Intensive treatment course to identify pseudoresistant epilepsy and expedite surgery referrals - A prospective intervention study.

INTRODUCTION: A significant proportion of patients do not achieve seizure freedom despite treatment attempts with two different anti-seizure medications (ASMs). A subset may not truly have drug-resistant epilepsy ("pseudoresistant"), while rapid referral of patients with genuine drug-resistant epilepsy to surgery is mandated. This study was designed to evaluate a structured and intensive treatment course with the objective of promptly identifying cases of pseudoresistance and accelerating the time to referral to epilepsy surgery. METHODS: From May 2017 to February 2021, this prospective interventional study recruited consecutive adult patients with epilepsy treated at Odense University Hospital, Denmark, who had at least one seizure per month despite attempts with two or more ASMs. The predefined endpoint was improvement in seizure activity. Secondary endpoints were referral to epilepsy surgery, patients with pseudoresistance, and achievement of seizure freedom. RESULTS: Of the 41 patients enrolled, 39 completed the study. The intervention comprised a initial seizure documentation, specialist evaluation, EEG monitoring as required, and an individualized plan for intensive treatment. The plans included e.g., optimization of medical treatment, seizure classification, and improvement of medication adherence. The subsequent intensive treatment (1-4 contacts/month; 1-13 contacts in total) was led by epilepsy nurses that executed the treatment plan. The intervention significantly improved seizure control, with 41.1 % of patients achieving seizure freedom and an additional 17.8 % of patients experiencing reduced seizure frequency. One-third of the patients turned out to be "pseudoresistant" due to various reasons, including wrong classification of seizures and inadequate adherence to ASMs. Ten patients were offered a referral for epilepsy surgery at the end of the study after an average of 34.8 weeks. CONCLUSION: This study demonstrates the efficacy of a standardized, intensive treatment course involving epilepsy nurses in identifying and managing patients with persisting seizures despite treatment attempts with two ASMs. This approach led to favourable seizure outcomes and facilitated expedited referrals for epilepsy surgery where appropriate.

Prodromal Phase of Idiopathic Generalized Epilepsy: A Register-Based Case Control Study.

BACKGROUND AND OBJECTIVES: Idiopathic generalized epilepsy (IGE) is associated with distinct behavioral traits, symptoms of frontal lobe dysfunction, and psychiatric comorbidity. Whether psychiatric symptoms are part of the IGE endophenotype or secondary to the burden of chronic disease is unknown. In this study, we aimed at describing the sequence of appearance of psychiatric and epilepsy symptoms in patients with IGE. METHODS: Inclusion criteria for this cohort study were diagnosis of IGE with age at diagnosis at 10-25 years. We created 2 mutually exclusive cohorts, 1 based on ICD-10 codes in Danish registers with a first IGE diagnosis from January 1, 2005, to December 31, 2018, and a second patient cohort treated at Odense University Hospital and the Danish Epilepsy Centre in the same period. Each case was matched with 10 age-matched, sex-matched, and geography-matched normal population controls from the Danish registers. We compared social status, health care utilization, and psychiatric diagnoses between the groups in the 5 years preceding epilepsy diagnosis, at diagnosis, and at the end of the study period using the Wilcoxon rank-sum test and confirmatory logistic regression models. RESULTS: We identified 1,009 patients for the register-based cohort (55.1% female; mean age at diagnosis [SD]: 15.9 [±3.8] years) and 402 patients for the hospital-based cohort (56.2% female; mean age at diagnosis [SD]: 18.3 [±7.4] years) and matched them to 10,090 and 4,020 controls, respectively. IGE cohorts and controls did not differ at birth. In the 5 years before their IGE diagnosis, register patients had an increasing number of contacts with hospitals (mean visits [SD]: cases: 8.3 [±5.6], controls: 6.6 [±4.5]) and their general practitioners (mean visits [SD]: cases: 48.7 [±26.3], controls: 45.3 [±24.5]) and received more prescriptions for psychiatric medications (prescriptions: cases: 4.2%, controls: 2.5%, p = 0.003) compared with controls. Patients had a higher rate of psychiatric comorbidity (comorbidity: cases: 26.5%, controls: 17.8%, p < 0.0001) at the end of the study than controls. Data were similar in the hospital-based cohort. DISCUSSION: Our data suggest a prodromal phase of IGE detectable approximately 5 years before the first seizure characterized by increased health care utilization and greater use of prescription medicine for psychiatric symptoms.

