A multicenter study of BRD2 as a risk factor for juvenile myoclonic epilepsy

PURPOSE: 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. METHODS: 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. RESULTS: We observed a significant effect in a small sample recruited in Britain (genotype p = 0.001, allele p = 0.001), a borderline significant effect in a sample recruited in Ireland and no association in larger samples 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. CONCLUSIONS: 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.     

<Emphasis Type="Italic">N</Emphasis>-methyl-<Emphasis Type="SmallCaps">d</Emphasis>-aspartate 2b receptor subtype (NR2B) promoter methylation in patients during alcohol withdrawal

NMDA receptors and especially the NR2B receptor subtype play a crucial role during chronic ethanol consumption and alcohol withdrawal. Therefore, the NR2B receptor subtype expression in peripheral blood cells of 32 male patients suffering from alcohol dependency were assessed through quantitative RT-PCR and to explore regulating epigenetic mechanisms, a methylation analysis was conducted using bisulfite sequencing of a fragment of the NR2B promoter region. The expression of the NR2B receptor increased significantly during the first 24 h of withdrawal treatment (day 1; t = 4.1, P = 0.001), and also on and day 3 (t = 2.4; P = 0.029). The severity of alcohol drinking pattern, measured by lifetime drinking and daily ethanol intake, was negatively correlated with the methylation of a defined cluster of five CPG-sites within the NR2B promoter (lifetime drinking: Spearman’s rho = −0.55; P = 0.013; daily ethanol intake: rho = −0.46; P = 0.043). These findings might explain the observation of an impact of alcohol consumption patterns on the gravity of withdrawal symptoms. T. Biermann and U. Reulbach contributed equally.     

The 1674+11C>T polymorphism of CHRNA4 is associated with juvenile myoclonic epilepsy

The α4 subunit gene (CHRNA4) of the neuronal nicotinic acetylcholine receptor (nAChR), linked to an idiopathic partial epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), may also play a key role in the development of the idiopathic generalized epilepsy syndrome (IGE), juvenile myoclonic epilepsy (JME). This study was designed to explore an association of four polymorphisms of the CHRNA4 with JME in Polish children and young patients. The study included 92 JME patients and 222 unrelated healthy individuals. In each group the frequencies of the CHRNA4 c.555C>T, c.594C>T, 1674⁺¹¹C>T, and 1674⁺¹⁴A>G polymorphisms were determined using PCR-RFLP analyses. An association between the 1674⁺¹¹C>T polymorphism of the CHRNA4 and JME was evidenced. Allele T (the risk factor) appeared with a significantly higher frequency in the JME patients than in the controls (p = 0.0299). The patients harboring the 1674⁺¹¹CT+TT genotypes showed an increased risk of JME (CT+TT versus CC: OR = 1.925; 95% CI = 1.021–3.629; p = 0.0408). No association was found for the other CHRNA4 polymorphisms tested. The CHRNA4 1674⁺¹¹C>T polymorphism may be a susceptibility factor for epilepsy, and its higher frequency in patients with juvenile myoclonic epilepsy suggests that the CHRNA4 may be one of the candidate genes for this epileptic syndrome.     

<Emphasis Type="Italic">MGMT</Emphasis> methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome,yielding a prediction model for comparisons across datasets,tumor grades,and CIMP-status

