Reduction In Seizure Frequency Research Articles

Modified Atkins diet for drug-resistant epilepsy: A systematic review and meta-analysis of randomized controlled trials.

To evaluate the effectiveness and side-effect profile of the modified Atkins diet (MAD) compared to the usual diet (UD) in reducing seizure frequency among patients with drug-resistant epilepsy (DRE). In February 2023, we conducted an extensive search in PubMed, EMBASE, and Cochrane databases to find randomized controlled trials (RCTs) comparing MAD to UD in patients with drug-resistant epilepsy (DRE) on standard anti-seizure medication (ASM). We used random-effects meta-analyses and the Risk of Bias 2 tool to evaluate treatment effects and assess the quality of the included RCTs, respectively. Six studies were evaluated in the meta-analysis, including 575 patients, of whom 288 (50.1%) were randomized to the MAD. Average follow-up period was 12 weeks. MAD plus standard drug therapy was associated with a higher rate of 50% or greater reduction in seizure frequency compared to UD plus drug therapy (RR 6.28; 95% CI 3.52-10.50; p<0.001), both in children (RR 6.28; 95% CI 3.43-11.49; p<0.001) and adults with DRE (RR 6.14; 95% CI 1.15-32.66; p=0.033). MAD was also associated with a higher seizure freedom rate compared to UD (RR 5.94; 95% CI 1.93-18.31; p=0.002). Five studies reported adverse events with MAD; constipation was reported in 17% of patients (95% CI 5-44%), lethargy in 11% (95% CI 4-25%), and anorexia in 12% (95% CI 8-19%). Due to limited information about the ASM regimens, we were unable to further analyze the interaction between MAD and ASM. This meta-analysis, comprising 575 patients from 6 RCTs, revealed that MAD led to higher rates of seizure freedom and underscored its role in seizure frequency reduction by 50% or more in both adults and children, with no significant adverse events concerns.

Vagus nerve stimulation in refractory idiopathic generalised epilepsy: An Irish retrospective observational study.

Refractory idiopathic generalised epilepsy (IGE; also known as genetic generalised epilepsy) is a clinical challenge due to limited available therapeutic options. While vagus nerve stimulation (VNS) is approved as an adjunctive treatment for drug-resistant focal epilepsy, there is limited evidence supporting its efficacy for refractory IGE. We conducted a single-centre retrospective analysis of adult IGE patients treated with VNS between January 2003 and January 2022. We analysed the efficacy, safety, tolerability, stimulation parameters and potential clinical features of VNS response in this IGE cohort. Twenty-three IGE patients were implanted with VNS between January 2003 and January 2022. Twenty-two patients (95.65%) were female. The median baseline seizure frequency was 30 per month (interquartile range [IQR]= 140), including generalised tonic-clonic seizures (GTCS), absences, myoclonus, and eyelid myoclonia with/without absences. The median number of baseline anti-seizure medications (ASM) was three (IQR= 2). Patients had previously failed a median of six ASM (IQR= 5). At the end of the study period, VNS therapy remained active in 17 patients (73.9%). amongst patients who continued VNS, thirteen (56.5% of the overall cohort) were considered responders (≥50% seizure frequency reduction). Amongst the clinical variables analysed, only psychiatric comorbidity correlated with poorer seizure outcomes, but was non-significant after applying the Bonferroni correction. Although 16 patients reported side-effects, none resulted in the discontinuation of VNS therapy. Over half of the patients with refractory IGE experienced a positive response to VNS therapy. VNS represents a viable treatment option for patients with refractory IGE, particularly for females, when other therapeutic options have been exhausted.

