Predictors of Seizure Recurrence in Women With Idiopathic Generalized Epilepsy Who Switch From Valproate to Another Medication.

BACKGROUND AND OBJECTIVES: To investigate the predictors of seizure recurrence in women of childbearing age with idiopathic generalized epilepsy (IGE) who switched from valproate (VPA) to alternative antiseizure medications (ASMs) and compare the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) as VPA alternatives after switch. METHODS: This multicenter retrospective study included women of childbearing age diagnosed with IGE from 16 epilepsy centers. Study outcomes included worsening or recurrence of generalized tonic-clonic seizure (GTCS) at 12 months and 24 months after the switch from VPA to an alternative ASM. The comparative effectiveness of LEV and LTG as alternative ASM following VPA discontinuation was assessed through inverse probability treatment-weighted (IPTW) Cox regression analysis. RESULTS: We included 426 women with IGE, with a median (interquartile range) age at VPA switch of 24 (19-30) years and a median VPA dosage of 750 (500-1,000) mg/d. The most common reason for VPA switch was teratogenicity concern in 249 women (58.6%), and the most common ASM used in place of VPA was LEV in 197 (46.2%) cases, followed by LTG in 140 (32.9%). GTCS worsening/recurrence occurred in 105 (24.6%) and 139 (32.6%) women at 12 and 24 months, respectively. Catamenial worsening of seizures, higher VPA dosage during switch, multiple seizure types, and shorter duration of GTCS freedom before switch were independent predictors of GTCS recurrence or worsening at 12 months according to mixed multivariable logistic regression analysis. After internal-external validation through 16 independent cohorts, the model showed an area under the curve of 0.71 (95% CI 0.64-0.77). In the subgroup of 337 women who switched to LEV or LTG, IPTW Cox regression analysis showed that LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG (adjusted hazard ratio 0.59, 95% CI 0.40-0.87, p = 0.008) during the 24-month follow-up. DISCUSSION: Our findings can have practical implications for optimizing counselling and treatment choices in women of childbearing age with IGE and may help clinicians in making informed treatment decisions in this special population of patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with IGE switching from VPA, LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG.

Topiramate ban in women of childbearing potential with idiopathic generalized epilepsy: Does effectiveness offset the teratogenic risks?

Regulatory agencies have recently discouraged the prescription of topiramate (TPM) to women of childbearing potential with epilepsy due to growing evidence of the teratogenic and neurodevelopmental risks associated with its use during pregnancy. It remains, however, unclear whether the use of TPM in this population can be supported to some extent by its high effectiveness. In this multicenter, retrospective, cohort study performed at 22 epilepsy centers, we investigated the comparative effectiveness of TPM and levetiracetam (LEV) given as first-line antiseizure medication in a cohort of women of childbearing potential with idiopathic generalized epilepsy (IGE). A total of 336 participants were included, of whom 24 (7.1%) received TPM and 312 (92.9%) LEV. Women treated with TPM had significantly higher risks of treatment failure and treatment withdrawal and were less likely to achieve seizure freedom at 12 months compared to women treated with LEV. In conclusion, this study highlighted a low tendency among clinicians to use TPM in women of childbearing potential with IGE, anticipating the recently released restrictions on its use. Furthermore, the available data on effectiveness do not appear to support the use of TPM in this population.

Epilepsy with generalized tonic-clonic seizures alone: Electroclinical features and prognostic patterns.

