Quantifying the burden of disease in patients with Lennox Gastaut syndrome.

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.

Long-term outcome and predictors of vagus nerve stimulation for drug-resistant epilepsy: Real-world evidence from the Korean national hospital consortium.

Introduction and purpose: Epilepsy affects 1% globally, with 2.6 to 6 million cases in Europe. 30-40% of the 50 million epilepsy patients globally don't respond to drugs. For those ineligible for surgery, Vagus Nerve Stimulation (VNS) therapy offers an alternative for drug-resistant epilepsy and major depression. A brief description of the state of knowledge: Vagus Nerve Stimulation (VNS) is a modern therapy using implanted or non-invasive devices to regulate nerve activity with controlled electrical impulses. Vagus Nerve Stimulation (VNS) is effective for focal seizures, including simple partial seizures and auras. It also shows promise in reducing seizures in generalized tonic-clonic seizures and benefits patients with epileptic encephalopathies like Lennox-Gastaut syndrome. VNS effectively decreases both the frequency and duration of seizures in individuals contending with intractable epilepsy. The use of vagus nerve stimulation is generally a safe and well-tolerated form of treatment. VNS therapy improves psychomotor functions in patients with severe drug-resistant epilepsy, showing positive effects on cognitive aspects. The precise mechanism through which VNS affects the body is not fully understood, but it has demonstrated effectiveness, especially in cases of drug-resistant epilepsy. Conclusions: Extensive research backs Vagus Nerve Stimulation (VNS) as an effective palliative for intractable epilepsy, reducing seizures. Yet, identifying specific patients who would benefit most from VNS treatment lacks clear criteria. Neuromodulation remains crucial for healthcare professionals handling drug-resistant epilepsy.

Evaluate the long-term efficacy of vagus nerve stimulation (VNS) in patients with developmental and epileptic encephalopathies (DEE) compared with epilepsy patients without intellectual disability (ID). Long-term outcomes from a Norwegian VNS quality registry are reported in 105 patients with DEEs (Lennox-Gastaut syndrome [LGS] n = 62; Dravet n = 16; Rett n = 9; other syndromes n = 18) were compared with 212 epilepsy patients without ID, with median follow-up of 88 and 72 months, respectively. Total seizure reduction was evaluated at 6, 12, 24, 36, and 60 months. Effect on different seizure types was evaluated at baseline and last observation carried forward (LOCF). Median monthly seizure frequency at LOCF was reduced by 42.2% (p < 0.001) in patients with DEE and by 55.8% (p < 0.001) in patients without ID. In DEE patients, ≥50% seizure reduction at 6 and 24 months were 17.1% and 37.1%, respectively, and 33.5% and 48.6% for patients without ID. Seizure reduction ≥75% at 60 months occurred in 14.3% of DEE patients and 23.1% of patients without ID. Highest median reduction was for atonic seizures, most notably 64.6% for LGS patients. A better effect was seen at 2 years among DEE patients with unchanged medication compared with those with changed medication (54.5% vs. 35.6% responders, p = 0.078). More DEE patients were reported to have greater improvement in ictal or postictal severity (43.8% vs. 28.3%, p = 0.006) and alertness (62.9% vs. 31.6%, p < 0.001) than patients without ID. For both groups, use of the magnet reduced seizure severity. Hoarseness was the most common adverse effect in both groups. In addition, DEE patients were frequently reported to have sleep disturbance, general discomfort, or abdominal problems. Our data indicate that VNS is very effective for atonic seizures. Patients without ID had best overall seizure reduction, however, patients with DEE had higher retention rates probably due to other positive effects. DEE refers to a group of patients with severe epilepsy and intellectual disability. Many of these patients have restricted lifestyles with frequent seizures. VNS is a treatment option for patients who do not respond well to medicines, either because of insufficient effect or serious adverse effects. Our study shows that VNS is well tolerated in this patient group and leads to a reduction in all seizure types, most notably for seizures leading to fall. Many patients experience other positive effects like shorter and milder seizures, as well as improvement in alertness.

