A systematic review and meta-analysis of factors related to first line drugs refractoriness in patients with juvenile myoclonic epilepsy (JME).

INTRODUCTION: Juvenile Myoclonic Epilepsy (JME) is a prevalent form of epileptic disorder, specifically categorized within the realm of Genetic Generalized Epilepsy (GGE). Its hallmark features encompass unprovoked bilateral myoclonus and tonic-clonic seizures that manifest during adolescence. While most JME patients respond favorably to anti-seizure medication (ASM), a subset experiences refractory JME, a condition where seizures persist despite rigorous ASM treatment, often termed "Drug-Resistant Epilepsy" (DRE). This systematic review and meta-analysis aims to determine the prevalence of refractory JME, and further to identify socio-demographic, electrophysiological and clinical risk factors associated with its occurrence. Pinpointing these factors is crucial as it offers the potential to predict ASM responsiveness, enabling early interventions and tailored care strategies for patients. MATERIAL AND METHODS: The systematic review and meta-analysis followed the Cochrane Handbook and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study evaluated outcomes post ASM treatment in JME cohorts by searching papers published up to September 2023 in PubMed/MEDLINE, Scopus, and Google Scholar databases. Predefined inclusion criteria were met by 25 eligible studies, forming the basis for analysis. RESULTS: A total of 22 potential risk factors for refractory JME were documented. Notably, robust risk factors for treatment resistance included Psychiatric Disorder (Odds Ratio (OR), 3.42 [2.54, 4.61] (95% Confidence Inverval (Cl)), Febrile Seizures (OR, 1.83 [1.14, 2.96] (95% Cl)), Alcohol Consumption (OR, 16.86 [1.94, 146.88] (95%Cl)), Aura (OR, 2.15 [1.04, 4.47] (95%Cl)), childhood absence epilepsy (CAE) evolving into JME (OR, 4.54 [1.61, 12.78] (95%CI)), occurrence of three seizure types (OR, 2.96 [1.96, 4.46] (95%CI)), and Focal EEG abnormalities (OR, 1.85 [1.13, 3.01] (95%Cl)). In addition, there were some non-significant risk factors for DRE because of noticeable heterogeneity. CONCLUSION: In aggregate, over 36% of JME patients demonstrated drug resistance, with seven significant risk factors closely linked to this refractoriness. The interplay between these factors and whether they denote treatment non-response or heightened disease burden remains an open question and more studies would be required to fully examine their influence.

Drug-resistant juvenile myoclonic epilepsy: A literature review.

The ILAE's Task Force on Nosology and Definitions revised in 2022 its definition of juvenile myoclonic epilepsy (JME), the most common idiopathic generalized epilepsy disorder, but this definition may well change again in the future. Although good drug response could almost be a diagnostic criterion for JME, drug resistance (DR) is observed in up to a third of patients. It is important to distinguish this from pseudoresistance, which is often linked to psychosocial problems or psychiatric comorbidities. After summarizing these aspects and the various definitions applied to JME, the present review lists the risk factors for DR-JME that have been identified in numerous studies and meta-analyses. The factors most often cited are absence seizures, young age at onset, and catamenial seizures. By contrast, photosensitivity seems to favor good treatment response, at least in female patients. Current hypotheses on DR mechanisms in JME are based on studies of either simple (e.g., cortical excitability) or more complex (e.g., anatomical and functional connectivity) neurophysiological markers, bearing in mind that JME is regarded as a neural network disease. This research has revealed correlations between the intensity of some markers and DR, and above all shed light on the role of these markers in associated neurocognitive and neuropsychiatric disorders in both patients and their siblings. Studies of neurotransmission have mainly pointed to impaired GABAergic inhibition. Genetic studies have generally been inconclusive. Increasing restrictions have been placed on the use of valproate, the standard antiseizure medication for this syndrome, owing to its teratogenic and developmental risks. Levetiracetam and lamotrigine are prescribed as alternatives, as is vagal nerve stimulation, and there are several other promising antiseizure drugs and neuromodulation methods. The development of better alternative treatments is continuing to take place alongside advances in our knowledge of JME, as we still have much to learn and understand.

Sarcopenia and anti-seizure medication response in juvenile myoclonic epilepsy.

