Introduction
Epilepsy, a neurological disease with seizure susceptibility, has a negative impact on 0.6% of the population in developed countries and 1.6% in developing countries (1,2). Refractory epilepsy (RE) is a kind of drug-resistant epilepsy, which is defined as refractory because it has no successful therapeutic response to a variety of antiepileptic drugs (3). Ten to twenty percent (%) of epileptic children progress to RE, and ~470,000 children suffer from epilepsy, which means there are tens of thousands of RE children (4,5). At present, antiepileptic drugs (AEDs) are the first-line therapy for RE, and the second-line is surgery, diet therapy, and vagus nerve stimulation (6). Although the treatment for RE has been continuously updated, the exploration of high-efficacy AED combinations is still ongoing (7). Our study explored the clinical efficacy and safety of AED regimens for RE children, which is of great value to improve their quality of life.
Sodium valproate (SV) is a first-line anti-epilepsy drug that can be applied to various seizure types in children, but it may also induce teratogenicity, neurocognitive impairment and other side effects (8). Studies have shown that SV plays a neuroprotective role by inhibiting endoplasmic reticulum stress and reducing neuronal apoptosis in epilepsy models induced by experiments (9). SV, an anticonvulsant through regulating neuronal pathways, has a close molecular structure with neurotransmitter γ-aminobutyric acid (GABA), resulting in GABA synergism, which inhibits the occurrence of epileptic onsets and epileptic states (10,11). Lamotrigine (LTG) is a second-generation AED after SV, and also has the function of resisting depression and stabilizing mood (12,13). It is applicable for children and adolescents with various seizure types and syndromes due to its good anticonvulsant, tolerance, broad spectrum activity, and safety (14). SV plus LTG, the most effective AED combination for RE, plays a synergistic role in pharmacodynamics and reduces the seizure frequency of children (15).
At present, there are few studies on the efficacy and safety of SV plus LTG in RE children. Therefore, we evaluated the clinical promotion value of these two AEDs by comparing the efficacy and clinical response.
Discussion
RE is a chronic and debilitating disease of the nervous system with epileptic seizure caused by accidental discharge of cerebral neurons, which may lead to stigma in patients (19-21). Therefore, appropriate inhibition of neuronal excitability is the key in selection of AEDs in RE children (22). SV has been proved to alleviate neuronal apoptosis in a kainic acid model of epilepsy by enhancing phosphorylation of PKC-dependent GABA A R γ2 Serine 327 (23,24). LTG acts as glutamate antagonist to exert anticonvulsant and sedative functions through its pharmacological mechanism affecting sodium and calcium channels. It can also disturb the pathogenesis of hyperactivity via regulating excitatory neurotransmitters (25). In this study, hair loss, hyperactivity, and lower limb soreness were the main adverse reactions of patients. The seizure frequency in the study group was significantly lower than that in the control group, and the total effective rate and safety of treatment were significantly higher than those in the control group. Therefore, SV plus LTG has high efficacy and safety on RE children and has better inhibitory effect on the seizure frequency compared with SV alone.
We screened two neurotrophic indexes, BDNF and NGF, to compare the improvement of neurotrophic level of RE children treated with drugs that have inhibitory effects on neuronal excitability. BDNF mediates survival, growth, and regeneration of neurons and participates in the regulation of neural plasticity, playing an important role in the healthy brain development, and being of high diagnostic and prognostic value for brain injury (26,27). Tan et al pointed out that BDNF protected neurons by inhibiting the secretion of excitatory amino acids, maintaining calcium homeostasis in neurons, as well as inhibiting the high expression of oxygen free radicals. Moreover, low BDNF level generally indicated the decline of cognitive function in epileptic patients (28). NGF, a typical representative of neurotrophic factors, is responsible for the growth, survival, and differentiation of mature neurons. In addition to being active in a wide array of non-nervous system cells, it is also synthesized by various cell types (29). NGF has a protective effect on basal forebrain cholinergic neurons and may reduce the susceptibility to generalized seizures (30,31). BDNF and NGF were reported to be closely related to epilepsy and involved in the occurrence and progression of focal RE (32). Our findings showed that BDNF and NGF levels in the study group were more significantly increased, indicating that SV combined with LTG was more useful than SV alone in improving neurotrophic levels of RE children.
Finally, we assessed the predictive value of serum NSE and S100β on the efficacy in RE children. NSE and S100β are brain-derived proteins whose high expression is related to the increase of brain injury (33). Shaik et al found that serum NSE of patients with convulsion showed abnormally high expression, suggesting that it was a marker of epilepsy-related neuron injury (34). Another study demonstrated that serum S100β protein level of patients with focal epilepsy was significantly higher than that in healthy controls, which can be a biomarker for neuronal damage in patients with focal RE (35). In this study, the effectively treated children had a significantly lower expression of serum NSE and S100β than those with ineffective treatment, so serum NSE and S100β gradually recovered to normal levels in RE children after treatment. From the ROC curve, we obtained AUC of serum NSE and S100β and the efficacy was 0.828 and 0.814, respectively, which showed that they had better predictive value in efficacy assessment for RE children.
This study confirmed that SV plus LTG has higher efficacy and fewer adverse reactions in the treatment of RE. However, statistics of various attack types and the efficacy of treatment in RE children need to be recorded to know which RE type of children treated by SV plus LTG achieves the highest curative effect.
In conclusion, SV combined with LTG is better and safer than SV alone in the treatment of RE in children, which is more worthy of clinical promotion. Serum NSE and S100β are of high value in predicting the efficacy.