OBJECTIVE: Epilepsy with generalized tonic-clonic seizures alone (GTCA) is a common but poorly characterized idiopathic generalized epilepsy (IGE) syndrome. Hence, we investigated electroclinical features, seizure outcome, and antiseizure medication (ASM) withdrawal in a large cohort of GTCA patients. METHODS: In this multicenter retrospective study, GTCA patients defined according to the diagnostic criteria of the International League Against Epilepsy (2022) were included. We investigated prognostic patterns, drug resistance at the last visit, and ASM withdrawal, along with their prognostic factors. RESULTS: We included 247 patients with a median (interquartile range [IQR]) age at onset of 17 years (13-22) and a median follow-up duration of 10 years (IQR = 5-20). Drug resistance at the last visit was observed in 40 (16.3%) patients, whereas the median latency to achieve 2-year remission was 24 months (IQR = 24-46.5) with a median number of 1 (IQR = 1-2) ASM. During the long-term follow-up (i.e., 202 patients followed ≥5-years after the first ASM trial), 69 (34.3%) patients displayed an early remission pattern and 36 (17.9%) patients displayed a late remission pattern, whereas 16 (8%) and 73 (36.3%) individuals had no-remission and relapsing-remitting patterns, respectively. Catamenial seizures and morning predominance of generalized tonic-clonic seizures (GTCS) independently predicted drug resistance at the last visit according to multivariable logistic regression. Treatment withdrawal was attempted in 63 (25.5%) patients, with 59 (93.7%) of them having at least a 12-month follow-up after ASM discontinuation. At the last visit, 49 (83%) of those patients had experienced GTCS recurrence. A longer duration of seizure freedom was the only factor predicting a higher chance of successful ASM withdrawal according to multivariable Cox regression. SIGNIFICANCE: GTCA could be considered a relatively easily manageable IGE syndrome, with a low rate of drug resistance and a high prevalence of early response to treatment. Nevertheless, a considerable proportion of patients experience relapsing patterns of seizure control, highlighting the need for appropriate counseling and lifestyle recommendations.

Levetiracetam vs Lamotrigine as First-Line Antiseizure Medication in Female Patients With Idiopathic Generalized Epilepsy.

Importance: After the recent limitations to prescribing valproate, many studies have highlighted the challenging management of female patients of reproductive age with idiopathic generalized epilepsy (IGE). However, no study, to the authors' knowledge, has addressed the comparative effectiveness of alternative antiseizure medications (ASMs) in these patients. Objective: To compare the effectiveness and safety of levetiracetam and lamotrigine as initial monotherapy in female patients of childbearing age with IGE. Design, Setting, and Participants: This was a multicenter, retrospective, comparative effectiveness cohort study analyzing data from patients followed up from 1994 to 2022. Patients were recruited from 22 primary, secondary, and tertiary adult and child epilepsy centers from 4 countries. Eligible patients were female individuals of childbearing age, diagnosed with IGE according to International League Against Epilepsy (2022) criteria and who initiated levetiracetam or lamotrigine as initial monotherapy. Patients were excluded due to insufficient follow-up after ASM prescription. Exposures: Levetiracetam or lamotrigine as initial monotherapy. Main Outcomes and Measures: Inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazards regression was performed to compare treatment failure (TF) among patients who received levetiracetam or lamotrigine as initial monotherapy. Results: A total of 543 patients were included in the study, with a median (IQR) age at ASM prescription of 17 (15-21) years and a median (IQR) follow-up of 60 (24-108) months. Of the study population, 312 patients (57.5%) were prescribed levetiracetam, and 231 (42.5%) were prescribed lamotrigine. An IPTW-adjusted Cox model showed that levetiracetam was associated with a reduced risk of treatment failure after adjustment for all baseline variables (IPTW-adjusted hazard ratio [HR], 0.77; 95% CI, 0.59-0.99; P = .04). However, after stratification according to different IGE syndromes, the higher effectiveness of levetiracetam was confirmed only in patients with juvenile myoclonic epilepsy (JME; IPTW-adjusted HR, 0.47; 95% CI, 0.32-0.68; P < .001), whereas no significant differences were found in other syndromes. Patients treated with levetiracetam experienced adverse effects more frequently compared with those treated with lamotrigine (88 of 312 [28.2%] vs 42 of 231 [18.1%]), whereas the 2 ASMs had similar retention rates during follow-up (IPTW-adjusted HR, 0.91; 95% CI, 0.65-1.23; P = .60). Conclusions and Relevance: Results of this comparative effectiveness research study suggest the use of levetiracetam as initial alternative monotherapy in female patients with JME. Further studies are needed to identify the most effective ASM alternative in other IGE syndromes.

SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10-9) and 10p11.21 (P = 3.6 × 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10-3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10-3) and increased seizure-like events (P = 6.8 × 10-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10-3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

Association of symptoms of psychiatric disease and electroencephalographic patterns in idiopathic generalized epilepsy.