To evaluate clinical outcomes, treatment response and predictors of seizure freedom after vagus nerve stimulation in patients with drug-resistant epilepsy in a Mexican cohort. We conducted a retrospective multicenter cohort across 13 epilepsy centers in Mexico (2003-2024) including patients aged ≥4 years with drug-resistant epilepsy or epileptic encephalopathy. Treatment response was defined as at least 50% seizure reduction and Engel outcomes. Logistic regression identified predictors of seizure freedom. Model performance was assessed with receiver operating characteristic analysis, area under the curve, Hosmer-Lemeshow test, and a confusion matrix. Ninety-three patients (51 children, 42 adults) were included. At 1 year, median monthly seizure frequency decreased by 82.5% (40-7; p < .001). The incidence of status epilepticus declined by 92.8%, acute prolonged seizures by 80.9%, the burden of antiseizure medications by 25%, and epilepsy-related hospitalizations by 100% (all p < .001). Overall, 68.8% achieved ≥50% reduction and 11.8% became seizure-free. On univariate analysis, comorbidities, multiple seizure types, higher baseline seizure frequency, greater number of antiseizure medications, and magnet use were inversely related to seizure freedom, while normal brain MRI showed a direct relationship. On multivariable analysis, only baseline seizure frequency ≥30/month independently predicted seizure freedom (p = .047), corresponding to 97.7% lower odds. A predictive model incorporating comorbidities and number of antiseizure medications improved discrimination (p < .001) with 86.6% sensitivity and 81.8% specificity. Vagus nerve stimulation was associated with substantial seizure frequency reduction, lower morbidity, and less healthcare utilization, with a favorable safety profile. Baseline seizure burden emerged as the key predictor of seizure freedom and may guide patient selection, supporting earlier vagus nerve stimulation consideration in drug-resistant epilepsy.

The aim of this commentary was to discuss from a rehabilitation perspective the published Cochrane Review ‘Sulthiame add-on therapy for epilepsy’1 by Bresnahan et al., under the direct supervision of the Cochrane Epilepsy Group. This Cochrane Corner is produced in agreement with Developmental Medicine & Child Neurology by Cochrane Rehabilitation. Epilepsy is one of the most common and disabling neurological disorders, affecting up to 65 million people worldwide.2 The main and recurrent symptoms of epilepsy are seizures, defined as paroxysmal events caused by atypical, involuntary rhythmic neuronal activity.3 Seizures are often unpredictable, causing distress in these patients, and therefore implicating cognitive, psychological, and social consequences.4 The principal therapeutic aim is to control the seizures and improve the quality of life of these patients. Antiseizure medication (ASM) is the first line of treatment for epilepsy.5 An appropriate ASM is selected on the basis of seizure type, epilepsy syndrome, or drug characteristics.6 If a single drug does not control the seizures, epilepsy is defined as drug-resistant epilepsy (DRE). DRE often requires polytherapy, combining ASM with different mechanisms of action.7 In this clinical scenario, use of sulthiame as add-on therapy seems to reduce seizure activity in people with DRE, as observed, for example, in children affected by Lennox–Gastaut syndrome.8 The aim of this Cochrane Review1 was to assess the efficacy and tolerability of sulthiame as add-on therapy for people with epilepsy of any aetiology. The population addressed in this review included individuals of any age with epilepsy of any aetiology, in a drug-resistant form. Sulthiame was compared to placebo or other ASM, as add-on therapy to the participant’s ASM regimen. The primary outcome was 50% or greater reduction in seizure frequency, from baseline to end of treatment. Secondary outcomes were: complete cessation of seizures during follow-up; main seizure frequency; tolerability in terms of both time to treatment withdrawal and proportion of participants who experienced at least one adverse event such as deterioration in cognitive ability, crystalluria, or respiratory and metabolic acidosis; and quality of life. The review authors searched for studies published on the Cochrane Register of Studies, which includes the Cochrane Epilepsy Group's Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform Search Portal, up to January 2019. They also checked the reference lists of retrieved reports for additional reports of relevant studies, and contacted manufactures of sulthiame and researchers in the field to seek any ongoing or unpublished articles. The review included one double-blind, randomized, placebo-controlled parallel study, that recruited 37 infants, aged from 3 to 15 months, with newly diagnosed West syndrome (infantile spasms). All participants received 3 days of baseline pyridoxine (150–300mg/kg/day) and were then randomized to receive sulthiame (5mg/kg/day) or placebo. After 3 days, non-responders received a double dose of sulthiame or placebo until day 9 when the study drug was disclosed after an electroencephalograph. No data were reported for the primary outcome and for main seizure frequency and quality of life. The study reported incomplete data both for time to treatment withdrawal and adverse effects (high risk of reporting bias). Moreover, the assessment risk of other bias was unclear due to the lack of baseline demographic data (unclear risk of other bias) and the study did not provide details of the method or effectiveness of the blinding process beyond the description given for allocation concealment (unclear risk of performance and detection bias). The authors concluded that 30% of infants treated with add-on sulthiame stopped seizures versus no infants in the placebo group. The risk ratio (RR) for sulthiame compared with placebo was 11.14 (95% confidence interval [CI] 0.67–184.47), with a statistically insignificant effect (p=0.09) and a very low quality of evidence. Moreover, the same number of participants experienced adverse effects in both groups (RR 0.85, 95% CI 0.44–1.64; very low certainty evidence; p=0.63), particularly somnolence in 4 out of 20 in the add-on sulthiame group versus 1 out of 17 in the placebo group. Considering the very low certainty of available evidence, small sample size, and significant risk of bias, the authors concluded that it was uncertain if sulthiame could lead to a cessation of seizures as add-on therapy to pyridoxine in infants with West syndrome. No conclusions can be drawn about the occurrence of adverse effects, change in quality of life, or mean reduction in seizure frequency. Further studies with large sample sizes are required to establish efficacy and tolerability of sulthiame as add-on therapy in West syndrome and other types of epilepsy. Epilepsy is a neurological disorder characterized by unprovoked seizures, with progressive impairment of independence and quality of life. Moreover, patients with epilepsy may develop cognitive disturbances due to chronic cortical damage.9 From a rehabilitation perspective, a holistic approach addressing both cognitive and mood disorders is strongly advised, particularly for DRE where memory impairment is common.10 The correct pharmacological approach, together with rehabilitation interventions, could provide an opportunity for clinical improvement in these patients. In DRE, seizure control is often difficult to achieve and requires polytherapy. However, this updated review does not provide sufficient evidence to encourage the use of sulthiame as a safe and effective add-on therapy for the treatment of patients with DRE. The author thanks Cochrane Rehabilitation and the Cochrane Epilepsy Group for reviewing the contents of the Cochrane Corner. The author has stated that they had no interests that could be perceived as posing a conflict or bias.