75 Mood and Quality of Life after Responsive Neurostimulation (RNS) in Epilepsy Patients

Objective:Poor mood and quality of life is common among patients with medically intractable seizures. Many of these patients are not candidates for seizure focus resection and continue to receive standard medical care. Responsive neurostimulation (RNS) has been an effective approach to reduce seizure frequency for nonsurgical candidates. Previous research using RNS clinical trial participants has demonstrated improved mood and quality of life when patients received RNS-implantation earlier in their medically resistant epilepsy work-up (Loring et al., 2021). We aimed to describe the level of depression and quality of life in adults with medical resistant epilepsy, treated with RNS, presenting to an outpatient clinic.Participants and Methods:This pilot study was conducted among 11 adult epilepsy patients treated with RNS at the epilepsy specialty clinic at Baylor College of Medicine. Ages of participants ranged from 18-56 (M=32.01, SD=12.37) with a mean education of 12.43 (SD=0.85). The majority of the participants identified as White (White=72.2%; Hispanic/Latino/a=14.3%, Other=7.1%). We also present pre- and post-RNS preliminary results of a subset of 4 patients for whom pre and post implantation data was available. Depression symptoms were assessed through the Beck Depression Inventory, 2nd Edition (BDI-II) and quality of life was determined using the Quality of Life in Epilepsy (QoLiE-31).Results:Patients reported minimal symptoms of depression (M=5.45, SD=4.03) and good overall quality of life (M=71.18, SD=14.83) after RNS. Participants’ scores on their overall quality of life ranged from 50 to 95 (100=better quality of life). The QoLiE-31 showed high scores on emotional wellbeing (M=69.45, SD=14.56) and cognitive functioning (M=65.36, SD=16.66) domains. Post-hoc analysis revealed a significant difference in the cognitive functioning domain of QoLiE-31 before (M=44.75, SD=12.58) and after (M=51.0, SD=11.58) RNS implantation(t(3)=-3.78, p=0.016. Additionally, overall QoLiE score approached statistical significance when comparing pre-RNS (M=44.75 SD=9.29) to post-RNS (M=49.75 SD=11.62; t(3)=-2.01, p = 0.069). No significant differences were evident on seizure worry, energy/fatigue, medication effects, and social functioning domains of QoLiE-31 before and after RNS treatment.Conclusions:These pilot study results suggest low levels of depression with this population post-RNS implantation. Additionally, there is preliminary evidence to suggest improved patient-rated cognitive functioning and overall quality of life. While this is a small study population, the results have important implications for patients with intractable epilepsy, even with those form who surgical resection may not be possible. Future studies with large enough samples to examine moderating and mediating factors to mood and quality of life changes post-RNS will be important.

Effectiveness and safety of thread embedding acupuncture for drug-resistant epilepsy outpatient in Viet Nam: a two-arm parallel design, randomized, controlled clinical trial

People with drug-resistant epilepsy (DRE) are at high risk of sudden unexpected deaths and lower quality of life. Experiments showed thread embedding acupuncture (TEA) has a seizure-reducing effect; however, data on DRE has been limited. This trial aimed to establish the efficacy and safety of TEA in people with DRE. This was a two-arm, randomized controlled trial conducted on 30 DRE outpatients, which was fulfilled drug-resistant International League Against Epilepsy. The study was conducted at the Epilepsy clinic, Nguyen Tri Phuong Hospital, Ho Chi Minh City, from December 2020 to March 2022. All procedures for TEA and sham TEA (STEA) groups were identical. Seizure frequency diaries at the baseline and monthly follow-up visits by the participants. The Quality of Life in Epilepsy Inventory (QOLIE-31) scores at the baseline and 16 weeks; the National Hospital Seizure Severity Scale (NHS3) scores at the baseline, 8 weeks, and 16 weeks and the adverse events at monthly follow-up visits by a researcher. A reduction in relative seizure frequency and the score change in QOLIE-31 and NHS3 in the TEA group were significantly different from the STEA group when analyzing each group separately (p&lt;0.05). However, when comparing two groups, no significant difference was found in the change in seizure freedom and QOLIE-31 (p&gt;0.05). Mild pain appeared in all participants after the intervention, but no serious adverse effects of TEA were observed. TEA is a safe technique to use in people with DRE. However, the effectiveness of TEA needs further study.

