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Objective: This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in the load of concomitant antiseizure medications (ASMs) and predictors of clinical response in people with focal epilepsy. Methods: This was a retrospective study at 21 centers participating in the Italian Expanded Access Program. Effectiveness outcomes included retention and responder rates (≥50% and 100% reduction in baseline seizure frequency). Tolerability/safety outcomes included the rate of treatment discontinuation due to adverse events (AEs) and their incidence. Total drug load was quantified as the number of concomitant ASMs and total defined daily dose (DDD). Concomitant ASMs were also classified according to their mechanism of action and pharmacokinetic interactions to perform explorative subgroup analyses. Results: A total of 236 subjects with a median age of 38 (Q1–Q3 = 27–49) years were included. At 12 months, cenobamate retention rate was 78.8% and responders were 57.5%. The seizure freedom rates during the preceding 3 months were 9.8%, 12.2%, 16.3%, and 14.0% at 3, 6, 9, and 12 months. A higher percentage of responders was observed among subjects treated with clobazam, although the difference was not statistically significant. A total of 223 AEs were recorded in 133 of 236 participants, leading to cenobamate discontinuation in 8.5% cases. At 12 months, a reduction of one or two concomitant ASMs occurred in 42.6% and 4.3% of the subjects. The median total DDD of all concomitant ASMs decreased from 3.34 (Q1–Q3 = 2.50–4.47) at baseline to 2.50 (Q1–Q3 = 1.67–3.50) at 12 months (p <.001, median percentage reduction = 22.2%). The highest rates of cotreatment withdrawal and reductions in the DDD were observed for sodium channel blockers and γ‐aminobutyric acidergic modulators (above all for those linked to pharmacokinetic interactions), and perampanel. Significance: Adjunctive cenobamate was associated with a reduction in seizure frequency and in the burden of concomitant ASMs in adults with difficult‐to‐treat focal epilepsy. The type of ASM associated did not influence effectiveness except for a favorable trend with clobazam. [ABSTRACT FROM AUTHOR]

Cenobamate has demonstrated efficacy in patients with treatment-resistant epilepsy, including patients who continued to have seizures after epilepsy surgery. This article provides recommendations for cenobamate use in patients referred for epilepsy surgery evaluation. A panel of six senior epileptologists from the United States and Europe with experience in presurgical evaluation of patients with epilepsy and in the use of antiseizure medications (ASMs) was convened to provide consensus recommendations for the use of cenobamate in patients referred for epilepsy surgery evaluation. Many patients referred for surgical evaluation may benefit from ASM optimization; both ASM and surgical treatment should be individualized. Based on previous clinical studies and the authors' clinical experience with cenobamate, a substantial proportion of patients with treatment-resistant epilepsy can become seizure-free with cenobamate. We recommend a cenobamate trial and ASM optimization in parallel with presurgical evaluations. Cenobamate can be started before phase two monitoring, especially in patients who are found to be suboptimal surgery candidates. As neurostimulation therapies are generally palliative, we recommend trying cenobamate before vagus nerve stimulation (VNS), deep brain stimulation, or responsive neurostimulation (RNS). In surgically remediable cases (mesial temporal sclerosis, benign discrete lesion in non-eloquent cortex, cavernous angioma, etc.), cenobamate use should not delay imminent surgery; however, a patient may decide to defer or even cancel surgery should they achieve sustained seizure freedom with cenobamate. This decision should be made on an individual, case-by-case basis based on seizure etiology, patient preferences, potential surgical risks (mortality and morbidity), and likely surgical outcome. The addition of cenobamate after unsuccessful surgery or palliative neuromodulation may also be associated with better outcomes. [ABSTRACT FROM AUTHOR]

Objective: The cannabidiol (CBD) Expanded Access Program provided compassionate access to CBD for patients with treatment‐resistant epilepsy, including tuberous sclerosis complex (TSC), at 35 US epilepsy centers. Here, we present the long‐term efficacy and safety outcomes for add‐on CBD treatment in patients with TSC. Methods: Patients received plant‐derived, highly purified CBD (Epidiolex® 100 mg/mL, oral solution), increasing from 2 to 10 mg/kg/d to tolerance or maximum of 25–50 mg/kg/d. Efficacy endpoints were percentage change from baseline in median monthly convulsive, focal, and total seizure frequency and ≥ 50%, ≥75%, and 100% responder rates across 12‐week visit windows through 144 weeks. Adverse events (AEs) are reported through 233 weeks. Results: Thirty‐four patients with confirmed TSC were included. Mean age was 12.4 years (range, 1.8–31.2), and patients were receiving a median of 3 (range, 1–7) antiseizure medications (ASMs) at baseline. Median CBD dose was 25–28 mg/kg/d for 36 weeks and then 20–50 mg/kg/d through 228 weeks. Dose reduction from baseline occurred for most ASMs, except topiramate. Median reduction in the frequency of convulsive, focal, and total seizures was 44%–81%, 51%–87%, and 44%–87%, respectively, through 144 weeks. Responder rates (≥50%, ≥75%, and 100% reduction) were 43%–71%, 14%–58%, and 0%–25% for convulsive seizures; 52%–75%, 35%–60%, and 7%–32% for focal seizures; and 46%–79%, 26%–65%, and 0%–13% for total seizures. A total of 94% of patients experienced ≥1 AE; 47% had serious AEs, considered treatment unrelated by the investigator. Treatment‐related AEs (TRAEs) occurred in 71% of patients. The most frequently reported TRAEs were somnolence, diarrhea, and ataxia. Two patients experienced AEs leading to discontinuation. There were no deaths. Significance: Long‐term add‐on CBD use was associated with reduced seizure frequency through 144 weeks. The safety profile was consistent with previous reports. Plain Language Summary: In this study, we evaluated efficacy and safety of cannabidiol (CBD) treatment in patients with tuberous sclerosis complex receiving CBD in addition to other antiseizure treatments in an Expanded Access Program. After starting CBD, 46%–79% of patients had at least 50% reduction and 26%–65% had at least 75% reduction in the number of seizures per month; up to 13% had no seizures through 144 weeks. Safety results were similar to prior studies; sleepiness and diarrhea were common treatment‐related side effects. These results show that long‐term CBD treatment was associated with fewer seizures and mild/moderate side effects. [ABSTRACT FROM AUTHOR]

Abstract Objective The cannabidiol (CBD) Expanded Access Program provided compassionate access to CBD for patients with treatment‐resistant epilepsy, including tuberous sclerosis complex (TSC), at 35 US epilepsy centers. Here, we present the long‐term efficacy and safety outcomes for add‐on CBD treatment in patients with TSC. Methods Patients received plant‐derived, highly purified CBD (Epidiolex® 100 mg/mL, oral solution), increasing from 2 to 10 mg/kg/d to tolerance or maximum of 25–50 mg/kg/d. Efficacy endpoints were percentage change from baseline in median monthly convulsive, focal, and total seizure frequency and ≥ 50%, ≥75%, and 100% responder rates across 12‐week visit windows through 144 weeks. Adverse events (AEs) are reported through 233 weeks. Results Thirty‐four patients with confirmed TSC were included. Mean age was 12.4 years (range, 1.8–31.2), and patients were receiving a median of 3 (range, 1–7) antiseizure medications (ASMs) at baseline. Median CBD dose was 25–28 mg/kg/d for 36 weeks and then 20–50 mg/kg/d through 228 weeks. Dose reduction from baseline occurred for most ASMs, except topiramate. Median reduction in the frequency of convulsive, focal, and total seizures was 44%–81%, 51%–87%, and 44%–87%, respectively, through 144 weeks. Responder rates (≥50%, ≥75%, and 100% reduction) were 43%–71%, 14%–58%, and 0%–25% for convulsive seizures; 52%–75%, 35%–60%, and 7%–32% for focal seizures; and 46%–79%, 26%–65%, and 0%–13% for total seizures. A total of 94% of patients experienced ≥1 AE; 47% had serious AEs, considered treatment unrelated by the investigator. Treatment‐related AEs (TRAEs) occurred in 71% of patients. The most frequently reported TRAEs were somnolence, diarrhea, and ataxia. Two patients experienced AEs leading to discontinuation. There were no deaths. Significance Long‐term add‐on CBD use was associated with reduced seizure frequency through 144 weeks. The safety profile was consistent with previous reports. Plain Language Summary In this study, we evaluated efficacy and safety of cannabidiol (CBD) treatment in patients with tuberous sclerosis complex receiving CBD in addition to other antiseizure treatments in an Expanded Access Program. After starting CBD, 46%–79% of patients had at least 50% reduction and 26%–65% had at least 75% reduction in the number of seizures per month; up to 13% had no seizures through 144 weeks. Safety results were similar to prior studies; sleepiness and diarrhea were common treatment‐related side effects. These results show that long‐term CBD treatment was associated with fewer seizures and mild/moderate side effects.

Abstract Cenobamate has demonstrated efficacy in patients with treatment-resistant epilepsy, including patients who continued to have seizures after epilepsy surgery. This article provides recommendations for cenobamate use in patients referred for epilepsy surgery evaluation. A panel of six senior epileptologists from the United States and Europe with experience in presurgical evaluation of patients with epilepsy and in the use of antiseizure medications (ASMs) was convened to provide consensus recommendations for the use of cenobamate in patients referred for epilepsy surgery evaluation. Many patients referred for surgical evaluation may benefit from ASM optimization; both ASM and surgical treatment should be individualized. Based on previous clinical studies and the authors’ clinical experience with cenobamate, a substantial proportion of patients with treatment-resistant epilepsy can become seizure-free with cenobamate. We recommend a cenobamate trial and ASM optimization in parallel with presurgical evaluations. Cenobamate can be started before phase two monitoring, especially in patients who are found to be suboptimal surgery candidates. As neurostimulation therapies are generally palliative, we recommend trying cenobamate before vagus nerve stimulation (VNS), deep brain stimulation, or responsive neurostimulation (RNS). In surgically remediable cases (mesial temporal sclerosis, benign discrete lesion in non-eloquent cortex, cavernous angioma, etc.), cenobamate use should not delay imminent surgery; however, a patient may decide to defer or even cancel surgery should they achieve sustained seizure freedom with cenobamate. This decision should be made on an individual, case-by-case basis based on seizure etiology, patient preferences, potential surgical risks (mortality and morbidity), and likely surgical outcome. The addition of cenobamate after unsuccessful surgery or palliative neuromodulation may also be associated with better outcomes.

