Childhood DRE risk is serious and can have catastrophic effects on neurodevelopment [22, 23]. The brain undergoes an extended period of growth and maturation during the first 2 years of life. Thus, intractable seizures are refractory during this critical time, particularly in the early infancy, can negatively affect the cognitive and motor development, consider by affecting the children’s cognitive, behavioral, and psychiatric function [24, 27]. Here, we investigated the risk of DRE in infants and younger children in a tertiary hospital over 5 years and noted a relatively higher risk of DRE combined with NDD caused by genetic factors (6.5 times (95% CI, 2.15–19.6). By contrast, the risk of DRE caused by nongenetic factors was relatively low, even in those with severe NDD.
Our results also demonstrated heterogenous genetic causes of epilepsy which range from neonate to late infancy (29.1%, n = 28/96). Single-gene mutations and cytogenetic abnormalities accounted for genetic causes of specific epilepsy phenotypes or selected recognizable syndromes with a high prevalence of seizures. Seizure control in this group was relatively difficult, and therefore, this group demonstrated a high DRE incidence rate (42.8%, n = 12/28), and the high risk of NDD.
To our knowledge, we carried out the first meta-analysis with regards to genetic causes of DRE. From the meta-analysis, we found high incidences of gene related DRE in children and infancy (pooled prevalence 22.8%, 95% CI 17.4–29.3). The result is consistent with our study although with different methodology. It goes without saying that we could not encompass all epilepsy genes in a single research and then estimate the incidence of DRE, and besides, the detected gene mutations vary between studies. Even so, after combining the two, bidirectional comparison as a result, we demonstrate that genetic factors play a crucial role in childhood and infantile epilepsy and otherwise provided a reliable evidence to make believe a high probability of DRE existing in patients with genetic factors during childhood and infancy
Additionally, we discovered some common genetic mutations among childhood DRE through our study (n = 96) and the meta-analysis (n = 1308). Namely, SCN1A, which presented in almost every study including ours, and the others were PCDH19, SCN8A, SCN2A, MECP2, KCNQ2, CDKL5, TSC1 and TSC2 (Table 3). Even now that molecular diagnostic tools are cutting prices for competition, the cost factor is still a major concern for most clinician and patients of DRE who sought for an accurate diagnosis for treatment . Hopefully, this result could serve as an informative reference for future DRE panel design to make it cost effective and more efficient, especially in which WES or comprehensive epilepsy panels are not easily available or affordable.
Perinatal and prenatal insults are major risk factors for infantile epilepsy . The proposed pathophysiological mechanism is that hypoxia–ischemia that can have deleterious effects on the vulnerable regions of the developing brain lead to substantive injuries that could affect not only seizure threshold but also cognition . Studies have also explored the mechanisms underlying neuronal injury, which could be a cause of epilepsy; first, hypoxic–ischemic encephalopathy (HIE) initially affects various processes that potentially contribute to energy failure and loss of mitochondrial function, including brain edema, membrane depolarization, increased levels of neurotransmitter release and uptake inhibition, and increased levels of intracellular calcium (which can cause the initiation of further pathological cascades) . Second, excitotoxic cellular injury occurring through excess activation of the four glutamate receptors (N-methyl-d-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid, kainate, and metabotropic glutamate receptors), which leads to several forms of cell death, is another possible seizure mechanism associated with HIE [32–34].
Traumatic brain injury (TBI), whether accidental or inflicted, is another common cause of epilepsy development in infancy . Notably, TBI often coexists with HIE, which worsens the condition of the already fragile brain through molecular injury mechanisms similar to those of HIE [36, 37], including excitotoxicity mediated by neurotransmitters that results in glutamate, free-radical injury to cell membranes, mitochondrial dysfunction, electrolyte imbalance, inflammatory response, focal microvascular occlusion, secondary ischemia from vasospasm, apoptosis, and vascular injury. These mechanisms result, in turn, in neuronal cell death concomitant with cerebral edema and an elevated risk of epilepsy [38–40].
Gene-related epilepsy involves various heterogenous seizure mechanisms that depend on the role of the genes. There are over 970 genes associated with epilepsy, and the number is increasing year by year [41, 42]. Although the seizure mechanisms are complex and diverse between the causative genes, we could roughly categorize them into ion and nonion channel genes. Given the role played by epigenetics in neuronal function from the time of embryogenesis and early brain development, as well as in tissue-specific gene expression, epigenetic regulation also contributes to neurodevelopment through gene–environment interaction influencing epilepsy occurrence. The same principle is likewise applicable to localized multiple loci in which susceptibility genes to epilepsy are harbored and can explain epilepsy cases with cytogenetic abnormalities .
Drug resistance mechanisms in epilepsy remain unclear. Margineanu DG et al proposed two current hypotheses that underscore the roles played by changes in the targets of medications that render them drug-insensitive and by the elevated actions of blood-brain barrier multidrug transporter proteins. However, the hypotheses in question do not seem to adequately account for the complicated nature of the brain alterations that occur in DRE . The current consensus on is that DRE mechanism is multifactorial, including factors relating to the environment and genetics, in addition to both disease-related and drug-related factors [45, 46].. Relatedly, the occurrence of at least two of these factors in combination may be of value in identifying those patients who are unlikely to be responsive to medical therapy [3, 47–51]. In our study, we proposed two explanations for genetic factors increasing DRE risk during infancy with epilepsy and NDD: First, during the neonatal or infancy period, early infantile epileptic encephalopathy accounts for a major part of genetic epilepsy, which are difficult to treat and often medically refractory . Second, on the basis of several hypotheses proposed on DRE, including hypotheses regarding pharmacokinetics, intrinsic severity, neural networks, gene variants, transporters, and targets , we assumed that a sustained “neuroimmunoinflammatory” status can be implicated as not only epileptogenic but also indicative of a drug-resistant profile . Additional relevant cell line– and animal model–based studies are thus warranted.
The present study had several limitations. First, while a risk of DRE in cases of genetic epilepsy was determined through this observational study, it is possible that the results may have been impacted by various confounding factors, such as the health status of the mother prior to and during pregnancy, socioeconomic status, pharmacological therapy of the children for conditions other than neurological conditions, poor nutrition (including malnutrition), or other environmental factors. Second, the size of the study sample was insufficient. We could not include patients of all types of genetic epilepsy in one study; moreover, one gene could have many different genotypes. Third, although our DRE definition was explicit, the seizure control results may have varied among physicians; that is, a DRE case for one physician could have attained seizure control with another. Fourth, although a comprehensive investigation was performed in all of the enrolled patients, an exact cause for epilepsy and NDD could not be determined in 19 patients; and thus the possibility of genetic factors’ involvement in those cases could not be completely dismissed, which was an inevitable confounder in the study. As such, further investigations of a thorough nature will be needed going forward in order to ascertain the related risks and pinpoint their underlying mechanisms in genetic and nongenetic epilepsy.
In summary, our study reveals that genetic factors act crucial role in younger children with epilepsy and NDD. Initiation of a genetic-based AED-development model, based on our current results, is warranted. In addition, the study can serve as a reference for further studies of epilepsy panel design and may also assist in the development of improved treatments and prevention strategies for DRE, particularly for drug control in more extensive and diverse genetic epilepsy, which has received insufficient attention thus far. That said, more data from relevant patients, as well as and more comprehensive studies of those data, will be needed in order to identify possible maternal, prenatal, perinatal, and postnatal confounders that could in turn help to clarify the effects of both genetic and nongenetic factors, as well as their associations with DRE.