INTRODUCTION: This study aimed to investigate the presence of sarcopenia in patients with juvenile myoclonic epilepsy (JME) and the association between sarcopenia and response to anti-seizure medication (ASM) in patients with JME. METHODS: We enrolled 42 patients with JME and 42 healthy controls who underwent brain magnetic resonance imaging with three-dimensional T1-weighted imaging. We measured the temporal muscle thickness (TMT), a radiographic marker for sarcopenia, using T1-weighted imaging. We compared the TMT between patients with JME and healthy controls and analyzed it according to the ASM response in patients with JME. We also performed a receiver operating characteristic (ROC) curve analysis to evaluate how well the TMT differentiated the groups. RESULTS: The TMT in patients with JME did not differ from that in healthy controls (9.630 vs. 9.956 mm, p = .306); however, ASM poor responders had a lower TMT than ASM good responders (9.109 vs. 10.104 mm, p = .023). ROC curve analysis revealed that the TMT exhibited a poor performance in differentiating patients with JME from healthy controls, with an area under the ROC curve of .570 (p = .270), but good performance in differentiating between ASM good and poor responders, with an area under the ROC curve of .700 (p = .015). CONCLUSION: The TMT did not differ between patients with JME and healthy controls; however, it was reduced in ASM poor responders compared to ASM good responders, suggesting a link between ASM response and sarcopenia in patients with JME. TMT can be used to investigate sarcopenia in various neurological disorders.

Increased Thalamic Connectivity in Juvenile Myoclonic Epilepsy Based on Electroencephalography Source-Level Analysis.

Background: This study investigated alterations in the intrinsic thalamic network of patients with juvenile myoclonic epilepsy (JME) based on an electroencephalography (EEG) source-level analysis. Materials and Methods: We enrolled patients newly diagnosed with JME as well as healthy controls. The assessments were conducted in the resting state. We computed sources based on the scalp electrical potentials using a minimum-norm imaging method and a standardized, low-resolution, brain electromagnetic tomography approach. To create a functional connectivity matrix, we used the Talairach atlas to define thalamic nodes and applied the coherence method to measure brain synchronization as edges. We then calculated the intrinsic thalamic network using graph theory. We compared the intrinsic thalamic network of patients with JME with those of healthy controls. Results: This study included 67 patients with JME and 66 healthy controls. EEG source-level analysis revealed significant differences in the intrinsic thalamic networks between patients with JME and healthy controls. The measures of functional connectivity (radius, diameter, and characteristic path length) were significantly lower in patients with JME than in healthy controls (radius: 2.769 vs. 3.544, p = 0.015; diameter: 4.464 vs. 5.443, p = 0.024; and characteristic path length: 2.248 vs. 2.616, p = 0.046). Conclusions: We demonstrated alterations in the intrinsic thalamic network in patients with JME compared with those in healthy controls based on the EEG source-level analysis. These findings indicated increased thalamic connectivity in the JME group. These intrinsic thalamic network changes may be related to the pathophysiology of JME.

Diffusion tensor imaging in photosensitive and nonphotosensitive juvenile myoclonic epilepsy.

INTRODUCTION/BACKGROUND: Juvenile myoclonic epilepsy (JME) syndrome is known to cause alterations in brain structure and white matter integrity. The study aimed to determine structural white matter changes in patients with JME and to reveal the differences between the photosensitive (PS) and nonphotosensitive (NPS) subgroups by diffusion tensor imaging (DTI) using the tract-based spatial statistics (TBSS) method. METHODS: This study included data from 16 PS, 15 NPS patients with JME, and 41 healthy participants. The mean fractional anisotropy (FA) values of these groups were calculated, and comparisons were made via the TBSS method over FA values in the whole-brain and 81 regions of interest (ROI) obtained from the John Hopkins University White Matter Atlas. RESULTS: In the whole-brain TBSS analysis, no significant differences in FA values were observed in pairwise comparisons of JME patient group and subgroups with healthy controls (HCs) and in comparison between JME subgroups. In ROI-based TBSS analysis, an increase in FA values of right anterior corona radiata and left corticospinal pathways was found in JME patient group compared with HC group. When comparing JME-PS patients with HCs, an FA increase was observed in the bilateral anterior corona radiata region, whereas when comparing JME-NPS patients with HCs, an FA increase was observed in bilateral corticospinal pathway. Moreover, in subgroup comparison, an increase in FA values was noted in corpus callosum genu region in JME-PS compared with JME-NPS. CONCLUSIONS: Our results support the disruption in thalamofrontal white matter integrity in JME, and subgroups and highlight the importance of using different analysis methods to show the underlying microstructural changes.

Clinical application of trio-based whole-exome sequencing in idiopathic generalized epilepsy.