In partial onset epilepsy, seizures arise focally in the brain and often propagate. Patients frequently become refractory to medical management, leaving neurosurgery, which can cause neurologic deficits, as a primary treatment. In the cortex, focal seizures spread through horizontal connections in layers II/III, suggesting that severing these connections can block seizures while preserving function. Focal neocortical epilepsy is induced in mice, sub‐surface cuts are created surrounding the seizure focus using tightly‐focused femtosecond laser pulses, and electrophysiological recordings are acquired at multiple locations for 3–12 months. Cuts reduced seizure frequency in most animals by 87%, and only 5% of remaining seizures propagated to the distant electrodes, compared to 80% in control animals. These cuts produced a modest decrease in cortical blood flow that recovered and left a ≈20‐µm wide scar with minimal collateral damage. When placed over the motor cortex, cuts do not cause notable deficits in a skilled reaching task, suggesting they hold promise as a novel neurosurgical approach for intractable focal cortical epilepsy. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the efficacy, safety, and tolerability of adjunctive lacosamide therapy against focal seizures in young children (1 month – 4 years). Methods: This non‐randomized, open‐label, and self‐controlled real‐world study included 105 children (1 month–4 years) with focal seizures treated with adjunctive lacosamide therapy at Children's Hospital of Chongqing Medical University. Results: (1) The 50% response rates at 3, 6, 9, and 12 months of follow‐up were 58.1%, 61.0%, 57.1%, and 56.2%, while the seizure‐free rates were 27.6%, 34.3%, 32.4%, and 37.1%, respectively. The 50% response rate of the first addition of lacosamide for focal seizures was much higher than the second and later added treatment at 3 months (p = 0.038). After 1 year of follow‐up, these children showed an improvement in neurodevelopmental levels (p < 0.05). (2) Lacosamide retention rate was 72.7% (64/88) after 1 year of follow‐up. Lack of efficacy and serious adverse events were independent risk factors for the lacosamide retention rate. (3) During adjunctive lacosamide therapy, 13 (12.4%) patients reported adverse events and five (4.7%) patients withdrew due to adverse events, including vomiting drowsiness, ataxia (0.94%), neck itching with eczema (0.94%), irritability (1.88%), and gastrointestinal discomfort (0.94%). Conclusion: Adjunctive lacosamide therapy was effective, safe, and well‐tolerated in young Chinese children with focal seizures in this study. [ABSTRACT FROM AUTHOR]

Objective: Focal to bilateral tonic–clonic seizures (FBTCS) represent a challenging subtype of focal temporal lobe epilepsy (TLE) in terms of both severity and treatment response. Most studies have focused on regional brain analysis that is agnostic to the distribution of white matter (WM) pathways associated with a node. We implemented a more selective, edge‐wise approach that allowed for identification of the individual connections unique to FBTCS. Methods: T1‐weighted and diffusion‐weighted images were obtained from 22 patients with solely focal seizures (FS), 43 FBTCS patients, and 65 age/sex‐matched healthy participants (HPs), yielding streamline (STR) connectome matrices. We used diffusion tensor‐derived STRs in an edge‐wise approach to determine specific structural connectivity changes associated with seizure generalization in FBTCS compared to matched FS and HPs. Graph theory metrics were computed on both node‐ and edge‐based connectivity matrices. Results: Edge‐wise analyses demonstrated that all significantly abnormal cross‐hemispheric connections belonged to the FBTCS group. Abnormal connections associated with FBTCS were mostly housed in the contralateral hemisphere, with graph metric values generally decreased compared to HPs. In FBTCS, the contralateral amygdala showed selective decreases in the structural connection pathways to the contralateral frontal lobe. Abnormal connections in TLE involved the amygdala, with the ipsilateral side showing increases and the contralateral decreases. All the FS findings indicated higher graph metrics for connections involving the ipsilateral amygdala. Data also showed that some FBTCS connectivity effects are moderated by aging, recent seizure frequency, and longer illness duration. Significance: Data showed that not all STR pathways are equally affected by the seizure propagation of FBTCS. We demonstrated two key biases, one indicating a large role for the amygdala in the propagation of seizures, the other pointing to the prominent role of cross‐hemispheric and contralateral hemisphere connections in FBTCS. We demonstrated topographic reorganization in FBTCS, pointing to the specific WM tracts involved. [ABSTRACT FROM AUTHOR]

Introduction: It is important to assess the effectiveness of an antiseizure medication in treating different epilepsy aetiologies to optimise individualised therapeutic approaches. Data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) Extension study were used to assess the effectiveness and safety/tolerability of perampanel (PER) when used to treat individuals with a range of epilepsy aetiologies in clinical practice. Methods: A post hoc analysis was conducted of PERMIT Extension data from individuals with a known aetiology. Retention was assessed after 3, 6 and 12 months. Effectiveness was assessed after 3, 6 and 12 months and at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥ 50% seizure frequency reduction) and seizure freedom rate (no seizures since at least the prior visit). Safety/tolerability was assessed by evaluating adverse events (AEs) and AEs leading to discontinuation. Results: PERMIT Extension included 1945 individuals with structural aetiology, 1012 with genetic aetiology, 93 with an infectious aetiology, and 26 with an immune aetiology. Retention rates at 12 months were 61.1% (structural), 65.9% (genetic), 56.8% (infectious) and 56.5% (immune). At the last visit, responder rates (total seizures) were 43.3% (structural), 68.3% (genetic), 37.0% (infectious) and 20.0% (immune), and corresponding seizure freedom rates were 15.8%, 46.5%, 11.1% and 5.0%, respectively. AE incidence rates were 58.0% (structural), 46.5% (genetic), 51.1% (infectious) and 65.0% (immune), and corresponding rates of discontinuation due to AEs over 12 months were 18.9%, 16.4%, 18.5% and 21.7%, respectively. The types of AEs reported were generally consistent across aetiology subgroups, with no idiosyncratic AEs emerging. Conclusion: Although PER was effective and generally well tolerated when used to treat individuals with a range of epilepsy aetiologies in clinical practice, variability in its effectiveness and tolerability across the subgroups indicates that PER may be particularly useful for individuals with specific epilepsy aetiologies. [ABSTRACT FROM AUTHOR]

Abstract Introduction It is important to assess the effectiveness of an antiseizure medication in treating different epilepsy aetiologies to optimise individualised therapeutic approaches. Data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) Extension study were used to assess the effectiveness and safety/tolerability of perampanel (PER) when used to treat individuals with a range of epilepsy aetiologies in clinical practice. Methods A post hoc analysis was conducted of PERMIT Extension data from individuals with a known aetiology. Retention was assessed after 3, 6 and 12 months. Effectiveness was assessed after 3, 6 and 12 months and at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥ 50% seizure frequency reduction) and seizure freedom rate (no seizures since at least the prior visit). Safety/tolerability was assessed by evaluating adverse events (AEs) and AEs leading to discontinuation. Results PERMIT Extension included 1945 individuals with structural aetiology, 1012 with genetic aetiology, 93 with an infectious aetiology, and 26 with an immune aetiology. Retention rates at 12 months were 61.1% (structural), 65.9% (genetic), 56.8% (infectious) and 56.5% (immune). At the last visit, responder rates (total seizures) were 43.3% (structural), 68.3% (genetic), 37.0% (infectious) and 20.0% (immune), and corresponding seizure freedom rates were 15.8%, 46.5%, 11.1% and 5.0%, respectively. AE incidence rates were 58.0% (structural), 46.5% (genetic), 51.1% (infectious) and 65.0% (immune), and corresponding rates of discontinuation due to AEs over 12 months were 18.9%, 16.4%, 18.5% and 21.7%, respectively. The types of AEs reported were generally consistent across aetiology subgroups, with no idiosyncratic AEs emerging. Conclusion Although PER was effective and generally well tolerated when used to treat individuals with a range of epilepsy aetiologies in clinical practice, variability in its effectiveness and tolerability across the subgroups indicates that PER may be particularly useful for individuals with specific epilepsy aetiologies.

IntroductionOur objective was to provide expert consensus recommendations to improve treatment tolerability through dose adjustments of concomitant antiseizure medications (ASMs) during addition of cenobamate to existing ASM therapy in adult patients with uncontrolled focal seizures.MethodsA panel of seven epileptologists experienced in the use of ASMs, including cenobamate, used a modified Delphi process to reach consensus. The panelists discussed tolerability issues with concomitant ASMs during cenobamate titration and practical strategies for dose adjustments that may prevent or mitigate adverse effects. The resulting recommendations consider concomitant ASM dose level and specify proactive (prior to report of an adverse effect) and reactive (in response to report of an adverse effect) dose adjustment suggestions based on concomitant ASM pharmacokinetic and pharmacodynamic interactions with cenobamate. Specific dose adjustment recommendations are provided.ResultsWe recommend proactively lowering the dose of clobazam, phenytoin, and phenobarbital due to their known drug-drug interactions with cenobamate, and lacosamide due to a pharmacodynamic interaction with cenobamate, to prevent adverse effects during cenobamate titration. Reactive lowering of a concomitant ASM dose is sufficient for other ASMs at standard dosing owing to quick resolution of adverse effects. For carbamazepine and lamotrigine doses exceeding the upper end of standard dosing (e.g., carbamazepine, greater than 1200 mg/day; lamotrigine, greater than 500 mg/day), we encourage consideration of proactive dose reduction at cenobamate 200 mg/day to prevent potential adverse effects. All dose reductions for adverse effects can be repeated every 2 weeks as dictated by the adverse effects. At cenobamate 200 mg/day, we recommend that patients be evaluated for marked improvement of seizures and further dose reductions be considered to reduce potentially unnecessary polypharmacy.ConclusionThe primary goal of the recommended dose reductions of concomitant ASMs is to prevent or resolve adverse effects, thereby allowing cenobamate to reach the optimal dose to achieve the maximal potential of improving seizure control.

