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

BACKGROUND: Surgical management of pediatric patients with nonlesional, drug-resistant epilepsy, including patients with Lennox-Gastaut syndrome (LGS), remains a challenge given the lack of resective targets in most patients and shows seizure freedom rates <50% at 5 years. The efficacy of deep brain stimulation (DBS) is less certain in children than in adults. This study examined clinical and seizure outcomes for pediatric patients with LGS undergoing DBS targeting of the centromedian thalamic nuclei (CMTN). METHODS: An institutional review board-approved retrospective analysis was performed of patients aged ≤19 years with clinical diagnosis of LGS undergoing bilateral DBS placement to the CMTN from 2020 to 2021 by a single surgeon. RESULTS: Four females and 2 males aged 6-19 years were identified. Before surgery, each child experienced at least 6 years of refractory seizures; 4 children had experienced seizures since infancy. All took antiseizure medications at the time of surgery. Five children had previous placement of a vagus nerve stimulator and 2 had a previous corpus callosotomy. The mean length of stay after DBS was 2 days. No children experienced adverse neurologic effects from implantation; the mean follow-up time was 16.3 months. Four patients had >60% reduction in seizure frequency after surgery, 1 patient experienced 10% reduction, and 1 patient showed no change. No children reported worsening seizure symptoms after surgery. CONCLUSIONS: Our study contributes to the sparse literature describing CMTN DBS for children with drug-resistant epilepsy from LGS. Our results suggest that CMTN DBS is a safe and effective therapeutic modality that should be considered as an alternative or adjuvant therapy for this challenging patient population. Further studies with larger patient populations are warranted.

One-year cost-effectiveness of callosotomy vs vagus nerve stimulation for drug-resistant seizures in Lennox-Gastaut Syndrome: A decision analytic model.

OBJECTIVE: Palliative epilepsy surgery via corpus callosotomy (CC) or vagus nerve stimulation (VNS) is commonly employed for drug-resistant seizures in Lennox-Gastaut Syndrome (LGS). VNS is less effective at reducing seizures but has fewer adverse events, CC is more effective for seizure control, particularly atonic seizures, but can be associated with serious adverse events, and yet their relative cost-effectiveness remains unknown. METHODS: To determine which option is most cost-effective, a decision analytic model was developed to evaluate the risks and benefits of CC and VNS at 1 year based on costs in the United States. Our primary outcome measure was positive seizure outcomes, defined as >50% seizure reduction without procedural complications. RESULTS: CC had a 15% greater likelihood of a positive seizure outcome, but per patient costs were $68 147 more than VNS, or $451 952 per positive seizure outcome gained. One-way sensitivity analyses demonstrate that probabilities of seizure freedom or reduction by VNS or CC and CC cost were most influential on results. When considering atonic seizures, CC had a 27% greater positive outcome likelihood than VNS, the same incremental cost, and cost $250 556 per positive seizure outcome gained. SIGNIFICANCE: This exploratory model suggests that VNS is more cost-effective relative to CC at 1 year.

Therapeutic approach to Lennox-Gastaut syndrome: a systematic review.

Lennox-Gastaut syndrome (LGS) is a rare, age-related syndrome, characterized by multiple seizure types, mental regression, and specific EEG abnormalities. It is one of the most challenging epilepsy: treatment is rarely effective and the final prognosis remains poor, despite the availability of several antiepileptic drugs, validated through well-designed, randomized, controlled trials. However, it is reasonable to consider non-medical treatments, such as surgery, after failure of two-to-three drugs. This review has as goal to describe systematically the different therapeutic options for LGS, including, not only recognized antiepileptic drugs, but also new oral drugs, immune therapy, diet, surgery, and neurostimulation techniques.

Lennox-Gastaut Syndrome: A State of the Art Review.

Lennox-Gastaut syndrome (LGS) is a severe age-dependent epileptic encephalopathy usually with onset between 1 and 8 years of age. Functional neuroimaging studies recently introduced the concept of Lennox-Gastaut as "secondary network epilepsy" resulting from dysfunctions of a complex system involving both cortical and subcortical structures (default-mode network, corticoreticular connections, and thalamus). These dysfunctions are produced by different disorders including hypoxic-ischemic encephalopathies, meningoencephalitis, cortical malformations, neurocutaneous disorders, or tumors. The list of etiologies was expanded to pathogenic copy number variants at whole-genome array comparative genomic hybridization associated with late-onset cases or pathogenic mutations involving genes, such as GABRB3, ALG13, SCN8A, STXBP1, DNM1, FOXG1, or CHD2. Various clinical trials demonstrated the usefulness of different drugs (including rufinamide, clobazam, lamotrigine, topiramate, or felbamate), ketogenic diet, resective surgery, corpus callosotomy, and vagus nerve stimulation in the treatment of epileptic manifestations. The outcome of LGS often remains disappointing regarding seizure control or cognitive functioning. The realization of animal models, which are still lacking, and the full comprehension of molecular mechanisms involved in epileptogenesis and cognitive impairment would give a relevant support to further improvements in therapeutic strategies for LGS patients.