PURPOSE: Idiopathic generalized epilepsies (IGEs) are a common group of genetic generalized epilepsies with high genetic heterogeneity and complex inheritance. However, the genetic basis is still largely unknown. This study aimed to explore the genetic etiologies in IGEs. METHODS: Trio-based whole-exome sequencing was performed in 60 cases with IGEs. The pathogenicity of candidate genetic variants was evaluated by the criteria of the American College of Medical Genetics and Genomics (ACMG), and the clinical causality was assessed by concordance between the observed phenotype and the reported phenotype. RESULTS: Seven candidate variants were detected in seven unrelated cases with IGE (11.7%, 7/60). According to ACMG, a de novo SLC2A1 (c.376C>T/p.Arg126Cys) variant identified in childhood absence epilepsy was evaluated as pathogenic with clinical concordance. Six variants were assessed to be uncertain significance by ACMG, but then considered causative after evaluation of clinical concordance. These variants included CLCN4 hemizygous variant (c.2044G>A/p.Glu682Lys) and IQSEC2 heterozygous variant (c.4315C>T/p.Pro1439Ser) in juvenile absence epilepsy, EFHC1 variant (c.1504C>T/p.Arg502Trp) and CACNA1H (c.589G>T/p.Ala197Ser) both with incomplete penetrance in juvenile myoclonic epilepsy, and GRIN2A variant (c.2011C>G/p.Gln671Glu) and GABRB1 variant (c.1075G>A/p.Val359Ile) both co-segregated with juvenile myoclonic epilepsy. Among them, GABRB1 was for the first time identified as potential novel causative gene for IGE. SIGNIFICANCE: Considering the genetic heterogeneity and complex inheritance of IGEs, a comprehensive evaluation combined the ACMG scoring and assessment of clinical concordance is suggested for the pathogenicity analysis of variants identified in clinical screening. GABRB1 is probably a novel causative gene for IGE, which warrants further studies.

EFHC1 gene mutation profile of Turkish JME patients and its association with disease risk.

OBJECTIVES: Juvenile myoclonic epilepsy (JME) is a common form of generalized epilepsy with an important genetic component. This cohort study aimed to examine the frequency of EFHC1 gene variants in Turkish JME patients and a healthy control group and evaluate the association between these mutations and disease risk. METHODS: We screened 72 JME patients with a mean age of 31.8 ± 9.9 (20-65) years and 35 controls with a mean age of 29.1 ± 7.6 (17-50) years from southern Turkey using direct sequencing analyses. RESULTS: EFCH1 single nucleotide variants were detected in 24 of 72 JME patients and 3 of 35 controls. The most common mutations were R182H in JME patients (p = 0.010) and 3'UTR in the control group (p < 0.001). The R182H mutation is a common variant in JME (95 % CI: 1.232-76.580, p = 0.031) and the 3'UTR mutation may be associated with lower risk of JME in the Turkish population (95 % CI: 13.89-166.67, p < 0.001). SIGNIFICANCE: Our results indicate that EFHC1 gene variants carry a risk for JME and the 3'UTR variant may have a protective role against JME in the Turkish population. Screening for other genes is needed to further clarify the genetic inheritance of JME in Turkish patients.

Association of variants in the ABCB1, CYP2C19 and CYP2C9 genes for Juvenile Myoclonic Epilepsy.

Juvenile myoclonic epilepsy (JME) is the most common of the generalized genetic epilepsies, with multiple causal and susceptibility genes; however, its etiopathogenesis is mainly unknown. The toxic effects caused by xenobiotics in cells occur during their metabolic transformation, mainly by enzymes belonging to cytochrome P450. The elimination of these compounds by transporters of the ABC type protects the central nervous system, but their accumulation causes neuronal damage, resulting in neurological diseases. The present study has sought the association between single nucleotide genetic variants of the CYP2C9, CYP2C19, and ABCB1 genes and the development of JME in patients compared to healthy controls. The CC1236 and GG2677 genotypes of ABCB1 in women; allele G 2677, genotypes GG 2677 and CC 3435 in men; the CYP2C19*2A allele, and the CYP2C19*3G/A genotype in both sexes were found to be risk factors for JME. Furthermore, carriers of the TTGGCC genotype combination of the ABCB1 gene (1236/2677/3435) have a 10.5 times higher risk of developing JME than non-carriers. Using the STRING database, we found an interaction between the proteins encoded by these genes and other possible proteins. These findings indicate that the CYP450 system and ABC transporters could interact with other genes in the JME.

[Reflex triggers in juvenile myoclonic epilepsy]. / Los desencadenantes reflejos en la epilepsia mioclónica juvenil.