The methylation status of the O⁶-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic glioma suggest a prognostic value for MGMT methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate MGMT classification to assess high throughput molecular databases. Promoter methylation-mediated gene silencing is strongly dependent on the location of the methylated CpGs, complicating classification. Using the HumanMethylation450 (HM-450K) BeadChip interrogating 176 CpGs annotated for the MGMT gene, with 14 located in the promoter, two distinct regions in the CpG island of the promoter were identified with high importance for gene silencing and outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg1243587 and cg12981137 provided good classification properties and prognostic value (kappa = 0.85; log-rank p < 0.001) using a training-set of 63 glioblastomas from homogenously treated patients, for whom MGMT methylation was previously shown to be predictive for outcome based on classification by methylation-specific PCR. MGMT-STP27 was successfully validated in an independent cohort of chemo-radiotherapy-treated glioblastoma patients (n = 50; kappa = 0.88; outcome, log-rank p < 0.001). Lower prevalence of MGMT methylation among CpG island methylator phenotype (CIMP) positive tumors was found in glioblastomas from The Cancer Genome Atlas than in low grade and anaplastic glioma cohorts, while in CIMP-negative gliomas MGMT was classified as methylated in approximately 50 % regardless of tumor grade. The proposed MGMT-STP27 prediction model allows mining of datasets derived on the HM-450K or HM-27K BeadChip to explore effects of distinct epigenetic context of MGMT methylation suspected to modulate treatment resistance in different tumor types.     

BRD2 and TAP-1 genes and juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy (JME) is a genetically determined common subtype of idiopathic generalized epilepsy. Linkage of JME to the chromosomal region 6p21.3 has been reported. An association has been previously observed between JME and the positional candidate, 6p21.3 linked, BRD2. Another candidate in this region is the TAP-1 gene encoding the Transporter Associated with Antigen Processing. The aim of the present study is to determine whether these two genes modulate the vulnerability to JME. While no difference was observed in the allele and genotype frequencies of BRD2 between JME and controls, an association was found between a TAP-1 haplotype and JME, suggesting that this gene may be another 6p21.3 linked vulnerability factor to JME.     

DNA methylation changes at TREM2 intron 1 and TREM2 mRNA expression in patients with Alzheimer's disease

ObjectivesRecent genome-wide association studies revealed that Triggering receptor expressed on myeloid cells 2 (TREM2) was associated with Alzheimer's disease (AD) and other neurodegenerative diseases. We previously reported that TREM2 mRNA is highly expressed in leukocytes of AD patients compared to those in healthy controls. However, the mechanism of TREM2 expression change is still not known. In this study, we examined the involvement of the DNA methylation status of TREM2 in its high gene expression.Materials and methodsFifty AD subjects and age- and sex-matched control subjects were recruited (25 males, 25 females; 79.9 ± 5.27 and 79.4 ± 3.92 years old, respectively). TREM2 mRNA expression and the percentage of DNA methylation at four CpG sites in intron 1 of TREM2 were studied using their peripheral leukocytes.ResultsWe confirmed that TREM2 mRNA expression in leukocytes was significantly higher in AD patients than in controls (p = 0.007). The percentage methylation at three CpG sites in TREM2 intron 1 was significantly lower in AD subjects than in control: CpG1, 9.4 ± 3.2 vs 11.9 ± 4.0 (p = 0.001); CpG2, 15.4 ± 4.9 vs 19.1 ± 4.8 (p = 0.001); CpG3, 20.8 ± 5.5 vs 25.5 ± 5.4 (p < 0.001); and the average percentage methylation of all CpG sites: 13.5 ± 3.7 vs 16.1 ± 3.8 (p = 0.002), respectively. In addition, there were significant negative correlations between TREM2 mRNA expression and the percentage DNA methylation of each of CpG sites (CpG1, r = −0.416, p < 0.001; CpG2, r = −0.510, p < 0.001; CpG3, r = −0.504, p < 0.001; CpG4, r = −0.356, p < 0.001).ConclusionsLower DNA methylation at TREM2 intron 1 caused higher TREM2 mRNA expression in the leukocytes of AD subjects versus controls and may be a biomarker for AD.     