Innovative gene therapy approaches for brain tumour-related epilepsy

Innovative gene therapy approaches for brain tumour-related epilepsy Professor Mark Cunningham and Dr Kate Connor from Trinity College Dublin discuss the burden of brain tumour-related epilepsy and why novel therapies are urgently needed to improve the quality of life for those affected. Brain tumour-related epilepsy (BTRE) is a unique and devastating condition which embraces two serious pathologies. BTRE incidence is inversely correlated to malignancy, with seizures as the first presenting symptom in 65-85% of patients with low-grade gliomas (LGG) and 30-60% with glioblastoma (GBM). (1) Seizures often manifest as complications throughout brain tumour evolution. Clinical management via radiotherapy, chemotherapy, and antiepileptic drugs (AEDs) can reduce seizure frequency, but many patients continue to experience seizures following therapeutic intervention. (2) Overall, BTRE is a debilitating and difficult-to-control condition, with seizures closely linked to tumour recurrence and progression.

Real-Life Experience With Purified Cannabidiol Treatment for Refractory Epilepsy: A Multicenter Retrospective Study

BackgroundDrug-resistant epilepsy (DRE) affects the development and quality of life of children and young adults. We analyzed the effectiveness and safety of purified CBD in this population. MethodsA retrospective analysis of medical records of 139 children and young adults (54.7% female, median age 12.0 years) with DRE treated with purified CBD from 2018 to 2022 at five medical centers in Israel. ResultsThe most common diagnosis was Lennox-Gastaut syndrome (37.4%) followed by Dravet syndrome (16.5%) and tuberous sclerosis complex (16.5%). Median purified CBD dose was 12.5 mg/kg (range 2.5 to 20.0), and median treatment duration was 9.0 months (range 0.5 to 48.0). Most patients (92.2%) had a reduced seizure frequency following treatment initiation; 41.1% had >50% reduction. Fifty-three patients (38.1%) had positive effects: improved alertness (31.7%), improved speech (10.1%), and achievement of new developmental milestones (2.2%). A multivariate linear model assessing predictive factors for seizure reduction demonstrated that patients previously treated with CBD oils, especially those with >50% seizure reduction on prior treatment, were also more likely to have a reduced seizure frequency while they were treated with purified CBD (P = 0.01, P < 0.0001). Development, diagnosis, age, purified CBD dose (0 to 10 mg/kg/day vs 10 to 20 mg/kg/day), and concomitant treatment with clobazam, valproic acid, or everolimus did not affect seizure reduction by purified CBD. The most common adverse events were irritability (20.9%) and drowsiness (12.9%). ConclusionPurified CBD is well-tolerated and effective in reducing seizure frequency in children and young adults with DRE.

The Response of Synthetic Adrenocorticotropic Hormone (ACTH) Treatment in Pediatric Drug-Resistant Epilepsy Other Than Infantile Epileptic Spasms Syndrome: A Retrospective Observational Study.

Adrenocorticotropic hormone (ACTH) is a tropic hormone naturally secreted by the anterior pituitary gland to stimulate the secretion of cortisol and androgens.ACTH is used innon-tuberous sclerosis infantile epileptic spasms syndrome (IESS), and ithas shown significant, promising results in epilepsy syndromes with possible inflammatory processes.However, many studies have also demonstrated a promising potential even in other types of drug-resistant epilepsy. Material and method: This study is a retrospective observational study that follows the clinical characteristics and outcomes of nine pediatric patients with drug-resistant epilepsy treated with short-term synthetic ACTH in Saudi Arabia. The response was assessed during the ACTH infusion and after three months. During infusion, six of the nine (66%) patients had a short-term (within two weeks) favorable response, with a more than 50% reduction in seizure frequency. Four of the nine (44%) patients had complete responses with seizure freedom. After three months, four patients (44%) had a three-month seizure frequency reduction of more than 30% attributed to ACTH, including one patient with an IESS history who had a 70% reduction in seizure frequency. Of the four patients who had a complete response, three (75%) had a seizure relapse after tapering in the following three months. Conclusion: This case series adds to the literature to suggest ACTH treatment of drug-resistant epilepsies other than IESS might benefit some patients in the acute settingbut they are less likely to maintain a sustained treatment response. Randomized and large sample size studies are necessary to assess treatment response and accurately aid in appropriate patient selection.

Autoimmune epilepsy, retrospective case series of clinical features, management, and outcomes.