INTRODUCTION: Juvenile myoclonic epilepsy (JME) is an epileptic syndrome with onset in childhood and adolescence with myoclonus, absences, and generalized tonic-clonic seizures. Reflex stimuli such as sensitivity to light or photosensitivity, eyelid opening and closing, and praxis induction produce epileptiform discharges and seizures. These reflex triggers are not all systematically studied. OBJECTIVE: Examine reflex features in patients with JME. METHODS: One hundred adolescents and adults with JME who received different anti-seizure treatments were evaluated consecutively. A standard electroencephalogram was performed with an intermittent light stimulation (SLI) protocol and another for the evaluation of praxias through neurocognitive activity (CNA). The statistical analysis was descriptive and of correlation with a p > 0.05. RESULTS: Current age was 28±11 (14-67). The seizure began at 15 years ±3 (Range 8-25 years). They presented myoclonus and generalized tonic-clonic seizures in 58%. 50% received valproic acid and 31% continued with seizures. Epileptiform discharges at rest 20%; hyperventilation 30%; eyelid opening and closing 12%; photoparoxysmal response in SLI 40%; CNA 23%. Higher percentage of discharges and delay in performing CNA in those who presented seizures. Valproic acid compared to other drugs did not demonstrate superiority in seizure control. CONCLUSIONS: These findings confirm the importance of studying reflex traits for diagnosis, follow-up, and therapeutic control.

Introducción: La epilepsia mioclónica juvenil (EMJ) es un síndrome epiléptico de inicio en la infancia y adolescencia con mioclonías, convulsiones tónico-clónicas generalizadas y ausencias. Los estímulos reflejos como la sensibilidad a la luz o fotosensibilidad, la apertura y cierre palpebral y la inducción por praxias producen descargas epileptiformes y crisis. Estos desencadenantes reflejos no son todos sistemáticamente estudiados. OBJETIVO: Examinar los rasgos reflejos en pacientes con EMJ. Métodos: Se evaluaron en forma consecutiva 100 adolescentes y adultos con EMJ que recibían diferentes tratamientos anticrisis. Se realizó un electroencefalograma standard con un protocolo de estimulación luminosa intermitente (ELI) y otro para la evaluación de las praxias a través de una actividad neurocognitiva (ANC). El análisis estadístico fue descriptivo y de correlación. Se consideró significativa una p > 0.05. RESULTADOS: La edad actual fue de 28±11 (14-67). Las crisis comenzaron a los 15 años ±3 (Rango 8-25 años). EL 58% presentaron mioclonías y convulsiones tónico clónicas generalizadas. El 50% recibían ácido valproico y el 31% continuaban con crisis. Descargas epileptiformes en reposo 20%; hiperventilación 30%; apertura y cierre palpebral 12%; respuesta fotoparoxística en la ELI 40%; ANC 23%. Mayor porcentaje de descargas y demora en la realización de la ANC en los que presentaban crisis. El ácido valproico comparado con los otros fármacos no demostró superioridad en el control de las crisis. CONCLUSIONES: Estos hallazgos confirman la importancia del estudio de los rasgos reflejos para el diagnóstico, seguimiento y el control terapéutico.

A comparison of comorbid headache between patients with temporal lobe epilepsy and juvenile myoclonic epilepsy.

Headache is one of the most common symptoms of epilepsy comorbidities. However, the relationship between the epilepsy and headache still needs clarification. Previous studies mostly investigated the overall incidence and clinical features of the headache in patients with the epilepsy. Temporal lobe epilepsy (TLE) and juvenile myoclonic epilepsy (JME) are the common types of focal epilepsy and generalized epilepsy, respectively. Nevertheless, there was no study comparing the clinical features of headache between TLE and JME. This study aimed to analyze the headache features of these two types of epilepsy. Patients with either TLE or JME diagnosed with headache and referred to the West China Hospital of Sichuan University were consecutively recruited from June 2021 to June 2022. The duration of epilepsy was longer than 6 months in these patients. Data on headache and epilepsy were obtained through face-to-face questionnaires. The headache was classified according to the International Classification Headache Disorders-3rd edition (ICHD-III) criteria. χ2-test, t-test, rank-sum test, logistic regression modeling and Mann Whitney test were used to compare the clinical differences of the headache in TLE and JME. A total of 151 TLE patients and 30 JME patients were enrolled in this study. There was no significant difference in the family history of headache, epilepsy durations, headache types, proportion receiving analgesic therapy, the frequency of inter-ictal headache (inter-IH), and the quality of life in epilepsy -10 inventory (QOLIE-10) between the TLE and JME patients. Patients in the TLE group were significantly older (p = 0.004), and a lower percentage of them had a family history of epilepsy (p = 0.007) compared with the JME patients. The proportion of cases with refractory epilepsy was higher in the TLE group than that in the JME group (p < 0.001). The types of seizures in the TLE group varied from those in the JME group (p < 0.001). The composition of the antiseizure medications (ASM) applied in the TLE group differed from that in the JME group (p = 0.047), and the usage of oxcarbazepine was more frequently in the TLE group than in the JME group (p = 0.003). There was no difference in the headache types among patients with TLE or JME. Specifically, 67 (44.37%), 12 (7.95%), and 118 (7.95%) patients were found with inter-IH, pre-ictal headache (Pre-IH) and post-ictal headache (Post-IH) in the TLE group; while 8 (26.67%), 4 (13.33%) and 26 (86.67%) patients had inter-IH, Pre-IH and Post-IH in the JME group. Thirty-nine patients in the TLE group and 4 patients in the JME group were identified with more than one type of headaches, respectively. Tension-type headache (TTH) were found in 38 patients (25.17%) in the TLE group and 3 patients (10.00%) in the JME group, respectively; migraines were found in 10 patients (6.62%) in the TLE group and in 2 patients (6.67%) in the JME group. Patients in the TLE group had a higher headache-attributed lost time-90 days (HLT-90) score than those in the JME group (p = 0.019). The proportion of patients with inter-IH accompanied by nausea in the TLE group was higher than that in the JME group (p = 0.029), while the proportion of patients with frontal headache was lower than that in the JME group (p < 0.05). There was no significant difference in headache severity, quality, headache nature, unilateral/bilateral, and headache duration either in inter-IH or peri-ictal headache (Peri-IH) between the two groups. The logistic regression analysis suggested that except for HLT-90 (AUC = 0.622, p = 0.027), other factors were not found to be correlated with refractory epilepsy. The clinical features of headache differed between TLE and JME patients. TLE patients had a higher ratio of refractory epilepsy, more headache time loss compared with JME patients. HLT-90 was associated with the occurrence of refractory epilepsy in TLE patients. Taken together, we suggested that the comorbid headache may essentially be different between TLE and JME patients.