Cognitive behavioral therapy in adults with functional seizures: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Randomized controlled clinical trials (RCTs) investigating cognitive-behavioral therapy (CBT) among adults with functional seizures (FS) have become increasingly available, prompting the opportunity to critically appraise the efficacy and safety of CBT in this population. METHODS: We conducted a systematic review and meta-analysis including RCTs comparing CBT in addition to standardized medical treatment (SMT) versus SMT alone for adults with FS. The primary outcome was seizure freedom at the end of treatment. Secondary outcomes included measures of quality of life, anxiety and depression assessed via standardized clinical questionnaires. RESULTS: Three RCTs were included comprising 228 participants treated with CBT and 222 with SMT. The intervention was significantly associated with seizure freedom (Odds Ratio [OR] 1.98; 95 % confidence interval [CI] 1.14, 3.46; p = 0.02; I2 = 0 %), reductions in anxiety (standardized mean difference [SMD] -0.21; 95 % CI -0.41, -0.003; p = 0.047; I2 = 0 %) and improvements in quality of life (SMD 0.34; 95 % CI 0.12, 0.57; p = 0.003; I2 = 0 %) at the end of treatment. Conversely, no significant differences between groups were observed in depression symptoms (SMD -0.19; 95 % CI -0.39, 0.02; p = 0.08; I2 = 0 %). There was no statistically significant increase in the risk of suicidal ideation and self-harm with CBT (OR 2.11; 95 % CI 0.81, 5.48; p = 0.13; I2 = 0 %) nor were there differences in terms of discontinuation rates during follow-up (OR 0.92; 95 % CI 0.49, 1.72; p = 0.79; I2 = 7 %). CONCLUSIONS: There is high-quality evidence supporting the efficacy and safety of CBT in treating FS. Future research should investigate whether combining CBT with other therapeutic methods could potentially enhance treatment efficacy.

Lamotrigine vs levetiracetam in female patients of childbearing age with juvenile absence epilepsy: A Bayesian reanalysis.

OBJECTIVE: Women of childbearing age with juvenile absence epilepsy (JAE) face treatment challenges due to limited access to safe and effective anti-seizure medications (ASMs). In a previous study we compared the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) in women with idiopathic generalized epilepsy (IGE), highlighting a superiority of LEV in juvenile myoclonic epilepsy. In this study, we specifically reanalyzed, through a Bayesian approach and by expanding the previously published cohort, the comparative effectiveness of these ASMs as initial monotherapy in JAE. METHODS: We conducted a multicenter, retrospective, comparative effectiveness study on women of childbearing age diagnosed with JAE and prescribed LEV or LTG as the initial ASM. Inverse probability treatment weighting (IPTW) Bayesian Cox proportional hazard models were employed to evaluate treatment failure (TF) due to ineffectiveness and ASM retention. The patients' center of provenance and year of prescription were considered as random effect factors. Posterior probabilities and relative log-risk distribution were computed, and the distribution of posterior draws was analyzed to assess the evidence supporting LTG superiority over LEV. RESULTS: Of 123 patients, those treated with LTG (n = 67) demonstrated lower TF and higher ASM retention than those treated with LEV (n = 56), with the IPTW-weighted Bayesian Cox proportional hazards model showing a 99.2% posterior probability of LTG being superior on TF and a 99.5% probability on ASM retention. Additional analyses on ≥50% and ≥75% seizure reduction through IPTW-weighted Bayesian logistic regression largely confirmed these findings, whereas the two ASMs did not show evident differences in terms of seizure freedom. The two ASMs showed comparable safety profiles, with only a minority of patients discontinuing treatment due to side effects. SIGNIFICANCE: Bayesian reanalysis supports LTG as first-line monotherapy for JAE in women of childbearing age, emphasizing the importance of individualized treatment strategies in women with IGE. This study underscores the value of Bayesian methods in refining clinical research and treatment decisions.

Slab steepening and rapid mantle wedge replacement during back-arc rifting in the New Hebrides.