To evaluate the clinical and electrographic features of patients with autoimmune epilepsy and assess the influence of early diagnosis and treatment on reducing seizure frequency. A retrospective observational case series was conducted utilizing medical records from King Abdullah Medical Hospital between 2017 and 2022. Cases of newly diagnosed seizures were chosen based on laboratory-proven autoimmunity. Five female inpatients were identified, primarily presenting with seizures suggestive of an autoimmune origin. Autoimmune antibodies were detected in all patients as follows: GAD (3), NMDA-R (2). One patient exhibited unilateral temporal lobe onset while three displayed bilateral onset. One patient had an associated malignancy. Rituximab was administered as an immunomodulatory therapy to four patients, resulting in successful seizure reduction post-immunotherapy initiation. Autoimmune epilepsy is recognized as a distinct condition. The clinical presentation can be complex and antibody testing may warrant repetition if initial results are negative or if specific antibodies are not detected. Early initiation of immunosuppression, coupled with prompt treatment escalation when required, is vital for achieving optimal patient outcomes.

Our experience of pediatric epilepsy surgery

Objective: to evaluate the effectiveness and safety of different operations in children with drug-resistant epilepsy. Materials and Method. 91 children with drug-resistant epilepsy were enrolled in a retrospective study. Mean age was 10.3±5.1 years. Anterior temporal lobectomy was performed in 16 (57.1%) patients, lesionectomy – in 9 (10.0%), microsurgical callosotomy in 18 (19.8%), stereotactic callosotomy in 7 (7.7%), multifocal resections in 4 (4.4%), functional hemispherotomy in 14 (15.6%). Stereotactic radiofrequency callosotomy was performed on a CRW Stereotactic frame (Radionics Inc., USA). Ultrasound navigation and neuronavigation were used in 6 (7%) and 14 (15%) cases correspondingly. Intraoperative corticography was applied in 8 (9%) cases. Postoperative long-term follow-up lasted from 1 to 17 years (mean - 8.2±2.1 years). Results. An epileptogenic zone within single hemisphere was indentified in 66 (72.2%) cases, while bilateral epileptiform activity was observed in 25 (27.5%) children. The most common etiologies of epilepsy included hypoxic-ischemic encephalopathy, intracerebral hemorrhage, meningoencephalitis, Rasmussen syndrome, cortical dysplasia, tumors.After surgery 51 (56%) patients became seizures free (Engel 1), 14 (15.4%) patients had rare auras or focal seizures (Engel 2). In 25 (27.5%) cases, seizure frequency reduction was less than 75% or did not change significantly. The most favorable outcomes were associated with resection procedures, resulting in complete seizure control in 46 (69.7%) out of 66 children, with significant improvement observed in 9 (13.6%) cases. After callosotomy drop-attacks stopped in 14 (78%) out of 18 who had them before surgery. Operative complications were encountered in 6 (6.6%) cases, postoperative mortality occurred in 1 (1.1%) case. Conclusions. The key to the effectiveness of surgical treatment of childhood epilepsy is early surgical intervention, which leads to the control of epileptic seizures, correction of psychological and cognitive emotional disorders and improvement of quality of life. The combination of resection procedures and disconnections contributes to the reduction of epileptogenic neurons and suppression of epileptic discharges.

Perampanel’s forgiveness factor in a variable medication adherence paradigm in a rat model of chronic epilepsy

