PCBI.1009521
Abstract: Inhibitory interneurons shape the spiking characteristics and computational properties of cortical networks. Interneuron subtypes can precisely regulate cortical function but the roles of interneuron subtypes for promoting different regimes of cortical activity remains unclear. Therefore, we investigated the impact of fast spiking and non-fast spiking interneuron subtypes on cortical activity using a network model with connectivity and synaptic properties constrained by experimental data. We found that network properties were more sensitive to modulation of the fast spiking population, with reductions of fast spiking excitability generating strong spike correlations and network oscillations. Paradoxically, reduced fast spiking excitability produced a reduction of global excitation-inhibition balance and features of an inhibition stabilised network, in which firing rates were driven by the activity of excitatory neurons within the network. Further analysis revealed that the synaptic interactions and biophysical features associated with fast spiking interneurons, in particular their rapid intrinsic response properties and short synaptic latency, enabled this state transition by enhancing gain within the excitatory population. Therefore, fast spiking interneurons may be uniquely positioned to control the strength of recurrent excitatory connectivity and the transition to an inhibition stabilised regime. Overall, our results suggest that interneuron subtypes can exert selective control over excitatory gain allowing for differential modulation of global network state.
Publisher: Wiley
Date: 13-01-2021
DOI: 10.1002/EPI4.12460
Abstract: ‘First seizure’ clinics (FSCs) aim to achieve early expert assessment for in iduals with possible new‐onset epilepsy. These clinics also have substantial potential for research into epilepsy evolution, outcomes, and costs. However, a paucity of FSCs details has implications for interpretation and utilization of this research. We reviewed investigation findings over 11 years (2000‐2010) from two established independent FSCs at Austin Health (AH) and Royal Melbourne Hospital (RMH), Australia. These adult clinics are in major public hospitals and operate with similar levels of expertise. Organizational differences include screening and dedicated administration at AH. Included were N = 1555 patients diagnosed with new‐onset unprovoked seizures/epilepsy (AH n = 901, RMH n = 654). Protocol‐driven interviews and investigations had been recorded prospectively and were extracted from medical records for study. Median patient age was 37 (IQR 26‐52, range 18‐94) years (AH 34 vs RMH 42 years P .001). Eighty‐six percent of patients attended FSC within three weeks postindex seizure (median AH 12 vs RMH 25 days P .01). By their first appointment, 42% had experienced ≥2 seizures. An EEG was obtained within three weeks postindex seizure in 73% of patients, demonstrating epileptiform discharges in 25% (AH 33% vs RMH 15%). Seventy‐six percent of patients had an MRI within 6 weeks. Of those with imaging (n = 1500), 19% had potentially epileptogenic abnormalities (RMH 28% vs AH 12% P .01). At both sites, changes due to previous stroke/hemorrhage were the commonest lesions, followed by traumatic brain injury. ≥WHO level 1 brain tumors diagnosed at presentation comprised a very small proportion ( %) at each clinic. At both sites, epilepsy type could be determined in 60% of patients RMH had more focal and AH more generalized epilepsy diagnoses. Differences between the clinics’ administrative and screening practices may contribute to differences in investigation findings. Insight into these differences will facilitate interpretation and utilization, and planning of future research.
Publisher: Wiley
Date: 07-2015
DOI: 10.1002/ANA.24457
Publisher: Oxford University Press (OUP)
Date: 09-07-2008
DOI: 10.1093/BRAIN/AWN138
Abstract: The early and late benign occipital epilepsies of childhood (BOEC) are described as two discrete electro-clinical syndromes, eponymously known as Panayiotopoulos and Gastaut syndromes. Our aim was to explore the clinical features, classification and clinical genetics of these syndromes using twin and multiplex family studies to determine whether they are indeed distinct. Sixteen probands including seven twins were studied. Non-twin probands (n = 9) with a family history of epilepsy were included. Electroclinical seizure semiology was characterized and probands were classified into BOEC syndromes. Detailed phenotyping of relatives was performed and phenotypic patterns within families were analysed. One-third of the children in this selected series of BOEC did not have a pure syndrome, rather a mixed syndrome with features of both Panayiotopoulos and Gastaut syndromes. Monozygotic twin pairs did not show a higher concordance rate than dizygotic twin pairs suggesting that BOEC may not be a purely genetic disorder. In relatives with epilepsy, there was a mixed pattern of focal and generalized epilepsies with focal epilepsies predominating. BOEC is an electro-clinical spectrum with Panayiotopoulos and Gastaut syndromes at either end many cases show mixed features. Clinical genetic studies highlight the multifactorial aetiology of BOEC as monozygotic twins have low concordance suggesting that non-conventional genetic influences or environmental factors play a major role. Family studies show both focal and generalized epilepsies reinforcing that these are not discrete categories of idiopathic epilepsies and are likely to share genetic determinants.
Publisher: Wiley
Date: 02-2000
DOI: 10.1002/1531-8249(200002)47:2<265::AID-ANA22>3.0.CO;2-N
Publisher: Wiley
Date: 28-05-2010
Publisher: Wiley
Date: 17-08-2022
DOI: 10.1002/AJMG.A.62950
Abstract: Verheij syndrome (VRJS) is a rare craniofacial spliceosomopathy presenting with craniofacial dysmorphism, multiple congenital anomalies and variable neurodevelopmental delay. It is caused by single nucleotide variants (SNVs) in PUF60 or interstitial deletions of the 8q24.3 region. PUF60 encodes a splicing factor which forms part of the spliceosome. To date, 36 patients with a sole diagnosis of VRJS due to disease-causing PUF60 SNVs have been reported in peer-reviewed publications. Although the depth of their phenotyping has varied greatly, they exhibit marked phenotypic heterogeneity. We report 10 additional unrelated patients, including the first described patients of Khmer, Indian, and Vietnamese ethnicities, and the eldest patient to date, with 10 heterozygous PUF60 variants identified through exome sequencing, 8 previously unreported. All patients underwent deep phenotyping identifying variable dysmorphism, growth delay, neurodevelopmental delay, and multiple congenital anomalies, including several unique features. The eldest patient is the only reported in idual with a germline variant and neither neurodevelopmental delay nor intellectual disability. In combining these detailed phenotypic data with that of previously reported patients (n = 46), we further refine the known frequencies of features associated with VRJS. These include neurodevelopmental delay/intellectual disability (98%), axial skeletal anomalies (74%), appendicular skeletal anomalies (73%), oral anomalies (68%), short stature (66%), cardiac anomalies (63%), brain malformations (48%), hearing loss (46%), microcephaly (41%), colobomata (38%), and other ocular anomalies (65%). This case series, incorporating three patients from previously unreported ethnic backgrounds, further delineates the broad pleiotropy and mutational spectrum of PUF60 pathogenic variants.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-1993
Abstract: There is a belief that perinatal factors are a major cause of epilepsy. We studied a community-based s le of twins, a group with a marked excess of adverse perinatal events. The observed number of non-twin siblings with seizures did not differ from that predicted by the age-specific cumulative incidence rate of seizures (4.2% at age 10 years) in the twins. The types of epilepsies in the twins were largely benign and self-limited and not those associated with brain damage. Zygosity, birth order, and birth weight did not predict affected status. Within affected sibships, the frequency of seizures in co-twins of dizygotic probands (9%) was not different from the frequency in non-twin siblings (12%) but was much less than the frequency in co-twins of monozygotic probands (38% p < 0.001), reflecting a major genetic component to certain epilepsies. These data show that twins do not have an increased risk of seizures and strongly suggest that perinatal factors have little bearing on the etiology of the common epilepsies in the community.