Increased methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of patients with generalized anxiety disorder

Previous findings on the dysfunction of hypothalamic-pituitary-adrenal (HPA) axis in generalized anxiety disorder (GAD) are controversial, and the molecular mechanisms underlying such dysfunction remain unclear. We analyzed the methylation status of the NR3C1 1_F promoter and the expression of glucocorticoid receptor-α isoform (GRα) in peripheral blood mononuclear cells (PMBCs), the basal cortisol level in serum, and a functional neuroendocrine marker for GR sensitivity in the PMBCs in 64 patients with current GAD and 85 healthy controls. We found that patients with GAD had significantly elevated levels of morning basal serum cortisol (P < 0.0001) and diminished GR sensitivity in the PBMCs (P < 0.0001) compared with healthy controls. The overall methylation levels across NR3C1 1_F promoter (P < 0.0001) and percent methylation at each of the 5 CpG sites including CpG12, 21, 30, 31, and 32 (P < 0.001) significantly increased. Accordingly, the mRNA levels of GRα significantly decreased (P < 0.0001) in the PBMCs in patients with GAD compared with healthy controls, with the effects specific in patients without childhood traumatic experience. Moreover, both serum basal cortisol levels and GR sensitivity in the PBMCs were negatively correlated with the overall methylation levels of the NR3C1 1_F promoter (P < 0.0001) and positively correlated with GRα mRNA levels (P = 0.007) in the PBMCs. In sum, our study revealed the increased activity of the HPA axis and diminished peripheral glucocorticoid responsiveness of GR underlying episodes of GAD. Furthermore, such dysfunction of the HPA axis is associated with both increased DNA methylation of NR3C1 1_F promoter and decreased GRα expression.     

Factor VII-activating protease in patients with acute deep venous thrombosis

Factor VII-activating protease (FSAP) is involved in haemostasis and inflammation. FSAP cleaves single chain urokinase-type plasminogen activator (scu-PA). The 1601GA genotype of the 1601G/A polymorphism in the FSAP gene leads to the expression of a FSAP variant with reduced ability to activate scu-PA, without affecting the ability to activate coagulation Factor VII (FVII). Previous studies have investigated the association of the 1601GA genotype with incidence and progression of carotid stenosis and deep venous thrombosis (DVT). The present study is the first to evaluate the potential association between the FSAP phenotype and DVT.We studied the association between the 1601G/A polymorphism, FSAP activity, FSAP antigen, Factor VIIa (FVIIa), prothrombin fragment 1 + 2 (F1 + 2), and C-reactive protein (CRP) in plasmas of 170 patients suspected for DVT. FSAP genotypes were equally distributed in patients with (n = 64) and without DVT (n = 106), (P = 0.94). The 1601GA genotype was associated with significant reduction of FSAP activity (P < 0.001) and FSAP antigen levels (P = 0.04). Patients with DVT showed significantly higher FSAP activity (P = 0.008), FSAP antigen (P = 0.003), and F1 + 2 levels (P < 0.001) than patients without DVT. The association between the FSAP measures and DVT disappeared when adjusted for CRP levels. F1 + 2 correlated positively to FSAP antigen (P = 0.01), while FVIIa-levels were comparable in patients with and without DVT.We conclude that even though FSAP measures are significantly increased in patients with acute DVT, alterations in the scu-PA activating properties of FSAP are presumably not markedly involved in the development of acute DVT, and that the association between FSAP and DVT disappears after adjustment for CRP.     

Clinical heterogeneity of juvenile myoclonic epilepsy: Follow-up after an interval of more than 20 years

PurposeThe view that juvenile myoclonic epilepsy (JME) is a uniform and life-long disorder is currently being challenged. The aim of this study was to assess the seizure and psychosocial outcome of JME at least 20 years after onset.MethodsIn 1992, 42 patients with JME were identified. In 2012, 37 agreed to a semi-structured interview. In the remaining five, only medical records were available.ResultsOf 40 patients with known seizure outcome, 21 were in remission for >5 years. Seven were off antiepileptic drugs (AEDs), four being seizure free for >10 years. Myoclonic seizures (MC) evolving to generalized tonic–clonic seizures (GTC) were associated with seizure persistence (p = 0.013), whereas >1 year between MC and GTC onset was associated with a trend to GTC remission (p = 0.069). Of 19 patients with uncontrolled seizures, eight experienced remission with second generation AEDs.Favorable psychosocial outcome by interview was found in a third, whereas another third had psychiatric comorbidity, seven with substance or alcohol abuse. Psychosocial and seizure outcome did not correlate.ConclusionThis study corroborates the heterogeneity of JME in terms of seizure and psychosocial outcome, but without a clear association between the two. It confirms that seizure control may persist after AED withdrawal in some and supports MC evolving to GTC as a predictor of seizure persistence. Moreover, it suggests that newer broad spectrum AEDs may improve the prognosis of JME; their impact should be focus of prospective studies.     