Combined surgical intervention with vagus nerve stimulation following corpus callosotomy in patients with Lennox-Gastaut syndrome.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is a drug-resistant pediatric epilepsy characterized by multiple seizure types, including drop attacks (DAs). Palliative procedures such as corpus callosotomy (CC) and vagus nerve stimulation (VNS) may be effective for adequate seizure control in LGS patients who are not candidates for resective surgery. We evaluated the efficacy of the combination of these two procedures for LGS-related seizures. METHOD: Ten patients with LGS (age 3-30 years at VNS implantation) underwent CC and subsequent VNS. We evaluated surgical outcomes, particularly with respect to the efficacy of VNS on seizure reduction rates for different residual seizure types after CC. We compared clinical parameters, including sex, age, seizure duration, history, MRI findings, extent of CC, number of antiepileptic drugs, and neuropsychological states, between VNS responders and non-responders to predict satisfactory seizure outcomes with respect to residual seizures after CC. FINDINGS: VNS was effective for residual seizures regardless of seizure type (except for DAs) after CC in patients with LGS. Six of ten (60%) patients had a satisfactory seizure outcome (≥50% seizure reduction) for all residual seizure types after VNS. Two of ten (20%) patients were seizure-free at 12 months post-VNS. Even those patients that were non-responders, with respect to all seizures including DAs, after prior CC showed favorable responses to subsequent VNS. Compared to VNS, excellent seizure outcomes for DAs were achieved after CC in seven of nine (77.8%) patients with DAs. Among the clinical parameters, only conversation ability before VNS was significantly different between responders and non-responders (p = 0.033). CONCLUSION: Combined VNS and prior CC produced satisfactory seizure outcomes in LGS patients with different seizure types, including DAs. Even non-responders to prior CC responded to subsequent VNS for residual seizures, except for DAs. There is a greater likelihood that these procedures may be more feasible in patients who possess conversation ability prior to VNS.

Vagus Nerve Stimulation for Epilepsy: An Evidence-Based Approach.

Medical treatment of seizures yields a satisfactory response in 75-80% of the patients; resective epilepsy surgery is a therapeutic option for those patients who are refractory to drug therapy, but there is still a considerable portion (20-30%) of patients who are ineligible for surgery or failed surgery. Vagus nerve stimulation (VNS) might be an option for these very refractory patients. We carried out an evidence-based search to identify the best evidence presently available related to the use of VNS. We used multiple searchable databases (primary: PubMed-MEDLINE, EMBASE, LILACS, and SciELO; secondary: Cochrane Library) and a standard structured approach know as the PICO scheme: P (patient), I (intervention), C (comparison), and O (outcome). Publications were selected based on study design, PICO components, language, and availability of full text. For study design, we included papers designed as 'randomized controlled trials'; these trials were evaluated according to the Jadad score; the type II error was not used while selecting studies to avoid further limitations. Twenty-eight papers were selected, all from PubMed-MEDLINE. The search results showed that patients older than 12 years with refractory partial seizures (with or without generalization) may benefit from VNS. Children might also benefit, but might need different stimulation parameters. We also noted that higher stimulation settings are associated with increased occurrence of hoarseness, throat pain, cough, and dyspnea. The available randomized controlled trials and cohorts made it clear that VNS is a useful palliative procedure in adult patients with partial epilepsy, and a 50-60% reduction in seizure frequency might be expected in at least 50% of the patients. VNS is a useful palliative procedure in patients with refractory epilepsy. As our practical experience and understanding of the mechanism of action of VNS increase, more homogeneous patient populations that might respond better to VNS are being recognized, such as children with secondary generalized epilepsy and some types of reflex epilepsy.

Long-term prognosis of patients with Lennox--Gastaut syndrome in recent decades.

PURPOSE: We investigated long term prognosis of Lennox-Gastaut syndrome (LGS) with active application of recent advanced treatment modalities such as ketogenic diet (KD) or epilepsy surgery (ES). METHODS: We retrospectively evaluated 68 patients with LGS, aged 18-35 years. We assessed seizure outcomes for a range of therapeutic modalities. Evolution of seizure types, EEG characteristics, cognition, ambulation, social outcomes and other clinical data were also evaluated. RESULTS: For a mean follow-up duration of 19.3 years (range 8.3-32.5 years), finally sixteen patients (23.5%) were seizure-free. Of the 68 patients, 26 (38.2%) were treated solely with AEDs and six became seizure-free. The KD was administered to 19 patients, five patients maintained a seizure free state during the KD but only one patient was able to maintain a seizure free state by continuing on a modified Atkins diet. Focal resective surgery was performed in 15 patients, ten out of the 15 patients had Engel class I outcomes, but only three patients maintained seizure freedom to adults. CC was performed in 17 patients, and VNS was performed in 14 patients. These palliative procedures were also effective but had limitations to obtain and maintain seizure freedom to adults. Characteristic EEG features of diffuse slow spike-wave and generalized paroxysmal fast activity ceased in half of the patients. In cognitive terms, 94.7% of patients exhibited moderate to profound mental retardation. Only 39.7% of patients had intact independent daily living skills, and 25.4% could not walk, even with support. CONCLUSIONS: KD and epilepsy surgery were effective for seizure control, but they did not necessarily lead to the maintenance of a seizure-free state. LGS remains a form of intractable epilepsy despite the application of recent advanced treatment modalities.

Nonpharmacologic care for patients with Lennox-Gastaut syndrome: ketogenic diets and vagus nerve stimulation.

Individuals with Lennox-Gastaut syndrome (LGS) often do not respond to or become resistant to pharmacologic treatments. Ketogenic diets (KDs) and vagus nerve stimulation (VNS) are nonpharmacologic treatment options for these intractable patients. The classic KD, a high-fat, low-carbohydrate diet with 90% of calories derived from fat, has been used in the treatment of seizures for >90 years. About half of patients with LGS respond to the KD with a >50% reduction in seizures and some patients may achieve a >90% reduction. Vagus nerve stimulation therapy involves a surgically implanted generator that delivers intermittent electrical stimuli to the brain via an electrode wrapped around the left vagus nerve. It is utilized as adjunctive therapy for patients with drug-resistant epilepsy (including patients with LGS) who are not suitable candidates for resective surgery. Similar to the KD, about half of LGS patients respond to VNS therapy, with a >50% reduction in seizures, and the response may improve over time. Both the KD and VNS are options for patients with LGS.