The effects of the composition and angle of the subducting slab and mantle wedge flow on tectonic and magmatic processes in island arcs and associated back-arcs are poorly understood. Here we analyse the ages and compositions of submarine lavas from the flanks and the floor of the back-arc Futuna Trough some 50 km east of Tanna Island in the New Hebrides arc front. Whereas >2.5 Ma-old back-arc lavas formed from an enriched mantle source strongly metasomatized by a slab component, the younger lavas show less slab input into a depleted mantle wedge. The input of the slab component decreased over the past 2.5 million years while the enriched mantle was replaced by depleted peridotite. The change of Futuna Trough lava compositions indicates rapid (10 s of km/million years) replacement of the mantle wedge by corner flow and slab steepening due to rollback, causing extensional stress and back-arc rifting in the past 2.5 million years.

Living with epilepsy in adolescence and young adulthood transitioning from pediatric to adult hospital services: A systematic review and meta-synthesis of qualitative studies.

BACKGROUND: Transition is characterized by developing greater self-identity and growing independence, but adolescents dealing with chronic illnesses encounter health-related and situational changes during transition. Despite the many suggestions made in recent years, the shift from pediatric to adult care continues to pose difficulties for adolescents and young adults with epilepsy (AWE). The holistic perspective of AWE's experiences and needs during transition is not as well understood. AIM: To synthesize the qualitative evidence related to AWE's experiences and needs transitioning from pediatric to adult hospital care. METHODS: This systematic review adhered to the rigorous Joanna Briggs methodology for qualitative evidence synthesis. A comprehensive search was conducted across multiple databases, including PubMed, CINAHL, Scopus, Embase, PsycINFO, and ProQuest Dissertations & Theses Global, from their inception to April 2024. The findings were critically appraised and aggregated using meta-synthesis. RESULTS: The search yielded a total of 3,985 studies, and twenty-one were included in the review. Two of the included studies were undertaken in a program where a transition clinic was established. The meta-synthesis reveals that the transition experience of AWE is more than a change from one clinic to another and is interwoven into a pattern of developmental, health-illness, situational, and organizational transition issues. Five synthesized findings were developed: 1) Feeling different from others and striving to address the impact of epilepsy in everyday life; 2) the transition from pediatric to adult care - a problematic intersection point; 3) the family's role - support or parental overprotectiveness 4) seeking knowledge and being familiar with epilepsy supported by healthcare professionals and technologies, and 5) development of independence and responsibility through involvement and support from healthcare professionals and parents. CONCLUSION: During the transition from pediatric to adult hospital care, AWEs encounter a loss of familiarity, increased responsibility, and feelings of not belonging. Therefore, it is essential to create an environment where they can thrive beyond the limitations of their illness. Understanding, acceptance, and inclusivity should characterize this environment to support AWEs in facilitating the development of responsibility, independence, and confidence as they navigate transitions.

Investigating the role of obesity, circadian disturbances and lifestyle factors in people with schizophrenia and bipolar disorder: Study protocol for the SOMBER trial.

The aim of this study is to investigate circadian rhythms in independently living adults with obesity and mental disease, exploring the interplay between biological markers and lifestyle factors. Eighty participants divided equally into four groups; (i) people with obesity and schizophrenia; (ii) people with obesity and bipolar disorder; (iii) people with obesity without mental disease or sleep disorders, and (iv) people without obesity, mental disease or sleep disorders. Over two consecutive days, participants engage in repeated self-sampling of hair follicle and saliva; concurrently, data is collected on diet, body temperature, light exposure, sleep parameters, and physical activity by accelerometry. Hair follicles are analyzed for circadian gene expression, saliva samples for cortisol and melatonin concentrations. Circadian rhythms are investigated by cosinor analysis. The study employs a participant-tailored sampling schedule to minimize disruptions to daily routine and enhance ecological validity. The methodology aims to provide a comprehensive insight into the factors contributing to circadian disruptions in people with obesity, bipolar disorder and schizophrenia, potentially informing strategies for future management and mitigation. Trial registration: (ClinicalTrials.gov Identifier: NCT05413486).

Magnetic Resonance Imaging Signs of Idiopathic Intracranial Hypertension.