Publisher: Cold Spring Harbor Laboratory
Date: 21-01-2019
DOI: 10.1101/525683
Abstract: Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected in iduals and 8,364 controls of European ancestry. We focused on three phenotypic groups the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, in iduals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABA A receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among in iduals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2 , and GABRG2 for GGE and LGI1, TRIM3 , and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.
Publisher: Wiley
Date: 08-2000
DOI: 10.1002/1531-8249(200008)48:2<264::AID-ANA20>3.0.CO;2-B
Publisher: European Respiratory Society (ERS)
Date: 07-1994
DOI: 10.1183/09031936.94.07071260
Abstract: Although asthma self-management plans are widely recommended as essential in the long-term treatment of adult asthma, there have been few studies examining their use. Our objective was to assess the effect of a "credit card" adult asthma self-management plan in a community experiencing major health problems from asthma, by means of a before and after intervention trial of the efficacy of the "credit card" plan, when introduced through community-based asthma clinics. The participants were 69 Maori people with asthma. The "credit card" plan consisted of written guidelines for the self-management of asthma, based on self-assessment of asthma severity, printed on a plastic card. On one side, management guidelines were based on the interpretation of peak expiratory flow rate (PEFR) recordings, whilst the reverse side was based on symptoms. The outcome measures used were before and after comparison of markers of asthma morbidity and requirement for acute medical treatment and a structured questionnaire assessing the acceptability and use of the credit card plan. Following the introduction of the plan, the mean PEFR increased from 347 to 389 l.min-1, the percentage of nights woken fell from 30.4 to 16.9%, and the number of days "out of action" fell from 3.8 to 1.7%. The requirements for acute medical treatment also fell during the intervention period. Most participants commented favourably on the content and usefulness of the plan. In the situation of worsening asthma, 28% of subjects found the peak flow side of the card most helpful, 7% the symptoms side, and 48% found both sides equally helpful.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: S. Karger AG
Date: 1999
DOI: 10.1159/000017400
Abstract: Hippoc al sclerosis (HS) is the most common pathological lesion underyling intractable temporal lobe epilepsy. It is not known whether HS exists before the onset of epilepsy or whether it is caused by seizures. Its has been proposed that childhood seizures cause HS. Optimized magnetic resonance imaging (MRI), hippoc al volumes and T sub /sub signal quantitation were performed 2 weeks and 8 months following at tonic-clonic seizure in a 23-year-old man. MRI 14 days after the seizure showed symmetrical hippoc al volumes (ratio R/L = 1.03) with intact internal architecture bilaterally but marked signal change in the right hippoc us (T sub /sub right = 121, T sub /sub left = 103, normal ≤108 ms). Eight months later this hippoc us showed severe atrophy with a volume ratio of 0.65 and T sub /sub values of 117 (right) and 109 ms (left). High-resolution imaging showed that volume loss occurred mainly in the CA1 region which showed high signal in the initial study. Characteristic MRI features of HS can develop in adults and HS cannot always be assumed to have its origins in childhood. Hypoxia in the context of seizures may be an important component in hippoc al damage. HS may be a preventable lesion and MRI signal change seen in the neuronal layers of the hippoc us may be an indication for neuroprotection.
Publisher: Wiley
Date: 04-2003
DOI: 10.1046/J.1528-1157.2003.20102.X
Abstract: Mutations in genes coding for the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor receptor (CHRN) are known to cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Here we examined the phenotypes in two families, from the same ethnic and geographic backgrounds, with ADNFLE as a result of mutations in these two different subunits of CHRN. All affected family members underwent a detailed clinical evaluation and review of available EEG, neuroimaging, and videotapes of seizures. The molecular study of family D is reported here family S has a previously reported mutation in the beta 2 subunit of CHRN. A total of 16 in iduals with ADNFLE were identified in the two families. In both families, seizure semiology, age at seizure onset, and the natural history of the seizure disorder was similar. Intrafamilial variation in terms of severity of epilepsy syndrome was present in both families. A significant number of in iduals from each family had a history of psychological problems. The molecular study of family D revealed a Ser248Phe mutation in the alpha 4 subunit of CHRN. The epilepsy phenotype is not distinguishable in the two families who have ADNFLE as a result of mutations in genes coding for different CHRN subunits. This is likely to be due to the similar functional consequences of each mutation on the CHRN receptor.
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.EPLEPSYRES.2004.09.005
Abstract: To evaluate the efficacy and tolerability of levetiracetam as add-on therapy in patients with refractory partial-onset seizures in a protocol designed to reflect clinical practice. All patients in this open-label, single-arm study entered an 8-week baseline period followed by a 4-week titration period and a 12-week maintenance period. Patients initially received levetiracetam 1000 mg/day (administered bid) and could increase to 2000 mg/day after 2 weeks, and to 3000 mg/day after another 2 weeks, to obtain adequate seizure control. During the 12-week maintenance period, the dose of levetiracetam could not be increased but could be decreased once if tolerability warranted. Seizure count and adverse events were recorded by patients in a diary. Quality of life and global evaluation of disease evolution were also evaluated. Ninety-nine patients were enrolled and 91 completed the study. A steady dose was maintained over the last 8 weeks of treatment or longer in 84 patients, with 89.3% of these patients receiving 3000 mg/day, 9.5% receiving 2000 mg/day, and 1.2% receiving 1000 mg/day. A 35.9% median percent reduction from baseline in weekly frequency of partial-onset seizures was observed over the entire treatment period. The median partial-onset seizure count decreased from 2.3 per week during the baseline period to 1.3 per week over the treatment period. A total of 42.4% of patients were responders (> or = 50% reduction from baseline in weekly seizure frequency) over the treatment period two patients were seizure-free from the first day of treatment throughout the treatment period. The most frequent drug-related adverse events were fatigue (27.3% of patients), somnolence (11.1%), headache (8.1%), and dizziness (8.1%). Levetiracetam as add-on therapy at doses up to 3000 mg/day effectively reduced the frequency of partial-onset seizures in patients with refractory epilepsy and was well-tolerated in this study, bridging conditions of placebo-controlled clinical trials and clinical practice.