Epilepsy Surgery is a Viable Treatment for Lennox Gastaut Syndrome

The aim of this study was to assess the safety and efficacy of combined active responsive neurostimulation (RNS) and vagus nerve stimulation (VNS) therapies in pediatric patients with drug-resistant epilepsy. A single-center retrospective chart review was conducted on pediatric patients implanted with the RNS System with a concomitant active VNS System (VNS+RNS) between 2015 and 2021. Patients with at least 1 month of overlapping concomitant VNS and RNS treatment were included. Patients who had an RNS device implanted after 21 years of age, those who had responsive neurostimulators implanted after their VNS was inactivated, or those in whom the VNS battery died and was not replaced before RNS System implantation were excluded. Seven pediatric VNS+RNS patients were identified, and their courses of treatment were evaluated. All patients tolerated concurrent VNS and RNS treatment well, no device-device interactions were identified, and no major treatment-related adverse effects were noted. The median follow-up after RNS System implantation was 1.2 years. By electroclinical criteria, all 7 patients achieved 75%-99% reductions in the frequency of disabling seizures after RNS System implantation. By patient and caregiver report, 2 patients (28.6%) had 75%-99% reductions in the frequency of their disabling seizures, 2 patients (28.6%) achieved 50%-74% reductions, 2 patients achieved 1%-24% reduction in frequency of disabling seizures, and 1 patient (14.3%) experienced a 1%-24% increase in seizure frequency. The available VNS magnet swipe data identified 2 patients with 75%-99% reductions in seizure frequency as measured by magnet swipes, one with 25%-49% reductions and the other with 1%-24% increases in seizure frequency as measured by magnet swipes. This study demonstrated that RNS and VNS therapies can safely be used simultaneously in pediatric patients. RNS may potentially augment the therapeutic effects of VNS treatment. Patients in whom a response to VNS has been suboptimal should still be considered for RNS therapy.

This observational retrospective study was conducted on patients with epilepsy (PWE) in China who had at least one dose of COVID-19 vaccine and it investigated the safety of vaccination by analyzing changes in epileptic seizures and their influencing factors. Consecutive PWE who were followed up in the epilepsy clinic between June 2021 and May 2022 were enrolled. Data on vaccine type, demographic information, clinical characteristics of epilepsy, and treatment were collected through a questionnaire survey and retrospectively analyzed. PWE were divided into a stable seizure group and a worsening seizure group based on seizure episodes at least 90 days after the first vaccine dose. A total of 79 PWE were included. After vaccination, 14 patients (17.7%) had worsening seizures, 92.9% of whom had an increased seizure frequency. Compared with patients in the stable seizure group, patients in the worsening seizure group had significant differences in baseline monthly seizure frequency (P = .012), improper antiseizure medication (ASM) administration (P = .003) and a disrupted sleep routine (P = .016). Multivariate logistic regression analysis showed that improper ASM administration (OR 6.186, 95% confidence interval [CI] 1.312–29.170; p = .021) and a disrupted sleep routine (OR 6.326, 95% CI 1.326–30.174; p = .021) were significantly associated with seizure worsening. In short, COVID-19 vaccination is safe for PWE, and only those with poor seizure control have the possibility of seizure exacerbation after COVID-19 vaccination. The vaccination per se does not represent a major influencing factor, but the improper use of ASMs and a disrupted sleep routine may be correlated with seizure aggravation after vaccination.