BackgroundPoor medication adherence contributes to increased morbidity and mortality in patients with epilepsy and may be under-addressed in clinical practice. Ethical concerns make it impossible to study the impact of medication nonadherence in clinical trials, but our previous work emphasizes the importance of using preclinical approaches to address these questions. With over 30 clinically available antiseizure medicines (ASM’s), it remains an important question to understand the relationship between poor adherence and seizure incidence across mechanistically distinct ASM’s, including the broad-spectrum ASM, perampanel (PER).MethodsWe formulated PER into chow pellets to deliver to rats in a 100% fully adherent or 50% variable nonadherent paradigm via our novel automated medication-in-food delivery system. Chronic oral dosing was initiated in male rats with chronic epilepsy while monitoring 24/7 for videoEEG evidence of seizures during a 4-week placebo baseline and 4-week treatment phase. PER concentrations were monitored in plasma at 1-week intervals and correlated with degree of seizure control. The relationship between missed doses and extended patterns of nonadherence were correlated with breakthrough seizures.ResultsFully adherent rats demonstrated a median reduction in seizure frequency of 50%, whereas nonadherent rats had a median increase of 54%. Plasma concentrations of PER were stable over the 4-week treatment period in both fully adherent and nonadherent groups, with levels being twice as high in fully adherent animals. There was no correlation between a single missed dose or series of missed doses and the incidence of breakthrough seizures. However, those animals in the nonadherent group that received PER for every meal during a 24-h period had a reduced likelihood of seizure incidence.ConclusionsIf our preclinical data is supported in the clinic, PER’s favorable pharmacokinetic profile in humans, combined with a lowered risk of breakthrough seizures suggests that it may provide a certain forgiveness factor if a dose is missed within a 24-h window.

Effect of vagus nerve stimulation against generalized seizure and status epilepticus recurrence.

Vagus nerve stimulation (VNS) is a palliative surgery for drug-resistant epilepsy. The two objectives of this study were to (1) determine the seizure type most responsive to VNS and (2) investigate the preventive effect on status epilepticus (SE) recurrence. We retrospectively reviewed 136 patients with drug-resistant epilepsy who underwent VNS implantation. We examined seizure outcomes at 6, 12, and 24 months following implantation of VNS as well as at the last visit to the Juntendo Epilepsy Center. Univariate analysis and multivariate logistic regression models were used to estimate the prognostic factors. 125 patients were followed up for at least 1 year after VNS implantation. The percentage of patients with at least a 50% reduction in seizure frequency compared with prior to VNS implantation increased over time at 6, 12, and 24 months after VNS implantation: 28, 41, and 52%, respectively. Regarding overall seizure outcomes, 70 (56%) patients responded to VNS. Of the 40 patients with a history of SE prior to VNS implantation, 27 (67%) showed no recurrence of SE. The duration of epilepsy, history of SE prior to VNS implantation and seizure type were correlated with seizure outcomes after VNS implantation in univariate analysis (p = 0.05, p < 0.01, and p = 0.03, respectively). In multivariate logistic regression analysis, generalized seizure was associated with VNS response [odds ratio (OR): 4.18, 95% CI: 1.13-15.5, p = 0.03]. A history of SE prior to VNS implantation was associated with VNS non-responders [(OR): 0.221, 95% CI: 0.097-0.503, p < 0.01]. The duration of epilepsy, focal to bilateral tonic-clonic seizure and epileptic spasms were not significantly associated with VNS responders (p = 0.07, p = 0.71, and p = 0.11, respectively). Following 125 patients with drug-resistant epilepsy for an average of 69 months, 56% showed at least 50% reduction in seizure frequency after VNS implantation. This study suggests that generalized seizure is the most responsive to VNS, and that VNS may reduce the risk of recurrence of SE. VNS was shown to be effective against generalized seizure and also may potentially influence the risk of further events of SE, two marker of disease treatment that can lead to improved quality of life.

Neuromodulation techniques in medically refractory epilepsy: A comprehensive assessment

The aim of this research is to explore the efficacy and safety of neurostimulation techniques, particularly responsive neurostimulation, in treating medically refractory epilepsy. The study reviews relevant literature, discusses the mechanisms of action, and presents evidence of reduced seizure frequency and improved quality of life in patients receiving neurostimulation. To evaluate invasive Neuromodulation’s efficiency for medically refractory epilepsy, we searched databases like Google Scholar, Medline, and Elsevier using keywords ‘Neuromodulation and epilepsy’. Numerous relevant results emerged. We conducted rapid abstract reviews to identify key articles, cross-referencing for valuable references, ensuring a comprehensive analysis of pertinent research. Neuromodulation techniques, particularly VNS, DBS, and RNS, offer promising therapeutic options for medically refractory epilepsy. Ongoing research and clinical trials are vital for refining these treatments, adapting them for diverse populations, and enhancing outcomes. The potential to improve patients’ quality of life through innovative approaches is encouraging, driving further progress in neuromodulation.