Objectives: Seizures are common in children undergoing cardiopulmonary bypass (CPB). Cerebral oxygen saturation (ScO2) by near-infrared spectroscopy is routinely monitored in many centers, but the relations between the levels and changes of ScO2 and brain injuries remain incompletely understood. We aimed to analyze the postoperative profiles of ScO2 and cerebral blood flow velocity in different types of EEG seizures in relation to brain injuries on MRI. Methods: We monitored continuous EEG and ScO2 in 337 children during the first 48 h after CPB, which were analyzed in 3 h periods. Cerebral blood flow peak systolic velocity (PSV) in the middle cerebral artery was measured daily by transcranial Doppler. Postoperative cerebral MRI was performed before hospital discharge. Results: Based on the occurrence and spreading types of seizures, patients were divided into three groups as patients without seizures (Group N; n = 309), those with focal seizures (Group F; n = 13), or with secondarily generalized seizures (Group G; n = 15). There were no significant differences in the onset time and duration of seizures and incidence of status epilepticus between the two seizures groups (Ps ≥ 0.27). ScO2 increased significantly faster across Group N, Group G, and Group F during the 48 h (p < 0.0001) but its overall levels were not significantly different among the three groups (p = 0.30). PSV was significantly lower (p = 0.003) but increased significantly faster (p = 0.0003) across Group N, Group G, and Group F. Group F had the most severe brain injuries and the highest incidence of white matter injuries on MRI among the three groups (Ps ≤ 0.002). Conclusion: Postoperative cerebral oxygenation showed distinct profiles in secondarily generalized and particularly focal types of EEG seizures in children after CPB. A state of 'overshooting' ScO2 with persistently low PSV was more frequently seen in those with focal seizures and more severe brain injury. Information from this study may have important clinical implications in detecting brain injuries when monitoring cerebral oxygenation in this vulnerable group of children after CPB. [ABSTRACT FROM AUTHOR]

Introduction: Seizure is the most common paediatric neurological condition with an increased predilection for early childhood. The recent definition of epilepsy includes first-onset seizures with an increased probability of future episodes. Thus, stringent evaluation of the initial episode of seizure is essential. Hence, this study estimated the aetiology, clinical profile, treatment and outcome of the first seizure episode in children at a tertiary hospital. Materials and Methods: This prospective observational study was carried out at a tertiary hospital in Barabanki, India. Children in the age group of 1 month to 12 years who presented with the first seizure episode and those admitted for other illnesses and developed the first seizure episode during hospital stay were included. Data collected were sociodemographics, clinical presentations, laboratory tests, brain imaging studies, electroencephalography (EEG), diagnosis, treatment and short-term outcomes. Results: A total of 113 patients were enrolled presenting with first-onset seizures. There were 78 (69%) males, 86 (76.1%) were below 5 years of age and 60 (53.1%) presented with fever. Most seizures had a generalised onset (58.4%). Febrile seizures (29.2%) were the most common type, followed by neurocysticercosis (20.3%). Central nervous system (CNS)-infective aetiology (58.7%) was the most common etiological classification. Abnormal findings were observed in cerebrospinal fluid examination of 24 out of 56, in brain imaging of 53 out of 80 and in EEG of 70 out of 113 cases examined. Anti-seizure medication (ASM) was prescribed to 68 patients, of which 10 had a recurrence in the 6-month follow-up period. Conclusion: The first episode of seizure in children usually had a generalised onset, with younger children of the male sex at an increased risk. CNS infections and febrile seizures were common causes. Complete history and neurological evaluation can guide the relevant investigations. ASM tailored to the aetiology controls the seizures in most cases. [ABSTRACT FROM AUTHOR]

Introduction: The study aimed to evaluate the effectiveness and safety of brivaracetam (BRV) as conversion monotherapy in adults with focal epilepsy treated in the context of real-world clinical practice. Methods: This was a retrospective, observational, non-interventional study in adults with focal epilepsy who converted to BRV monotherapy following the withdrawal of background antiseizure medications (ASMs). Primary effectiveness outcome was the retention rate of BRV as single ASM at 6 and 12 months. Secondary outcomes included the 6- and 12-month rates of seizure freedom. Safety and tolerability outcomes included the frequency and type of adverse events (AEs) and the occurrence of treatment discontinuation due to AEs. Results: A total of 44 participants with a median age of 63.5 (interquartile range 44–73.5) years were included; 17 subjects were seizure free at baseline, and 9 of them switched from levetiracetam because of lack of tolerability. The retention rate of BRV monotherapy was 88.6% (39/44) at 6 months and 83.9% (26/31) at 12 months. The rates of seizure freedom were 72.7% (32/44) in subjects with 6-month follow-up and 58.1% (18/31) in subjects with 12-month follow-up. The median maintenance dosage of BRV monotherapy was 150 (100–200) mg/day at 6 months and 125 (100–200) mg/day in subjects with 12-month follow-up. Adverse events were recorded in 6/44 (13.6%) participants and led to BRV discontinuation in 2/44 (4.5%) cases. The reported AEs were somnolence (n = 3), fatigue (n = 2), and irritability (n = 1); no serious AEs were experienced. In 21/44 (47.7%) participants, BRV monotherapy resulted from the direct switch from levetiracetam. The rates of treatment retention and seizure freedom at 6 and 12 months were higher among people who switched from levetiracetam to BRV monotherapy. Conclusion: Brivaracetam may be a valuable treatment of focal seizures in people who converted to monotherapy in a real-life setting. [ABSTRACT FROM AUTHOR]

Abstract In partial onset epilepsy, seizures arise focally in the brain and often propagate. Patients frequently become refractory to medical management, leaving neurosurgery, which can cause neurologic deficits, as a primary treatment. In the cortex, focal seizures spread through horizontal connections in layers II/III, suggesting that severing these connections can block seizures while preserving function. Focal neocortical epilepsy is induced in mice, sub‐surface cuts are created surrounding the seizure focus using tightly‐focused femtosecond laser pulses, and electrophysiological recordings are acquired at multiple locations for 3–12 months. Cuts reduced seizure frequency in most animals by 87%, and only 5% of remaining seizures propagated to the distant electrodes, compared to 80% in control animals. These cuts produced a modest decrease in cortical blood flow that recovered and left a ≈20‐µm wide scar with minimal collateral damage. When placed over the motor cortex, cuts do not cause notable deficits in a skilled reaching task, suggesting they hold promise as a novel neurosurgical approach for intractable focal cortical epilepsy.

Abstract Introduction The study aimed to evaluate the effectiveness and safety of brivaracetam (BRV) as conversion monotherapy in adults with focal epilepsy treated in the context of real-world clinical practice. Methods This was a retrospective, observational, non-interventional study in adults with focal epilepsy who converted to BRV monotherapy following the withdrawal of background antiseizure medications (ASMs). Primary effectiveness outcome was the retention rate of BRV as single ASM at 6 and 12 months. Secondary outcomes included the 6- and 12-month rates of seizure freedom. Safety and tolerability outcomes included the frequency and type of adverse events (AEs) and the occurrence of treatment discontinuation due to AEs. Results A total of 44 participants with a median age of 63.5 (interquartile range 44–73.5) years were included; 17 subjects were seizure free at baseline, and 9 of them switched from levetiracetam because of lack of tolerability. The retention rate of BRV monotherapy was 88.6% (39/44) at 6 months and 83.9% (26/31) at 12 months. The rates of seizure freedom were 72.7% (32/44) in subjects with 6-month follow-up and 58.1% (18/31) in subjects with 12-month follow-up. The median maintenance dosage of BRV monotherapy was 150 (100–200) mg/day at 6 months and 125 (100–200) mg/day in subjects with 12-month follow-up. Adverse events were recorded in 6/44 (13.6%) participants and led to BRV discontinuation in 2/44 (4.5%) cases. The reported AEs were somnolence (n = 3), fatigue (n = 2), and irritability (n = 1); no serious AEs were experienced. In 21/44 (47.7%) participants, BRV monotherapy resulted from the direct switch from levetiracetam. The rates of treatment retention and seizure freedom at 6 and 12 months were higher among people who switched from levetiracetam to BRV monotherapy. Conclusion Brivaracetam may be a valuable treatment of focal seizures in people who converted to monotherapy in a real-life setting.

Introduction: Seizure is the most common paediatric neurological condition with an increased predilection for early childhood. The recent definition of epilepsy includes first-onset seizures with an increased probability of future episodes. Thus, stringent evaluation of the initial episode of seizure is essential. Hence, this study estimated the aetiology, clinical profile, treatment and outcome of the first seizure episode in children at a tertiary hospital. Materials and Methods: This prospective observational study was carried out at a tertiary hospital in Barabanki, India. Children in the age group of 1 month to 12 years who presented with the first seizure episode and those admitted for other illnesses and developed the first seizure episode during hospital stay were included. Data collected were sociodemographics, clinical presentations, laboratory tests, brain imaging studies, electroencephalography (EEG), diagnosis, treatment and short-term outcomes. Results: A total of 113 patients were enrolled presenting with first-onset seizures. There were 78 (69%) males, 86 (76.1%) were below 5 years of age and 60 (53.1%) presented with fever. Most seizures had a generalised onset (58.4%). Febrile seizures (29.2%) were the most common type, followed by neurocysticercosis (20.3%). Central nervous system (CNS)-infective aetiology (58.7%) was the most common etiological classification. Abnormal findings were observed in cerebrospinal fluid examination of 24 out of 56, in brain imaging of 53 out of 80 and in EEG of 70 out of 113 cases examined. Anti-seizure medication (ASM) was prescribed to 68 patients, of which 10 had a recurrence in the 6-month follow-up period. Conclusion: The first episode of seizure in children usually had a generalised onset, with younger children of the male sex at an increased risk. CNS infections and febrile seizures were common causes. Complete history and neurological evaluation can guide the relevant investigations. ASM tailored to the aetiology controls the seizures in most cases.

Abstract Objective NPRL3‐related epilepsy (NRE) is an emerging condition set within the wide GATOR‐1 spectrum with a particularly heterogeneous and elusive phenotypic expression. Here, we delineated the genotype–phenotype spectrum of NRE, reporting an illustrative familial case and reviewing pertinent literature. Methods Through exome sequencing (ES), we investigated a 12‐year‐old girl with recurrent focal motor seizures during sleep, suggestive of sleep‐related hypermotor epilepsy (SHE), and a family history of epilepsy in siblings. Variant segregation analysis was performed by Sanger sequencing. All previously published NRE patients were thoroughly reviewed and their electroclinical features were analyzed and compared with the reported subjects. Results In the proband, ES detected the novel NPRL3 frameshift variant (NM_001077350.3): c.151_152del (p.Thr51Glyfs*5). This variant is predicted to cause a loss of function and segregated in one affected brother. The review of 76 patients from 18 publications revealed the predominance of focal‐onset seizures (67/74–90%), with mainly frontal and frontotemporal (32/67–47.7%), unspecified (19/67–28%), or temporal (9/67–13%) onset. Epileptic syndromes included familial focal epilepsy with variable foci (FFEVF) (29/74–39%) and SHE (11/74–14.9%). Fifteen patients out of 60 (25%) underwent epilepsy surgery, 11 of whom achieved complete seizure remission (11/15–73%). Focal cortical dysplasia (FCD) type 2A was the most frequent histopathological finding. Significance We reported an illustrative NPRL3‐related epilepsy (NRE) family with incomplete penetrance. This condition consists of a heterogeneous spectrum of clinical and neuroradiological features. Focal‐onset motor seizures are predominant, and almost half of the cases fulfill the criteria for SHE or FFEVF. MRI‐negative cases are prevalent, but the association with malformations of cortical developments (MCDs) is significant, especially FCD type 2a. The beneficial impact of epilepsy surgery in patients with MCD‐related epilepsy further supports the inclusion of brain MRI in the workup of NRE patients.