Deep Brain Stimulation of Bilateral Centromedian Thalamic Nuclei in Pediatric Patients with Lennox-Gastaut Syndrome: An Institutional Experience

IntroductionDespite new anti-seizure medications (ASMs) being introduced into clinical practice, about one-third of people with epilepsy do not reach seizure control. Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. In randomized controlled trials, adjunctive cenobamate reduced the frequency of focal seizures in people with uncontrolled epilepsy. Studies performed in real-world settings are useful to complement this evidence and better characterize the drug profile.MethodsThe Italian BLESS (“Cenobamate in Adults With Focal-Onset Seizures”) study is an observational cohort study aimed to evaluate the effectiveness, tolerability, and safety of adjunctive cenobamate in adults with uncontrolled focal epilepsy in the context of real-world clinical practice. The study is ongoing and conducted at 50 centers in Italy. This first interim analysis includes participants enrolled until June 2023 and with 12-week outcome data available.ResultsForty participants with a median age of 36.5 (interquartile range [IQR] 26.0–47.5) years were included. The median monthly seizure frequency at baseline was 6.0 (IQR 2.5–17.3) seizures and 31 (77.5%) participants had failed four or more ASMs before cenobamate. At 12 weeks from starting cenobamate, the median reduction in monthly seizure frequency was 52.8% (IQR 27.1–80.3%); 22 (55.0%) participants had a ≥ 50% reduction in baseline seizure frequency and six (15.0%) reached seizure freedom. The median number of concomitant ASMs decreased from 3 (IQR 2–3) at baseline to 2 (IQR 2–3) at 12 weeks and the proportion of patients treated with > 2 concomitant ASMs decreased from 52.5% to 40.0%. Seven (17.5%) patients reported a total of 12 adverse events, 11 of which were considered adverse drug reactions to cenobamate.ConclusionIn adults with uncontrolled focal seizures, the treatment with adjunctive cenobamate was well tolerated and was associated with improved seizure control and a reduction of the burden of concomitant ASMs.Trial Registration NumberNCT05859854 (ClinicalTrials.gov Identifier).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-024-00634-5.

Introduction Lennox-Gastaut syndrome (LGS) is a severe childhood-onset epileptic encephalopathy, characterized by multiple seizure types, generalized slow spike-and-wave complexes in the EEG, and cognitive impairment. Seizures in LGS are typically resistant to treatment with antiseizure medications (ASMs). Tonic/atonic (‘drop’) seizures are of particular concern, due to their liability to cause physical injury. Areas covered We summarize evidence for current and emerging ASMs for the treatment of seizures in LGS. The review focuses on findings from randomized, double-blind, placebo-controlled trials (RDBCTs). For ASMs for which no double-blind trials were identified, lower quality evidence was considered. Novel pharmacological agents currently undergoing investigation for the treatment of LGS are also briefly discussed. Expert opinion Evidence from RDBCTs supports the use of cannabidiol, clobazam, felbamate, fenfluramine, lamotrigine, rufinamide, and topiramate as adjunct treatments for drop seizures. Percentage decreases in drop seizure frequency ranged from 68.3% with high-dose clobazam to 14.8% with topiramate. Valproate continues to be considered the first-line treatment, despite the absence of RDBCTs specifically in LGS. Most individuals with LGS will require treatment with multiple ASMs. Treatment decisions should be individualized and take into account adverse effects, comorbidities, general quality of life, and drug interactions, as well as individual efficacy.

