Infantile spasms (IS) is a type of developmental and epileptic encephalopathy (DEE), with an incidence of 0.43 per 1,000 live births, occurs mostly between the ages of 3 and 12 months, and with a peak occurring around 4–7 months (1–3). Studies have shown that nearly 60% of the cases have an underlying etiology (4–6), however, data from the Chinese population is lacking. Moreover, only a few studies have explored the distribution and etiology of IS in different scenarios (5, 7).

In 2015, the National Infantile Spasms Consortium (NISC) in North America divided the etiologies into eight groups, including genetic, genetic-structural, structural-congenital, structural-acquired, metabolic, immune, infectious, and unknown etiologies (8). Considering the rationality and operability of this consortium, we adopted it as the standard etiological classification and used it to investigate the underlying etiology of 541 cases of IS in the central south of China. Moreover, this study also explored the distribution of the patients based on different scenarios, such as the age of onset, gestation age at birth, sex, and the presence/absence of both pre-spasm seizures, and hypsarrhythmia to guide clinical management.

To the best of our knowledge, this is the largest cohort study that summarizes the underlying etiologies of IS. The study found that 53.4% of the cases had an underlying etiology. Correspondingly, 64.4 and 58% of the cases in NISC and International Collaborative Infantile Spasms Study (ICISS) studies, respectively, had an identified cause (6, 8). In conjunction with NISC, the leading group was structural acquired followed by genetic IS, and in both studies, there was no immune cause. This study also highlighted the efficacy of brain MRI as a first-line investigation (yield, 37.5%). Furthermore, there are still some differences when comparing the listed cohorts, which might be characteristic of the Chinese population.

Neonatal hypoglycemic brain injury remains an important cause of epilepsy in developing nations, especially for West syndrome, although it has been excluded in studies done in developed nations. The advanced perinatal care and routinely monitored blood glucose in the Western world might be the explanation for the difference (11). The proportion of hypoglycemic brain injuries in structural-acquired IS in this study was much higher than in previous reports, ranking second only to HIE, indicating the importance of strengthening routine glucose monitoring and hypoglycemia management in perinatal care in China.

Down syndrome is one of the major causes of infantile spasms, contributing to around 10–20% of all known etiologies (6, 8, 12). Surprisingly, Down syndrome was not found in our sample. The disparity might be explained by the introduction of non-invasive prenatal screening for Down syndrome in China, as well as a decrease in the number of live births in infants with Down syndrome (13).

Chromosomal aberrations were only identified in a few of the patients while monogenic variants accounted for a vast majority of the genetic disorders. The most commonly implicated genes were STXBP1, CDKL5, TSC2, KCNQ2, IRF2BPL, and TSC1, which accounted for almost half of the patients with genetic disorders in our study. Except for the genes linked to TSC, the rest were highly consistent with the major genes highlighted in the group with early-onset epilepsies and/or early-onset epileptic encephalopathy with burst suppression (14–16). In retrospect, patients with spasms onset <2 months and those who had previously been diagnosed with Ohtahara syndrome were included in this study. As a result, differences in the major causative genes between studies should be attributed to the broader inclusion criteria used. Differs from the high-frequency genes, other causative genes (ARX, SCN2A, etc.) were only found in <3% of the cases with genetic disorders, respectively. It is evident that IS is highly heterogeneous in terms of genetic etiology. Moreover, the majority of genes involved in our group also showed phenotypic heterogeneity, as it occurs with other neurological disorders in OMIM.

The proportion of metabolic disorders was low in this study, as well as in the NISC study (8). Literature shows that the frequency of inborn errors of metabolism in infants with spasms varies widely (3–22%), depending on the number of patients enrolled and the extent of investigations investigations (4, 8, 17, 18). The fact, that majority of the cases in our cohort showed non-specific changes in routine metabolic screening and were discovered by genetic testing, reflects that metabolic etiologies are likely to be the overlooked contributors of IS, particularly in regions where genetic testing is not available and/or affordable. Genetic testing should, therefore, be considered for cases suspected to have metabolic IS.