Background: In terms of the severity of the disease, the nature of the sickness, and its effects on the individual, the family, and the community, seizure disorder is a significant public health concern. Aims and Objectives: This study evaluated the clinical and etiological profile of new-onset focal or generalized seizures in adult patients. Materials and Methods: A cross-sectional study was conducted with 100 new-onset seizure patients admitted to the Government Ariyalur Medical College Hospital. A detailed history was taken from the relatives about the type of seizure and comorbid conditions. An examination of the central nervous system was done to find any underlying neurological deficits. Investigations done in all patients were blood sugar, urea, creatinine, serum electrolytes, and liver function tests. ECG, chest X-ray, electroencephalographic, and computerized tomography of the brain. Magnetic resonance imaging brain was done in the indicated cases. Results: Of the 100 patients, 76% were males and 24% were females. The majority of the patients belonged to the age group of 41–60 years (40%). The most common type of seizure observed was the generalized tonic-clonic type (49%), followed by the focal type of seizure (23%). Of the various comorbid illnesses observed, diabetes mellitus was seen in about 41% of the patients; hypertension was seen in 40% of the patients; chronic kidney disease was seen in 24%; and cerebrovascular diseases were seen in 15%. The commonest etiology of new-onset seizures observed in this study was metabolic causes, constituting 41% of the cases, cerebrovascular diseases (32%), and alcohol-related seizures (10%). Conclusion: Accurate identification of the cause of adult-onset seizures is crucial, and knowledge of clinical and etiological profiles will facilitate better treatment.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurometabolic disorder leading to severe combined serotonin, dopamine, norepinephrine, and epinephrine deficiency. We report on a female patient with borderline functioning and sporadic clear-cut focal to bilateral seizures from age 10 years. A neuropsychological assessment highlighted a mild impairment in executive functions, affecting attention span and visual-spatial abilities. Following the diagnosis of epilepsy with a presumed genetic etiology, we applied a diagnostic approach inclusive of a next-generation sequencing (NGS) gene panel, which uncovered two variants in trans in the DOPA decarboxylase (DDC) gene underlying an AADC deficiency. This compound heterozygous genotype was associated with a mild reduction of homovanillic acid, a low level of the norepinephrine catabolite, and a significant reduction of 5-hydroxyindoleacetic acid in cerebrospinal fluid. Remarkably, 3-O-methyldopa (3-OMD) and 5-hydroxytryptophan were instead increased. During the genetically guided re-evaluation process, some mild signs of dysautonomic dysfunction (nasal congestion, abnormal sweating, hypotension and fainting, excessive sleepiness, small hands and feet, and increased levels of prolactin, tiredness, and fatigue), more typical of AADC deficiency, were evaluated with new insight. Of the two AADC variants, the R347Q has already been characterized as a loss-offunction with severe catalytic impairments, while the novel L391P variant has been predicted to have a less severe impact. Bioinformatic analyses suggest that the amino acid substitution may affect affinity for the PLP coenzyme. Thus, the genotype corresponds to a phenotype with mild and late-onset symptoms, of which seizures were the clinical sign, leading to medical attention. This case report expands the spectrum of AADC deficiency phenotypes to encompass a less-disabling clinical condition including borderline cognitive functioning, drugresponsive epilepsy, and mild autonomic dysfunction. [ABSTRACT FROM AUTHOR]

Phase 2 studies showed that focal seizures could be detected by algorithms using heart rate variability (HRV) in patients with marked autonomic ictal changes. However, wearable surface electrocardiographic (ECG) devices use electrode patches that need to be changed often and may cause skin irritation. We report the first study of automated seizure detection using a subcutaneously implantable cardiac monitor (ICM; Confirm Rx, Abbott). For this proof‐of‐concept (phase 1) study, we recruited six patients admitted to long‐term video‐electroencephalographic monitoring. Fifteen‐minute epochs of ECG signals were saved for each seizure and for control (nonseizure) epochs in the epilepsy monitoring unit (EMU) and in the patients' home environment (1–8 months). We analyzed the ICM signals offline, using a previously developed HRV algorithm. Thirteen seizures were recorded in the EMU, and 41 seizures were recorded in the home‐monitoring period. The algorithm accurately identified 50 of 54 focal seizures (sensitivity = 92.6%, 95% confidence interval [CI] = 85.6%–99.6%). Twelve of the 13 seizures in the EMU were detected (sensitivity = 92.3%, 95% CI = 77.2%–100%), and 38 of the 41 seizures in the out‐of‐hospital setting were detected (sensitivity = 92.7%, 95% CI = 84.7%–100%). Four false detections were found in the 141 control (nonseizure) epochs (false alarm rate = 2.7/24 h). Our results suggest that automated seizure detection using a long‐term, subcutaneous ICM device is feasible and accurate in patients with focal seizures and autonomic ictal changes. [ABSTRACT FROM AUTHOR]

Objective: Postseizure functional decline is a concern in poststroke epilepsy (PSE). However, data on electroencephalogram (EEG) markers associated with functional decline are scarce. Thus, we investigated whether periodic discharges (PDs) and their specific characteristics are associated with functional decline in patients with PSE. Methods: In this observational study, patients admitted with seizures of PSE and who had scalp EEGs were included. The association between the presence or absence of PDs and postseizure short‐term functional decline lasting 7 days after admission was investigated. In patients with PD, EEG markers were explored for risk stratification of short‐term functional decline, according to the American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology. The association between EEG markers and imaging findings and long‐term functional decline at discharge and 6 months after discharge, defined as an increase in the modified Rankin Scale score compared with the baseline, was evaluated. Results: In this study, 307 patients with PSE (median age = 75 years, range = 35–97 years, 64% males; hemorrhagic stroke, 47%) were enrolled. Compared with 247 patients without PDs, 60 patients with PDs were more likely to have short‐term functional decline (12 [20%] vs. 8 [3.2%], p <.001), with an adjusted odds ratio (OR) of 4.26 (95% confidence interval [CI] = 1.44–12.6, p =.009). Patients with superimposed fast‐activity PDs (PDs+F) had significantly more localized (rather than widespread) lesions (87% vs. 58%, p =.003), prolonged hyperperfusion (100% vs. 62%, p =.023), and a significantly higher risk of short‐term functional decline than those with PDs without fast activity (adjusted OR = 22.0, 95% CI = 1.87–259.4, p =.014). Six months after discharge, PDs+F were significantly associated with long‐term functional decline (adjusted OR = 4.21, 95% CI = 1.27–13.88, p =.018). Significance: In PSE, PDs+F are associated with sustained neuronal excitation and hyperperfusion, which may be a predictor of postseizure short‐ and long‐term functional decline. [ABSTRACT FROM AUTHOR]

Background: In terms of the severity of the disease, the nature of the sickness, and its effects on the individual, the family, and the community, seizure disorder is a significant public health concern. Aims and Objectives: This study evaluated the clinical and etiological profile of new-onset focal or generalized seizures in adult patients. Materials and Methods: A cross-sectional study was conducted with 100 new-onset seizure patients admitted to the Government Ariyalur Medical College Hospital. A detailed history was taken from the relatives about the type of seizure and comorbid conditions. An examination of the central nervous system was done to find any underlying neurological deficits. Investigations done in all patients were blood sugar, urea, creatinine, serum electrolytes, and liver function tests. ECG, chest X-ray, electroencephalographic, and computerized tomography of the brain. Magnetic resonance imaging brain was done in the indicated cases. Results: Of the 100 patients, 76% were males and 24% were females. The majority of the patients belonged to the age group of 41-60 years (40%). The most common type of seizure observed was the generalized tonic-clonic type (49%), followed by the focal type of seizure (23%). Of the various comorbid illnesses observed, diabetes mellitus was seen in about 41% of the patients; hypertension was seen in 40% of the patients; chronic kidney disease was seen in 24%; and cerebrovascular diseases were seen in 15%. The commonest etiology of newonset seizures observed in this study was metabolic causes, constituting 41% of the cases, cerebrovascular diseases (32%), and alcohol-related seizures (10%). Conclusion: Accurate identification of the cause of adult-onset seizures is crucial, and knowledge of clinical and etiological profiles will facilitate better treatment. [ABSTRACT FROM AUTHOR]

Objective: NPRL3‐related epilepsy (NRE) is an emerging condition set within the wide GATOR‐1 spectrum with a particularly heterogeneous and elusive phenotypic expression. Here, we delineated the genotype–phenotype spectrum of NRE, reporting an illustrative familial case and reviewing pertinent literature. Methods: Through exome sequencing (ES), we investigated a 12‐year‐old girl with recurrent focal motor seizures during sleep, suggestive of sleep‐related hypermotor epilepsy (SHE), and a family history of epilepsy in siblings. Variant segregation analysis was performed by Sanger sequencing. All previously published NRE patients were thoroughly reviewed and their electroclinical features were analyzed and compared with the reported subjects. Results: In the proband, ES detected the novel NPRL3 frameshift variant (NM_001077350.3): c.151_152del (p.Thr51Glyfs*5). This variant is predicted to cause a loss of function and segregated in one affected brother. The review of 76 patients from 18 publications revealed the predominance of focal‐onset seizures (67/74–90%), with mainly frontal and frontotemporal (32/67–47.7%), unspecified (19/67–28%), or temporal (9/67–13%) onset. Epileptic syndromes included familial focal epilepsy with variable foci (FFEVF) (29/74–39%) and SHE (11/74–14.9%). Fifteen patients out of 60 (25%) underwent epilepsy surgery, 11 of whom achieved complete seizure remission (11/15–73%). Focal cortical dysplasia (FCD) type 2A was the most frequent histopathological finding. Significance: We reported an illustrative NPRL3‐related epilepsy (NRE) family with incomplete penetrance. This condition consists of a heterogeneous spectrum of clinical and neuroradiological features. Focal‐onset motor seizures are predominant, and almost half of the cases fulfill the criteria for SHE or FFEVF. MRI‐negative cases are prevalent, but the association with malformations of cortical developments (MCDs) is significant, especially FCD type 2a. The beneficial impact of epilepsy surgery in patients with MCD‐related epilepsy further supports the inclusion of brain MRI in the workup of NRE patients. [ABSTRACT FROM AUTHOR]

Summary: Background: Adjunctive newer antiseizure medications (ASMs) are being used in patients with treatment-resistant focal-onset seizures (FOS). An updated network meta-analysis (NMA) was necessary to compile evidence in this critical area. Methods: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and Scopus from their inception until 17 January 2024, evaluating the efficacy, tolerability, and safety of rufinamide (RUF), brivaracetam (BRV), cenobamate (CNB), eslicarbazepine (ESL), lacosamide (LCM), retigabine (RTG), and perampanel (PER) as adjunctive treatments for FOS. Efficacy outcomes included seizure response and seizure freedom. Tolerability was assessed by discontinuation due to adverse events (AEs). Safety outcomes were evaluated based on the number of patients experiencing at least one AE and serious adverse events (SAEs). This review is registered with PROSPERO (CRD42023485130). Findings: A total of 29 studies involving 11,750 participants were included. For seizure response, all ASMs were significantly superior to placebo, with RTG ranking highest, followed by CNB. Considering dosage, CNB 400 mg/d was top-ranked, followed by RTG 1200 mg/d. For seizure freedom, BRV was highest-ranked, followed by CNB, with BRV 100 mg/d leading, followed by CNB 400 mg/d. Regarding tolerability, LCM 600 mg/d had the lowest ranking, followed by CNB 400 mg/d. For the safety outcome of AEs, ESL 1200 mg/d was ranked lowest, followed by CNB 400 mg/d. Regarding SAEs, LCM 400 mg/d was ranked lowest, followed by RTG 1200 mg/d. Interpretation: ASMs at different dosages have varying efficacy and tolerability profiles. We have provided hierarchical rankings of ASMs for efficacy and safety outcomes. Our findings offer the most comprehensive evidence available to inform patients, families, physicians, guideline developers, and policymakers about the choice of ASMs in patients with treatment-resistant FOS. Funding: None.