Publisher: Elsevier BV
Date: 06-2022
Publisher: Wiley
Date: 11-1989
Abstract: Effective surgical treatment of patients with intractable complex partial seizures depends on accurate preoperative seizure focus localization. We evaluated seizure localization with interictal and immediate postictal single photon emission computed tomographic images of cerebral perfusion using technetium-99m-hexamethyl-propyleneamineoxime (99mTc-HMPAO) in comparison with conventional ictal electroencephalographic (EEG) localization. Thirty-two patients with intractable complex partial seizures were studied. The mean delay from seizure onset to injection was 6.3 +/- 5.3 (SD) minutes. Independent blinded observers assessed the scans for interictal hypoperfusion and postictal focal hyperperfusion. Interictal scans alone were unreliable, indicating the correct localization in 17 patients (53%) and an incorrect site in 3 (9%). When interictal and postictal scans were interpreted together, the focus was correctly localized in 23 patients (72%). There was 1 false-positive study, and 8 patients had inconclusive changes, including 2 with inconclusive depth EEG studies. Postictal hyperperfusion was predominantly mesial temporal and frequently associated with hypoperfusion of lateral temporal cortex. Secondarily generalized seizures tended to show focal hyperperfusion less often than complex partial seizures did (Fisher's exact test p = 0.09). Combined interictal and immediate postictal single photon emission computed tomography with 99mTc-HMPAO is a useful noninvasive technique for independent confirmation of electrographic seizure localization. It may provide a suitable alternative to the use of depth electrode studies for confirmation of surface EEG findings in many patients with complex partial seizures.
Publisher: Cambridge University Press (CUP)
Date: 28-04-2023
DOI: 10.1017/NEU.2023.25
Abstract: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL 582 pg/mL as indicative of ND/MCI/other. Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.
Publisher: Elsevier BV
Date: 11-2007
Publisher: Wiley
Date: 09-1999
DOI: 10.1111/J.1528-1157.1999.TB00853.X
Abstract: A benign syndrome of partial seizures in adolescents (BPSA) was described by Loiseau et al. in 1978, but confirmation of this syndrome has been lacking. We sought to identify BPSA among teenagers with new-onset focal seizures enrolled in our prospective first-seizure study and to assess the EEG and magnetic resonance imaging (MRI) findings. We searched the study database for patients aged between 10 and 20 years with focal seizures who did not have idiopathic partial epilepsies, epileptogenic lesions on MRI, or recurrent tonic-clonic seizures during 2 years of follow-up. The database contained 92 adolescents, including 37 with partial epilepsy, of whom eight (22%) patients matched the description of BPSA. All eight patients had seizures with a sensory/motor "march." Six had a secondarily generalized seizure and two had simple partial seizures alone. Epileptiform abnormalities were documented in five cases but lacked a distinctive morphology or distribution. No lesions were seen on MRI. BPSA can be provisionally diagnosed in teenagers with unprovoked focal seizures characterized by a march of sensory/motor symptoms, whose MRI is normal. The psychosocial consequences of chronic epilepsy in adolescence are considerable, so early recognition of this benign syndrome is important.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2000
DOI: 10.1097/00042752-200010000-00002
Abstract: The purpose of this pilot study was to document the nature and temporal profile of the clinical symptoms of acute sport-related concussion. Prospective cohort study A total of 303 elite Australian football players participating in a national competition during a single season. Number and duration of symptoms, digit symbol substitution test (DSST) scores, time of return to play post injury. A total of 23 concussions were recorded over the course of the 20-week football season. No catastrophic head injuries occurred. Headache was the most common symptom and the most persistent, with 40% of players reporting headache symptoms lasting more than 15 minutes. Ten of the players (43%) returned to sport on the day of the injury with the remainder resuming play within 2 weeks. A low likelihood of return to play on the day of injury was found where 3 or more symptoms were present or where the symptoms lasted more than 15 minutes. These findings were significantly correlated with poor DSST performance. This pilot study suggests that both the number of postconcussive symptoms and their duration may be used as a measure of injury severity and a guide for return to play.
Publisher: Wiley
Date: 15-01-2022
DOI: 10.1111/EPI.17166
Abstract: We aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with in iduals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE. We performed a case–control whole exome sequencing study in unrelated in iduals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry‐matched controls. The association of ultra‐rare variants (URVs in 18 834 protein‐coding genes) with epilepsy was examined in 1928 in iduals with GGE (vs. 8578 controls), then separately in 945 in iduals with familial GGE (vs. 8626 controls), and finally in 1005 in iduals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19 genes encoding γ‐aminobutyric acid type A [GABA A ] receptors, 113 genes representing the GABAergic pathway). GABRG2 was associated with GGE ( p = 1.8 × 10 −5 ), approaching study‐wide significance in familial GGE ( p = 3.0 × 10 −6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABA A receptors were associated with familial GGE (odds ratio [OR] = 3.9, 95% confidence interval [CI] = 1.9–7.8, false discovery rate [FDR]‐adjusted p = .0024), whereas their association with sporadic GGE had marginally lower odds (OR = 3.1, 95% CI = 1.3–6.7, FDR‐adjusted p = .022). URVs in GABAergic pathway genes were associated with familial GGE (OR = 1.8, 95% CI = 1.3–2.5, FDR‐adjusted p = .0024) but not with sporadic GGE (OR = 1.3, 95% CI = .9–1.9, FDR‐adjusted p = .19). URVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.
Publisher: Wiley
Date: 03-07-2015
DOI: 10.1002/ACN3.224
Publisher: SAGE Publications
Date: 21-07-2023
DOI: 10.1177/00048674231187312
Abstract: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD ( n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of in idual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in erse neurodegenerative and primary psychiatric conditions in real-world clinical settings.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-11-2000
Abstract: Repetitive seizures may be associated with progressive neuronal damage measurable by quantitative MRI. To investigate whether gender is a risk factor for this damage. Sixty patients with refractory temporal lobe epilepsy (TLE) (28 men, 32 women) and 54 healthy controls (28 men, 26 women) were compared by quantitative MRI methods. Male patients had ipsilateral hemicranial volume loss of 12% (CI 8% to 16%) and contralateral volume loss of 7% (CI:3% to 11%) compared with male controls (p < or =0.004, analysis of variance). Female patients were 4% (CI:0.3% to 8%, p = 0.04) smaller than controls in the ipsilateral hemicranium, and not different contralaterally. The patient-to-control difference was greater in men than in women for the ipsilateral (p = 0.003) and contralateral hemicranial volume (p = 0.02). In men, 14% of the ipsilateral (F = 4.7, p = 0.004) and 16% of the contralateral (F = 5.1, p = 0.03) hemicranial volume loss could be attributed to generalized tonic clonic seizures. Compared with controls, patients averaged a 29% smaller ipsilateral and a 5% smaller contralateral hippoc us. Men with TLE have more brain atrophy than women with TLE. Seizure frequency is a factor contributing to reduced brain volumes in men but not in women. Men, therefore, may be more vulnerable to seizure-associated brain abnormalities.