OBJECTIVE: Idiopathic generalized epilepsies (IGE) are genetic epilepsies with alterations of thalamo-frontocortical circuits that play a major role in seizure generation and propagation. Psychiatric diseases and drug resistance are strongly associated, but it remains unknown if they are symptoms of the same pathophysiological process. Hypothesizing that the same network alterations are associated with the frequency of epileptic discharges (ED) and psychiatric symptoms, we here tested the association of self-reported psychiatric symptoms and IGE severity estimated by electroencephalographic (EEG) biomarkers. METHODS: Idiopathic generalized epilepsies patients were asked to fill out four validated psychiatric screening tools assessing symptoms of personality disorders (Standard Assessment of Personality- Abbreviated Scale), depression (Major Depression Inventory), impulsiveness (Barratt Impulsiveness Scale), and anxiety (brief Epilepsy Anxiety Survey Instrument). Blinded to results and clinical data on the patients, we analyzed the patients' EEGs, assessed, and quantified ED. The number and duration of ED divided by the duration of the EEG served as a proxy for the severity of IGE that was correlated with the results of the psychiatric screening. RESULTS: Paired data from 64 patients were available for analysis. The duration of EDs per minute EEG was inversely associated with the time since the last seizure. The number of patients with generalized polyspike trains (n = 2), generalized paroxysmal fast activity (n = 3), and prolonged epileptiform discharges (n = 10) were too low for statistically meaningful analyses. Self-reported symptoms of depression, personality disorder, and impulsivity were not associated with EDs. In contrast, the duration of EDs per minute EEG was associated with self-reported symptoms of anxiety in univariate analyses, not significant, however, following adjustment for time since the last seizure in regression models. SIGNIFICANCE: Self-reported symptoms of psychiatric diseases were not strongly associated with EDs as the best available quantifiable biomarker of IGE severity. As expected, the duration of EDs per minute and anxiety was inversely associated with time since the last seizure. Our data argue against a direct link between the frequency of EDs - as an objective proxy of IGE severity - and psychiatric symptoms.

Variation in prognosis and treatment outcome in juvenile myoclonic epilepsy: a Biology of Juvenile Myoclonic Epilepsy Consortium proposal for a practical definition and stratified medicine classifications.

Reliable definitions, classifications and prognostic models are the cornerstones of stratified medicine, but none of the current classifications systems in epilepsy address prognostic or outcome issues. Although heterogeneity is widely acknowledged within epilepsy syndromes, the significance of variation in electroclinical features, comorbidities and treatment response, as they relate to diagnostic and prognostic purposes, has not been explored. In this paper, we aim to provide an evidence-based definition of juvenile myoclonic epilepsy showing that with a predefined and limited set of mandatory features, variation in juvenile myoclonic epilepsy phenotype can be exploited for prognostic purposes. Our study is based on clinical data collected by the Biology of Juvenile Myoclonic Epilepsy Consortium augmented by literature data. We review prognosis research on mortality and seizure remission, predictors of antiseizure medication resistance and selected adverse drug events to valproate, levetiracetam and lamotrigine. Based on our analysis, a simplified set of diagnostic criteria for juvenile myoclonic epilepsy includes the following: (i) myoclonic jerks as mandatory seizure type; (ii) a circadian timing for myoclonia not mandatory for the diagnosis of juvenile myoclonic epilepsy; (iii) age of onset ranging from 6 to 40 years; (iv) generalized EEG abnormalities; and (v) intelligence conforming to population distribution. We find sufficient evidence to propose a predictive model of antiseizure medication resistance that emphasises (i) absence seizures as the strongest stratifying factor with regard to antiseizure medication resistance or seizure freedom for both sexes and (ii) sex as a major stratifying factor, revealing elevated odds of antiseizure medication resistance that correlates to self-report of catamenial and stress-related factors including sleep deprivation. In women, there are reduced odds of antiseizure medication resistance associated with EEG-measured or self-reported photosensitivity. In conclusion, by applying a simplified set of criteria to define phenotypic variations of juvenile myoclonic epilepsy, our paper proposes an evidence-based definition and prognostic stratification of juvenile myoclonic epilepsy. Further studies in existing data sets of individual patient data would be helpful to replicate our findings, and prospective studies in inception cohorts will contribute to validate them in real-world practice for juvenile myoclonic epilepsy management.

