Unilateral thalamic lesion mimicking genetic generalized epilepsy.
Ontology highlight
ABSTRACT:
SUBMITTER: Kulick-Soper CV
PROVIDER: S-EPMC8327384 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveSome patients with genetic generalized epilepsy (GGE) may present with ambiguous and atypical findings and even focal brain abnormalities. Correct diagnosis may therefore be difficult.MethodsWe retrospectively collected six patients investigated on the epilepsy monitoring unit with MRI abnormalities mimicking focal cortical dysplasia (FCD-like) or heterotopias, but with semiology and EEG features of GGE. We compared them to four additional patients with GGE and nonmigratory abnormalities.ResultsAll six patients presented with frontal MRI lesions: radial ("transmantle," n = 4), cortical-subcortical (n = 1), and periventricular heterotopia (n = 1). Five had positive family histories. Semiologic lateralizing signs compatible with the lesion were seen in four. Five patients had 3/s spike-wave complexes, with an asymmetric appearance in three. Regional EEG changes matched with the side of the abnormality in three patients. Invasive EEG (n = 2) or postoperative outcomes (n = 3) argued against an ictogenic role of the MRI abnormalities. Histology showed mild malformation of cortical development, but no focal cortical dysplasia. The six patients were finally diagnosed with juvenile myoclonic epilepsy (n = 2), juvenile absence epilepsy (n = 2), or GGE not further specified (nfs, n = 2). Compared to these patients, the other four (final diagnoses: childhood absence epilepsy, n = 1; perioral myoclonia with absences, n = 1; and GGE nfs, n = 2) had no lateralizing EEG findings.SignificancePatients with GGE may have coincidental MRI abnormalities. These cases are challenging as frontal epilepsy and GGE can present with similar semiologies. GGE with coincidental FCD-like lesions/heterotopias is in particular difficult to diagnose as patients have more lateralizing features (in semiology and EEG) than those with tumors. A detailed noninvasive presurgical evaluation may be justified. We point out red flags that may help to distinguish GGE from frontal epilepsy, even in the presence of brain abnormalities: 3/s spike waves (even if asymmetric), changing lateralizing signs at different times, and a positive family history hinting at GGE.
| S-EPMC7278548 | biostudies-literature
Project description:ObjectiveParoxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.MethodsConfounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses.ResultsOur analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations.SignificanceOur results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.
| S-EPMC8672363 | biostudies-literature
Project description:Altered vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic encephalopathy, which can be treated with high doses of vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic generalized epilepsy (GGE). However, it is not known whether any of these GGE-associated SNPs influence vitamin B6 metabolite levels. Such an influence would suggest that vitamin B6 could play a role in GGE therapy. Here, we performed genome-wide association studies (GWAS) to assess the influence of GGE associated genetic variants on measures of vitamin B6 metabolism in blood plasma in 2232 healthy individuals. We also asked if SNPs that influence vitamin B6 were associated with GGE in 3122 affected individuals and 20,244 controls. Our GWAS of vitamin B6 metabolites reproduced a previous association and found a novel genome-wide significant locus. The SNPs in these loci were not associated with GGE. We found that 84 GGE-associated SNPs influence expression levels of PNPO in the brain as well as in blood. However, these SNPs were not associated with vitamin B6 metabolism in plasma. By leveraging polygenic risk scoring (PRS), we found suggestive evidence of higher catabolism and lower levels of the active and transport forms of vitamin B6 in GGE, although these findings require further replication.
| S-EPMC6796782 | biostudies-literature
Project description:ObjectiveTo evaluate the efficacy of cortical responsive neurostimulation (CRN) in a male baboon with epilepsy and with genetic generalized epilepsy (GGE), as well as the alteration of seizure patterns and their circadian rhythms due to treatment.MethodsThe baboon was implanted with two subdural frontoparietal strips, bridging the medial central sulci bilaterally. Electrocorticography (ECoG) data were downloaded daily during a three-month baseline, then every 2-3 days over a five-month treatment period. Long episodes, reflecting ictal or interictal epileptic discharges, were also quantified.ResultsTwenty-three generalized tonic-clonic seizures (GTCS) and 2 episodes of nonconvulsive status epilepticus (NCSE) were recorded at baseline (median 8 events/month), whereas 26 GTCS were recorded under treatment (median 5/month). Similarly, daily indices of long episodes decreased from 0.46 at baseline to 0.29 with treatment. Ictal ECoG patterns and the circadian distribution of GTCS were also altered by RNS therapy.SignificanceThis case study provides the proof-of-concept for RNS therapy in the baboon model of GGE. Cortical responsive neurostimulation (CRN) demonstrated a 38% median reduction in GTCS. Distinct ictal patterns were identified, which changed over the treatment period; the circadian pattern of his GTCS also shifted gradually from night to daytime with treatment. Future studies targeting the thalamic nuclei, or combining cortical and subcortical sites, may further improve detection and control of GTCS as well as other generalized seizure types. More broadly, this study demonstrates opportunities for evaluating seizure detection as well as chronic therapeutic interventions over long term in the baboon.