Importance: The magnetic resonance imaging (MRI) criteria currently used to diagnose idiopathic intracranial hypertension (IIH) are based on expert opinion and have limited accuracy. Additional neuroimaging signs have been proposed and used with contradictory results; thus, prospective evidence is needed to improve diagnostic accuracy. Objective: To provide evidence-based, accurate MRI signs for IIH diagnosis. Design, Setting, and Participants: This prospective cohort study was conducted from January 2018 to May 2021 with 3 validation cohorts at 2 Danish headache centers and with 3 independent international cohorts. Consecutive patients with suspected IIH were enrolled. Eligibility required the clinical suspicion of IIH, age 18 years or older, and written informed consent. The validation cohorts comprised patients with confirmed IIH from Austria and the US, and patients without IIH from the US. Data analysis was performed from December 2021 to August 2023. Exposure: Standardized diagnostic workup was performed to classify cases according to current criteria, and blinded evaluation of cerebral radiological diagnostics and papilledema was performed. Main Outcomes and Measures: The primary outcomes were MRI signs associated with IIH as assessed by univariate analyses. An MRI score estimating papilledema was calculated using machine learning. Internal validation of associations with lumbar puncture opening pressure and outcome and external validation of accuracy were performed in 3 cohorts. Results: Of 192 eligible patients (185 women [96.4%]; median [IQR] age, 28.0 [23.0-35.0] years), 110 were classified as having IIH, 4 as having probable IIH, and 1 as having suspected IIH without papilledema; 77 did not have IIH and served as controls, with corresponding age, sex, and weight. Papilledema at diagnosis was associated with perioptic subarachnoid space distension (56 patients [68.3%] vs 21 patients [41.2%]), posterior globe flattening (53 patients [66.3%] vs 10 patients [21.3%]), optic nerve disc protrusion (35 patients [30.4%] vs 2 patients [2.3%]), and transverse sinus venous stenosis (75 patients [79.8%] vs 29 patients [46.8%]). The papilledema-estimating MRI score showed optimal balance between sensitivity (49%) and specificity (87%) when 2 of the 3 latter signs were present and was associated with the lumbar puncture opening pressure and ophthalmological outcome. The score showed strong diagnostic accuracy in the external validation cohorts (587 patients; area under the receiver operating characteristic curve, 0.86) and outperformed the current (2013) diagnostic MRI criteria. Conclusions and Relevance: The findings of this cohort study of patients with IIH and controls suggest that an evidence-based MRI score including posterior globe flattening, optic nerve disc protrusion, and transverse sinus stenosis can estimate the presence of papilledema more accurately than the current diagnostic criteria.

Being an adolescent with epilepsy during the transition from pediatric to adult hospital care: A qualitative descriptive study.

BACKGROUND: The transition from pediatric to adult care is challenging for adolescent patients despite numerous recommendations in recent decades. However, the perspective of the patients is sparsely investigated. AIM: To explore the experiences and needs of adolescents with epilepsy (AWE) during the transition from pediatric to adult hospital care. METHODS: We conducted 15 semi-structured interviews with AWEs aged 13-20 years and 10 h of field observations of consultations. Interviews were audio-recorded, transcribed, anonymized, and entered into NVivo (version 12, QSR International) with the transcribed field notes. Data were analyzed using systematic text condensation. RESULTS: Three themes were identified: (1) Navigating epilepsy in everyday life; (2) The difficult balance between concealment and openness about epilepsy; and (3) Being seen as an individual and not an illness. AWEs' needs in transition are closely associated with their experiences and perceptions of illness, treatment, consultations, and seizures. Notably, AWEs reveal a significant concern about being overlooked beyond their medical condition in appointments. CONCLUSIONS: This study highlights the vulnerability and challenges of AWEs transitioning to adult care. Overall, AWEs seek understanding, acceptance, and autonomy in managing their epilepsy and transitioning to adult care. Their experiences underscore the importance of holistic support and communication in healthcare settings. A concerted effort from healthcare professionals (HCP) is necessary to foster the recognition of AWEs as individuals with distinct personalities, needs, and capabilities.

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.

NORSE seasonality may vary geographically in adults.