A novel GABRG2 variant in Sunflower syndrome: a case report and video EEG monitoring.

Sunflower syndrome is a unique photosensitive epilepsy, characterized by heliotropism and stereotyped seizures associated with handwaving. These handwaving events (HWE) are thought to be an ictal phenomenon, although current data are contrasting. Photosensitive epilepsy occurs in 2-5% of the epilepsy forms and several pathogenic gene variants have been associated with photosensitive epilepsy. However, the genetic etiology of Sunflower syndrome remains unknown. Antiseizure medications (ASM) efficacious in treating photosensitive epilepsy are valproic acid (VPA) and levetiracetam (LEV) although some forms, such as Sunflower syndrome, can be drug-resistant. Here, we report an 8-year-old boy with an early onset of episodes of HWE that was initially categorized as behavioral problems for which risperidone was started. However, the medical history was suggestive of Sunflower syndrome and subsequent video EEG showed focal mostly temporal and fronto-temporal (right and left) epileptiform activity and confirmed the epileptic nature of the HWE. Thus, VPA was started and initially led to seizure frequency reduction. Molecular analyses showed a pathogenic variant in GABRG2 (c.1287G>A p.(Trp429Ter)), which has been associated with photosensitive and generalized epilepsy. Overall, clinicians worldwide should be cautious by interpreting HWE and/or other tic-like movements, since an epileptic origin cannot be ruled out. A prompt and correct diagnosis can be made by performing a video EEG early on in the diagnostic process when epileptic seizures are part of the differential diagnosis. Even though the genetic etiology of Sunflower syndrome remains poorly understood, this constellation supports further genetic testing since the detection of a pathogenic variant can help in making correct decisions regarding ASM management.

Remarkable anecdotes illustrating the nature and effect of seizure-precipitating factors in Border Collies with idiopathic epilepsy.

Epilepsy is one of the most common chronic neurological syndromes in dogs and has serious implications for the quality of life of both the dogs and owners. Seizure-precipitating factors (SPFs) (also termed "triggers" or "provocative factors") have been studied and reported in both humans and dogs with idiopathic epilepsy. In dogs stress, hormones, sleep deprivation, and the weather have been reported as SPFs. The Border Collie (BC) is a breed of dog that is predisposed to idiopathic epilepsy, and the outcome is often poor. BC is described as a very sensitive dog with a strong focus on their owners, and this may have an influence on their and their owners' stress level. In this article, we described six unrelated BCs with idiopathic epilepsy in which several remarkable SPFs were identified, and avoiding them improved the outcome of these dogs. The possible SPFs were different for each dog. The SPFs were, among others, the other dog in the family, the lack of intellectual challenge, the presence of an autistic child, a busy street, the relation with the owner, and throwing a ball at the beach. These cases illustrate that recognizing the SPF(s) and taking measures with regard to management can lead to a reduction in epileptic seizure frequency or even achieving seizure freedom.

Adjunctive brivaracetam and sustained seizure frequency reduction in very active focal epilepsy

AbstractObjectiveThis 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).MethodsBRIVAFIRST 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 &lt;5, 5–20, and &gt;20 seizures per month, and the number of prior antiseizure medications (ASMs) as &lt;5 and ≥6.ResultsA 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 &lt;5, 5–20, and &gt;20 seizures per month (p &lt; .001); the corresponding figures for the SSF were 23.4%, 9.8%, and 2.8% (p &lt; .001). SSR was reached by 51.2% and 26.5% participants with a history of 1–5 and ≥6 ASMs (p &lt; .001); the corresponding rates of SSF were 24.7% and 4.5% (p &lt; .001). Treatment discontinuation due to lack of efficacy was more common in participants with &gt;20 seizures compared to those with &lt;5 seizures per month (25.8% vs. 9.3%, p &lt; .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.SignificanceThe baseline seizure frequency and the number of previous ASMs were predictors of sustained seizure frequency reduction with adjunctive BRV in subjects with focal epilepsy.