| S-EPMC8483259 | biostudies-literature
Project description:Background: Genetic generalized epilepsies (GGE) including childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and GGE with tonic–clonic seizures alone (GGE-TCS), are common types of epilepsy mostly determined by a polygenic mode of inheritance. Recent studies showed that susceptibility genes for GGE are numerous, and their variants rare, challenging their identification. In this study, we aimed to assess GGE genetic etiology in a Sudanese population. Methods: We performed whole-exome sequencing (WES) on DNA of 40 patients from 20 Sudanese families with GGE searching for candidate susceptibility variants, which were prioritized by CADD software and functional features of the corresponding gene. We assessed their segregation in 138 individuals and performed genotype–phenotype correlations. Results: In a family including three sibs with GGE-TCS, we identified a rare missense variant in ADGRV1 encoding an adhesion G protein-coupled receptor V1, which was already involved in the autosomal recessive Usher type C syndrome. In addition, five other ADGRV1 rare missense variants were identified in four additional families and absent from 119 Sudanese controls. In one of these families, an ADGRV1 variant was found at a homozygous state, in a female more severely affected than her heterozygous brother, suggesting a gene dosage effect. In the five families, GGE phenotype was statistically associated with ADGRV1 variants (0R = 0.9 103). Conclusion: This study highly supports, for the first time, the involvement of ADGRV1 missense variants in familial GGE and that ADGRV1 is a susceptibility gene for CAE/JAE and GGE-TCS phenotypes.
| S-EPMC8567843 | biostudies-literature
Project description:ObjectiveWe studied the frequency of auras in generalized epilepsy (GE) using a detailed semistructured diagnostic interview.MethodsIn this cross-sectional study, participants with GE were drawn from the Epilepsy Phenome/Genome Project (EPGP). Responses to the standardized diagnostic interview regarding tonic-clonic (grand mal) seizures were then examined. This questionnaire initially required participants to provide their own description of any subjective phenomena before their "grand mal seizures." Participants who provided answers to these questions were considered to have an aura. All participants were then systematically queried regarding a list of specific symptoms occurring before grand mal seizures, using structured (closed-ended) questions.ResultsSeven hundred ninety-eight participants with GE were identified, of whom 530 reported grand mal seizures. Of these, 112 (21.3%) reported auras in response to the open-ended question. Analysis of responses to the closed-ended questions suggested that 341 participants (64.3%) experienced at least one form of aura.ConclusionsAuras typically associated with focal epilepsy were reported by a substantial proportion of EPGP subjects with GE. This finding may support existing theories of cortical and subcortical generators of GE with variable spread patterns. Differences between responses to the open-ended question and closed-ended questions may also reflect clinically relevant variation in patient responses to history-taking and surveys. Open-ended questions may underestimate the prevalence of specific types of auras and may be in part responsible for the underrecognition of auras in GE. In addition, structured questions may influence participants, possibly leading to a greater representation of symptoms.
