Vagus nerve stimulation for drug-resistant epilepsy induced by tuberous sclerosis complex
Introduction
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder attributed to TSC1 or TSC2 gene mutations. These mutations hyperactivate the rapamycin (mTOR) pathway. Dysregulated mTOR signaling has been found to cause disorders of the skin, eyes, kidneys, and heart [1]. In addition, dysregulated mTOR signaling affects neural progenitor cells (NPCs) in the fetal nervous system, causing abnormal cell differentiation, proliferation, growth, and migration. For instance, abnormal mTOR signaling has been shown to cause three characteristic encephalopathies: cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs) [2].
Epilepsy is the most prevalent clinical symptom of TSC, occurring in about 90% of patients with TSC [3]. Most patients develop seizures during their first years of life, at the age of three months. However, in others, the first seizure might occur at adolescence or adulthood [2], [4]. Most patients with TSC experience developmental delay and neuropsychiatric symptoms [5], [6]. According to previous studies, early onset of seizures may be associated with significant cognitive deficits [7]. Therefore, effective treatment of TSC-induced epilepsy is essential not only for seizure control but also for normal intellectual development.
Although antiepileptic drugs (AEDs) are the first-line of treatment for epilepsy induced by TSC, at least 50% of patients with TSC-induced epilepsy develop drug resistance to AEDs [8]. If pre-surgical evaluation identifies localized epileptogenic foci, resective surgery is preferred than medication alone. For patients who cannot benefit from resective surgery or epileptic lesions cannot be localized, neuromodulation therapy such as vagus nerve stimulation (VNS) is recommended.
Currently, the benefits of VNS in patients with TSC-induced epilepsy are not well defined, especially, the dynamic and long-term efficacy remains unclear [9], [10], [11], [12]. This study presented the VNS therapeutic efficacy changes over time, and investigated the potential impact of VNS on cognition and emotion.
Section snippets
Subjects
A total of 17 patients diagnosed with TSC-induced drug-resistant epilepsy (DRE) were recruited at the Epilepsy Center of Sanbo Brain Hospital of Capital Medical University (Beijing, China) between 2008 and 2020. All patients were clinically diagnosed based on the TSC diagnostic criteria of 1998 or 2012 [13], [14]. Drug-resistant epilepsy was defined as the failure of two adequate AEDs deemed appropriate to the condition of patient [15]. In our comprehensive epilepsy center, each patient was
Demographics and clinical characteristics
Patient demographics and clinical characteristics are summarized in Table 1. The patients comprised seven females (41.2%) and ten males (58.8%), with mean age at VNS implantation of 11.4 years old (range: 0.9–30, SD: 8.4, median: 11). Before VNS implantation; the mean age at seizure onset was 3.7 years (range: 0.25–11, SD: 3.6, median: 3); the mean monthly seizure frequency was 154.5 (range: 0.33–600, SD: 167.6, median: 122) and the mean number of failed AEDs was 3.8 (range: 3–6, SD: 0.8,
Discussion
Based on the results of this study and other literature reports, VNS seems to be an effective and safe treatment for TSC-induced DRE [9], [10], [11], [12]. At the last follow-up, 70.6% of the patients had at least a 50% reduction in seizure frequency, and three patients achieved seizure-free status. Moreover, all patients experienced seizure frequency reduction within one year after the initiation of VNS treatment although a few patients experienced more frequent seizures later. Wechsler
Conclusion
Vagus nerve stimulation is an effective and safe treatment for patients with DRE caused by TSC. Seizure control by VNS tended to stabilize one year after surgery, thus, a follow-up of at least one year is required to determine the long-term effects of VNS therapy in patients. Moreover, VNS may improve depression in patients with DRE caused by TSC, further studies are needed to validate this finding.
Sources of financial support
This study was supported by funds from the Major Program of the National Natural Science Foundation of China (grant numbers 81790654, 81790650, 81790651 and 11932003) and Capital’s Funds for Health Improvement and Research (grant number 2020-4-8012).
Authorship statement
All persons who meet authorship criteria are listed as authors, and all authors confirm that they have participated sufficiently in the work to take responsibility for the content, including participation in the conception, design, analysis, writing, or revision of the manuscript. Furthermore, each author confirms that this material or similar materials have not been and will not be submitted to or published in any publication before its appearance in the Epilepsy & Behavior.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References (35)
- et al.
Vagal nerve stimulation in tuberous sclerosis complex patients
Pediatric Neurol
(2001) - et al.
Vagus nerve stimulation for refractory epilepsy in tuberous sclerosis
Pediatric Neurol
(2010) - et al.
Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference
J Pediatric Neurol
(2013) - et al.
Calcification in cerebral parenchyma affects pharmacoresistant epilepsy in tuberous sclerosis
.
(2018) - et al.
Health-related risky behaviors in Chinese adolescents with autism: a cross-sectional study
Child Adolesc Psychiatry Mental Health
(2021) - et al.
Correlation between GABA(A) receptor density and vagus nerve stimulation in individuals with drug-resistant partial epilepsy
Epilepsy Res
(2003) - et al.
Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of tuberous sclerosis complex-associated lesions
Cell Stem Cell
(2011) - et al.
Behavioural and cognitive effects during vagus nerve stimulation in children with intractable epilepsy - a randomized controlled trial
Eur J Paediatr Neurol
(2013) - et al.
Vagus nerve stimulation has a positive effect on mood in patients with refractory epilepsy
Child Neurol Neurosurg
(2012) - et al.
Long-term outcome of vagus nerve stimulation for refractory partial epilepsy
Epilepsy Behav
(2003)
Tuberous sclerosis complex: a review
Pediatric Ann
Genetic Etiologies, Diagnosis, and Treatment of Tuberous Sclerosis Complex
Annu Rev Genomics Hum Genet
Is autism driven by epilepsy in infants with tuberous sclerosis complex?
Randomized Controlled Trial
Cited by (18)
Updated clinical recommendations for the management of tuberous sclerosis complex associated epilepsy
2023, European Journal of Paediatric NeurologyAdvances in the genetics and neuropathology of tuberous sclerosis complex: edging closer to targeted therapy
2022, The Lancet NeurologyCitation Excerpt :About half of patients have a reduction in seizure frequency of at least 50% with this technique. Vagal nerve stimulation implantation before 6 years of age has also been associated with a greater improvement in neurocognitive functions and substantial improvements in behaviour—independently of seizure outcome—and quality of life.81 From the perspective of the caregiver, tuberous sclerosis complex-associated neuropsychiatric disorders can be as much of a concern as seizures.
Predicting Antiseizure Medication Treatment in Children with Rare Tuberous Sclerosis C omplex Related Epilepsy Using Deep Learning
2023, American Journal of Neuroradiology