Scientific relevance. Epileptic syndromes associated with focal seizures often develop in children and adolescents and may be accompanied by cognitive impairment, mental disorders, and endocrine disorders, which require additional medication apart from anti-epileptic medicinal products. Currently, the selection of safe and effective therapies for epileptic syndromes, especially in paediatric populations, is a pressing challenge for epileptology.Aim. This study aimed at a comprehensive assessment of the safety and efficacy of lamotrigine in therapeutic doses for children and adolescents with epileptic syndromes associated with focal seizures.Materials and methods. A total of 53 patients aged 3 to 18 years with various epileptic syndromes associated with focal seizures were under observation in 2020–2023. During this period, 37 patients (69.8%) received monotherapy with lamotrigine, and 16 patients (30.2%) received combination therapy including lamotrigine and two or more other medicinal products. When evaluating the safety and efficacy of pharmacotherapy in adolescent patients, the authors selectively used the Software for Post-marketing Studies of Anti-epileptic Medicinal Products developed at the Scientific Centre for Expert Evaluation of Medicinal Products.Results. With lamotrigine, the highest rate of complete clinical remission was observed in patients with focal epilepsy with onset in childhood and adolescence (90.9% of cases). For structural focal epilepsy, 16.7% of patients achieved complete freedom from seizures, and 50% demonstrated a pronounced response to treatment. However, patients with epilepsy due to local structural changes in the neocortex (33.3% of cases) had a prognosis of severe epilepsy. For epileptic encephalopathies with onset in childhood, 66.7% of patients achieved a ≥50% reduction in the frequency of seizures. Seizure reduction improved the quality of life of patients and their parents, especially of those with a long history of unsuccessful treatment attempts. There were no adverse reactions associated with lamotrigine except those listed in the summary of product characteristics. The Software for Post-marketing Studies of Anti-epileptic Medicinal Products provided a means for scoring and plotting the changes in the condition of adolescents without severe cognitive and memory impairment undergoing lamotrigine treatment.Conclusions. According to the study results, lamotrigine is highly effective and has a favourable safety profile in patients with early-onset epileptic syndromes associated with focal seizures. Moreover, lamotrigine is applicable to the treatment of attention, memory, expressive speech disorders, and aggressive behaviour. Therefore, lamotrigine may be recommended for treating children and adolescents with comorbid epileptic syndromes and cognitive and emotional disorders. Specialised software improves the quality of real-world evidence regarding the safety and efficacy of anti-epileptic medication.

Roughly two-thirds of all people report having experienced déjà vu-the odd feeling that a current experience is both novel and a repeat or replay of a previous, unrecalled experience. Reports of an association between déjà vu and seizure aura symptomatology have accumulated for over a century, and frequent déjà vu is also now known to be associated with focal seizures, particularly those of a medial temporal lobe (MTL) origin. A longstanding question is whether seizure-related déjà vu has the same basis and is the same subjective experience as non-seizure déjà vu. Survey research suggests that people who experience both seizure-related and non-seizure déjà vu can often subjectively distinguish between the two. We present a case of a person with a history of focal MTL seizures who reports having experienced both seizure-related and non-seizure common déjà vu, though the non-seizure type was more frequent during this person's youth than it is currently. The patient was studied with a virtual tour paradigm that has previously been shown to elicit déjà vu among non-clinical, young adult participants. The patient reported experiencing déjà vu of the common non-seizure type during the virtual tour paradigm, without associated abnormalities of the intracranial EEG. We situate this work in the context of broader ongoing projects examining the subjective correlates of seizures. The importance for memory research of virtual scenes, spatial tasks, virtual reality (VR), and this paradigm for isolating familiarity in the context of recall failure are discussed.

Due to the complexity of focal epilepsy and its risk for transiting to the generalized epilepsy, the development of reliable classification methods to accurately predict and classify focal and generalized seizures is critical for the clinical management of patients with epilepsy. In order to holistically understand the seizure propagation behavior of focal epilepsy, we propose a three-node motif reduced network by respectively simplifying the focal region, surrounding healthy region and their critical regions as the single node. Because three-node motif can richly characterize information evolutions, the motif analysis method could comprehensively investigate the seizure behavior of focal epilepsy. Firstly, we define a new seizure propagation marker value to capture the seizure onsets and intensity. Based on the three-node motif analysis, it is shown that the focal seizure and spreading can be categorized as inhibitory seizure, focal seizure, focal-critical seizure and generalized seizures, respectively. The four types of seizures correspond to specific modal types respectively, reflecting the strong correlation between seizure behavior and information flow evolution. In addition, it is found that the intensity difference of outflow and inflow information from the critical node (connection heterogeneity) and the excitability of the critical node significantly affected the distribution and transition of the four seizure types. In particular, the method of local linear stability analysis also verifies the effectiveness of four types of seizures classification. In sum, this paper computationally confirms the complex dynamic behavior of focal seizures, and the study of criticality is helpful to propose novel seizure control strategies.

In this patient, now 42 years old, genetic generalized epilepsy (juvenile myoclonic epilepsy) manifested itself at the age of 13. At the age of 39, she experienced a status episode with prolonged ICU treatment. She was left with a left-sided hippocampal sclerosis and probably focal seizures. In addition, since the age of 24, the patient also experiences functional seizures on the background of a borderline personality disorder. While generalized epileptic seizures could be controlled with antiseizure medication (ASM), the patient was multiple times admitted to Emergency Departments for her functional seizures with subsequent intensive care treatments, including intubation. As a complication, the patient developed critical illness polyneuropathy and myopathy, resulting in wheelchair dependence. Additionally, she acquired a complex regional pain syndrome after extravasation of ASM. The report demonstrates the uncommon development of hippocampal sclerosis after a generalized tonic-clonic status epilepticus and the poor treatability of functional seizures as compared to generalized and focal seizures.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurometabolic disorder leading to severe combined serotonin, dopamine, norepinephrine, and epinephrine deficiency. We report on a female patient with borderline functioning and sporadic clear-cut focal to bilateral seizures from age 10 years. A neuropsychological assessment highlighted a mild impairment in executive functions, affecting attention span and visual–spatial abilities. Following the diagnosis of epilepsy with a presumed genetic etiology, we applied a diagnostic approach inclusive of a next-generation sequencing (NGS) gene panel, which uncovered two variants in trans in the DOPA decarboxylase (DDC) gene underlying an AADC deficiency. This compound heterozygous genotype was associated with a mild reduction of homovanillic acid, a low level of the norepinephrine catabolite, and a significant reduction of 5-hydroxyindoleacetic acid in cerebrospinal fluid. Remarkably, 3-O-methyldopa (3-OMD) and 5-hydroxytryptophan were instead increased. During the genetically guided re-evaluation process, some mild signs of dysautonomic dysfunction (nasal congestion, abnormal sweating, hypotension and fainting, excessive sleepiness, small hands and feet, and increased levels of prolactin, tiredness, and fatigue), more typical of AADC deficiency, were evaluated with new insight. Of the two AADC variants, the R347Q has already been characterized as a loss-of-function with severe catalytic impairments, while the novel L391P variant has been predicted to have a less severe impact. Bioinformatic analyses suggest that the amino acid substitution may affect affinity for the PLP coenzyme. Thus, the genotype corresponds to a phenotype with mild and late-onset symptoms, of which seizures were the clinical sign, leading to medical attention. This case report expands the spectrum of AADC deficiency phenotypes to encompass a less-disabling clinical condition including borderline cognitive functioning, drug-responsive epilepsy, and mild autonomic dysfunction.

This work aimed to develop and produce lacosamide-loaded niosomes coated with chitosan (LCA-CTS-NSM) using a thin-film hydration method and the Box-Behnken design. The effect of three independent factors (Span 60 amount, chitosan concentration, and cholesterol amount) on vesicle size, entrapment efficiency, zeta potential, and cumulative release (8 h) was studied. The optimal formulation of LCA-CTS-NSM was chosen from the design space and assessed for morphology, in vitro release, nasal diffusion, stability, tolerability, and in vivo biodistribution for brain targeting after intranasal delivery. The vesicle size, entrapment, surface charge, and in vitro release of the optimal formula were found to be 194.3 nm, 58.3%, +35.6 mV, and 81.3%, respectively. Besides, it exhibits sustained release behavior, enhanced nasal diffusion, and improved physical stability. Histopathological testing revealed no evidence of toxicity or structural damage to the nasal mucosa. It demonstrated significantly more brain distribution than the drug solution. Overall, the data is encouraging since it points to the potential for non-invasive intranasal administration of LCA as an alternative to oral or parenteral routes.

Objective: This study was undertaken to evaluate the long‐term safety, tolerability, and efficacy of adjunctive brivaracetam (BRV) treatment in pediatric patients with epilepsy. Methods: A phase 3, open‐label, multicenter, long‐term follow‐up trial (N01266; NCT01364597) was conducted on patients (aged 1 month to <17 years at core trial entry; direct enrollers aged 4 to <17 years) treated with BRV. Outcomes included treatment‐emergent adverse events (TEAEs), behavior assessments (Achenbach Child Behavior Checklist [CBCL], Behavior Rating Inventory of Executive Function [BRIEF]/BRIEF‐Preschool version [BRIEF‐P]), and efficacy outcomes (percent change in focal seizure frequency, 50% responder rate for all seizure types for patient subgroups <2 years and ≥2 years of age using daily record card data). Results: Of 257 patients with ≥1 dose of BRV (141 [54.9%] male; mean age = 8.0 years [SD = 4.5]), 36 patients were <2 years of age, and 72.0% of patients had a history of focal seizures. Mean BRV exposure was 3.2 patient‐years. At least one TEAE occurred in 93.4% patients, and 32.3% had serious TEAEs. Seven patients died during the trial; no deaths were considered treatment‐related. Patients ≥2 years of age had a median decrease in 28‐day adjusted focal seizure frequency of 62.9%, and 50.9% had a ≥50% response in all seizures. Patients <2 years of age had a median decrease in 28‐day adjusted focal seizure frequency of 96.9%, and 68.2% had a ≥50% response in all seizures. Kaplan–Meier estimated treatment retention was 72.7%, 64.5%, 57.8%, 53.3%, 50.1%, and 44.8% at 1, 2, 3, 4, 5, and 6 years, respectively. Mean changes (baseline to last evaluation) for all Achenbach CBCL and BRIEF‐P/BRIEF subscale scores were negative, reflecting stability/slight improvement. Significance: Long‐term adjunctive BRV treatment was generally well tolerated and efficacious in reducing seizure frequency, and had high retention rates, with generally stable cognitive/behavioral scores in pediatric patients with epilepsy. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore the effectiveness of brivaracetam (BRV) according to baseline seizure frequency and past treatment history in subjects with focal epilepsy who were included in the Brivaracetam Add‐On First Italian Network Study (BRIVAFIRST). Methods: BRIVAFIRST was a 12‐month retrospective, multicenter study including adults prescribed adjunctive BRV. Study outcomes included sustained seizure response (SSR), sustained seizure freedom (SSF), and the rates of treatment discontinuation and adverse events (AEs). Baseline seizure frequency was stratified as <5, 5–20, and >20 seizures per month, and the number of prior antiseizure medications (ASMs) as <5 and ≥6. Results: A total of 994 participants were included. During the 1‐year study period, SSR was reached by 45.8%, 39.3%, and 22.6% of subjects with a baseline frequency of <5, 5–20, and >20 seizures per month (p <.001); the corresponding figures for the SSF were 23.4%, 9.8%, and 2.8% (p <.001). SSR was reached by 51.2% and 26.5% participants with a history of 1–5 and ≥6 ASMs (p <.001); the corresponding rates of SSF were 24.7% and 4.5% (p <.001). Treatment discontinuation due to lack of efficacy was more common in participants with >20 seizures compared to those with <5 seizures per month (25.8% vs. 9.3%, p <.001), and in participants with history of ≥6 prior ASMs compared to those with history of 1–5 ASMs (19.6% vs. 12.2%, p =.002). There were no differences in the rates of BRV withdrawal due to AEs and the rates of AEs across the groups of participants defined according to the number of seizures at baseline and the number of prior ASMs. Significance: The baseline seizure frequency and the number of previous ASMs were predictors of sustained seizure frequency reduction with adjunctive BRV in subjects with focal epilepsy. [ABSTRACT FROM AUTHOR]