Recognition and perception of emotions in juvenile myoclonic epilepsy.

OBJECTIVE: Perception and recognition of emotions are fundamental prerequisites of human life. Patients with juvenile myoclonic epilepsy (JME) may have emotional and behavioral impairments that might influence socially desirable interactions. We aimed to investigate perception and recognition of emotions in patients with JME by means of neuropsychological tests and functional magnetic resonance imaging (fMRI). METHODS: Sixty-five patients with JME (median age = 27 years, interquartile range [IQR] = 23-34) were prospectively recruited at the Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University, Salzburg, Austria. Patients were compared to 68 healthy controls (median age = 24 years, IQR = 21-31), matched for sex, age, and education. All study participants underwent the Networks of Emotion Processing test battery (NEmo), an fMRI paradigm of "dynamic fearful faces," a structured interview for psychiatric and personality disorders, and comprehensive neuropsychological testing. RESULTS: JME patients versus healthy controls demonstrated significant deficits in emotion recognition in facial and verbal tasks of all emotions, especially fear. fMRI revealed decreased amygdala activation in JME patients as compared to healthy controls. Patients were at a higher risk of experiencing psychiatric disorders as compared to healthy controls. Cognitive evaluation revealed impaired attentional and executive functioning, namely psychomotor speed, tonic alertness, divided attention, mental flexibility, and inhibition of automated reactions. Duration of epilepsy correlated negatively with parallel prosodic and facial emotion recognition in NEmo. Deficits in emotion recognition were not associated with psychiatric comorbidities, impaired attention and executive functions, types of seizures, and treatment. SIGNIFICANCE: This prospective study demonstrated that as compared to healthy subjects, patients with JME had significant deficits in recognition and perception of emotions as shown by neuropsychological tests and fMRI. The results of this study may have importance for psychological/psychotherapeutic interventions in the management of patients with JME.

Multi-spectral diffusion MRI mega-analysis in genetic generalized epilepsy: Relation to outcomes.