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.

Individualised prediction of drug resistance and seizure recurrence after medication withdrawal in people with juvenile myoclonic epilepsy: A systematic review and individual participant data meta-analysis.

Background: A third of people with juvenile myoclonic epilepsy (JME) are drug-resistant. Three-quarters have a seizure relapse when attempting to withdraw anti-seizure medication (ASM) after achieving seizure-freedom. It is currently impossible to predict who is likely to become drug-resistant and safely withdraw treatment. We aimed to identify predictors of drug resistance and seizure recurrence to allow for individualised prediction of treatment outcomes in people with JME. Methods: We performed an individual participant data (IPD) meta-analysis based on a systematic search in EMBASE and PubMed - last updated on March 11, 2021 - including prospective and retrospective observational studies reporting on treatment outcomes of people diagnosed with JME and available seizure outcome data after a minimum one-year follow-up. We invited authors to share standardised IPD to identify predictors of drug resistance using multivariable logistic regression. We excluded pseudo-resistant individuals. A subset who attempted to withdraw ASM was included in a multivariable proportional hazards analysis on seizure recurrence after ASM withdrawal. The study was registered at the Open Science Framework (OSF; https://osf.io/b9zjc/). Findings: Our search yielded 1641 articles; 53 were eligible, of which the authors of 24 studies agreed to collaborate by sharing IPD. Using data from 2518 people with JME, we found nine independent predictors of drug resistance: three seizure types, psychiatric comorbidities, catamenial epilepsy, epileptiform focality, ethnicity, history of CAE, family history of epilepsy, status epilepticus, and febrile seizures. Internal-external cross-validation of our multivariable model showed an area under the receiver operating characteristic curve of 0·70 (95%CI 0·68-0·72). Recurrence of seizures after ASM withdrawal (n = 368) was predicted by an earlier age at the start of withdrawal, shorter seizure-free interval and more currently used ASMs, resulting in an average internal-external cross-validation concordance-statistic of 0·70 (95%CI 0·68-0·73). Interpretation: We were able to predict and validate clinically relevant personalised treatment outcomes for people with JME. Individualised predictions are accessible as nomograms and web-based tools. Funding: MING fonds.

Drug resistance in idiopathic generalized epilepsies: Evidence and concepts.

Although approximately 10%-15% of patients with idiopathic generalized epilepsy (IGE)/genetic generalized epilepsy remain drug-resistant, there is no consensus or established concept regarding the underlying mechanisms and prevalence. This review summarizes the recent data and the current hypotheses on mechanisms that may contribute to drug-resistant IGE. A literature search was conducted in PubMed and Embase for studies on mechanisms of drug resistance published since 1980. The literature shows neither consensus on the definition nor a widely accepted model to explain drug resistance in IGE or one of its subsyndromes. Large-scale genetic studies have failed to identify distinct genetic causes or affected genes involved in pharmacokinetics. We found clinical and experimental evidence in support of four hypotheses: (1) "network hypothesis"-the degree of drug resistance in IGE reflects the severity of cortical network alterations, (2) "minor focal lesion in a predisposed brain hypothesis"-minor cortical lesions are important for drug resistance, (3) "interneuron hypothesis"-impaired functioning of γ-aminobutyric acidergic interneurons contributes to drug resistance, and (4) "changes in drug kinetics"-genetically impaired kinetics of antiseizure medication (ASM) reduce the effectiveness of available ASMs. In summary, the exact definition and cause of drug resistance in IGE is unknown. However, published evidence suggests four different mechanisms that may warrant further investigation.

Salzburg consensus criteria are associated with long-term outcome after non-convulsive status epilepticus.