Family-based association analysis of alcohol dependence in the COGA sample and replication in the Australian twin-family study

Family, twin, and adoption studies have indicated that genetic and environmental factors contribute to the development of alcohol dependence (AD). We conducted a low-density genome-wide association analysis to identify genetic variants influencing AD. We used 11,120 SNPs from the Affymetrix 10K Genechips genotyped in 116 Caucasian pedigrees (272 nuclear families) from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). Family-based association analyses for AD were performed by the PBAT program for autosomal SNPs and by the FBAT program for X-chromosome SNPs. We identified 37 SNPs associated with AD (P < 10⁻³), thirteen of which were located in known genes. The most significant association with AD was observed with SNP rs1986644 (P = 8.51 × 10⁻⁶) at 13q22 near EDNRB gene. The next best signal was at 1q41 in USH2A (rs532342, P = 1.07 × 10⁻⁵) and the third region was at 3q25.31 in TIPARP (rs1367311, P = 2.31 × 10⁻⁵). Furthermore, we found support for association of MAOA gene (P = 4.14 × 10⁻⁴ for rs979606). Six of the 37 AD associated SNPs were confirmed to be associated with AD in Australian twin-family study sample (P < 0.05). Interestingly, four SNPs in DSCAML1 at 11q23 reached the genome-wide significance (the top SNP is rs10892169 with P = 5.31 × 10⁻⁹), while rs637547 in NKAIN2 at 6q21 showed strong association with AD (P = 5.11 × 10⁻⁷) in the replication sample. These findings offer the potential for new insights into the pathogenesis of AD and will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in AD.     

Thalamic and cortical hyperexcitability in juvenile myoclonic epilepsy

ObjectivesJuvenile myoclonic epilepsy (JME) is a genetic generalized epilepsy marked by cortical hyperexcitability. Recent neuroimaging data suggested also a thalamic role in sustaining epileptic propensity in JME. However, thalamic hyperexcitability was not demonstrated so far. Low-frequency (LF-SEPs) and high-frequency somatosensory evoked potentials (HF-SEPs) are very sensitive to thalamic (early HF-SEPs burst, eHFO) and cortical (late HF-SEPs burst, lHFO) excitability. The aim of our experiment was to explore and discern the role of thalamic and cortical excitability in epileptic susceptibility of JME through a LF-SEPs and HF-SEPs study.MethodsTwenty-three subjects with JME (11 females, 30.2 ± 9.8-year-old) and 23 healthy control subjects (12 females, age: 34.7 ± 7.7-year-old) underwent right median LF-SEPs scalp recordings. Cp3′-Fz traces were filtered (400–800 Hz) to reveal HF-SEPs. All JME patients were on drug treatment and seizure free, except for sporadic myoclonus.ResultsN20 LF-SEPs amplitude (p < 0.009), areas of totHFO, eHFO and lHFO (all p < 0.005) and totHFO duration (p = 0.013) were increased in JME respect to healthy subjects. totHFO area was negatively correlated with the number of antiepileptic drugs (rho = -0.505, sig.: 0.027), while eHFO area was positively correlated with the myoclonus frequency (rho = 0.555, sig = 0.014).ConclusionsWe demonstrated that in JME the thalamic hyperexcitability assists the cortical one in sustaining epileptic susceptibility.SignificanceOur results support the concept of JME as a network and genetic disorder.     