BACKGROUND AND OBJECTIVES: Genetic generalized epilepsy (GGE) is the most common form of generalized epilepsy. Although individual patients with GGE typically present without structural alterations, group differences have been demonstrated in GGE and some GGE subtypes like juvenile myoclonic epilepsy (GGE-JME). Previous studies usually involved only small cohorts from single centers and therefore could not assess imaging markers of multiple GGE subtypes. METHODS: We performed a diffusion MRI mega-analysis in 192 participants consisting of 126 controls and 66 patients with GGE from four different cohorts and two different epilepsy centers. We applied whole-brain multi-site harmonization and analyzed fractional anisotropy (FA), as well as mean, radial and axial diffusivity (MD/RD/AD) to assess differences between controls, patients with GGE and the common GGE subtypes, i.e. GGE with generalized tonic-clonic seizures only (GGE-GTCS), GGE-JME and absence epilepsy (GGE-AE). We also analyzed relationships with patients' response to anti-seizure-medication (ASM). RESULTS: Relative to controls, we identified decreased anisotropy and increased RD in patients with GGE. We found no significant effects of disease duration, age of onset or seizure frequency on diffusion metrics. Patients with JME had increased MD and RD when compared to controls, while patients with GGE-GTCS showed decreased MD/AD when compared to controls. Compared to patients with GGE-AE, patients with GGE-GTCS had lower AD/MD. Compared to patients with GGE-GTCS, patients with GGE-JME had higher MD/RD and AD. Moreover, we found lower FA in patients with refractory when compared to patients with non-refractory GGE in the right cortico-spinal tract, but no significant differences in patients with active versus controlled epilepsy. DISCUSSION: We provide evidence that clinically defined GGE as a whole and GGE-subtypes harbor marked microstructural differences detectable with diffusion MRI. Moreover, we found an association between microstructural changes and treatment resistance. Our findings have important implications for future full-resolution multi-site studies when assessing GGE, its subtypes and ASM refractoriness.

Outpatient visit behavior in patients with epilepsy: Generalized Epilepsy is more frequently non-attendance than Focal Epilepsy.

BACKGROUND: Patients with epilepsy (PWE), especially those with Idiopathic Epilepsy (GE), are at a high risk of disadvantage caused by non-adherence. It has been suggested that medical visit behavior may be a surrogate indicator of medication adherence. We hypothesized that patients with IGE would adhere poorly to visits. METHODS: This was a retrospective study of PWE who visited the Department of Psychiatry and Neurology at Hokkaido University Hospital between January 2017 and December 2019. Demographic and clinical information on PWE were extracted from medical records and visit data from the medical information system. Non-attendance of outpatient appointments was defined as "not showing up for the day of an appointment without prior notice." Mixed-effects logistic regression analysis was conducted with non-attendance as the objective variable. RESULTS: Of the 9151 total appointments, 413 were non-attendances, with an overall non-attendance rate of 4.5%. IGE was a more frequent non-attendance than Focal Epilepsy (FE) (odds ratio (OR) 1.94; 95% confidence interval (CI) 1.17-3.21; p = 0.010). History of public assistance receipt was associated with higher non-attendance (OR 2.04; 95% CI 1.22-3.43; p = 0.007), while higher education (OR 0.64; 95% CI 0.43-0.93; p = 0.021) and farther distance to a hospital (OR 0.33; 95% CI 0.13-0.88; p = 0.022), and higher frequency of visits (OR 0.18; 95% CI 0.04-0.86; p = 0.031) were associated with fewer non-attendances. In a subgroup analysis of patients with GE, women were associated with fewer non-attendance (OR 0.31; 95% CI 0.14-0.72; p = 0.006). CONCLUSIONS: GE was more frequent in the non-attendance group than in the FE group. Among patients with GE, females were found to have non-attendance less frequently; however, there was no clear difference in the odds of non-attendance between Juvenile Myoclonic Epilepsy (JME) and IGE other than JME.

Cognitive phenotype of juvenile absence epilepsy: An investigation of patients and unaffected siblings.

OBJECTIVE: The cognitive profile of juvenile absence epilepsy (JAE) remains largely uncharacterized. This study aimed to: (1) elucidate the neuropsychological profile of JAE; (2) identify familial cognitive traits by investigating unaffected JAE siblings; (3) establish the clinical meaningfulness of JAE-associated cognitive traits; (4) determine whether cognitive traits across the idiopathic generalized epilepsy (IGE) spectrum are shared or syndrome-specific, by comparing JAE to juvenile myoclonic epilepsy (JME); and (5) identify relationships between cognitive abilities and clinical characteristics. METHODS: We investigated 123 participants-23 patients with JAE, 16 unaffected siblings of JAE patients, 45 healthy controls, and 39 patients with JME-who underwent a comprehensive neuropsychological test battery including measures within four cognitive domains: attention/psychomotor speed, language, memory, and executive function. We correlated clinical measures with cognitive performance data to decode effects of age at onset and duration of epilepsy. RESULTS: Cognitive performance in individuals with JAE was reduced compared to controls across attention/psychomotor speed, language, and executive function domains; those with ongoing seizures additionally showed lower memory scores. Patients with JAE and their unaffected siblings had similar language impairment compared to controls. Individuals with JME had worse response inhibition than those with JAE. Across all patients, those with older age at onset had better attention/psychomotor speed performance. SIGNIFICANCE: JAE is associated with wide-ranging cognitive difficulties that encompass domains reliant on frontal lobe processing, including language, attention, and executive function. JAE siblings share impairment with patients on linguistic measures, indicative of a familial trait. Executive function subdomains may be differentially affected across the IGE spectrum. Cognitive abilities are detrimentally modulated by an early age at seizure onset.