Publisher: Cold Spring Harbor Laboratory
Date: 09-2017
Abstract: Gene panel and exome sequencing have revealed a high rate of molecular diagnoses among diseases where the genetic architecture has proven suitable for sequencing approaches, with a large number of distinct and highly penetrant causal variants identified among a growing list of disease genes. The challenge is, given the DNA sequence of a new patient, to distinguish disease-causing from benign variants. Large s les of human standing variation data highlight regional variation in the tolerance to missense variation within the protein-coding sequence of genes. This information is not well captured by existing bioinformatic tools, but is effective in improving variant interpretation. To address this limitation in existing tools, we introduce the missense tolerance ratio (MTR), which summarizes available human standing variation data within genes to encapsulate population level genetic variation. We find that patient-ascertained pathogenic variants preferentially cluster in low MTR regions ( P 0.005) of well-informed genes. By evaluating 20 publicly available predictive tools across genes linked to epilepsy, we also highlight the importance of understanding the empirical null distribution of existing prediction tools, as these vary across genes. Subsequently integrating the MTR with the empirically selected bioinformatic tools in a gene-specific approach demonstrates a clear improvement in the ability to predict pathogenic missense variants from background missense variation in disease genes. Among an independent test s le of case and control missense variants, case variants (0.83 median score) consistently achieve higher pathogenicity prediction probabilities than control variants (0.02 median score Mann-Whitney U test, P 1 × 10 −16 ). We focus on the application to epilepsy genes however, the framework is applicable to disease genes beyond epilepsy.
Publisher: Springer Science and Business Media LLC
Date: 26-05-2015
DOI: 10.1007/S11910-015-0559-8
Abstract: While genetic causes of epilepsy have been hypothesized from the time of Hippocrates, the advent of new genetic technologies has played a tremendous role in elucidating a growing number of specific genetic causes for the epilepsies. This progress has contributed vastly to our recognition of the epilepsies as a erse group of disorders, the genetic mechanisms of which are heterogeneous. Genotype-phenotype correlation, however, is not always clear. Nonetheless, the developments in genetic diagnosis raise the promise of a future of personalized medicine. Multiple genetic tests are now available, but there is no one test for all possible genetic mutations, and the balance between cost and benefit must be weighed. A genetic diagnosis, however, can provide valuable information regarding comorbidities, prognosis, and even treatment, as well as allow for genetic counseling. In this review, we will discuss the genetic mechanisms of the epilepsies as well as the specifics of particular genetic epilepsy syndromes. We will include an overview of the available genetic testing methods, the application of clinical knowledge into the selection of genetic testing, genotype-phenotype correlations of epileptic disorders, and therapeutic advances as well as a discussion of the importance of genetic counseling.
Publisher: Wiley
Date: 22-07-2019
DOI: 10.1002/EPI4.12350
Publisher: Wiley
Date: 31-08-2023
DOI: 10.1002/ANA.26765
Abstract: Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippoc al sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in in iduals with FMTLE. We studied 134 families with ≥ 2 first or second‐degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one in idual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls. The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13–28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug‐resistance and/or hippoc al sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007) in contrast, no enrichment for the febrile seizure PRS was observed. FMTLE is a generally mild drug‐responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub‐genome‐wide significant focal epilepsy genome‐wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023
Publisher: Elsevier BV
Date: 05-2009
Publisher: Elsevier BV
Date: 2012
Publisher: Wiley
Date: 09-2002
DOI: 10.1046/J.1528-1157.2002.45401.X
Abstract: This randomised, double-blind study compared the newer antiepileptic drugs (AEDs) gabapentin (GBP) and lamotrigine (LTG) as monotherapy in newly diagnosed epilepsy. Patients with partial seizures with and/or without secondary generalization or primary generalized tonic-clonic seizures were randomized to either GBP or LTG. During 2- and 6-week titration periods, respectively, GBP dosage reached 1,800 mg/day, and LTG, 150 mg/day. In the subsequent 24-week maintenance phase, the dose could be adjusted based on seizure control or adverse events between 1,200 and 3,600 mg/day for GBP and 100 and 300 mg/day for LTG. The primary end point was time to exit, a composite of efficacy and tolerability. Evaluable patients were used for the primary efficacy analysis, whereas tolerability was examined on an intent-to-treat basis. A total of 309 patients was randomized, and 291 (148 GBP, 143 LTG) were included in the evaluable population. Nineteen patients in each group had an exit event. The median time to exit was 69 days for GBP and 48 days for LTG. The hazard ratio was estimated as 1.043 (90% confidence intervals, 0.602-1.809). Overall, 106 (71.6% of the evaluable population) GBP-treated and 96 (67.1%) LTG-treated patients completed the study. Of those, 80 (75.5%) patients taking GBP and 73 (76.0%) taking LTG remained seizure free during the final 12 weeks of treatment. Only 14 (8.9%) GBP-treated patients and 15 (9.9%) LTG-treated patients withdrew because of study drug-related adverse events. GBP and LTG monotherapy were similarly effective and well tolerated in patients with newly diagnosed epilepsy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-07-2000
DOI: 10.1212/WNL.55.2.169
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-08-2008
DOI: 10.1212/01.WNL.0000316192.52731.77
Abstract: Mutations of the neuronal nicotinic acetylcholine (nACh) receptor identified in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) lead to increased sensitivity to ACh. As activation of presynaptic nicotinic receptors augments the release of dopamine in the striatum and the prefrontal regions, we tested the hypothesis that that the alpha4-Ser248Phe mutation affects dopaminergic transmission. We measured D(1) receptor binding using [(11)C]-SCH23390 and PET in 12 subjects with the alpha4-Ser248Phe mutation (3 men, mean age 41 +/- 16 years) and 19 controls (8 men, mean age 36 +/- 13 years) matched for gender, smoking status, and age. Parametric images were produced using the simplified reference region method. Both MRI-based regions of interest and voxel based analyses were used. Reduced striatal [(11)C]-SCH23390 binding occurred with the mutation (controls 1.1 +/- 0.1 ADNFLE 0.97 +/- 0.2 p < 0.01). Statistical parametric mapping confirmed a region of reduced [(11)C]-SCH23390 binding in the right putamen in alpha4-Ser248Phe subjects compared to controls (309 voxels, local maxima 20 16 -2 mm Z(score) 3.57, p < 0.05). Reduced D(1) receptor binding may represent increased extracellular dopamine levels or, more likely, receptor downregulation. Alterations in mesostriatal dopaminergic circuits may contribute to nocturnal paroxysmal motor activity in autosomal dominant nocturnal frontal lobe epilepsy.