| S-EPMC4206156 | biostudies-literature
Project description:The baboon provides a natural model of genetic generalized epilepsy (GGE). This study compares the intrinsic connectivity networks of epileptic and healthy control baboons using resting-state functional magnetic resonance imaging (rs-fMRI) and data-driven functional connectivity mapping.Twenty baboons, matched for gender, age, and weight, were classified into two groups (10 epileptic [EPI], 10 control [CTL]) on the basis of scalp electroencephalography (EEG) findings. Each animal underwent one MRI session that acquired one 5-min resting state fMRI scan and one anatomic MRI scan-used for registration and spatial normalization. Using independent component analysis, we identified 14 unique components/networks, which were then used to characterize each group's functional connectivity maps of each brain network.The epileptic group demonstrated network-specific differences in functional connectivity when compared to the control animals. The sensitivity and specificity of the two groups' functional connectivity maps differed significantly in the visual, motor, amygdala, insular, and default mode networks. Significant increases were found in the occipital gyri of the epileptic group's functional connectivity map for the default mode, cingulate, intraparietal, motor, visual, amygdala, and thalamic regions.This is the first study using resting-state fMRI to demonstrate intrinsic functional connectivity differences between epileptic and control nonhuman primates. These results are consistent with seed-based GGE studies in humans; however, our use of a data-driven approach expands the scope of functional connectivity mapping to include brain regions/networks comprising the whole brain.
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Project description:The present study in rats was conducted to identify brain regions affected by the interruption of vestibular transmission and to explore selected aspects of their functional connections. We analyzed, by positron emission tomography (PET), the regional cerebral glucose metabolism (rCGM) of cortical, and subcortical cerebral regions processing vestibular signals after an experimental lesion of the left laterodorsal thalamic nucleus, a relay station for vestibular input en route to the cortical circuitry. PET scans upon galvanic vestibular stimulation (GVS) were conducted in each animal prior to lesion and at post-lesion days (PLD) 1, 3, 7, and 20, and voxel-wise statistical analysis of rCGM at each PLD compared to pre-lesion status were performed. After lesion, augmented metabolic activation by GVS was detected in cerebellum, mainly contralateral, and in contralateral subcortical structures such as superior colliculus, while diminished activation was observed in ipsilateral visual, entorhinal, and somatosensory cortices, indicating compensatory processes in the non-affected sensory systems of the unlesioned side. The changes in rCGM observed after lesion resembled alterations observed in patients suffering from unilateral thalamic infarction and may be interpreted as brain plasticity mechanisms associated with vestibular compensation and substitution. The second set of experiments aimed at the connections between cortical and subcortical vestibular regions and their neurotransmitter systems. Neuronal tracers were injected in regions processing vestibular and somatosensory information. Injections into the anterior cingulate cortex (ACC) or the primary somatosensory cortex (S1) retrogradely labeled neuronal somata in ventral posteromedial (VPM), posterolateral (VPL), ventrolateral (VL), posterior (Po), and laterodorsal nucleus, dorsomedial part (LDDM), locus coeruleus, and contralateral S1 area. Injections into the parafascicular nucleus (PaF), VPM/VPL, or LDDM anterogradely labeled terminal fields in S1, ACC, insular cortex, hippocampal CA1 region, and amygdala. Immunohistochemistry showed tracer-labeled terminal fields contacting cortical neurons expressing the ?-opioid receptor. Antibodies to tyrosine hydroxylase, serotonin, substance P, or neuronal nitric oxide-synthase did not label any of the traced structures. These findings provide evidence for opioidergic transmission in thalamo-cortical transduction.
| S-EPMC7256190 | biostudies-literature
Project description:Up to 20% of pediatric patients with primary generalized epilepsy (PGE) will not respond effectively to medication for seizure control. Responsive neurostimulation (RNS) is a promising therapy for pediatric patients with drug-resistant epilepsy and has been shown to be an effective therapy for reducing seizure frequency and severity in adult patients. RNS of the centromedian nucleus of the thalamus may help to prevent loss of awareness during seizure activity in PGE patients with absence seizures. Here we present a 16-year-old male, with drug-resistant PGE with absence seizures, characterized by 3 Hz spike-and-slow-wave discharges on EEG, who achieved a 75% reduction in seizure frequency following bilateral RNS of the centromedian nuclei. At 6-months post-implant, this patient reported complete resolution of the baseline daily absence seizure activity, and decrease from 3-4 generalized convulsive seizures per month to 1 per month. RNS recordings showed well-formed 3 Hz spike-wave discharges in bilateral CM nuclei, further supporting the notion that clinically relevant ictal discharges in PGE can be detected in CM. This report demonstrates that CM RNS can detect PGE-related seizures in the CM nucleus and deliver therapeutic stimulation.
| S-EPMC8113700 | biostudies-literature
Project description: Not available
| S-EPMC7525200 | biostudies-literature