The -141C Ins/Del and Taq1A polymorphism in the dopamine D2 receptor gene may confer susceptibility to schizophrenia in Asian populations

It has been reported that two single nucleotide polymorphisms (SNP) Taq1A and -141C Ins/Del in the DRD2 gene may be associated with susceptibility to schizophrenia. Due to inconclusive and mixed results, a meta-analysis was conducted to further clarify the relationship between the two SNP and schizophrenia susceptibility. A systematic literature search for the association of these two SNP with schizophrenia susceptibility was conducted using PubMed, ScienceDirect, Chinese Biomedical Literature Database, and Chinese National Knowledge Infrastructure. Odds ratios (OR) with 95% confidence intervals (CI) were used to assess the strength of the associations reported. A total of 5558 schizophrenic patients and 6792 healthy controls from 31 articles were included in this study. Evidence regarding the association between -141C Ins/Del polymorphism and schizophrenia was found in the allele frequency comparison (Ins versus Del: OR 1.29, 95% CI 1.06–1.57; p = 0.01, P_raw = 0.1, P_{False Discovery Rate} = 0.023). In ethnic subgroup analysis, the result revealed that the 141C Ins/Del polymorphism was associated with schizophrenia in all genetic models in Asians, but not in Caucasians. For Taq1A polymorphism, a significant association was found in the allele frequency (A1 versus A2: OR 0.71, 95% CI 0.52–0.98, p = 0.03). Stratification by ethnicity indicated an association between the Taq1A polymorphism and schizophrenia in Asians, but not Caucasians. The present study suggests that the -141C Ins/Del polymorphism carries a significantly increased risk of schizophrenia, while the Taq1A polymorphism carries a significantly decreased risk of schizophrenia susceptibility in Asians.     

Investigating the genetic basis of fever‐associated syndromic epilepsies using copy number variation analysis

Fever‐associated syndromic epilepsies ranging from febrile seizures plus (FS+) to Dravet syndrome have a significant genetic component. However, apart from SCN1A mutations in >80% of patients with Dravet syndrome, the genetic underpinnings of these epilepsies remain largely unknown. Therefore, we performed a genome‐wide screening for copy number variations (CNVs) in 36 patients with SCN1A‐negative fever‐associated syndromic epilepsies. Phenotypes included Dravet syndrome (n = 23; 64%), genetic epilepsy with febrile seizures plus (GEFS+) and febrile seizures plus (FS+) (n = 11; 31%) and unclassified fever‐associated epilepsies (n = 2; 6%). Array comparative genomic hybridization (CGH) was performed using Agilent 4 × 180K arrays. We identified 13 rare CNVs in 8 (22%) of 36 individuals. These included known pathogenic CNVs in 4 (11%) of 36 patients: a 1q21.1 duplication in a proband with Dravet syndrome, a 14q23.3 deletion in a proband with FS+, and two deletions at 16p11.2 and 1q44 in two individuals with fever‐associated epilepsy with concomitant autism and/or intellectual disability. In addition, a 3q13.11 duplication in a patient with FS+ and two de novo duplications at 7p14.2 and 18q12.2 in a patient with atypical Dravet syndrome were classified as likely pathogenic. Six CNVs were of unknown significance. The identified genomic aberrations overlap with known neurodevelopmental disorders, suggesting that fever‐associated epilepsy syndromes may be a recurrent clinical presentation of known microdeletion syndromes.     

No evidence of a role for cystatin B gene in juvenile myoclonic epilepsy

Genetic factors play a major role in the etiology of juvenile myoclonic epilepsy (JME), a common form of idiopathic generalized epilepsy, but so far, genes related to JME remain largely unknown. JME shares electroclinical features with Unverricht‐Lundborg disease (progressive myoclonic epilepsy type 1; EPM1), a form of progressive myoclonus epilepsy characterized by myoclonus, epilepsy, and gradual neurologic deterioration. EPM1 is caused by mutations in the gene that codes for cystatin B (CSTB), an inhibitor of cysteine protease. In the present study, we wished to investigate the role of the CSTB gene in patients with JME. Fifty‐seven unrelated patients (35 women; mean age ± standard deviation [SD], 24.1 ± 7.7; mean age ± SD at onset, 15.3 ± 2.4) with JME were enrolled. Twenty‐three of 57 patients were the probands of families with JME. The molecular diagnosis was carried out to identify the common dodecamer repeat expansion mutation or other disease‐causing mutations in the CSTB gene. The molecular analysis did not depict mutations in any of the 57 patients with JME. Our study did not support a role for the CSTB gene in patients with familial or sporadic JME.     