PURPOSE: To investigate differences in long-term survival and short-term neurological deficits in adult patients fulfilling either sub-criterion of the Salzburg Consensus Criteria (SC) for non-convulsive status epilepticus (NCSE). METHODS: We retrospectively identified a cohort of patients with first-time NCSE epilepticus at Odense University Hospital from 2014 to 2017. Results of electroencephalograms at admission were dichotomized according to the SC (more than 25 epileptiform discharges/10 s was defined as the fast criterion), and groups were compared statistically through survival analysis and in a logistic regression model adjusting for established prognostic determinants in status epilepticus. Secondary outcomes were the associations between SC and neurological deficits at discharge. RESULTS: One-hundred and six patients fulfilled the SC and were included in the main analysis. In addition, 27 patients had possible NCSE. The fast criterion was significantly associated with decreased mortality 2 years following NCSE (OR 0.31, 95% CI 0.11-0.85, p = 0.039) in a logistic regression analysis after correction for age, etiology, semiology and comorbidity. None of the individual subcomponents of the slow criterion could explain the difference in survival in an exploratory analysis. Functional outcome did not differ between patients fulfilling fast and slow criteria. Patients with a clinical diagnosis of NCSE not fulfilling the SC more often had non-refractory NCSE and a more favorable functional outcome. CONCLUSION: The fast diagnostic criterion for NCSE was identified as a new, independent variable associated with long-term survival after NCSE. The results may allow prognostication in patients with NCSE at the time of diagnosis, which could guide decision-making in the clinical setting.

Pseudoresistance in idiopathic/genetic generalized epilepsies - Definitions, risk factors, and outcome.

OBJECTIVE: The aim of the study was to determine risk factors associated with pseudoresistance in a large, representative cohort of patients with Idiopathic/Genetic Generalized Epilepsy (IGE) and the impact of pseudoresistance on socioeconomic parameters. METHODS: We performed a literature review on definitions of pseudoresistance in IGE. In an established cohort of patients with IGE from Funen, patients with current or previous pseudoresistant seizures were retrospectively identified based on a comprehensive evaluation of the patients' medical records and direct patient contact, if required. In addition, clinical characteristics, socioeconomic, and demographic data were assessed. Personal interviews were used to determine the brief version of Barratts (BIS-8) impulsivity score. RESULTS: The literature review provided the following definition of pseudoresistance: Seizures due to (I) lacking adherence to antiseizure medication (ASM), (II) incompliance to general rule of conduct, (III) psychogenic nonepileptic seizures (PNES), (IV) inadequate choice of ASM/dosage, and (V) incorrect classification of epilepsy. Applying criteria I-III to a cohort of patients with IGE (n = 499), 73 patients (14.6%) were currently pseudoresistant and 62 (12.4%) were previously pseudoresistant, but currently seizure free. Current pseudoresistance was associated with younger age, drug/alcohol abuse, lower rate of full-time employment, and higher BIS-8 scores. We found no associations of pseudoresistance with juvenile myoclonic epilepsy, psychiatric disease, specific seizure types, or number of seizure types. Patients with previously pseudoresistant seizures have tried more ASMs and were characterized by male preponderance, higher BIS-8, and higher rates of abuse. Surrogate markers for social outcome did not differ. SIGNIFICANCE: In IGE, pseudoresistance may be defined as PNES or insufficient adherence to medication/conduct and is associated with younger age, drug/alcohol abuse, and higher scores for impulsivity. If transient, its impact on socioeconomic status remains limited but may be associated with a risk of overtreatment with ASM.

Sex-specific disease modifiers in juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sectional data collected by The Biology of Juvenile Myoclonic Epilepsy (BIOJUME) consortium. 765 individuals met strict inclusion criteria for JME (female:male, 1.8:1). 59% of females and 50% of males reported triggered seizures, and in females only, this was associated with experiencing absence seizures (OR = 2.0, p < 0.001). Absence seizures significantly predicted drug resistance in both males (OR = 3.0, p = 0.001) and females (OR = 3.0, p < 0.001) in univariate analysis. In multivariable analysis in females, catamenial seizures (OR = 14.7, p = 0.001), absence seizures (OR = 6.0, p < 0.001) and stress-precipitated seizures (OR = 5.3, p = 0.02) were associated with drug resistance, while a photoparoxysmal response predicted seizure freedom (OR = 0.47, p = 0.03). Females with both absence seizures and stress-related precipitants constitute the prognostic subgroup in JME with the highest prevalence of drug resistance (49%) compared to females with neither (15%) and males (29%), highlighting the unmet need for effective, targeted interventions for this subgroup. We propose a new prognostic stratification for JME and suggest a role for circuit-based risk of seizure control as an avenue for further investigation.