Structural insights of novel mutational frames in Bromodomain Containing-2 gene (BRD2) in juvenile myoclonic epilepsy: bed, bench, and laptop profiles.

PURPOSE: Juvenile myoclonic epilepsy (JME) is an adolescent onset type of idiopathic generalized epilepsies. Bromodomain containing protein-2 gene (BRD2), a transcriptional regulatory protein, has a susceptible role in the expression of JME. Considering the polymorphic variations observed in exon 3 of the BRD2 gene, we evaluated the molecular interactions with anti-seizure medication in individuals diagnosed with JME. METHODS: The genomic DNA was extracted from 5 mL of peripheral venous blood of JME participants (n = 55) and healthy control subjects (n = 55). Detailed anti-seizure medication and outcomes were noted during the study period. Identified novel mutations at nucleotide and protein sequences, compared by multiple sequence alignment. Wild-type (WT) and mutated-type (MT) structures were investigated for molecular docking and interactions with anti-seizure drugs. RESULTS: A common variant at c.1707G>A was found among 23 participants, while a single variant at c.1663ins C was found in one participant. The deletion positions were observed at c.1890delA, c.1892A>T, c.1895A>T, c.1896G>T, c.1897T>C, c.1898T>C, c.1899C>T, c.1900G>T, c.1901C>T and c.1902A>T exhibiting stop codon after p.111Pro>stop; these variants resulted in a truncated protein. In silico analysis was conducted to validate changes; docking analysis showed that novel variant has a significant role in the interactions with anti-seizure drugs. SIGNIFICANCE: Besides clinical and genetic outcomes, ∼5.45% unique genetical variations were observed in the participants. Significant mimicked at the binding site position (92-111) of human BRD2 ranges ∼8.2%, ∼16.4%, and ∼10.6%. Further, research is needed to identify the importance of polymorphism alterations at the binding site and their molecular interactions with anti-seizure drugs, which might be confirmed in a diverse population with JME.

A cognitive rehabilitation program to improve hot and cool executive dysfunction in juvenile myoclonic epilepsy: Preliminary findings.

OBJECTIVE: Executive and attentional deficits are often described in Juvenile Myoclonic Epilepsy (JME). We aimed to evaluate the short-term impact of rehabilitation developed for the most frequent cognitive deficits of persons with JME. METHODS: Thirty-three patients entered this study which consisted of 12 individual sessions once a 60-minute week, divided into planning/organization, attention, and impulsivity. Twenty-seven patients finished the protocol, and all patients had pre-and-post evaluations from neuropsychological tests and self-rating questionnaires. Generalized Estimating Equations (GEE) inferential statistics were used to verify the protocol's effect, and a 95% confidence interval was adopted. RESULTS: We found significant improvement in selective attention (TMT A [p < 0.01] and Stroop test 2 [p = 0.03]), inhibitory control (Stroop test 3 [p = 0.02], FAS [p < 0.01], CPT commissions [p < 0.01]), mental flexibility [WCST categories p < 0.01] and implicit decision making (IGT blocks A [p < 0.01], B [p = 0.02], C [p < 0.01] and D [p < 0.01]). All components of the Behavioral Rating Index of Executive Functions metacognition index and the general quotient had significant improvement (initiative [p ≤ 0.01], working memory [p ≤ 0.01], planning and organization [p ≤ 0.01], task monitor [p = 0.02] and organization of materials [p = 0.02]). Regarding the Behavioral Regulation Index, the "Emotional Control" was improved [p = 0.03]. The attentional component and general scores of the Adult Self-Report Scale for Adults also changed significantly [p ≤ 0.01]. SIGNIFICANCE: Executive function and attention had an improvement in objective and subjective tests. The context-dependent reactive mechanism of impulsivity improved in instruments based on the ecological evaluation. Our findings, though preliminary due to a lack of controls and practice effect corrections, support that cognitive rehabilitation may be a valuable resource to alleviate cognitive deficits in patients with JME.

Two-year efficacy of lacosamide as adjunctive therapy for generalized tonic-clonic seizures in patients with juvenile myoclonic epilepsy.