<h3>Objective:</h3> To determine effectiveness of vagus nerve stimulator (VNS) and surgical resection in patients with drug-resistant epilepsy associated with glutamic acid decarboxylase 65 (GAD65) antibodies. <h3>Background:</h3> Epilepsy associated with high-titer GAD65 antibodies is often refractory to immunotherapies and antiseizure medications (ASMs), underscoring the need for alternate treatment strategies. <h3>Design/Methods:</h3> We retrospectively identified Mayo Clinic Rochester patients (January 2003 – April 2022) with drug-resistant epilepsy and high serum GAD65-antibody titers (&gt;20 nnmol/L) who underwent surgical resection and/or VNS implantation. A "favorable" surgical outcome was defined as Engel I-II, and a responder to VNS was defined as a &gt;50% reduction in seizure frequency from baseline. <h3>Results:</h3> We identified 15 patients (13 females, 86.7%) who underwent surgical resection (n=7), VNS implantation (n=6), and both (n=2). Patients had failed a median of 5.5 anti-seizure medications. Twelve patients had GAD65 tested in the CSF, all were positive (median titer 3.8). Of the nine patients who underwent surgical intervention (all involving the temporal region), three (33.3%) had a favorable outcome, which was sustained for at least 3.5 years in one, 10 years in another, and the third was lost to follow-up after 1 year. Pathology was available in four patients, only one had evidence of inflammation. Of the 8 patients who underwent VNS implantation, 3 (37.5%) were initially considered a responder, but this was not sustained in two of the three. No clinical factors were statistically associated with favorable surgical or VNS outcomes. <h3>Conclusions:</h3> Temporal surgical resection and VNS are not highly effective in drug-resistant autoimmune-associated epilepsy related to high-titer GAD65 antibodies. Additional therapies are greatly needed for this challenging clinical scenario. <b>Disclosure:</b> Dr. Zhao-Fleming has nothing to disclose. Dr. Britton has received personal compensation in the range of $0-$499 for serving as a Online course with American Clinical Neurophysiology Society. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. The institution of Dr. Dubey has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Astellas. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argenx. Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for AGRIMS. Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Advances in Neurology . Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Moffit Cancer Center . Dr. Dubey has received research support from Department of Defense . Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Smith has received research support from CURE Epilepsy.

Vagus nerve stimulation (VNS) is approved for use for refractory partial seizures. Nevertheless, information regarding VNS therapy for special populations, including Lennox-Gastaut syndrome (LGS) is limited. We discuss the effectiveness, tolerability, and safety of VNS therapy in patients with LGS. A six-center, retrospective study evaluated the effectiveness of VNS therapy in patients with LGS at 3 and 6 months and compared preimplant and postimplant seizure frequency. Adverse effects and quality of life (QOL) were included as secondary measures. Fifty patients, median age 13 years, with medically refractory epilepsy, were implanted. Median age at onset of seizures was 1.4 years, and a median of nine anticonvulsants (AEDs) had been tried before implantation. Data-collection forms were designed for retrospectively gathering data on each patient's preimplant history, seizures, implants, device settings, QOL, and adverse events. Median reductions in total seizures were 42% at 1 month, 58.2% at 3 months, and 57.9% at 6 months. The most common adverse events reported were voice alteration and coughing during stimulation. Other uncommon adverse events included increased drooling and behavioral changes. Investigators noted that QOL had improved for some patients in the study. VNS is an effective treatment for medically refractory epilepsy in LGS. This treatment is well tolerated, safe, and may improve QOL.

Lacosamide (LCM) is a third-generation antiseizure medication (ASM), and its effect on sleep architecture was supported by a few studies in patients with drug-resistant epilepsy in which LCM was used as an add-on treatment. To gather knowledge on ASMs effects on sleep, this study aimed at evaluating the effects of LCM monotherapy on sleep in patients with focal epilepsy. Ten patients diagnosed with epilepsy (mean age 58.00 ± 14.77, 60.0% female, mean monthly seizure frequency 1.20 ± 2.48) starting LCM as monotherapy were included. Sleep architecture was assessed through polysomnography at baseline and at the 6-month follow-up visit. A significant decrease was observed in seizure frequency (p = 0.004), being all patients seizure-free at follow-up. At baseline, eight patients had poor sleep efficiency (< 85%). Sleep efficiency increased at follow-up, with onlythree patients having an index < 85% (p = 0.022). From baseline to follow-up, a significant decrease was observed in sleep latency (p = 0.022) and wakefulness after sleep onset (p = 0.047). Moreover, a significant decrease was observed in the percentage of stage 1 (Md = 6.70 vs Md = 3.85, p = 0.005) and stage 3 (Md = 27.70 vs Md = 22.35, p = 0.01) of Non-REM sleep. This study suggests that LCM monotherapy may positively impact sleep architecture in patients with epilepsy. The sleep efficiency improvement and the decrease of sleep latency and wakefulness after sleep onset observed at follow-up highlight better sleep stability and continuity in patients treated with LCM. Notably, all patients were seizure-free at follow-up, and seizure freedom may also concur to sleep structure improvement.