PHARMACOLOGICAL EVALUATION OF LEVETIRACETAM AS ADD-ON DRUG TO EITHER PHENYTOIN OR SODIUM VALPROATE IN PATIENTS OF GENERALIZED ONSET TONIC-CLONIC SEIZURES HAVING BREAKTHROUGH SEIZURES: A RANDOMIZED AND COMPARATIVE STUDY

Objective: Breakthrough seizures are sudden and unexpected seizures that occur in people with epilepsy who generally have good control over the symptoms. The present study is aimed to compare phenytoin plus levetiracetam versus sodium valproate plus levetiracetam to control breakthrough seizures. Methods: A prospective, comparative study was carried out in Generalized onset tonic-clonic seizures (GTCS) patients with breakthrough seizures in Gajra Raja Medical College, Gwalior (M.P.) from February 2021 to August 2022. Participants were randomly allocated to 2 groups, namely phenytoin + levetiracetam (PL) (n=62) and sodium valproate + levetiracetam (SL) (n=61). Patients in group PL received phenytoin at the dose of 200 mg twice a day in adults, 5 mg/kg/day in two divided doses in children plus levetiracetam 500 mg twice a day in adults and 30 mg/kg/day in three divided doses in children. Patients in group SL received sodium valproate 600 mg 3 times a day in adults, 30 mg/kg/day in three divided doses in children plus levetiracetam 500 mg twice a day in adults and 30 mg/kg/day in three divided doses in children. The mean reduction in seizure frequency and patients response to the treatment in the last 30 days were recorded before the start of therapy and at 3 and 6 months after therapy. Adverse drug reactions were recorded during the study period. Statistical analysis was performed using (Statistical Package for the Social Sciences) software. Results: Mean seizure frequency decreased by 59 and 85% in PL and by 59 and 91% in the SL group and is significant (p&lt;0.05) from baseline value at 3 and 6 months, respectively, in both the groups. SL group showed significantly (p&lt;0.05) better response, than PL group in controlling seizures at 6 months. Excellent response by patients was seen by 21% and 49% in PL and SL groups, respectively. Adverse effects noted during the study were mild, including somnolence, headache, dizziness, GIT stress, and fatigue, and responded to symptomatic treatment. Twenty-nine (29%) of PL cases and 6% of SL cases underwent fatigue as adverse drug reactions that showed better tolerability of the SL group. Conclusion: Sodium valproate plus levetiracetam is more efficacious and safer than phenytoin plus levetiracetam in the management of breakthrough seizures in GTCS patients.

Long-term safety and efficacy of adjunctive brivaracetam in pediatric patients with epilepsy: An open-label, follow-up trial.

To evaluate the long-term safety, tolerability, and efficacy of adjunctive brivaracetam (BRV) treatment in pediatric patients with epilepsy. Phase 3, open-label, multicenter, long-term follow-up trial (N01266; NCT01364597; 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-P/BRIEF]), 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). 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. Long-term adjunctive BRV treatment was generally well tolerated, efficacious in reducing seizure frequency, and had high retention rates, with generally stable cognitive/behavioral scores in pediatric patients with epilepsy.

Epilepsy surgery in patients with hypothalamic hamartomas - Population-based two-year and long-term outcomes.

Hypothalamic hamartomas are benign lesions associated with drug resistant epilepsy. Surgical treatment has become an increasingly utilised approach with promising results. This study aims to evaluate seizure outcome and complications after surgery in a population-based series of patients with intractable epilepsy and hypothalamic hamartoma. All patients with hypothalamic hamartoma treated with epilepsy surgery in Sweden since 1995 with at least two years of follow-up were included. Preoperative, two-, five- and ten-year prospective longitudinal data were collected from The Swedish National Epilepsy Surgery Register. Data included seizure types and frequency, duration of epilepsy, clinical characteristics, neurological deficits, cognitive level and complications. In a subgroup from Gothenburg, we also analysed data not included in the register such as classification of hamartomas, surgical procedures and gelastic seizures. Eighteen patients were operated on during the period 1995-2020. The median age at epilepsy onset was 6 months and age at surgery 13 years. Four were seizure free and another four had ≥75% reduction in seizure frequency at the two-year follow-up. Two of the 13 patients with a long-term follow-up (five or ten years) were seizure-free and four had ≥75% reduction in seizure frequency. Three had an increased seizure frequency. No major complications were seen. Five had minor complications. In the Gothenburg subgroup all had open pterional disconnection or intraventricular endoscopic disconnection. Six of 12 were free from gelastic seizures at the two-year follow-up and six of eight at the long-term follow-up. This study supports surgical treatment of hypothalamic hamartomas as a safe method with a low risk of permanent complications. The seizure reduction seems to be persistent over time.