Publisher: Elsevier BV
Date: 2019
Publisher: Wiley
Date: 12-2017
Abstract: Aims . Somatic mutation of the lissencephaly‐1 gene is a cause of subcortical band heterotopia (“double cortex”). The severity of the phenotype depends on the level of mutation in brain tissue. Detecting and quantifying low‐level somatic mosaic mutations is challenging. Here, we utilized droplet digital PCR, a sensitive method to detect low‐level mutation. Methods . Droplet digital PCR was used in concert with classic genotyping techniques (SNaPshot assays and pyrosequencing) to detect and characterize the tissue mosaicism of a somatic mutation ( LIS1 c.190A T p.K64X) in a patient with posterior bilateral SBH and refractory epilepsy. Results . The high sensitivity of droplet digital PCR and the ability to target in idual DNA molecules allowed us to detect the mutation at low level in the brain, despite the low quality of the DNA s le derived from formalin‐fixed paraffin‐embedded tissue. This low mutation frequency in the brain was consistent with the relatively subtle malformation resolved by magnetic resonance imaging. The presence of the mutation in other tissues from the patient permitted us to predict the timing of mutagenesis. Conclusion . This sensitive methodology will have utility for a variety of other brain malformation syndromes associated with epilepsy for which historical pathological specimens are available and specific somatic mosaic mutations are predicted.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-01-2000
DOI: 10.1212/WNL.54.1.272
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-12-2007
Publisher: Wiley
Date: 22-04-2022
DOI: 10.1111/EPI.17254
Abstract: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of premature death in epilepsy. The underlying pathological mechanisms are likely to be multifactorial. Cardiac arrhythmia has been suggested as a cause of death in some patients with SUDEP. SCN5A encodes the cardiac Na v 1.5 sodium channel. SCN5A variants that result in either loss or gain of channel function cause cardiac arrhythmias. Rare SCN5A variants have been reported in SUDEP cases, but the impact of these variants on channel function is unknown. Here, we use whole‐cell voltage cl recordings to perform functional analyses of rare SCN5A SUDEP variants, p.V223G, p.I397V, and p.R523C. Expression and biophysical properties, including activation, inactivation, and recovery from inactivation, were probed. Each SCN5A variant significantly impacted human Na V 1.5 channel function, indicating that they could cause cardiac arrhythmias. The patient carrying the p.R523C variant was on lamotrigine, an antiseizure medication implicated in SUDEP. Therapeutic concentration of lamotrigine caused a slowing of the rate of recovery from inactivation and a hyperpolarizing shift in the voltage of inactivation of human Na V 1.5 wild‐type, but not p.R523C channels, implicating a gene‐by‐drug interaction. These data suggest that SCN5A arrhythmogenic variants may confer increased risk of sudden death in in iduals with epilepsy.
Publisher: Wiley
Date: 05-2007
Publisher: Elsevier BV
Date: 07-1997
Publisher: Oxford University Press (OUP)
Date: 2010
DOI: 10.1093/BRAIN/AWP332
Publisher: Wiley
Date: 09-2001
DOI: 10.1046/J.1528-1157.2001.39900.X
Abstract: To analyze the results of surgical treatment of intractable epilepsy in patients with subcortical band heterotopia, or double cortex syndrome, a diffuse neuronal migration disorder. We studied eight patients (five women) with double cortex syndrome and intractable epilepsy. All had a comprehensive presurgical evaluation including prolonged video-EEG recordings and magnetic resonance imaging (MRI). All patients had partial seizures, with secondary generalization in six of them. Neurologic examination was normal in all. Three were of normal intelligence, and five were mildly retarded. Six patients underwent invasive EEG recordings, three of them with subdural grids and three with stereotactic implanted depth electrodes (SEEG). Although EEG recordings showed multilobar epileptic abnormalities in most patients, regional or focal seizure onset was recorded in all. MRI showed bilateral subcortical band heterotopia, asymmetric in thickness in three. An additional area of cortical thickening in the left frontal lobe was found in one patient. Surgical procedures included multiple subpial transections in two patients, frontal lesionectomy in one, temporal lobectomy with amygdalohippoc ectomy in five, and an additional anterior callosotomy in one. Five patients had no significant improvement, two had some improvement, and one was greatly improved. Our results do not support focal surgical removal of epileptogenic tissue in patients with double cortex syndrome, even in the presence of a relatively localized epileptogenic area.
Publisher: Wiley
Date: 09-2010
DOI: 10.1111/J.1528-1167.2010.02558.X
Abstract: A family with dominantly inherited neonatal seizures and intellectual disability was atypical for neonatal and infantile seizure syndromes associated with potassium (KCNQ2 and KCNQ3) and sodium (SCN2A) channel mutations. Microsatellite markers linked to KCNQ2, KCNQ3, and SCN2A were examined to exclude candidate locations, but instead revealed a duplication detected by observation of three alleles for two markers flanking SCN2A. Characterization revealed a 1.57 Mb duplication at 2q24.3 containing eight genes including SCN2A, SCN3A, and the 3¢ end of SCN1A. The duplication was partially inverted and inserted within or near SCN1A, probably affecting the expression levels of associated genes, including sodium channels. Rare or unique microchromosomal copy number mutations might underlie familial epilepsies that do not fit within the clinical criteria for the established syndromes.
Publisher: Elsevier BV
Date: 06-2005
Publisher: Wiley
Date: 02-02-2016
DOI: 10.1002/ANA.24596
Abstract: The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome-based analysis of rare variants. Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools. The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome-wide significance with rare variant collapsing analysis however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome-wide. A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at-risk family members.
Publisher: AMPCo
Date: 03-2000
DOI: 10.5694/J.1326-5377.2000.TB123912.X
Abstract: To determine the frequency and nature of fatal brain injuries occurring in Australian football. State of Victoria, January to July 1999. Retrospective case series of football-related deaths identified from the coronial autopsy records of the Victorian Institute of Forensic Medicine (1990-1999) and newspaper reports (1968-1989). Coronial autopsy findings and circumstances of injury. 25 deaths associated with Australian football were identified, nine due to brain injury. Coronial findings in the brain-injury deaths were intracranial haemorrhage in eight patients and infarct in the territory of the middle cerebral artery in one. In three of four cases of subarachnoid haemorrhage, vertebral artery trauma was noted. In all but one case, injury occurred as an accidental part of play. The most common findings in deaths due to brain injury in Australian football were intracranial haemorrhage, including subarachnoid haemorrhage from vertebral artery injury.
