IS is more prevalent in male infants and is characterized by spasticity, electroencephalographic cerebral dysrhythmia, and etiology-specific delay. IS is caused by cranial nerve dysfunction in infants during the prenatal, perinatal, or postpartum period. IS can also be regarded as fetal epilepsy because the lesions usually occur in the embryo-fetal period (accounting for approximately 61%), and only a small group of lesions occur in the perinatal or postpartum period [16,17,18]. In agreement with previous studies, our results demonstrated that IS is more common in male children, and the main onset time of IS was 0–1 year old.

Significant differences in gender, family history, birth status, and brain MRI status were detected between the etiology-specific and non-etiology-specific groups. In a previous study exploring the clinical characteristics of 50 children with IS, 96% of the cases were etiology-specific IS and 4% were non-etiology-specific IS; intrapartum asphyxia was the leading cause of etiology-specific IS [19]. Gender may affect brain development and neonatal long-term neurological prognosis [20], which may explain why gender is a risk factor for non-etiology-specific IS in this study. Notably, MRI brain scans are recommended as the main neuroimaging modality to assess the etiology of IS [21]. Cortical structural abnormalities, mainly occurring in the frontal and temporal lobes, may be associated with non-etiology-specific IS [22]. However, in this study, brain MRI abnormalities were not risk factors for non-etiology-specific IS. This discrepancy may be due to the low number of non-etiology-specific infants in this study whose abnormal cortical structures mainly occurred in the frontal and temporal lobes.

Malformations of the cerebral cortex are usually associated with severe epilepsy and spasticity [23]. In this study, a high proportion of brain MRI abnormalities were observed in the non-etiology-specific and nonremission groups, including pachygyria, polymicrogyria, dysplastic corpus callosum, cortical dysplasia, and hemimegalencephaly. Verloes et al. [24] pointed out that brain malformations are the main cause of epileptic attacks in infants. In this study, brain MRI examination of IS patients revealed brain deformities; the findings of Howell et al. [25] were consistent with our results.

Additionally, the metabolic results of majority of the children in this study were not listed in the table because of the lack of metabolic diagnosis. However, two children exhibited a significant association of IS with inheritance, including one child with typical genetic epilepsy and one child with a TUBA1A 12q13.12, Exon4 heterozygous mutation. TUBA1A mutations may disrupt neuronal migration, are associated with brain malformations, and are characteristic of familial recurrence, indicating that TUBA1A mutations may result in IS [26, 27]. Furthermore, 25 innate metabolic errors resulting from single mutated genes cause heterogeneous conditions and may contribute to the etiology of IS [28]. Vitamin B12 deficiency results in severe neurological symptoms such as seizures and spasms, which gradually improve with vitamin B12 supplementation [29]. In this study, metabolic abnormalities were identified as a risk factor for non-etiology-specific IS.

Genetic testing, imaging, and other techniques can help determine the etiology of children with typical IS symptoms. In children with known IS etiologies, epilepsy can be controlled by inhibiting the negative feedback regulation produced by excessive corticotropin-releasing hormone secretion in the brain using adrenocorticotropic hormone (ACTH) [30, 31]. However, ACTH exhibits poor efficacy in children with non-etiology-specific IS, and these children are treated with anticonvulsant drugs [32]. In this study, 83 (83.38%) children were treated with ACTH in combination with anticonvulsants, such as sodium valproate and topiramate, and the symptom control rate was only 52.63% (50/95). Thus, the overall clinical efficacy was poor. Therefore, unless more etiologies of non-etiology-specific IS are discovered, clinical consideration should first be given to symptom relief, risk factor assessment, and preventive measures.

In agreement with a previous study, etiological grouping was a risk factor for unrelieved symptoms after treatment in children with IS [33]. Most children with etiology-specific IS received etiology-specific treatments. However, once neuronal damage occurs, the prognosis is poor even if clinical symptoms are controlled. Neuronal damage in children with non-etiology-specific IS may not appear before the onset but the efficacy and prognosis of established therapies for etiology-specific IS are often unsuitable for the treatment of non-etiology-specific IS. In this study, the age of IS onset was more than 3 months. After treatment, no significant difference in the age of onset between the remission and nonremission groups was detected, and the age of onset was not a risk factor for unrelieved symptoms after treatment.

A family history of epilepsy is associated with poor prognosis in epilepsy patients, while gender does not substantially affect the prognosis [34]. This is consistent with our study showing that family history, but not gender, is a risk factor for unrelieved IS symptoms after treatment. Perinatal neonatal hypoxia may also affect the occurrence of IS [35, 36]. In a clinical report of 30 cases of IS, premature infants accounted for about 26% of children with IS. In our study, asphyxia at birth increased the probability of drug treatment failure, which is consistent with the report by Gul et al. [33] showing that the long-term prognosis of IS is related to the etiology and family history.

There are several limitations to this study. Firstly, this paper was a single-center retrospective study with a relatively small sample size. Secondly, due to the limited data available, we could not establish the association of all risk factors with IS. Thus, further verification needs to be performed in large-scale, multicenter prospective studies.