Background: Etiological profile of seizure is different from region to region owing to socio, economic and cultural differences between countries. Etiological profile will determine the outcome along with mortality and morbidity associated with the disease. Few studies till date report the etiological profile in adult new onset seizures. Aim: We here report a study to evaluate the etiological profile in adult patients reporting their first seizure at a tertiary hospital with the objective of identifying the variation in aetiology pertaining to socio economic status and prevalent culture of the population. Material and methods: Hundred adult patients (18years and above) presenting with new onset seizures, were recruited over a period of one year and evaluated for identification of the cause of their seizures. Results: Neuro infections (37%) were the most commonly observed cause of seizure in the present study. Males (male: female 1.22:1) were predominantly affected and generalized tonic clonic seizures (GTCS) was the predominant seizure type observed in these participants. Conclusion: Tuberculous meningitis was the most common cause due to its endemic nature in the area of study. Stroke was the most common cause in adults over 50 years while, in younger adults neuro infection was the leading cause in the present study group. Etiological profile of a population is dependent on the socio-economic status and prevalent culture of the population. [ABSTRACT FROM AUTHOR]

• Post hoc analyses of patients with temporal lobe epilepsy (TLE). • Patients on lacosamide (LCM) or controlled-release carbamazepine (CBZ-CR) monotherapy. • Stratified Kaplan–Meier estimates for seizure freedom were similar for LCM and CBZ-CR. • TEAEs were reported by numerically fewer patients on LCM (73.9%) than CBZ-CR (81.0%). • LCM was efficacious and generally well tolerated as monotherapy in patients with TLE. Temporal lobe epilepsy (TLE) is often associated with drug-resistant seizures. We evaluated the efficacy and tolerability of lacosamide (LCM) versus controlled-release carbamazepine (CBZ-CR) monotherapy in adults with newly diagnosed TLE. Exploratory post hoc analysis of patients with temporal focus of localization (indicated as the only localization focus) in a double-blind, noninferiority, phase 3 trial (SP0993; NCT01243177) in patients aged ≥ 16 years with newly diagnosed epilepsy randomized 1:1 to LCM or CBZ-CR monotherapy. Of 886 treated patients in this trial, temporal lobe focus of localization (TLE) was reported as the single focus for 287 (32.4%) patients (LCM 134, CBZ-CR 153). A similar proportion of patients with TLE on LCM (82 [61.2%]) and CBZ-CR (99 [64.7%]) completed the trial. Kaplan-Meier estimates for 6- and 12-month seizure freedom at the last evaluated dose level (stratified by number of seizures in the 3 months before screening [≤2 or >2 seizures]) were similar with LCM and CBZ-CR (6 months overall: 88.7% and 89.7%; 12 months overall: 78.3% and 81.7%). Treatment-emergent adverse events (TEAEs) were reported by fewer patients on LCM (73.9%) than CBZ-CR (81.0%). Drug-related TEAEs (assessed by the investigator) were reported in 41.8% of patients on LCM and 52.3% of patients on CBZ-CR; 11.2% of patients on LCM and 15.0% on CBZ-CR discontinued due to TEAEs. Lacosamide was efficacious and generally well tolerated as monotherapy in patients with TLE with efficacy outcomes comparable with CBZ-CR, and fewer patients on LCM reported any TEAEs, drug-related TEAEs, or discontinued due to TEAEs. [ABSTRACT FROM AUTHOR]

Objective: In this post hoc analysis of a subset of patients from a long‐term, open‐label phase 3 study, we assessed ≥50%, ≥75%, ≥90%, and 100% seizure reduction and sustainability of these responses with cenobamate using a time‐to‐event analytical approach. Methods: Of 240 patients with uncontrolled focal seizures who had adequate seizure data available, 214 completed the 12‐week titration phase and received ≥1 dose of cenobamate in the maintenance phase (max dose 400 mg/day) and were included in this post hoc analysis. Among patients who met an initial given seizure‐reduction level (≥50%, ≥75%, ≥90%, or 100%), sustainability of that response was measured using a time‐to‐event methodology. An event was defined as the occurrence of a study visit at which the seizure frequency during the interval since the prior study visit exceeded the initially attained reduction level. Study visits during the maintenance phase occurred at 3‐month intervals. Results: Of the 214 patients analyzed, 188 (88%), 177 (83%), 160 (75%), and 145 (68%) met ≥50%, ≥75%, ≥90%, and 100% seizure‐reduction responses, respectively, for at least one study visit interval during the maintenance phase. The median (95% confidence interval [CI]) time to first visit without a ≥50% seizure reduction was not reached by 30 months of follow‐up (53% of patients maintained their initial ≥50% seizure reduction). Median (95% CI) time to first visit without sustaining the initial ≥75%, ≥90%, or 100% seizure reduction was 13.0 (7.5–21.9) months, 7.5 (5.4–11.6) months, and 7.0 (5.3–10.4) months, respectively. Among the 145 patients who had 100% seizure reduction during at least one study visit, 22% remained seizure‐free for at least 30 months and 63% had ≤3 study visits with seizures. Significance: Adjunctive treatment with cenobamate led to sustained seizure reductions during the maintenance phase of the phase 3 safety study. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to describe extracerebral biosignal characteristics of overall and various seizure types as compared with baseline physical activities using multimodal devices (Empatica E4); develop predictive models for overall and each seizure type; and assess diagnostic performance of each model. Methods: We prospectively recruited patients with focal epilepsy who were admitted to the epilepsy monitoring unit for presurgical evaluation during January to December 2020. All study participants were simultaneously applied gold standard long‐term video‐electroencephalographic (EEG) monitoring and an index test, E4. Two certified epileptologists independently determined whether captured events were seizures and then indicated ictal semiology and EEG information. Both were blind to multimodal biosignal findings detected by E4. Biosignals during 5‐min epochs of both seizure events and baseline were collected and compared. Predictive models for occurrence overall and of each seizure type were developed using a generalized estimating equation. Diagnostic performance of each model was then assessed. Results: Thirty patients had events recorded and were recruited for analysis. One hundred eight seizure events and 120 baseline epochs were collected. Heart rate (HR), acceleration (ACC), and electrodermal activity (EDA) but not temperature were significantly elevated during seizures. Cluster analysis showed trends of greatest elevation of HR and ACC in bilateral tonic–clonic seizures (BTCs), as compared with non‐BTCs and isolated auras. HR and ACC were independent predictors for overall seizure types, BTCs, and non‐BTCs, whereas only HR was a predictor for isolated aura. Diagnostic performance including sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve of the predictive model for overall seizures were 77.78%, 60%, and.696 (95% confidence interval =.628–.764), respectively. Significance: Multimodal extracerebral biosignals (HR, ACC, EDA) detected by a wrist‐worn smartwatch can help differentiate between epileptic seizures and normal physical activities. It would be worthwhile to implement our predictive algorithms in commercial seizure detection devices. However, larger studies to externally validate our predictive models are required. [ABSTRACT FROM AUTHOR]

Background: Antiseizure medications can have negative effects on plasma lipid levels. Objectives: To evaluate plasma lipid changes in patients with newly diagnosed focal epilepsy treated with eslicarbazepine acetate (ESL) or controlled-release carbamazepine (CBZ-CR) monotherapy during a phase III, randomized, double-blind (DB) trial and 2 years of ESL treatment in an open-label extension (OLE). Design: Post hoc analysis of a phase III trial and OLE study. Methods: Proportions of patients with elevated levels of total cholesterol and low-density lipoprotein (LDL) cholesterol were assessed at DB baseline, OLE baseline (last visit of DB trial), and end of OLE. Results: A total of 184 patients received ESL monotherapy during the OLE: 96 received ESL monotherapy in the DB trial and 88 patients received CBZ-CR monotherapy. The proportions of patients with elevated total cholesterol and LDL cholesterol increased significantly during the DB trial in those treated with CBZ-CR monotherapy [total cholesterol, +14.9% (p < 0.001); LDL cholesterol, +11.5% (p = 0.012)] but decreased significantly after switching to ESL monotherapy in the OLE [total cholesterol, −15.3% (p = 0.008); LDL cholesterol, −11.1% (p = 0.021)]. No significant changes were observed in those treated with ESL monotherapy during the DB trial and OLE. At the end of the DB trial, between-group differences (ESL–CBZ-CR) in the proportions of patients with elevated total and LDL cholesterol were −13.6% (p = 0.037) and −12.3% (p = 0.061), respectively; at the end of the OLE, these between-group differences were −6.0% (p = 0.360) and −0.6% (p = 1.000), respectively. Conclusion: A lower proportion of patients with newly diagnosed focal epilepsy had increased levels of total and LDL cholesterol, compared to baseline, following monotherapy with ESL versus CBZ-CR; after switching from CBZ-CR to ESL, the proportions of patients with increased levels decreased significantly. Registration: ClinicalTrials.gov NCT01162460/NCT02484001; EudraCT 2009-011135-13/2015-001243-36. Plain language summary The impact of treatment with either eslicarbazepine acetate or controlled-release carbamazepine on cholesterol levels in patients with newly diagnosed focal epilepsy Patients with epilepsy have an increased risk of having cardiovascular and cerebrovascular diseases (e.g., myocardial infarction and stroke). Treatment with antiseizure medications can have a negative effect on blood cholesterol levels [such as total cholesterol and low-density lipoprotein (LDL) cholesterol], which can further increase the risk of cardiovascular and cerebrovascular diseases. We examined the impact of monotherapy treatment (i.e., treatment with only one antiseizure medication) using either eslicarbazepine acetate (ESL) or a controlled-release formulation of carbamazepine (CBZ-CR) in 184 patients with newly diagnosed focal epilepsy (ESL, 96 patients; CBZ-CR, 88 patients). Patients received monotherapy with ESL or CBZ-CR for approximately 1 year in a phase III clinical trial. After this, the patients could continue into a 2-year extension study during which they all received monotherapy with ESL. We assessed the proportions of patients with elevated levels of total cholesterol and LDL cholesterol at the beginning and end of the phase III trial, and at the end of the extension study. At the beginning of the phase III trial, the proportions of patients with elevated total cholesterol and elevated LDL cholesterol were similar between treatment groups. During the phase III trial, the proportions of patients with elevated total cholesterol and elevated LDL cholesterol increased in those treated with CBZ-CR monotherapy (total cholesterol, +14.9%; LDL cholesterol, +11.5%) but decreased after switching to ESL monotherapy in the extension study (total cholesterol, −15.3%; LDL cholesterol, −11.1%). By contrast, the proportions of patients with elevated levels of total cholesterol and LDL cholesterol remained relatively stable in those treated with ESL monotherapy during the phase III trial and extension study. These findings indicate that ESL monotherapy may be an appropriate treatment option for patients with newly diagnosed focal epilepsy who either already have, or who are at risk of developing, high levels of cholesterol, since this may reduce their likelihood of having cardiovascular and cerebrovascular diseases. [ABSTRACT FROM AUTHOR]