The mechanisms causing new onset refractory status epilepticus (NORSE) are often unknown. Recently, a seasonal variation with NORSE peaking during the summer was described in a mixed cohort of adults and children why we here studied the seasonal variation in a Danish status epilepticus (SE) cohort. This retrospective cohort study comprised SE patients aged ≥18 diagnosed and treated 2008-2017 at the Odense University Hospital. Clinical characteristics and seasonality of patients fulfilling the diagnostic criteria for NORSE were compared with patients with refractory SE (RSE) due to other reasons and with the seasonal variation of autoantibodies associated with autoimmune encephalitis in the Danish autoimmune encephalitis register. In this cohort, 26 patients met NORSE criteria. As compared to RSE patients not fulfilling NORSE criteria (n = 152), NORSE patients were more likely to have symptoms of systemic inflammation (C-reactive protein concentrations ≥10 mg/L or fever ≥38°C) at admission; nine fulfilled the criteria for febrile infection related epilepsy syndrome (FIRES). In contrast to the even seasonal distribution of patients with RSE not fulfilling the NORSE criteria, admissions due to NORSE peaked during the winter (46.1%, p = 0.04 as compared to non-NORSE RSE); six out of nine FIRES episodes occurred in the winter season. The seasonal variation was not explained by a seasonal variation of the detection rates of autoantibodies associated with autoimmune encephalitis (incl. NMDAR, LGI1, CASPR2, GABAR, GFAP) in a Danish nationwide register (n = 259). In conclusion, we confirm the seasonality of NORSE in a Danish cohort, however, with a peak during winter suggesting a geographical variation not solely explained by autoimmune encephalitis associated with known autoantibodies. PLAIN LANGUAGE SUMMARY: The study investigated the seasonal patterns of new-onset refractory status epilepticus (NORSE), i.e. severe seizures that occur without an obvious cause and require very intensive treatment. In contrast to the previously observed peak frequency in summer, this Danish study found that NORSE cases peak in winter. Furthermore, the seasonal variation in NORSE cases was not found to be associated with autoimmune encephalitis caused by known autoantibodies. Together with the high rate of patients showing symptoms of systemic inflammation compared to other status epilepticus patients, the data suggest a link between misdirected immune system responses and NORSE. The study can therefore help in the further search for the currently unknown causes of NORSE.

Sustained effort network for treatment of status epilepticus/European academy of neurology registry on adult refractory status epilepticus (SENSE-II/AROUSE).

BACKGROUND: Status Epilepticus (SE) is a common neurological emergency associated with a high rate of functional decline and mortality. Large randomized trials have addressed the early phases of treatment for convulsive SE. However, evidence regarding third-line anesthetic treatment and the treatment of nonconvulsive status epilepticus (NCSE) is scarce. One trial addressing management of refractory SE with deep general anesthesia was terminated early due to insufficient recruitment. Multicenter prospective registries, including the Sustained Effort Network for treatment of Status Epilepticus (SENSE), have shed some light on these questions, but many answers are still lacking, such as the influence exerted by distinct EEG patterns in NCSE on the outcome. We therefore initiated a new prospective multicenter observational registry to collect clinical and EEG data that combined may further help in clinical decision-making and defining SE. METHODS: Sustained effort network for treatment of status epilepticus/European Academy of Neurology Registry on refractory Status Epilepticus (SENSE-II/AROUSE) is a prospective, multicenter registry for patients treated for SE. The primary objectives are to document patient and SE characteristics, treatment modalities, EEG, neuroimaging data, and outcome of consecutive adults admitted for SE treatment in each of the participating centers and to identify factors associated with outcome and refractoriness. To reach sufficient statistical power for multivariate analysis, a cohort size of 3000 patients is targeted. DISCUSSION: The data collected for the registry will provide both valuable EEG data and information about specific treatment steps in different patient groups with SE. Eventually, the data will support clinical decision-making and may further guide the planning of clinical trials. Finally, it could help to redefine NCSE and its management. TRIAL REGISTRATION: NCT number: NCT05839418.

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.

Postictal Encephalopathy After Status Epilepticus: Outcome and Risk Factors.