Complex discharge‐affecting networks in juvenile myoclonic epilepsy: A simultaneous EEG‐fMRI study

Juvenile myoclonic epilepsy (JME) is a common subtype of idiopathic generalized epilepsies (IGEs) and is characterized by myoclonic jerks, tonic‐clonic seizures and infrequent absence seizures. The network notion has been proposed to better characterize epilepsy. However, many issues remain not fully understood in JME, such as the associations between discharge‐affecting networks and the relationships among resting‐state networks. In this project, eigenspace maximal information canonical correlation analysis (emiCCA) and functional network connectivity (FNC) analysis were applied to simultaneous EEG‐fMRI data from JME patients. The main findings of our study are as follows: discharge‐affecting networks comprising the default model (DMN), self‐reference (SRN), basal ganglia (BGN) and frontal networks have linear and nonlinear relationships with epileptic discharge information in JME patients; the DMN, SRN and BGN have dense/specific associations with discharge‐affecting networks as well as resting‐state networks; and compared with controls, significantly increased FNCs between the salience network (SN) and resting‐state networks are found in JME patients. These findings suggest that the BGN, DMN and SRN may play intermediary roles in the modulation and propagation of epileptic discharges. These roles further tend to disturb the switching function of the SN in JME patients. We also postulate that emiCCA and FNC analysis may provide a potential analysis platform to provide insights into our understanding of the pathophysiological mechanism of epilepsy subtypes such as JME. Hum Brain Mapp 37:3515–3529, 2016. © 2016 Wiley Periodicals, Inc.     

DAT1 methylation changes in alcohol-dependent individuals vs. controls

IntroductionThe dopaminergic system plays a crucial role in the development of alcohol dependence. Regulation of the extracellular dopamine concentration is driven by dopamine transporter. Both, the expression and function of dopamine transporter, are influenced by chronic alcohol intake. Dopamine transporter (DAT) gene is also supposed to be differentially methylated in alcohol-dependent patients than in controls.Material and methodsDNA was extracted from peripheral blood leukocytes. We analyzed the methylation status in 23 CpG islands of DAT gene promoter in alcohol dependent subjects (n = 171) and control (n = 160) group.ResultsNo statistical differences in the general frequency of DAT CpG islands was revealed between patients (altogether 175 methylated islands) and control subjects (170 methylated islands (p = 0.86). However it was revealed that one of analyzed positions is significantly more often methylated in control subjects than in alcohol dependent individuals (p = 0.0296).ConclusionFurther subsequent studies are necessary to determine whether the methylation change of one (out of 23) CpG site results in DAT expression changes.     

Neuroimaging alterations related to status epilepticus in an adult population: Definition of MRI findings and clinical‐EEG correlation