The burden of disease of idiopathic/genetic generalized epilepsy - A nationwide online survey.

The aim of the study was to assess the self-reported burden of disease in people with idiopathic/genetic generalized epilepsy and risk factors associated with high disease burden. We performed a nationwide online survey on epilepsy characteristics/treatment, quality of life/daily living followed by Standardized Assessment of Personality-Abbreviated Scale, Major Depression Inventory, Barratt Impulsiveness Scale (brief) and the brief Epilepsy Anxiety Survey Instrument. The survey was sent to 275 representative patients with IGE ('Funen cohort') and later publicly distributed via the Danish Epilepsy Association. The characteristics of the responders of the 'Funen cohort' (n = 119) did not differ from non-responders and previously assessed data. Out of 753 persons accessing the public survey, 167 had probable IGE. As compared to the 'Funen cohort', patients from the public survey reported similar age, time since last seizure, years with disease, seizure types, and IGE syndromes but more current and previously tried anti-seizure medications (ASMs). In both cohorts, patients had higher scores for depression, impulsivity, and personality disorders as compared to Danish normal values irrespective of seizure control or medication. Higher depression and anxiety scores but neither impulsivity nor personality disorders were associated with ongoing seizures. Overall health condition was estimated as bad by 28%. In the last four weeks, 20.4% reported limitations of activities of daily living due to epilepsy; 27.8% felt fed up because of their epilepsy. Patients with high subjective disease burden had more current ASMs, shorter time since last seizure and increased scores for depression, anxiety, impulsivity, and personality disorders. In conclusion, having IGE was associated with higher scores for impulsivity, depression, and personality disorders irrespective of seizure control and current treatment. High subjective disease burden was common and associated with ongoing seizures, absence/myoclonic seizures and high scores for impulsivity, depression, anxiety, and personality disorders.

Magnetic evoked potential polyphasia in idiopathic/genetic generalized epilepsy: An endophenotype not associated with treatment response.

OBJECTIVE: Increased Motor Evoked Potential (MEP) polyphasia was recently described in idiopathic/genetic generalized epilepsy (IGE). Here, we studied the association of MEP polyphasia with treatment response and other clinical characteristics in patients with IGE. METHODS: MEPs were recorded from the biceps brachii, flexor carpi radialis and interosseus dorsalis muscles bilaterally during tonic contraction in IGE patients (n = 72) and historical controls (n = 54) after single pulse transcranial magnetic stimulation. Detailed clinical data was available for all IGE patients; predefined endpoint was the association of MEP polyphasia with treatment response. RESULTS: The mean number of phases was higher in the interosseus dorsalis muscle (2.33 vs. 2.13, p = 0.002) in IGE patients as compared to normal controls, as was the proportion of MEPs with more than two phases in at least one test (59.4% vs. 30%, p < 0.002). MEP polyphasia did not differ between IGE patients and controls in the biceps brachii or the flexor carpi radialis muscles and was not associated with treatment response. Extensive exploratory analyses unveiled fewer phases under valproic acid treatment (p = 0.04) but no additional associations of MEP polyphasia in the interosseous muscle with other clinical characteristics. CONCLUSION: MEP polyphasia is a subclinical symptom of IGE patients but is not associated with treatment response or other routinely assessed clinical characteristics. SIGNIFICANCE: MEP polyphasia is a fixed feature of IGE not modified by clinical variables.

Social outcome and psychiatric comorbidity of generalized epilepsies - A case-control study.