BACKGROUND: Postictal encephalopathy is well known after status epilepticus (SE), but its prognostic impact and triggers are unknown. Here, we aimed to establish risk factors for the development of postictal encephalopathy and to study its impact on survival after discharge. METHODS: This retrospective cohort study comprised adult patients diagnosed with first nonanoxic SE at Odense University Hospital between January 2008 and December 2017. Patients with ongoing SE at discharge or unknown treatment success were excluded. Postictal symptoms of encephalopathy were estimated retrospectively using the West Haven Criteria (WHC). WHC grade was determined for postictal day 1 to 14 or until the patient died or was discharged from the hospital. Cumulative postictal WHC during 14 days after SE-cessation was used to quantify postictal encephalopathy. Clinical characteristics, patient demographics, electroencephalographic and imaging features, and details on intensive care treatment were assessed from medical records. RESULTS: Of all eligible patients (n = 232), 198 (85.3%) had at least WHC grade 2 postictal encephalopathy that lasted for > 14 days in 24.5% of the surviving patients. WHC grade at discharge was strongly associated with poor long-term survival (p < 0.001). Postictal encephalopathy was not associated with nonconvulsive SE, postictal changes on magnetic resonance imaging, or distinct ictal patterns on electroencephalography. Although duration of SE and treatment in the intensive care unit showed an association with cumulative postictal WHC grade, they were not independently associated with the degree of encephalopathy when controlling for confounders. In a linear regression model, etiology, duration of sedation, age, and premorbid modified Rankin Scale were significant and consistent predictors for higher cumulative postictal WHC grade. Exploratory analyses showed an association of a cumulative midazolam dosage (mg/kg/h) with higher cumulative postictal WHC grade. DISCUSSION: In this cohort, postictal encephalopathy after SE was common and associated with poor long-term survival. Seizure characteristics were not independently associated with postictal encephalopathy; the underlying etiology, long (high-dose midazolam) sedation, high age, and poor premorbid condition were the major risk factors for its development.

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.

Outcomes and Treatment Approaches for Super-Refractory Status Epilepticus: A Systematic Review and Meta-Analysis.

Importance: Super-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that continues or recurs 24 hours or more after the onset of anesthetic therapy or recurs on the reduction/withdrawal of anesthesia. Current clinical knowledge of the disease and optimal treatment approach is sparse. Objective: To systematically assess clinical characteristics, causes, outcomes, prognostic factors, and treatment approaches for patients with SRSE. Design, Setting, and Participants: In this systematic review and meta-analysis, all studies reporting adult patients (18 years or older) diagnosed with nonanoxic SRSE were considered for inclusion, irrespective of study design. The databases used were MEDLINE, Cochrane Library, EMBASE, and ClinicalTrials.org (database inception through May 5, 2022). Data extraction and synthesis: The study complied with the PRISMA guidelines for reporting, data extraction, and data synthesis. Different tools were used to assess risk of bias. All available data were extracted and missing data were neither imputed nor completed by contacting the study authors. Main outcome and measures: Successful treatment of SRSE, in-hospital mortality, and disability at discharge (estimated modified Rankin Scale). Results: The study team identified a total of 95 articles and 30 conference abstracts reporting 1200 patients with nonanoxic SRSE (266 individual patients were available for meta-analysis). They had a mean SRSE duration of 36.3 days, mean age of 40.8 years, and equal sex distribution. Patients with SRSE had a distinct pattern of etiologies where acute cerebral events and unknown etiologies accounted for 41.6% and 22.3% of all etiologies, respectively. Reports of SRSE caused by, eg, alcohol, drugs, or tumors were rare. At discharge, only 26.8% had none to slight disability (none, 16 [8.4%]; nonsignificant and slight disability, 35 [18.4%]). In-hospital mortality was 24.1%. Mortality stabilized after long-term treatment (more than 28 days) but with increased rates of seizure cessation and moderate to severe disability. Established prognostic factors, such as age and etiology, were not associated with in-hospital mortality. Reported treatment with ketamine, phenobarbital, other barbiturates, vagus nerve stimulator, and ketogenic diet were not associated with outcome. Conclusion and Relevance: Patients with SRSE are distinct due to their pattern of care (eg, long-term treatment to younger patients without negative prognostic factors and unknown/nonmalignant etiologies) and their natural course of SE. Very long-term treatment was associated with lower mortality and high odds of cessation of SRSE but increased risk of moderate to severe disability.

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.