Efficacy and safety of VNS therapy or continued medication management for treatment of adults with drug-resistant epilepsy: systematic review and meta-analysis

Vagus nerve stimulation (VNS) Therapy® is an adjunctive neurostimulation treatment for people with drug-resistant epilepsy (DRE) who are unwilling to undergo resective surgery, have had unsuccessful surgery or are unsuitable for surgery. A systematic review and meta-analysis were conducted to determine the treatment effects of VNS Therapy as an adjunct to anti-seizure medications (ASMs) for the management of adults with DRE. A literature search was performed in August 2020 of the Medline®, Medline® Epub Ahead of Print, Embase, and the Cochrane library databases. Outcomes examined included reduction in seizure frequency, seizure freedom, ASM load, discontinuations, and serious adverse events (SAEs). Comparators included best medical practice, ASMs, low-stimulation or sham VNS Therapy. Four RCTs and six comparative observational studies were identified for inclusion. Against comparators, individuals treated with VNS had a significantly better odds of experiencing a ≥ 50% reduction in seizure frequency (OR: 2.27 [95% CI 1.47, 3.51]; p = 0.0002), a ≥ 75% reduction in seizure frequency (OR: 3.56 [95% CI 1.59, 7.98]; p = 0.002) and a reduced risk for increased ASM load (risk ratio: 0.36 [95% CI 0.21, 0.62]; p = 0.0002). There was no difference in the odds of discontinuation or the rate of SAEs between VNS versus comparators. This meta-analysis demonstrated the benefits of VNS Therapy in people with DRE, which included improvement in seizure frequency without an increase in the rate of SAEs or discontinuations, thereby supporting the consideration of VNS Therapy for people who are not responding to ASMs and those unsuitable or unwilling to undergo surgery.

Special Considerations in the Management of Women with Epilepsy in Reproductive Years

Anti-seizure medications (ASMs) fail to prevent seizure recurrence in more than 30% of patients with epilepsy. The treatment is more difficult in premenopausal women with epilepsy (WWE) because changes in plasma estrogen and progesterone concentrations during the menstrual cycle often affect seizure frequency and intensity. Interactions between enzyme-inducin ASMs and hormonal contraceptives can lead to both a loss of seizure control and failure of contraception. Significant changes in the function of the liver and kidneys during pregnancy can accelerate metabolism and elimination of ASMs, causing breakthrough seizures. In addition, the teratogenic, cognitive, and psychological effects of ASMs on potential offspring have to be considered when choosing the best ASM regimen. Therefore, aspecialized approach is necessary for the treatment of premenopausal WWE.

Efficacy and Tolerability of Lacosamide in Lennox–Gastaut Syndrome: A Systematic Review and Meta-analysis

Purpose Lennox–Gastaut syndrome (LGS) is one of the most difficult to treat childhood-onset epileptic encephalopathies. There is growing evidence that lacosamide is safe and efficacious in patients and adults with refractory epilepsy. However, the evidence regarding the efficacy of lacosamide in LGS is controversial so far. We aimed to evaluate the efficacy and tolerability of lacosamide in patients with LGS. Methods We conducted a systematic review on MEDLINE, EMBASE, COCHRANE CENTRAL, Google Scholar, and Web of Science, collating all available literature till July 31, 2020. The qualitative review included case reports, case series, and both controlled/uncontrolled trials as well as retrospective studies, but for determining pooled estimates, we only included studies with a sample size of 5 or more. The primary outcome was the efficacy of lacosamide in patients with LGS. Clinical variables related to efficacy and adverse events attributed to lacosamide were extracted from each publication. The pooled estimate of variables related to these parameters was performed using a random-effect model. Results Of the 68 items identified by the search, 14 were reviewed as full-text. Eleven articles including two prospective and six retrospective studies fulfilled eligibility criteria and described outcomes in 81 patients (42 adults, 39 children, 60% male, range—1.4–61 years). On average, 35.2%, 27.9%, 7.3%, and 29.4% patients had > 50% reduction, < 50% reduction, no change, and worsening of seizure frequency, respectively. Although 36% of patients had adverse events like somnolence, behavioral abnormalities including irritability, aggressiveness, nausea, tremor, memory problems, dizziness, gastrointestinal discomfort, vomiting, and weight loss, no serious adverse events were noted. Conclusion The evidence available in the current literature is not sufficient to support or refute the use of lacosamide in patients with LGS. Although it is one of the possible therapeutic options worth exploring in patients with LGS, caution is still necessary, as there are reports of worsening of seizure frequency in some patients.