Publisher: Wiley
Date: 04-2007
DOI: 10.1002/ANA.21087
Abstract: Different pathophysiological mechanisms related to the balance of cortical excitatory and inhibitory influences may underlie focal and generalized epilepsies. We used transcranial magnetic stimulation to search for interictal excitability differences between patients with idiopathic generalized epilepsy (IGE) and focal epilepsy. Sixty-two drug-naive patients with newly diagnosed epilepsy (35 IGE, 27 focal epilepsy) were studied. In the latter group, the seizure focus was not located in the motor cortex. Motor threshold at rest, cortical silent period threshold, recovery curve analysis using paired-pulse stimulation at a number of interstimulus intervals), and cortical silent period were determined. Results were compared with those of 29 control subjects. Hyperexcitability was noted in the recovery curves at a number of interstimulus intervals in both hemispheres in patients with IGE and in the hemisphere ipsilateral to the seizure focus in those with focal epilepsy compared with control subjects and the contralateral hemisphere in focal epilepsy. Motor threshold and cortical silent period threshold were higher in the ipsilateral hemisphere in focal epilepsy compared with the contralateral hemisphere. No other intragroup or intergroup differences were found in the other measures. The disturbance of cortical excitatory/inhibitory function was found to be bilateral in IGE, whereas in focal epilepsy it spread beyond the epileptic focus but remained lateralized. This finding confirms that there are differences in cortical pathophysiology comparing the two major types of epilepsy.
Publisher: Massachusetts Medical Society
Date: 26-04-2018
DOI: 10.1056/NEJMC1714579
Publisher: Elsevier BV
Date: 1997
DOI: 10.1016/S0387-7604(96)00060-5
Abstract: Single gene disorders offer the best opportunity for identification of genetic linkage and of abnormal genes. Epilepsies with single gene inheritance include symptomatic epilepsies where there is associated diffuse brain dysfunction, and idiopathic epilepsies where seizures are the major neurological abnormality. There are over 200 single gene symptomatic epilepsies most are rare. Gene identification has been achieved in a number of these conditions but these important advances have not yet led to a better understanding of epileptogenesis, because of the associated brain disease. Idiopathic single gene epilepsies include benign familial neonatal convulsions, where genetic linkage to chromosomes 20q and 8q has been found in different families, and benign familial infantile convulsions where linkage is presently unknown. Recently, four autosomal dominant partial epilepsies have been described. In autosomal dominant nocturnal frontal lobe epilepsy a genetic defect in the alpha 4 subunit of the nicotinic acetylcholine receptor was found in one family. This is the first genetic defect described in an idiopathic epilepsy. The other three syndromes are autosomal dominant partial epilepsy with variable foci, autosomal dominant rolandic epilepsy with speech dyspraxia, and familial temporal lobe epilepsy. In the latter condition, linkage to chromosome 10q has been reported in one family, but the genetic defect is unknown. It is likely that other idiopathic single gene epilepsies will be identified. Molecular genetic study of these disorders is likely to lead to discovery of other epilepsy genes. This will lead to an improved understanding of human epileptogenesis with implications for clinical diagnosis, genetic counselling, pharmacological therapy and possibly prevention of epilepsy.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2017
DOI: 10.1038/EJHG.2017.61
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1993
DOI: 10.1212/WNL.43.4.747
Abstract: We retrospectively studied 12 consecutive patients with gelastic seizures and hypothalamic hamartomas who, because of intractable epilepsy, underwent chronic intracranial EEG monitoring or epilepsy surgery. All patients had medically refractory seizures that included laughter as an ictal behavior (gelastic seizures). The hypothalamic hamartomas were identified with neuroimaging studies (12 of 12) and by pathologic verification (four of 12). Associated clinical features included behavioral disorders (n = 5), developmental delay (n = 4), and precocious puberty (n = 2). Interictal extracranial EEG predominantly showed bi-hemispheric epileptiform changes suggesting a secondary generalized epileptic disorder. Intracranial EEG recordings, performed in eight patients, indicated the apparent focal onset of seizure activity (anterior temporal lobe [n = 7] and frontal lobe [n = 1]). None of the seven patients who underwent a focal cortical resection, however, experienced a significant reduction in seizure tendency. An anterior corpus callosotomy, performed in two patients with symptomatic generalized epilepsy, resulted in a worthwhile reduction in drop attacks. Results of this study may modify the surgical strategies in patients with gelastic seizures and hypothalamic hamartomas.
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.JNS.2022.120439
Abstract: Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non-neurodegenerative 'non-progressor' mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay. Cerebrospinal fluid (CSF) NfL, amyloid beta 1-42 (AB42), total and phosphorylated tau (T-tau, P-tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow-up information, patients were categorised as Progressors or Non-Progressors: further subtyped into Non-Progressor Revised (non-neurological/neurodegenerative final diagnosis), and Non-Progressor Static (static deficits, not fully explained by non-neurological/neurodegenerative causes). Forty-three patients were included: 20 Progressors, 23 Non-Progressors (15 Non-Progressor Revised, 8 Non-Progressor Static), and 20 controls. NfL concentrations were lower in Non-Progressors (Non-Progressors Mean, M = 554 pg/mL, 95%CI:[461, 675], Non-Progressor Revised M = 459 pg/mL, 95%CI:[385, 539], and Non-Progressor Static M = 730 pg/mL, 95%CI:[516, 940]), compared to Progressors (M = 2397 pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non-Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Non-Progressor Static tended to have higher T-tau and P-tau levels compared to Non-Progressor Revised Diagnoses. This study demonstrated strong diagnostic utility of CSF NfL to distinguish bvFTD from non-progressor variants, at baseline, with high accuracy, in a real-world clinical setting. This has important clinical implications, to improve outcomes for patients and clinicians facing this challenging clinical dilemma, healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non-progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL.
Publisher: Elsevier BV
Date: 10-2003
DOI: 10.1016/S1059-1311(02)00352-7
Abstract: We performed a controlled prospective study of pathologically verified sudden unexpected death in epilepsy (SUDEP) in a coronial setting, to identify risk factors. We prospectively studied coronial deaths of people with epilepsy in Vic., Australia, during a 21-month period. Fifty SUDEP and 50 subjects with epilepsy who died of other causes (controls) were collected sequentially. Clinical data was obtained shortly after death from questionnaires completed by treating doctors, discussion with family members and coronial files, including police reports of death, autopsy and toxicology reports. Factors assessed were age, sex, duration of epilepsy, type of seizure(s), seizure frequency, symptomatic epilepsy, including post-traumatic epilepsy, presence of structural brain lesion, idiopathic epilepsy, mental retardation, psychiatric illness, including dementia, recent stressful life event, particular antiepileptic drugs (AEDs) and AED polytherapy, compliance with AED treatment, psychotropic drug prescription, alcohol and other substance abuse, place of death and evidence of terminal seizure. The SUDEP group was characterised by younger age and higher proportion found dead in bed and with evidence of terminal seizure compared to controls. The profile of patients at risk for SUDEP are young people with epilepsy. They are most likely to die in sleep and our data support the view that SUDEP is a seizure-related event. This, taken in conjunction with the finding that there was no increased risk associated with a particular AED in monotherapy or multiple AEDs suggests that attempts to better treat patients' epilepsy with AEDs might decrease the risk of SUDEP. Although the literature suggests that SUDEP is more frequent in patients with severe epilepsy, we did not find a correlation with seizure frequency suggesting that other clinical indices may be more important.
