Success Of Vagus Nerve Stimulation In Epileptic Encephalopathies
Developmental and epileptic encephalopathies (DEE) encompass epilepsies accompanied by developmental impairments, which may arise from underlying causes or epileptic activity, leading to cognitive and behavioral issues. Conditions like Dravet and Rett syndromes, linked to single gene defects, typically manifest in infancy or early childhood. Lennox–Gastaut syndrome (LGS), with various causes, typically appears before age 8, although late-onset cases occur in 10%–20% of patients.
DEEs are characterized by recurrent, severe and abnormal electroencephalography (EEG) readings with frequent epileptic activity, often causing substantial lifestyle limitations including movement disorders, infections, feeding difficulties, and cognitive and behavioral challenges such as intellectual disability (ID) and autism spectrum disorders. Increased risks of injuries, status epilepticus, and mortality, including a syndrome-specific sudden unexpected death in epilepsy (SUDEP) rate of 9.3/1000-person years for Dravet syndrome, further burden individuals with DEEs.
Prognosis varies; LGS typically presents poor seizure control and cognitive outcomes, whereas stabilization usually occurs in patients with Dravet and Rett syndromes after age 10–12. Despite advancements in antiseizure medications (ASM), achieving complete seizure freedom remains unlikely for DEE patients. Non-pharmacological interventions like ketogenic diets, corpus callosotomy (CC), and vagus nerve stimulation (VNS) play crucial roles in managing this treatment-resistant population. VNS has demonstrated efficacy in 40%–65% of LGS patients and ≥50% seizure reduction in 55% and 63% of Dravet syndrome patients at 24 and 36 months, respectively. Limited data exist on VNS effects in Rett syndrome patients, primarily from case series, reporting ≥50% seizure reduction in 9/11 cases.
Previously, we investigated the long-term effects and safety of VNS in drug-resistant epilepsy, noting an increasing efficacy over time, although ID negatively impacted response. This study aims to assess VNS efficacy in DEE patients compared to those without ID. Given previous studies often reported overall effects without distinguishing seizure types, we also aim to evaluate VNS effects on different seizure types.
The Study
By comparing the long-term efficacy of VNS in these two groups of patients, researchers aimed to understand if there are differences in how well VNS works in patients with DEE compared to those without intellectual disability. This information could be valuable for improving treatment strategies and outcomes for individuals with DEE.
Methods
Patient data was gathered from the Norwegian National Center for Epilepsy’s VNS-quality registry. The study encompassed all patients who underwent implants between July 1, 1993, and December 31, 2012, and were subsequently monitored for a minimum of 6 months until the conclusion of 2017.
A specialized team evaluated all patients for epilepsy surgery within the framework of the national epilepsy surgery program. Diagnostic protocols involved long-term video EEG recordings of seizures, imaging scans, and, if required, immunological, metabolic, and genetic tests. Based on these findings, coupled with clinical information, patients received specific electroclinical syndrome diagnoses whenever feasible. VNS treatment was offered to individuals deemed unsuitable for or who had previously experienced failure with epilepsy surgery.
Through the VNS quality registry, 105 patients with developmental and epileptic encephalopathies (DEE) were identified from a pool of 436 patients with efficacy data (NCE cohort). This DEE cohort comprised individuals with Lennox-Gastaut syndrome (LGS), Dravet syndrome, Rett syndrome, and other syndromes. A comparison was made between these DEE patients and 212 patients without intellectual disability (ID), determined through standard clinical and neuropsychological assessments. No additional neuropsychological evaluations were administered for the purposes of this study.
Before the VNS implantation, a baseline assessment was conducted over a 3-month period. Seizure counts were tallied using patient diaries or hospital records. Patients experiencing absences or myoclonic jerks frequently had numerous seizures daily, many of which went unnoticed by them or their caregivers. Consequently, changes in the frequency of these seizure types were not included in the overall analysis but were described separately. Analysis was performed for total seizures and specific types, such as tonic-clonic seizures (TCS), focal seizures with impaired awareness (FIAS), and tonic and atonic seizures. The impact of VNS treatment on various seizure types was assessed both at baseline and the latest observation.
Follow-up appointments occurred every three months. Seizure frequency at each visit was calculated by averaging the monthly totals from the preceding three months. The total number of seizures (excluding absences and myoclonus) at 6, 12, 24, 36, and 60 months follow-up, as well as the last observation carried forward (LOCF), were compared with baseline figures. The analysis was conducted on an intention-to-treat basis.
VNS implantation was conducted as outpatient surgery at Oslo University Hospital’s Department of Neurosurgery. The initial implantations primarily utilized models 100–106, with model 103 being the most common (45%), while 12% received model 106 Aspire. For reimplantations, the latest available models were used. Patients were then admitted to NCE for hospitalization, typically lasting 10–14 days, which remains the current practice.
Standard initial stimulation parameters included 30 seconds on and 5 minutes off, with an output current (OC) of 0.25 mA, frequency set at 20 Hz, and pulse width of 250 μs. Before 2002, a frequency of 30 Hz and pulse width of 500 μs were used. The OC target of 0.75–1.25 mA was achieved in over 95% of patients during hospitalization. It was recommended that patients routinely utilize the magnet for all detected seizures.
Results
At the last observation carried forward (LOCF), median monthly seizure frequency decreased significantly by 42.2% (p < 0.001) in patients with developmental and epileptic encephalopathies (DEE) and by 55.8% (p < 0.001) in patients without intellectual disability (ID). Among DEE patients, the proportion achieving ≥50% seizure reduction at 6 and 24 months was 17.1% and 37.1%, respectively, compared to 33.5% and 48.6% for patients without ID.
At 60 months, ≥75% seizure reduction occurred in 14.3% of DEE patients and 23.1% of patients without ID. The greatest median reduction was observed for atonic seizures, notably 64.6% for Lennox-Gastaut syndrome (LGS) patients. DEE patients with unchanged medication showed a better effect at 2 years compared to those with changed medication (54.5% vs. 35.6% responders, p = 0.078). DEE patients reported 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) compared to patients without ID.
Both groups experienced reduced seizure severity with the use of the magnet. Hoarseness was the most common adverse effect in both groups, with DEE patients also frequently reporting sleep disturbance, general discomfort, or abdominal problems.
Final Thoughts
The study offers novel insights suggesting that the efficacy of VNS therapy improves with time across various patient demographics, even in cases where medication remains unchanged. Particularly notable was the significant benefit observed for atonic seizures, suggesting that VNS may be especially advantageous for individuals experiencing this seizure type.
Despite a lower seizure reduction compared to epilepsy patients without intellectual disability (ID), those with developmental and epileptic encephalopathies (DEE) exhibited a high retention rate at the 5-year mark. This likely indicates additional favorable outcomes of VNS treatment, such as enhanced alertness and mitigated severity and duration of seizures.
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