Objective: Stigmatization in patients with epilepsy is seen in varying degrees at all times, all over the world. To determine whether the stigma value and depression scores perceived by patients with epilepsy were different in focal and generalized seizures and to reveal the factors that might be effective in stigmatization. Methods: A total of 130 patients who were diagnosed as having epilepsy, 76 females and 54 males, were included in the study. Educational status, marital status, duration of illness, seizure control, and the number of drugs used were recorded. A questionnaire for depression and stigmatization was administered to all participants. Results: The mean age of the women was 35.26 ± 12.82 (mean ± standard deviation) years and 33.67 ± 12.55 years for men. Of the patients, 44.6% had focal seizures, 44.6% had generalized seizures, and 10.8% had unknown seizures. Stigmatization was detected in 70% and depression was detected in 54.6% of the patients. There was no difference between the stigmatization and depression scores of focal and generalized seizures (P=.338; P=.857, respectively). There was no difference between the stigmatization and sex, age, and marital status (P=.730; P=.657; P=.320, respectively). In our subgroup analyses, the stigmatization rate decreased as the education level increased (P=.000). There was a significant correlation between depression and stigmatization severity. We find a weak relationship between insufficiency and duration of the disease (r=0.217, P < .01). Conclusion: The stigmatization rate was independent of seizure type, seizure frequency, sex, age, and marital status. Stigmatization severity was significantly correlated with the presence of depression. Although seizures are well controlled with treatment, patients with epilepsy should be followed closely in terms of psychological and social support. [ABSTRACT FROM AUTHOR]

Background: Many factors underlying basic epileptic conditions determine the characteristics of epileptic seizures and the therapeutic outcome. Visual obvious abnormalities in resting baseline EEG are cardinal but incompletely understood like feature of seizure onset zone in focal epilepsy and interictal epileptiform discharge. Present study is an attempt to diagnose that evidence of epileptic discharge in temporal lobe epilepsy (TLE), would persist during interictal period in absence of abnormalities in baseline EEG, which could increase the impact of automatic analysis of EEG waves for clinical relevance. Materials and Methods: By using 10-20 system, functional connectivity was estimated in the 20 channels of delta, theta, alpha, beta and gamma frequency bands of EEG, from 16 diagnosed focal epileptic seizure patients and 16 age and sex matched controls. To observe the dynamics of the healthy brain, differ from the brain of dynamically focal epileptic patients during interictal period treated with anti-epileptic drugs in the context of resting state during eye close session of EEG. Such differences can be observed by using absolute spectral power from BESS ((Brain Electro Scan Software) of the Axxonet System and statistically measure by applied unpaired student t -test. Result: The high significance results in slow frequency EEG waves (delta and theta) in power spectral analysis were observed that demonstrates the potential epileptic discharge occurring during interictal period without visible pathological activity for helping in the diagnosis and lateralization of TLE. Conclusion: The detailed spectral analysis of EEG waves offers novel insight into focal epileptic patients when visually EEG findings were normal. This linear analysis helpful in extracting information from EEG signals in diagnosing specific neuronal correlates for TLE. Present findings concluded that epileptic discharges occur at different topographical regions of brain during interictal period and power spectral analysis plays a new insight in diagnosis of focal discharge. [ABSTRACT FROM AUTHOR]

Dear Madam, Around 52.5 million people worldwide suffer from the neurological illness known as epilepsy, which is frequently characterized by recurring seizures. (1, 2) As epilepsy is a chronic disorder that can lead to cognitive deficits, sadness, and anxiety in sufferers, it has a considerable negative impact on individuals and society. The most common type of seizures, affecting around 61% of persons with epilepsy, are focal seizures, which raise the risk of injury and early death (2). One of the most common forms of focal epilepsy, temporal lobe epilepsy (TLE), is characterized by recurring spontaneous seizures that begin in the temporal lobe. (s). (3) In the last two decades, many new antiseizure medications (ASMs)have been developed; however, about 40% of people with epilepsy may be drug-resistant, meaning ASMs are unable to control their seizures; therefore, despite the advent of new treatments, a high unmet need remains unaddressed. (2) Surgery is an alternate treatment, however, it cannot be used if larger areas of the brain are affected, in such cases, neuromodulation is a novel and successful therapeutic tool developed. (4) Conventionally, neural activity in epilepsy is categorized into interictal, and post-ictal states. With the help of continuous EEG, researchers have subdivided interictal state into a pre-ictal and pro-ictal state in temporal lobe epilepsy patients (which is the typical drug-resistant focal epilepsy targeted for interventions such as neuromodulation). The pre-ictal states indicate imminent seizure onset, while pro-ictal states reflect changes in neural activity that create a propensity for seizures over longer periods. The EEG-based pro-ictal state detection is critical to adaptive neuromodulation, with early detection of seizure allowing electrodes to be applied therapeutically to the brain's seizure onset zone and thalamus enabling treatment to be modified as per seizure risk. (5) A prospective cohort study was conducted on adults with drug-resistant temporal lobe epilepsy at UTHealth Houston, in which pro-ictal state – i.e., pathologic brain activities during periods of heightened seizure risk could be detected up to one-half hour prior to seizure onset. A classifier was developed that could reasonably accurately distinguish between physiological and pathologic brain states in temporal lobe epilepsy. Thalamocortical dynamics were used to identify pro-ictal states in each patient. As the limbic thalamus exerts a diverse influence on cortex activity, thalamocortical EEG was used for pro-ictal state detection as opposed to previous paradigms derived solely from cortical structures. ---Continue

Mechanosensors are emerging players responding to hemodynamic and physical inputs. Their significance in the central nervous system remains relatively uncharted. Using human-derived brain specimens or cells and a pre-clinical model of mesio-temporal lobe epilepsy (MTLE), we examined how the mRNA levels of the mechanosensitive channel PIEZO1 adjust to disease-associated pro-inflammatory trajectories.In brain tissue micro-punches obtained from 18 drug-resistant MTLE patients, PIEZO1 expression positively correlated with pro-inflammatory biomarkers TNFα, IL-1β, and NF-kB in the epileptogenic hippocampus compared to the adjacent amygdala and temporal cortex tissues. In an experimental MTLE model, hippocampal Piezo1 and cytokine expression levels were increased post-status epilepticus (SE) and during epileptogenesis. Piezo1 expression positively correlated with Tnfα, Il1β, and Nf-kb in the hippocampal foci. Next, by combining RNAscope with immunohistochemistry, we identified Piezo1 in glio-vascular cells. Post-SE and during epileptogenesis, ameboid IBA1 microglia, hypertrophic GFAP astrocytes, and damaged NG2DsRed pericytes exhibited time-dependent patterns of increased Piezo1 expression. Digital droplet PCR analysis confirmed the Piezo1 trajectory in isolated hippocampal microvessels in the ipsi and contralateral hippocampi. The combined examinations performed in this model showed Piezo1 expression returning towards basal levels after the epileptogenesis-associated peak inflammation. From these associations, we next asked whether pro-inflammatory players directly regulate PIEZO1 expression. We used human-derived brain cells and confirmed that endothelium, astrocytes, and pericytes expressed PIEZO1. Exposure to human recombinant TNFα or IL1β upregulated NF-kB in all cells. Furthermore, TNFα induced PIEZO1 expression in a dose and time-dependent manner, primarily in astrocytes.This exploratory study describes a spatiotemporal dialogue between PIEZO1 brain cell-mechanobiology and neuro-inflammatory cell remodeling. The precise functional mechanisms regulating this interplay in disease conditions warrant further investigation.

Abstract Objective Eslicarbazepine acetate (ESL) is a once‐daily (QD), oral anti‐seizure medication for the treatment of focal (partial‐onset) seizures. Here, we evaluate risk factors for the development of psychiatric treatment‐emergent adverse events (TEAEs) in clinical trials of adjunctive ESL in adults with focal seizures. Methods This post‐hoc analysis evaluated data pooled from three Phase III, randomized, double‐blind, placebo‐controlled trials (BIA‐2093‐301, ‐302, ‐304). After an 8‐week baseline period, patients were randomized equally to receive placebo, ESL 400 mg (not reported here), 800 mg, or 1200 mg QD (up to 2‐week titration; 12‐week maintenance; optional open‐label extension [OLE]). Incidences of psychiatric TEAEs were evaluated according to three separate criteria: medical history of psychiatric disorders (yes/no); baseline use of psychotropic drugs (yes/no); Montgomery–Åsberg Depression Rating Scale (MADRS) score at baseline (0–6: normal; 7–19: mild depression; 20–34: moderate depression). Results The analysis populations comprised 1251 patients for the controlled study period and 1137 patients for the 1‐year OLE. Psychiatric TEAE incidence was similar between patients taking ESL and placebo in the controlled and OLE study periods and was not related to ESL dose. Psychiatric TEAEs generally occurred more frequently in patients with a medical history of psychiatric disorders, using psychotropic drugs, or with depressive symptoms than in those without a history, not using psychotropic drugs, or with no depressive symptoms. Depression and anxiety were the most frequently reported psychiatric TEAEs. Significance Overall, in clinical trials of ESL in adults with focal seizures, incidences of psychiatric events were not statistically different between patients taking ESL and placebo, were not related to ESL dose, and generally occurred more frequently in patients with baseline psychiatric symptoms or a history of psychiatric disorders. Long‐term exposure to ESL was not associated with a marked increase in the incidence of psychiatric TEAEs.