L-Serine Treatment is Associated with Improvements in Behavior, EEG, and Seizure Frequency in Individuals with GRIN-Related Disorders Due to Null Variants

Pathogenic missense variants in GRIN2A and GRIN2B may result in gain or loss of function (GoF/LoF) of the N-methyl-D-aspartate receptor (NMDAR). This observation gave rise to the hypothesis of successfully treating GRIN-related disorders due to LoF variants with co-agonists of the NMDAR. In this respect, we describe a retrospectively collected series of ten individuals with GRIN2A- or GRIN2B-related disorders who were treated with L-serine, each within an independent n-of-1 trial. Our cohort comprises one individual with a LoF missense variant with clinical improvements confirming the above hypothesis and replicating a previous n-of-1 trial. A second individual with a GoF missense variant was erroneously treated with L-serine and experienced immediate temporary behavioral deterioration further supporting the supposed functional pathomechanism. Eight additional individuals with null variants (that had been interpreted as loss-of-function variants despite not being missense) again showed clinical improvements. Among all nine individuals with LoF missense or null variants, L-serine treatment was associated with improvements in behavior in eight (89%), in development in four (44%), and/or in EEG or seizure frequency in four (44%). None of these nine individuals experienced side effects or adverse findings in the context of L-serine treatment. In summary, we describe the first evidence that L-serine treatment may not only be associated with clinical improvements in GRIN-related disorders due to LoF missense but particularly also null variants.

Efficacy and Safety of VNS Therapy or Continued Medication Management for Treatment of Adults with Drug-Resistant Epilepsy: Systematic Review and Meta-Analysis

Vagus nerve stimulation (VNS) Therapy® is an adjunctive neurostimulation treatment for people withdrug-resistant epilepsy (DRE) who are unwilling to undergo resective surgery, have had unsuccessfulsurgery or are unsuitable for surgery. A systematic review and meta-analysis were conducted todetermine the treatment effects of VNS Therapy as an adjunct to anti-seizure medications (ASMs) forthe management of adults with DRE.A literature search was performed in August 2020 of the Medline®, Medline® Epub Ahead of Print,Embase, and the Cochrane library databases. Outcomes examined included reduction in seizurefrequency, seizure freedom, ASM load, discontinuations, and serious adverse events (SAEs).Comparators included best medical practice, ASMs, low-stimulation or sham VNS Therapy.Four RCTs and six comparative observational studies were identified for inclusion. Against comparators,individuals treated with VNS had a significantly better odds of experiencing a ≥50% reduction in seizurefrequency (OR: 2.27 [95% CI: 1.47, 3.51]; p=0.0002), a ≥75% reduction in seizure frequency (OR: 3.56[95% CI: 1.59, 7.98]; p=0.002) and a reduced risk for increased ASM load (risk ratio: 0.36 [95% CI: 0.21,0.62]; p=0.0002). There was no difference in the odds of discontinuation or the rate of SAEs betweenVNS versus comparators.This meta-analysis demonstrated the benefits of VNS Therapy in people with DRE, which includedimprovement in seizure frequency without an increase in the rate of SAEs or discontinuations, therebysupporting the consideration of VNS Therapy for people who are not responding to ASMs and thoseunsuitable or unwilling to undergo surgery.

Efficacy and potential predictors of vagus nerve stimulation therapy in refractory postencephalitic epilepsy

Background: Vagus nerve stimulation (VNS) is a therapeutic approach for patients with refractory postencephalitic epilepsy (PEE), which is characterized by drug resistance and disappointing surgical outcomes. However, the efficacy of VNS has not yet been studied in patients with refractory PEE. The present study aimed to demonstrate the efficacy of VNS and evaluate potential clinical predictors in patients with refractory PEE. Methods: We retrospectively collected the outcomes of VNS with at least a 1-year follow-up in all patients with refractory PEE. Subgroups were classified as responders and non-responders according to the efficacy of VNS (⩾50% or < 50% reduction in seizure frequency). Preoperative data were analyzed to screen for potential predictors of VNS responsiveness. Results: A total of 42 refractory PEE patients who underwent VNS therapy were enrolled, with an average age of 21.13 ± 9.70 years. Seizure frequency was reduced by more than 50% in 64.25% of patients, and 7.14% of patients achieved seizure-free events after VNS therapy. In addition, the response rates increased over time, with 40.5%, 50.0% and 57.1%, respectively at 6 months, 12 months, and 24 months after VNS therapy. Preoperative duration of epilepsy, monthly seizure frequency, and spatial distribution of interictal epileptic discharges (IEDs) were correlated with responders ( p < 0.05) in the univariate analysis. Further multivariate regression analysis demonstrated that refractory PEE patients with high monthly seizure frequency or Focal IEDs (focal or multifocal epileptiform discharges) achieved better efficacy on VNS ( p = 0.010, p = 0.003, respectively). Conclusion: VNS is an effective palliative therapy for patients with refractory PEE. Focal IEDs (focal or multifocal epileptiform discharges) and high seizure frequency were potential preoperative predictors of effectiveness after VNS therapy.