OBJECTIVE: To investigate social outcome and psychiatric comorbidity of patients with idiopathic/genetic generalized epilepsies (IGEs) and its subtypes (epilepsy with generalized tonic-clonic seizures alone [EGTCS], juvenile absence epilepsy [JAE], and juvenile myoclonic epilepsy [JME]). METHODS: A cohort of 402 adult patients with IGE from the Danish island Funen was matched with 4020 randomly selected geography-, age-, and sex-matched controls via the Danish Civil Registration System. Based on register data, we compared social status measured by cohabitant status, educational attainment, income, affiliation to labor market, and psychiatric comorbidity. RESULTS: As compared to controls, patients with IGE had similar cohabitant status but fewer children (no children: 59.0% vs 50.9%), and lower educational level (primary school only: 46.0% vs 37.3%), employment rate (outside of workforce: 56.7% vs 46.5%), and income (low income: 32.6% vs 24.9%) (P < 0.001 for all comparisons). Having IGE was associated with higher a proportion of psychiatric comorbidity (IGE, 22.6%; controls, 13.0%) (P < 0.001). Seizure-free patients did not differ from controls; patients with persistent seizures had lower incomes and employment rates. In the IGE subgroup analyses, JME was associated with worse social status in all parameters studied (eg, 65.9% of JME patients were outside the workforce vs 44.5% of matched controls; P < 0.001), whereas no adverse social status was identified in patients with EGTCS and JAE. SIGNIFICANCE: Patients with IGE in general and JME in particular have poorer social status and more psychiatric comorbidity than matched population controls without epilepsy. Poor seizure control was associated with social status and may contribute to negative socioeconomic consequences associated with IGE.

Risk factors of paradoxical reactions to anti-seizure medication in genetic generalized epilepsy.

This study aimed at providing valid estimates for the risk of clinically relevant seizure aggravation by recommended anti-seizure medications in patients with Genetic Generalized Epilepsy (GGE). To this aim, treatment response, side effects and paradoxical reactions to anti-seizure treatment were retrospectively assessed in a near-population based cohort comprising 471 adult GGE patients. A total of 1046 treatment attempts were analyzed (lamotrigine: 351, valproic acid: 295, levetiracetam: 249, primidone/phenobarbital: 94, zonisamide: 57). Under lamotrigine, seizure aggravation was observed in 15 patients (two patients during levetiracetam, one patient during zonisamide, none during phenobarbital and valproic acid). All but two patients with paradoxical reactions to lamotrigine were diagnosed with juvenile myoclonic epilepsy (JME), otherwise, the clinical and electroencephalographic characteristics of patients with paradoxical reactions did not differ. At treatment start, the estimated risk of a paradoxical reaction to lamotrigine was 7.9 % in JME patients (n = 190). For all GGE patients (incl. JME), the estimated risk of clinically relevant seizure aggravation under treatment with lamotrigine was 3.7 % (1.8 % for zonisamide and 0.8 % for levetiracetam). In conclusion, clinical significant aggravation of seizure frequency is common in lamotrigine-treated JME patients but rare in patients with other GGE subsyndromes or under treatment with other recommended anti-seizure medication.

Trait impulsivity in Juvenile Myoclonic Epilepsy.

OBJECTIVE: Impulsivity is a multidimensional construct that can predispose to psychopathology. Meta-analysis demonstrates an association between response impulsivity and Juvenile Myoclonic Epilepsy (JME), a common genetic generalized epilepsy. Here, we test the hypotheses that trait impulsivity is (i) elevated in JME compared to controls; (ii) moderated by specific seizure characteristics; and (iii) associated with psychiatric adverse effects of antiepileptic drugs (AEDs). METHODS: 322 participants with JME and 126 age and gender-matched controls completed the Barratt's Impulsiveness Scale (BIS-brief) alongside information on seizure history and AED use. We compared group BIS-brief scores and assessed associations of JME BIS-brief scores with seizure characteristics and AED adverse effects. RESULTS: The mean BIS-brief score in JME was 18.1 ± 4.4 compared with 16.2 ± 4.1 in controls (P = 0.0007). Elevated impulsivity was associated with male gender (P = 0.027), frequent absence seizures (P = 0.0004) and lack of morning predominance of myoclonus (P = 0.008). High impulsivity significantly increased the odds of a psychiatric adverse event on levetiracetam (P = 0.036), but not any other psychiatric or somatic adverse effects. INTERPRETATION: Trait impulsivity is elevated in JME and comparable to scores in personality and neurotic disorders. Increased seizure frequency and absence of circadian seizure pattern moderate BIS score, suggesting disruption of both cortico-striatal and thalamocortical networks as a shared mechanism between seizures and impulsivity in JME. These findings warrant consideration of impulsivity as a distinct target of intervention, and as a stratifying factor for AED treatment in JME, and perhaps other types of epilepsy. The role of impulsivity in treatment adherence and psychosocial outcome requires further investigation.