• HRV-based seizure detection achieves good detection sensitivity of focal seizures. • Patient adaptive seizure detection threshold outperformed generic threshold. • The proposed machine learning method reduced FAR by 31% compared to previous methods. Wearable automated detection devices of focal epileptic seizures are needed to alert patients and caregivers and to optimize the medical treatment. Heart rate variability (HRV)-based seizure detection devices have presented good detection sensitivity. However, false alarm rates (FAR) are too high. In this phase-2 study we pursued to decrease the FAR, by using patient-adaptive logistic regression machine learning (LRML) to improve the performance of a previously published HRV-based seizure detection algorithm. ECG-data were prospectively collected using a dedicated wearable electrocardiogram-device during long-term video-EEG monitoring. Sixty-two patients had 174 seizures during 4,614 h recording. The dataset was divided into training-, cross-validation-, and test-sets (chronological) in order to avoid overfitting. Patients with >50 beats/min change in heart rate during first recorded seizure were selected as responders. We compared 18 LRML-settings to find the optimal algorithm. The patient-adaptive LRML-classifier in combination with using only responders to train the initial decision boundary was superior to both the generic approach and including non-responders to train the LRML-classifier. Using the optimal setting of the LRML in responders in the test dataset yielded a sensitivity of 78.2% and FAR of 0.62/24 h. The FAR was reduced by 31% compared to the previous method, upholding similar sensitivity. The novel, patient-adaptive LRML seizure detection algorithm outperformed both the generic approach and the previously published patient-tailored method. The proposed method can be implemented in a wearable online HRV-based seizure detection system alerting patients and caregivers of seizures and improve seizure-count which may help optimizing the patient treatment. [ABSTRACT FROM AUTHOR]

Introduction: Mechanisms underlying sudden unexpected death in epilepsy (SUDEP) are unclear, but autonomic disorders are thought to play a critical role. However, those dysfunctions have mainly been reported in the peri-ictal context of generalized tonic--clonic seizures. Here, we explored whether heart rate variability (HRV), heart rate (HR), and breathing rate (BR) changes could be observed perictally during focal seizures with or without impaired awareness as well as interictally to assess the risk of SUDEP. We report the case of a 33-year-old patient with drug-resistant bilateral temporal lobe epilepsy who died at home probably from an unwitnessed nocturnal seizure ("probable SUDEP"). Methods: Ictal and interictal HRV as well as postictal cardiorespiratory analyses were conducted to assess autonomic functions and overall SUDEP risk. The SUDEP patient was compared to two living male patients from our local database matched for age, sex, and location of the epileptic focus. Results: Interictal HRV analysis showed that all sleep HRV parameters and most awake HRV parameters of the SUDEP patient were significantly lower than those of our two control subjects with bitemporal lobe epilepsy without SUDEP (p < 0.01). In two focal with impaired awareness seizures (FIAS) of the SUDEP patient, increased postictal mean HR and reduced preictal mean high frequency signals (HF), known markers of increased seizure severity in convulsive seizures, were seen postictally. Furthermore, important autonomic instability and hypersensitivity were seen through fluctuations in LF/HF ratio following two seizures of the SUDEP patient, with a rapid transition between sympathetic and parasympathetic activity. In addition, a combination of severe hypopnea (202 s) and bradycardia (10 s), illustrating autonomic dysfunction, was found after one of the SUDEP patient's FIAS. Discussion: The unusual cardiorespiratory and HRV patterns found in this case indicated autonomic abnormalities that were possibly predictive of an increased risk of SUDEP. It will be interesting to perform similar analyses in other SUDEP cases to see whether our findings are anecdotal or instead suggestive of reliable biomarkers of high SUDEP risk in focal epilepsy, in particular focal with or without impaired awareness seizures. [ABSTRACT FROM AUTHOR]

A myriad of neurological manifestations can occur in association with ketotic and non ketotic hyperglycaemic states. Contrary to diabetic coma, which is a universal complication under relatively established metabolic circumstances, the pathophysiology beyond hyperglycaemic-associated positive neurological manifestations, including seizures, remains to be elucidated. The occurrence of symptomatic focal epilepsy as a manifestation of diabetes-related hyperglycaemia is seldom reported. Herein, we present a case of focal epilepsy with alternating positive and negative neurological manifestations as the initial manifestation of diabetes-related hyperglycaemia. The electroencephalogram confirmed the diagnosis of focal occipital seizures, and the brain magnetic resonance imaging depicted the associated typical transient imaging findings in the occipital lobe. Seizures were refractory to antiepileptics, and symptomatic control was achieved after achieving normoglycemia. On follow-up, complete clinical and imaging recovery occurred. Reflex focal epilepsy in the context of hyperglycaemic states is a rare condition, and the possibility of misdiagnosis is likely high. As reported in similar cases, seizures can be resistant to antiepileptics. An important message to highlight is that seizures associated with hyperglycaemic status can be resistant to antiepileptic treatment and only cease with glycaemic control.

Epilepsy is based on abnormal neuronal activities that have historically been suggested to arise from an excess of excitation and a defect of inhibition, or in other words from an excessive glutamatergic drive not balanced by GABAergic activity. More recent data however indicate that GABAergic signaling is not defective at focal seizure onset and may even be actively involved in seizure generation by providing excitatory inputs. Recordings of interneurons revealed that they are active at seizure initiation and that their selective and time-controlled activation using optogenetics triggers seizures in a more general context of increased excitability. Moreover, GABAergic signaling appears to be mandatory at seizure onset in many models. The main pro-ictogenic effect of GABAergic signaling is the depolarizing action of GABAA conductance which may occur when an excessive GABAergic activity causes Cl− accumulation in neurons. This process may combine with background dysregulation of Cl−, well described in epileptic tissues. Cl− equilibrium is maintained by (Na+)/K+/Cl− co-transporters, which can be defective and therefore favor the depolarizing effects of GABA. In addition, these co-transporters further contribute to this effect as they mediate K+ outflow together with Cl− extrusion, a process that is responsible for K+ accumulation in the extracellular space and subsequent increase of local excitability. The role of GABAergic signaling in focal seizure generation is obvious but its complex dynamics and balance between GABAA flux polarity and local excitability still remain to be established, especially in epileptic tissues where receptors and ion regulators are disrupted and in which GABAergic signaling rather plays a 2 faces Janus role.

IntroductionMechanisms underlying sudden unexpected death in epilepsy (SUDEP) are unclear, but autonomic disorders are thought to play a critical role. However, those dysfunctions have mainly been reported in the peri-ictal context of generalized tonic–clonic seizures. Here, we explored whether heart rate variability (HRV), heart rate (HR), and breathing rate (BR) changes could be observed perictally during focal seizures with or without impaired awareness as well as interictally to assess the risk of SUDEP. We report the case of a 33-year-old patient with drug-resistant bilateral temporal lobe epilepsy who died at home probably from an unwitnessed nocturnal seizure (“probable SUDEP”).MethodsIctal and interictal HRV as well as postictal cardiorespiratory analyses were conducted to assess autonomic functions and overall SUDEP risk. The SUDEP patient was compared to two living male patients from our local database matched for age, sex, and location of the epileptic focus.ResultsInterictal HRV analysis showed that all sleep HRV parameters and most awake HRV parameters of the SUDEP patient were significantly lower than those of our two control subjects with bitemporal lobe epilepsy without SUDEP (p < 0.01). In two focal with impaired awareness seizures (FIAS) of the SUDEP patient, increased postictal mean HR and reduced preictal mean high frequency signals (HF), known markers of increased seizure severity in convulsive seizures, were seen postictally. Furthermore, important autonomic instability and hypersensitivity were seen through fluctuations in LF/HF ratio following two seizures of the SUDEP patient, with a rapid transition between sympathetic and parasympathetic activity. In addition, a combination of severe hypopnea (202 s) and bradycardia (10 s), illustrating autonomic dysfunction, was found after one of the SUDEP patient’s FIAS.DiscussionThe unusual cardiorespiratory and HRV patterns found in this case indicated autonomic abnormalities that were possibly predictive of an increased risk of SUDEP. It will be interesting to perform similar analyses in other SUDEP cases to see whether our findings are anecdotal or instead suggestive of reliable biomarkers of high SUDEP risk in focal epilepsy, in particular focal with or without impaired awareness seizures.

Summary: The World Health Assembly approved the Intersectoral Global Action Plan for epilepsy and neurological disorders. Member states, including those in Southeast Asia, must now prepare to achieve IGAP's strategic targets by embracing novel approaches and strengthening existing policies and practices. We propose and present evidence to support four such processes. The opening course should engage all stakeholders to develop people-centric instead of outcome-centric approaches. Rather than caring for convulsive epilepsy alone, as currently done, primary care providers should also be skilled in diagnosing and treating focal and non-motor seizures. This could reduce the diagnostic gap as over half of epilepsies present with focal seizures. Currently, primary care providers lack knowledge and skills to manage focal seizures. Technology-enabled aids can help overcome this limitation. Lastly, there is need to add newer “easy to use” epilepsy medicines to Essential Medicines lists in light of emerging evidence for better tolerability, safety and user-friendliness.

Introduction: In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Most real-world research on BRV has focused on refractory epilepsy. The aim of this analysis was to assess the 12-month effectiveness and tolerability of adjunctive BRV when used as early or late adjunctive treatment in patients included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). Methods: BRIVAFIRST was a 12-month retrospective, multicenter study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of sustained seizure response, sustained seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Data were compared for patients treated with add-on BRV after 1–2 (early add-on) and ≥ 3 (late add-on) prior antiseizure medications. Results: A total of 1029 patients with focal epilepsy were included in the study, of whom 176 (17.1%) received BRV as early add-on treatment. The median daily dose of BRV at 12 months was 125 (100–200) mg in the early add-on group and 200 (100–200) in the late add-on group (p < 0.001). Sustained seizure response was reached by 97/161 (60.3%) of patients in the early add-on group and 286/833 (34.3%) of patients in the late add-on group (p < 0.001). Sustained seizure freedom was achieved by 51/161 (31.7%) of patients in the early add-on group and 91/833 (10.9%) of patients in the late add-on group (p < 0.001). During the 1-year study period, 29 (16.5%) patients in the early add-on group and 241 (28.3%) in the late add-on group discontinued BRV (p = 0.001). Adverse events were reported by 38.7% and 28.5% (p = 0.017) of patients who received BRV as early and late add-on treatment, respectively. Conclusion: Brivaracetam was effective and well tolerated both as first add-on and late adjunctive treatment in patients with focal epilepsy. [ABSTRACT FROM AUTHOR]