Magnetic resonance imaging (MRI) provides an opportunity for identifying peri‐ictal MRI abnormalities (PMAs) related to status epilepticus (SE). Extremely variable MRI alterations have been reported previously during or after SE, mainly in small selected populations. In a retrospective monocentric study, we analyzed brain MRI changes observed in the ictal/postictal periods of SE in an adult population. We included all consecutive patients observed in a 5‐year period with an electroclinical diagnosis of SE and an MRI performed within 30 days from the beginning of SE. We identified 277 patients. Among them, 32 (12%) showed PMAs related to SE. The duration of SE was strongly associated with MRI alterations, showing a mean duration of 6 days vs 2 days (P = .011) in the group with and without MRI alterations, respectively. Focal electroencephalography (EEG) abnormalities (P = .00003) and in particular, lateralized periodic discharges (LPDs) (P < .0001) were strongly associated with PMAs. MRI alterations were unilateral (23 patients, 72%), located in multiple brain structures (19 patients, 59%), and involving mesiotemporal structures (17 patients, 53%). Sixteen patients (50%) had good spatial correspondence between cortical PMAs and the focal EEG pattern; 12 patients (38%) with focal EEG pattern showed cortical PMAs plus MRI signal changes also involving subcortical structures. A follow‐up MRI was available for 14 of 32 patients (44%): 10 patients presented a disappearance of PMAs, whereas in 4, PMAs were still present. This study demonstrates that a long duration SE and the presence of certain EEG patterns (LPDs) are associated with the occurrence of PMAs. A good spatial concordance was observed between cortical PMA location and the EEG focus.     

Brivaracetam as add‐on treatment in focal epilepsy: A real‐world time‐based analysis

The study assessed the clinical response to add‐on brivaracetam (BRV) in real‐world practice by means of time‐to‐baseline seizure count methodology. Patients with focal epilepsy who were prescribed add‐on BRV were identified. Primary endpoint was the time‐to‐baseline seizure count defined as the number of days until each patient experienced the number of focal seizures that occurred in the 90 days before BRV initiation. Subgroup analysis was performed according to levetiracetam (LEV) status (naive vs prior use). Three‐hundred eighty‐seven patients were included. The overall median time‐to‐baseline seizure count was 150 (95% confidence interval [CI] = 130‐175) days. The median time‐to‐baseline seizure count was 198 (lower limit of 95% CI = 168) days for LEV‐naive patients, 126 (95% CI = 105‐150) days for patients with prior LEV use and withdrawal due to insufficient efficacy, and 170 (95% CI = 128‐291) days for patients who discontinued LEV due to adverse events (P = .002). The number of prior antiseizure medications (adjusted hazard ratio [_adjHR] = 1.07, 95% CI = 1.02‐1.13, P = .009) and baseline monthly seizure frequency (_adjHR = 1.004, 95% CI = 1.001‐1.008, P = .028) were independently associated with the primary endpoint. Add‐on BRV improved seizure control in LEV‐naive and LEV‐prior patients. The time‐to‐baseline seizure count represents an informative endpoint alongside traditional study outcomes and designs.     

Juvenile myoclonic epilepsy: Long-term prognosis and risk factors

ObjectiveOur goal was to investigate the long-term clinical course of juvenile myoclonic epilepsy (JME) in a cohort of patients and to identify prognostic factors for refractoriness and seizure relapse after anti-seizure medications (ASMs) withdrawal. A literature review is also presented to consolidate and compare our findings with the previously reported cases.MethodsWe retrospectively studied a series of patients diagnosed with JME with 15 years or more of evolution. We collected clinical, neurophysiological and neuroimaging data from patients who met defined inclusion and exclusion criteria.ResultsStudy involved 61 patients (65.5% female) with mean age at study of 37.6 years, and mean age at its outset of 14.8 years. Median follow-up was 31.0 years (mean 28.9, range 15–53). They presented more frequently with a combination of myoclonic and generalized tonic-clonic seizures (GTCS) (65.6%). Sixty-five percent of patients (n = 40) had a 5-year terminal remission with a mean age at last seizure of 27.4 years. Thirty-two percent of seizure-free patients (n = 13) withdrew ASMs: 6 out of 13 had a recurrence of the seizures while 7 remained seizure-free (mean age at ASMs withdrawal 21.0 versus 35.7 years, p < 0.05). In the multivariate model, a high GTCS frequency at onset (p = 0.026) was a prognostic factor of drug resistance.ConclusionJME is often regarded as a benign epileptic syndrome, although a quarter of the individuals have refractory epilepsy. The possibility of withdrawing ASMs in patients who have been free of seizures over an extended time seems feasible.