As reported, WES explained 28% of cases with IS and also revealed 1–3 de novo variants with interesting candidate genes in 64% of the remaining cases (19). In the current study, about 6.0% of the cases that underwent WES revealed 12 candidate genes (ALPL, CACNA1C, MED12, TCF4, TCF20, CD99L2, TAF1, CLCN6, CYFIP1, GPT2, ATP2A2, and MYO18A) which need to be confirmed by reanalyzing the data and functional studies. CYFIP2 was identified as the causative gene for DEE 65 in OMIM soon after we recognized and reported it as a causative gene for IS (20, 21). Thus, despite the customized multigene panels, WES had much higher diagnostic yields compared to other genetic tests in our study. WES should therefore be considered as the most suitable test when brain MRI fails to detect the underlying etiology. WES is cost-effective, can detect a wide range of genes, and the results can be re-analyzed with time.

The distribution of etiologies is influenced by different factors. Both males and preterm babies independently had higher proportions of structural-acquired etiologies. The male predominance in many acquired diseases such as viral/bacterial meningitis, other uncommon infections, and neonatal stroke (22–25) in children and the association between the low gestational age and high incidence of perinatal brain injury (26, 27) might explain the aforementioned observation in different genders and gestational ages.

Genetic causes play an important role (>20%) in initiating early-onset IS compared with other onset ages. The distribution of STXBP1 was concentrated in early-onset IS cases (P = 0.017). Except for cases with acquired-structural abnormalities, genetic etiology was also a major contributor to neonatal IS and the involved genes were STXBP1, KCNQ2, and SCN2A. Knowledge of the common causative genes for early-onset IS and neonatal IS might guide clinicians in prescribing precise medication for cases lacking genetic results.

Cases without hypsarrhythmia had a higher ratio of non-acquired structural etiologies, and the reason for this is currently unknown. Patients with previous seizures had a lower proportion of unknown causes and higher proportions of structural-acquired and genetic causes. Consistent with our present study, cases with previous seizures have a high proportion of known etiology (5). The NISC study (2017) indicates that preexisting epilepsy reduces the likelihood of receiving standard therapy, including adrenocorticotropic hormone, prednisolone, or vigabatrin and is associated with low treatment response (7).

This study is the largest cohort study that attempts to investigate the etiology and distribution of IS. However, it is limited by the fact that it was retrospective thus, prone to bias. Besides, the sample size is limited to cases from 18 central-southern Chinese provinces thus, the findings cannot be generalized to other geographical locations.

More than half of the IS cases in China had an underlying etiology. The most common cause was structural-acquired followed by genetic causes. HIE and hypoglycemic brain injuries were the major causes of structural-acquired IS. Down syndrome was absent in this cohort. Monogenic variants were very heterogeneous. The most commonly implicated genes were STXBP1, CDKL5, TSC2, KCNQ2, IRF2BPL, and TSC1. WES had a diagnostic yield of 26.9% and should be explored when brain MRI fails to find the underlying cause.

The etiological makeup differed in different scenarios. Male and preterm patients were more likely to have a structural-acquired etiology. Early-onset IS cases had a higher ratio of genetic causes. There was a significant proportion of known etiology in those with prior seizures. Cases without hypsarrhythmia had higher ratios of non-acquired structural etiologies compared with those with hypsarrhythmia.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by the Institutional Ethics Committee of Xiangya Hospital, Central South University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

PP collected, analyzed the data, and drafted the initial manuscript. MK drafted and revised the final manuscript. LM and ZP collected data and carried out the initial analyses. FH, CZ, CC, NP, and FY coordinated and supervised data collection. JP and ZP conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content. All authors reviewed the manuscript and approved the submitted version (and any substantially modified version that involves the author's contribution to the study) and have agreed to be personally accountable for the author's contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

This study was funded by the National Natural Science Foundation of China (grant numbers 81771409 and 82071462), and the Hunan Province Key Technology Support Program (2015SK2019).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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