OBJECTIVE: To report the long-term efficacy of adjunctive lacosamide therapy in patients with juvenile myoclonic epilepsy whose generalized tonic-clonic seizures were significantly reduced by treatment. METHODS: A retrospective study was conducted in patients who visited the Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital and the Department of Pediatrics, National Hospital Organization Nagasaki Medical Center. Among patients who had been diagnosed with juvenile myoclonic epilepsy, those who received lacosamide as adjunctive therapy for refractory generalized tonic-clonic seizures for at least 2 years from January 2017 to December 2022, and who achieved seizure freedom or >50% seizure reduction in tonic-clonic seizures were included. The medical records and neurophysiological data of the patients were reviewed retrospectively. RESULTS: Four patients met the inclusion criteria. The mean age at the onset of epilepsy was 11.3 years (range 10-12), and the mean age of starting lacosamide was 17.5 years (range 16-21). All patients received two or more antiseizure medications prior to lacosamide. Three of four patients had seizure freedom for more than 2 years, and the one remaining patient had >50% seizure reduction for more than one year. Only one patient had recurrent myoclonic seizures after starting lacosamide. The mean lacosamide dose at the last visit was 425 mg/day (range 300-600). CONCLUSION: Adjunctive lacosamide therapy might be a treatment option for juvenile myoclonic epilepsy with generalized tonic-clonic seizures, which are not responsive to standard antiseizure medications.

Neuropsychological profile and drug treatment response in Idiopathic Generalized Epilepsy.

PURPOSE: The endophenotype of Idiopathic Generalized Epilepsies (IGE) comprises distinct neuropsychological deficits compared to normal controls. It is unknown if the severity of features of the endophenotype correlates with resistance to anti-seizure medication. Therefore, we here studied the association of neuropsychological profiles with treatment response. METHODS: We evaluated 106 Danish patients aged ≥18 and diagnosed with IGE using a neuropsychological test battery comprising tests for executive dysfunction, visual attention, episodic memory, and verbal comprehension. Tests were complemented by the Purdue Pegboard test. Patients with suspected ongoing psychogenic non-epileptic seizures were excluded. RESULTS: At testing, 72 patients were seizure free, and 34 patients had recent seizures despite anti-seizure medication. As compared to age corrected Danish normative values, IGE patients showed significant impairments in semantic fluency and performed significantly worse in the Purdue Pegboard test. The vocabulary subtest of the WAIS-IV suggested lower verbal comprehension in IGE patients. We found no signs of memory impairment. Comparisons between results of the test battery, drug resistance, and the different IGE subsyndromes revealed consistent null-associations in various predefined and exploratory univariate and multivariate analyses. CONCLUSION: We here found and confirmed the distinct neuropsychological profile comprising impaired executive functions, reduced psychomotor speed, and normal memory previously described in juvenile myoclonic epilepsy. This profile was, however, not restricted to juvenile myoclonic epilepsy but equally affected all IGE patients. The neuropsychological deficits were not significantly associated with drug treatment outcome.

Prevalence, nature, and severity of the psychiatric comorbidities and their impact on quality of life in adolescents with Juvenile myoclonic epilepsy.

INTRODUCTION: Adults with Juvenile myoclonic epilepsy (JME) are at increased risk for psychiatric comorbidities, personality traits, and abnormality in executive function. But studies on adolescents and their impact on quality of life are scarce in the literature. MATERIALS AND METHODS: This cross-sectional study was performed between August 2019 and October 2022 to compare the prevalence of psychiatric comorbidities in adolescents with JME and age and gender-matched healthy controls. After completing DSM-5 Structured Clinical Interview (SCID-5) initially in all patients, we measured the severity of individual psychiatric problems like anxiety, depression, and somatic symptoms by using an appropriate psychometric scale. We also measured both groups' intelligence quotient (IQ), executive function, and quality of life. RESULTS: One hundred patients with JME (14.3 ± 2.5 years, 48 boys) and 100 controls were enrolled. Psychiatric disorders were observed in 46% of JME and 6% of controls (p < 0.01). Psychiatric comorbidities noted in the patients with JME were: somatic symptom and related disorders(n = 14), anxiety (n = 13), adjustment disorders (n = 12), depression (n = 11), oppositional defiant disorder (n = 6), conduct disorder (n = 5), anorexia nervosa (n = 3), narcissistic (n = 3), histrionic (n = 1), substance-related disorder (n = 1), borderline (n = 2) and antisocial personality disorder (n = 2). The prevalence of depressive disorders, anxiety disorders, adjustment disorders, somatic symptoms, related disorders, and any personality disorder was significantly more in the JME group (p < 0.01 for all). Female gender, higher Epilepsy Stigma Scale score, and lower Epilepsy Outcome Expectancy Scale were significantly associated with depressive disorders (p = 0.04, 0.03, 0.03 respectively). Similarly, for anxiety, only female gender and lower Epilepsy Outcome Expectancy Scale were significant associated factors (p = 0.03, 0.02 respectively). CONCLUSIONS: Psychiatric disorders like anxiety, depression, and personality disorders are more frequent in adolescents with JME than in controls.