Cognitive Effects of Lacosamide in Patients with Drug Refractory Focal Epilepsy: A Prospective Observational Study

Objectives: This study was conducted to obtain data on the cognitive effects of lacosamide in Indian population. Methodology: An open labelled prospective observational study in 22 patients who suffered from focal epilepsy. Results: All the pre and post lacosamide cognition scores showed statistically significant positive correlation in this study. Average initial seizure frequency per month was 3.56 (SD 2.58) and median frequency 2.5 seizures per month. Range being 1-8 per month. At the final follow-up at 6months, 87.5% of the study subjects had no seizures. In the remaining12.5% of patients, reduction in seizure frequency was observed. The difference in frequency is statistically significant (Wilcoxon Signed Ranks TestP <0.001). Conclusion: Excellent seizure control is observed in patients with refractory focal epilepsy treated with lacosamide. Also, lacosamide has no serious adverse effects or drug interactions. In this study, it is observed that unlike many AEDs, lacosamide contributed to significant improvement in cognition.

Efficacy and Safety of VNS Therapy or Continued Medication Management for Treatment of Adults with Drug-Resistant Epilepsy: Systematic Review and Meta-Analysis

Vagus nerve stimulation (VNS) Therapy® is an adjunctive neurostimulation treatment for people withdrug-resistant epilepsy (DRE) who are unwilling to undergo resective surgery, have had unsuccessfulsurgery or are unsuitable for surgery. A systematic review and meta-analysis were conducted todetermine the treatment effects of VNS Therapy as an adjunct to anti-seizure medications (ASMs) forthe management of adults with DRE.A literature search was performed in August 2020 of the Medline®, Medline® Epub Ahead of Print,Embase, and the Cochrane library databases. Outcomes examined included reduction in seizurefrequency, seizure freedom, ASM load, discontinuations, and serious adverse events (SAEs).Comparators included best medical practice, ASMs, low-stimulation or sham VNS Therapy.Four RCTs and six comparative observational studies were identified for inclusion. Against comparators,individuals treated with VNS had a significantly better odds of experiencing a ≥50% reduction in seizurefrequency (OR: 2.27 [95% CI: 1.47, 3.51]; p=0.0002), a ≥75% reduction in seizure frequency (OR: 3.56[95% CI: 1.59, 7.98]; p=0.002) and a reduced risk for increased ASM load (risk ratio: 0.36 [95% CI: 0.21,0.62]; p=0.0002). There was no difference in the odds of discontinuation or the rate of SAEs betweenVNS versus comparators.This meta-analysis demonstrated the benefits of VNS Therapy in people with DRE, which includedimprovement in seizure frequency without an increase in the rate of SAEs or discontinuations, therebysupporting the consideration of VNS Therapy for people who are not responding to ASMs and thoseunsuitable or unwilling to undergo surgery.

Variations in Seizure Frequency During Pregnancy and Postpartum by Epilepsy Type

Objective:To assess whether increased seizure frequency during pregnancy and post-partum is influenced by epilepsy type, seizure location, and antiseizure medications.Methods:Clinical data was collected in a longitudinal prospective database of pregnant women with epilepsy at Brigham and Women’s Hospital. Within each individual participant, baseline seizure frequency was calculated for the 9 months preconception, and it was determined if seizure frequency increased during pregnancy or the postpartum period. Seizure frequency was calculated for each 4-week interval during pregnancy. Generalized estimating equations for logistic regression were applied.Results:Ninety-nine patients contributing 114 pregnancies were included from 2013-2018. Increased seizure frequency occurred more often during pregnancies of women with focal versus generalized epilepsy (21.1% vs 5.3%, OR 4.70; 95% CI (1.00, 22.00); p = 0.0497). Among women with focal epilepsy, increased seizure frequency occurred more often in those with frontal lobe epilepsy (OR 8.00; 95 % CI (2.19, 29.21); p = 0.0017). There was no difference in seizure worsening in the postpartum period between focal and generalized (11.1% vs 9.1%, p=0.4478), or frontal and other focal (18.8% vs 6.0%; p=0.1478) epilepsy groups. Pregnancies on polytherapy had higher odds of seizure worsening compared to monotherapy (OR = 8.36, 95% CI = (2.07, 33.84), p = 0.0029), regardless of the medication or epilepsy type. A lack of preconception seizure freedom was also associated with increased seizure frequency during pregnancy (OR = 6.418; p = 0.0076).Conclusion:Women with focal epilepsy have higher likelihood of seizure worsening during pregnancy compared to women with generalized epilepsy; frontal lobe epilepsy poses an especially elevated risk. Polytherapy and lack of preconception seizure freedom are additional predictors for an increased likelihood of seizure worsening.