Prognostic Value of Generalized Polyspike Trains and Prolonged Epileptiform EEG Runs.

INTRODUCTION: A considerable proportion of patients with genetic/idiopathic generalized epilepsy (IGE) suffer from persistent seizures. In this study, it was questioned if generalized polyspike trains (GPT) or prolonged epileptiform EEG runs allow identification of difficult-to-treat patients in a first seizure clinic setting or after recurrent seizures. METHODS: The first routine outpatient EEGs from untreated patients (later diagnosed with IGE) and routine EEGs from IGE patients with persistent seizures despite medical treatment were analyzed. Seizure outcome and clinical characteristics were retrospectively assessed based on the patients' records. RESULTS: In routine EEGs recorded after first seizure in untreated patients (n = 79), the prevalence of GPT (n = 1; 1.3%) and prolonged epileptiform EEG runs (n = 13; 16.5%) was low. At follow-up, 24 patients (30.4%) were not seizure free, and 3 (3.8%) of them developed drug-resistant IGE. None of the interictal discharges studied was associated with long-term seizure outcome. Treated IGE patients with recurrent seizures (n = 69) had a similar prevalence of GPT (n = 3; 4.3%) and prolonged epileptiform EEG runs (n = 7; 10.1%). At follow-up, 42 patients (60.8%) suffered persistent seizures, and 18 (26%) were drug resistant. Generalized polyspike train and prolonged epileptiform EEG runs had a higher prevalence in patients with drug-resistant epilepsy (GPT: 11.1% vs. 2%; P = 0.1; prolonged epileptiform EEG runs: 27.8% vs. 3.9%; P = 0.004) and persistent seizures (GPT: 7.1% vs. 0%; P = 0.16; prolonged epileptiform EEG runs: 16.7% vs. 0%; P = 0.03) as compared with nonresistant patients. CONCLUSIONS: Generalized polyspike train and prolonged epileptiform EEG runs were associated with persistent seizures and drug-resistant IGE, but the overall prevalence was low. In a first seizure clinic setting, the diagnostic value of these biomarkers was limited.

Patterns and prognostic markers for treatment response in generalized epilepsies.

OBJECTIVE: To determine the pattern of treatment response in patients with idiopathic generalized epilepsy (IGE) and whether routinely assessed clinical and neurophysiological parameters allow predicting response to lamotrigine, levetiracetam, or valproic acid. METHODS: In 328 adult patients with IGE, demographic data, imaging, EEG data, current and prior antiepileptic treatment, treatment outcome, and side effects were analyzed from the patients' medical files and patient interviews. RESULTS: Seizure freedom with acceptable side effects at the first attempt was achieved in 61 (18.6%) patients. One hundred four (31.7%) patients tried ≥3 antiepileptic drugs before achieving seizure control at the last follow-up. Lamotrigine, levetiracetam, and valproic acid showed differential response rates (39.8% vs 47.5% vs 71.1%) that were most pronounced in patients with juvenile myoclonic epilepsy. The risk of having side effects was higher with valproic acid (23.7%) than with lamotrigine (10.4%) or levetiracetam (20.4%) treatment, contributing to the low retention rate of valproic acid (53.7%). Treatment resistance was associated with established risk factors. Multivariate analyses aiming at identifying clinical indicators for response to specific drugs did not reveal putative biomarkers when corrected for drug resistance. CONCLUSION: Despite a high rate of seizure control, the chance of achieving seizure control and acceptable side effects at first attempt was low due to an inverse association of effectiveness and side effects of the 3 most commonly used drugs. Routinely assessed clinical parameters were not indicative for response to specific drugs. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with IGE, various clinical factors do not predict a response to specific antiepileptic drugs.