Publisher: Wiley
Date: 07-1990
Abstract: The cytosolic free calcium concentration ([Ca2+]i) and exocytosis of chromaffin granules were measured simultaneously from single, intact bovine adrenal chromaffin cells using a novel technique involving fluorescent imaging of cocultured cells. Chromaffin cell [Ca2+]i was monitored with fura-2. To simultaneously follow catecholamine secretion, the cells were cocultured with fura-2-loaded NIH-3T3t cells, a cell line chosen because of their irresponsiveness to chromaffin cell secretagogues but their large Ca2+ response to ATP, which is coreleased with catecholamine from the chromaffin cells. In response to the depolarizing stimulus nicotine (a potent secretagogue), chromaffin cell [Ca2+]i increased rapidly. At the peak of the response, [Ca2+]i was evenly distributed throughout the cell. This elevation in [Ca2+]i was followed by a secretory response which originated from the entire surface of the cell. In response to the inositol 1,4,5-trisphosphate (InsP3)-mobilizing agonist angiotensin II (a weak secretagogue), three different responses were observed. Approximately 30% of chromaffin cells showed no rise in [Ca2+]i and did not secrete. About 45% of the cells responded with a large (greater than 200 nM), transient elevation in [Ca2+]i and no detectable secretory response. The rise in [Ca2+]i was nonuniform, such that peak [Ca2+]i was often recorded only in one pole of the cell. And finally, approximately 25% of cells responded with a similar Ca2+-transient to that described above, but also gave a secretory response. In these cases secretion was polarized, being confined to the pole of the cell in which the rise in [Ca2+]i was greatest.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Wiley
Date: 07-2010
DOI: 10.1111/J.1528-1167.2009.02392.X
Abstract: We have previously found that the developmental time frame of epilepsy onset influences adult personality traits and subsequent adjustment to intractable seizures. In the same cohort of patients we now investigate the influence of these factors on psychosocial outcome after surgical treatment. Fifty-seven adult patients with focal epilepsy were prospectively assessed before and after surgery. Measures of psychosocial outcome included mood, health-related quality of life (HRQOL), and psychosocial adjustment, collected longitudinally at 1-, 3-, and 12-months after surgery. Patients with high neuroticism and low extraversion were predisposed to greater depression after surgery. More than 70% of patients with high neuroticism also reported disrupted family dynamics and difficulties adjusting to seizure freedom. The latter was associated with changes in self-identity that increased over time. Patients with epilepsy onset before or during the self-defining period of adolescence reported the greatest perceived self-change after surgery that had positive effects for HRQOL. Psychosocial outcome after epilepsy surgery appears intrinsically linked to a change in self and a transition from chronically sick to well. The development of personality traits and self-identity in the context of habitual seizures can impact psychosocial outcome and the extent of self-change reported after surgery, and paradoxically, can concur more beneficial effects.
Publisher: Cold Spring Harbor Laboratory
Date: 24-02-2023
DOI: 10.1101/2023.02.22.23286310
Abstract: Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date to investigate rare variants that confer risk for a spectrum of epilepsy syndromes. With an unprecedented s le size of ,000 human exomes, composed of 20,979 deep-phenotyped patients with epilepsy and 33,444 controls, we replicate previous gene findings at exome-wide significance using a hypothesis-free approach, we identify potential novel associations. Most discoveries are specific to a particular subtype of epilepsy, highlighting distinct genetic contributions to different epilepsies. Combining evidence from rare single nucleotide/short indel-, copy number-, and common variants, we find convergence of different genetic risk factors at the level of in idual genes. Further comparing to other exome-sequencing studies, we implicate shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our study also demonstrates the value of collaborative sequencing and deep-phenotyping efforts, which will continue to unravel the complex genetic architecture underlying the heterogeneity of epilepsy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-04-2016
Publisher: Frontiers Media SA
Date: 24-10-2014
Publisher: Wiley
Date: 05-2000
DOI: 10.1111/J.1528-1157.2000.TB00205.X
Abstract: To describe the clinical features of a family from Northern Norway in which autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is associated with a Ser248Phe amino acid exchange in the second transmembrane domain of the neuronal nicotinic acetylcholine receptor alpha4 subunit (CHRNA4). We also tested for evidence of a de novo mutation or founder effect by comparing haplotypes with the original Australian family where the Ser248Phe mutation was first described. Clinical details were obtained from 19 family members. Personal interviews and genetic analysis were carried out in 17. Parts of the coding region of CHRNA4 were sequenced, and two known polymorphisms (bp555/FokI, bp594/CfoI) were typed by restriction analysis. Eleven in iduals had ADNFLE. The haplotypes of the mutation-carrying alleles of affected in iduals from the Northern Norwegian and the Australian ADNFLE family are different. The phenotypic expressions are remarkably similar. The Ser248Phe mutation occurred independently in both families. Given the rarity of the disease, this suggests that not only the position of a mutation in the coding sequence but also the type of an amino acid exchange is important for the etiology of ADNFLE. The phenotypic similarity of these two families with different genetic backgrounds suggests that the Ser248Phe mutation largely determines the phenotype, with relatively little influence of other background genes.