Reduced Cholecystokinin-Expressing Interneuron Input Contributes to Disinhibition of the Hippocampal CA2 Region in a Mouse Model of Temporal Lobe Epilepsy.

A significant proportion of temporal lobe epilepsy (TLE) patients experience drug-resistant seizures associated with mesial temporal sclerosis, in which there is extensive cell loss in the hippocampal CA1 and CA3 subfields, with a relative sparing of dentate gyrus granule cells and CA2 pyramidal neurons (PNs). A role for CA2 in seizure generation was suggested based on findings of a reduction in CA2 synaptic inhibition (Williamson and Spencer, 1994) and the presence of interictal-like spike activity in CA2 in resected hippocampal tissue from TLE patients (Wittner et al., 2009). We recently found that in the pilocarpine-induced status epilepticus (PILO-SE) mouse model of TLE there was an increase in CA2 intrinsic excitability associated with a loss of CA2 synaptic inhibition. Furthermore, chemogenetic silencing of CA2 significantly reduced seizure frequency, consistent with a role of CA2 in promoting seizure generation and/or propagation (Whitebirch et al., 2022). In the present study, we explored the cellular basis of this inhibitory deficit using immunohistochemical and electrophysiological approaches in PILO-SE male and female mice. We report a widespread decrease in the density of pro-cholecystokinin-immunopositive (CCK+) interneurons and a functional impairment of CCK+ interneuron-mediated inhibition of CA2 PNs. We also found a disruption in the perisomatic perineuronal net in the CA2 stratum pyramidale. Such pathologic alterations may contribute to an enhanced excitation of CA2 PNs and CA2-dependent seizure activity in the PILO-SE mouse model.SIGNIFICANCE STATEMENT Impaired synaptic inhibition in hippocampal circuits has been identified as a key feature that contributes to the emergence and propagation of seizure activity in human patients and animal models of temporal lobe epilepsy (TLE). Among the hippocampal subfields, the CA2 region is particularly resilient to seizure-associated neurodegeneration and has been suggested to play a key role in seizure activity in TLE. Here we report that perisomatic inhibition of CA2 pyramidal neurons mediated by cholecystokinin-expressing interneurons is selectively reduced in acute hippocampal slices from epileptic mice. Parvalbumin-expressing interneurons, in contrast, appear relatively conserved in epileptic mice. These findings advance our understanding of the cellular mechanisms underlying inhibitory disruption in hippocampal circuits in a mouse model of spontaneous recurring seizures.

Effects of Levetiracetam on Childhood-onset Refractory Epilepsy Classified by Level of Intellectual Disability

The efficacy of levetiracetam (LEV) for childhood-onset refractory epilepsy was retrospectively evaluated from medical records, based on the level of intellectual disability. The study sample included 84 patients (68 adults, 16 children) with childhood- onset refractory epilepsy who had been treated with LEV (dose: adult, 1000 mg/day; children, 30 mg/kg/day) for approximately 1.7 years. The responder rates (≥ 50% and ≥ 75% reduction in seizure frequency from baseline) were 85.7% and 42.9% for focal seizures in adults with normal intelligence; the responder rates for focal seizures in adults with intellectual disabilities were average 69.0% and 6.9%, respectively. Serious adverse events were not observed. A high level (≧75%) of reduction can be expected for focal seizures in adults with normal intelligence but cannot be expected in adults with intellectual disabilities. Further studies are required to investigate these.