Publisher: Elsevier BV
Date: 2017
Publisher: Wiley
Date: 04-2014
DOI: 10.1002/ANA.24128
Publisher: Wiley
Date: 15-02-2023
DOI: 10.1002/EPI4.12693
Abstract: In vitro data prompted U.S Food and Drug Administration warnings that lamotrigine, a common sodium channel modulating anti‐seizure medication (NaM‐ASM), could increase the risk of sudden death in patients with structural or ischaemic cardiac disease, however, its implications for Sudden Unexpected Death in Epilepsy (SUDEP) are unclear. This retrospective, nested case–control study identified 101 sudden unexpected death in epilepsy (SUDEP) cases and 199 living epilepsy controls from Epilepsy Monitoring Units (EMUs) in Australia and the USA. Differences in proportions of lamotrigine and NaM‐ASM use were compared between cases and controls at the time of admission, and survival analyses from the time of admission up to 16 years were conducted. Multivariable logistic regression and survival analyses compared each ASM subgroup adjusting for SUDEP risk factors. Proportions of cases and controls prescribed lamotrigine ( P = 0.166), one NaM‐ASM ( P = 0.80), or ≥2NaM‐ASMs ( P = 0.447) at EMU admission were not significantly different. Patients taking lamotrigine (adjusted hazard ratio [aHR] = 0.56 P = 0.054), one NaM‐ASM (aHR = 0.8 P = 0.588) or ≥2 NaM‐ASMs (aHR = 0.49 P = 0.139) at EMU admission were not at increased SUDEP risk up to 16 years following admission. Active tonic–clonic seizures at EMU admission associated with ‐fold SUDEP risk, irrespective of lamotrigine (aHR = 2.24 P = 0.031) or NaM‐ASM use (aHR = 2.25 P = 0.029). Sensitivity analyses accounting for incomplete ASM data at follow‐up suggest undetected changes to ASM use are unlikely to alter our results. This study provides additional evidence that lamotrigine and other NaM‐ASMs are unlikely to be associated with an increased long‐term risk of SUDEP, up to 16 years post‐EMU admission.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-06-2018
Abstract: Consistent classification of neuropsychiatric diseases is problematic because it can lead to misunderstanding of etiology. The Brainstorm Consortium examined multiple genome-wide association studies drawn from more than 200,000 patients for 25 brain-associated disorders and 17 phenotypes. Broadly, it appears that psychiatric and neurologic disorders share relatively little common genetic risk. However, different and independent pathways can result in similar clinical manifestations (e.g., psychosis, which occurs in both schizophrenia and Alzheimer's disease). Schizophrenia correlated with many psychiatric disorders, whereas the immunopathological affliction Crohn's disease did not, and posttraumatic stress syndrome was also largely independent of underlying traits. Essentially, the earlier the onset of a disorder, the more inheritable it appeared to be. Science , this issue p. eaap8757
Publisher: Elsevier BV
Date: 06-2000
DOI: 10.1016/S0920-1211(00)00098-X
Abstract: Heart weights have been reported to be increased in those dying suddenly and unexpectedly from epilepsy (SUDEP) and it has been suggested that cardiac pathology including cardiac conduction pathology and coronary artery atheroma may contribute to SUDEP. The purpose of this study was to perform a detailed controlled study of the microscopic pathology of the cardiac conduction system in SUDEP cases, in addition to assessing coronary artery atheroma and other cardiac pathology. The hearts of ten SUDEPs and ten control subjects (no history of epilepsy and a cause of death not primarily cardiac) were examined macroscopically and microscopically by two pathologists blinded to the patient group. Morphological abnormalities of the cardiac conduction system that could have possibly contributed to death were not increased in the SUDEP group (four cases showed such changes in the SUDEP group vs. six in the control). There was no significant difference between the maximal percentage coronary artery stenoses between the two groups and no increased prevalence of other cardiac pathology in the SUDEP group. However, since subtle abnormalities of the conduction system were identified in some of the epileptic deaths, it is still feasible that these may contribute to death by causing cardiac arrhythmia, when associated with apnoea, bradycardia or other cardiac arrhythmia related to an epileptic seizure.
Publisher: Wiley
Date: 14-04-2014
DOI: 10.1002/ANA.24126
Abstract: We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5-associated malformations include bottom-of-the-sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 in idual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-01-2002
DOI: 10.1212/WNL.58.2.265
Abstract: Background: The MR and pathologic features of hippoc al sclerosis (HS) are well described and include volume decrease and T2-weighted signal increase for MRI, and neuron cell loss and gliosis for pathology. Objective: To confirm the established correlation between hippoc al volumes and neuron cell counts, and to study the still controversial association between signal change and gliosis. Methods: The authors studied 44 patients (22 men and 22 women mean age at surgery, 37 years) with refractory temporal lobe epilepsy. Quantitative assessment of hippoc al volumes and T2 relaxometry, and neuron and glial cell count in the region CA1 and molecular layer of the dentate gyrus was performed. The proportion of glial fibrillary acidic protein (GFAP)-positive glial cells (reactive astrocytes) was indicated. Results: In a stepwise regression, the ipsilateral hippoc al volume was predicted best by the neuron cell count in the dentate gyrus ( p = 0.005, r = 0.4). Hippoc al T2 time, however, was predicted best by the glial cell count in the dentate gyrus ( p = 0.01, r = 0.4). None of the other cell counts contributed to either model. In the dentate, 31% of the glial cells were reactive astrocytes, whereas in CA1, 5% were reactive. Conclusion: The results confirmed the correlation between hippoc al volumes and neuron cell counts. T2-weighted signal increase in the hippoc us was mainly influenced by gliosis in the dentate gyrus, where a high proportion of glial cells show abnormal activity. This activity may reflect changes important in the development of hippoc al epileptogenicity.
Publisher: BMJ
Date: 10-1992
Abstract: The ictal increase of regional cerebral blood flow has yet to be fully utilised in the investigation of focal seizures. Although single photon emission tomography (SPECT) is being increasingly used in the localisation of epileptic foci, the evolution and time courses of the peri-ictal perfusion changes have yet to be clarified. We performed serial SPECT studies in the interictal, ictal and immediate postictal states in 12 patients with refractory temporal lobe epilepsy to define the patterns and duration of peri-ictal cerebral blood flow changes. Visual analysis showed a constant pattern of unilateral global increases in temporal lobe perfusion during seizures which suddenly switched to a pattern of relative mesial temporal (hippoc al) hyperperfusion and lateral temporal hypoperfusion in the immediate postictal period. Quantitative analysis confirmed the visual assessment. Lateral temporal cortex ictal/normal side to side ratios were increased by mean 35.1% (95% confidence interval 21.8% to 48.4%) more in the ictal studies than in the interictal studies and mesial temporal cortex ratios increased by mean 30.8% (22.4% to 39.2%). In the postictal state, however, lateral temporal ratios were reduced by mean 7.7% (-15.8% to 0.4%) compared with interictal values, whereas mesial temporal perfusion was maintained compared with the interictal studies. These observations provide critical information for interpreting scans which can be used in the localisation of epileptic foci. This postictal switch in blood flow patterns may reflect the underlying metabolic processes of neuronal activation and recovery and have implications for understanding the neurobiology of human epileptic seizures.
Start Date: 02-2017
End Date: 01-2020
Amount: $421,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 10-2004
End Date: 12-2008
Amount: $130,050.00
Funder: Australian Research Council
View Funded ActivityStart Date: 06-2020
End Date: 12-2024
Amount: $539,394.00
Funder: Australian Research Council
View Funded Activity