Infantile epileptic spasms syndrome (IESS), which is characterized by epileptic spasms (ES) irrespective of hypsarrhythmia on electroencephalogram (EEG) and neurodevelopmental delay, accounts for 10% of epileptic cases that begin before 36 months of age (1). The incidence of IESS is estimated to be 2–3 per 10,000 live births, and the prevalence is ~0.015 cases per 1,000 people (2, 3). Despite the efficacy of adrenocorticotropic hormone (ACTH), vigabatrin (VGB), and some antiseizure medications, more than half of the patients show severe developmental delay and two-thirds have long-lasting seizures (4, 5).

Seizure control and cognitive status are considered major outcome parameters in any study on IESS (4, 6), and several reports have demonstrated the long-term clinical prognosis of IESS. Regarding seizure prognosis, underlying etiology, persistent ES, and the appearance of epileptic discharges after ACTH therapy are considered the prognostic factors (4, 6). Regarding developmental prognosis, underlying etiology, early treatment initiation, persistent ES, and the presence of focal seizures and developmental delay before the onset of spasms are considered the prognostic factors (4, 6, 7).

Thus, factors associated with prognosis have been identified; however, no study has integrated these factors into a predictive model. Understanding the natural history of childhood-onset epilepsy is imperative for improving the management of the disease and providing children, parents, and families with prognostic information regarding long-term health and social outcomes (8). We aimed to clarify the factors that influence the long-term prognosis of seizures and their development and to create a prediction model.

We performed a retrospective cohort study of pediatric patients diagnosed with IESS at the Department of Child Neurology at Tottori University Hospital. These patients were subsequently divided into two groups according to their development and seizure outcomes. Furthermore, we extracted the risk factors associated with poor seizure and developmental prognosis and created predictive models.

We clarified the factors that influence the long-term outcomes of seizures and development and developed a prediction model after 3 years of the ES onset. We could not develop the prediction model after 7 years of ES onset; however, all participants with poor seizures and development at 7 years also demonstrated poor seizures and development at 3 years.

Persisting ES/TS after 90 days of onset was an important predictor of both seizure and developmental outcomes. Prolonged ES/TS indicates extensive damage from the cerebrum to the brainstem due to the underlying pathological mechanisms of ES involving both the cortex and subcortical structures, including the brainstem, thalamus, and basal ganglia (12, 13). Therefore, if seizures are refractory to the initial ACTH therapy, clinicians should promptly initiate the subsequent treatments for IESS, including second ACTH therapy, VGB, surgical interventions, and dietary therapy (14–17).

Moreover, moderate or severe MRI abnormalities are important predictors of both seizure and developmental prognoses. MRI may provide complementary information regarding etiology and seizure and developmental prognosis in IESS, particularly when assessed together with EEG (11). Indeed, 69.2% of the participants with moderate or severe MRI abnormalities demonstrated poor seizure outcomes, due to underlying etiologies (Supplementary Table 1). However, the outcome of participant 4 with TSC may have been improved by early VGB initiation (Supplementary Table 1). Corpus callosotomy and focal resection for IESS with unilateral or bilateral lesions have become widespread (15–19). Therefore, clinicians should consider the most appropriate treatment including for moderate or severe degrees of MRI abnormality.

Developmental delay before ES onset is an important predictor of both seizures and developmental prognosis. Classically, if patients with IESS have an identified etiology and/or substantial developmental delay before ES onset, they are categorized into the symptomatic infantile spasms group, which generally demonstrates poor developmental outcomes (4, 20). However, some patients with IESS and precedent developmental delay have structural and metabolic etiologies that can improve developmental prognosis with early intervention (20, 21). We should carefully consider the development potential and not easily determine ES treatment including in patients with precedent developmental delay.

In contrast, all patients in our study demonstrated favorable developmental outcomes if there was no developmental delay before ES onset and ES disappeared within 90 days (Supplementary Table 3). Therefore, early ES cessation is crucial, particularly in patients without developmental delay before ES onset, and clinicians are required to develop a treatment plan in cases with no responses to the initial treatment (4).

This study has several limitations. First, this study included only 44 participants from a single site because this was an exploratory study. Second, we did not evaluate the generalizability of the model on new data. Third, variables were selected by univariate screening. Therefore, larger prognostic research and validation of the generalizability of the model should be considered in future research.

Our scoring system may be useful for predicting the long-term prognosis after 3 and 7 years of ES onset. Understanding the long-term prognosis of seizures and their development during the initial treatment may facilitate appropriate treatment selection. Moreover, the early cessation of ES leads to improved long-term prognosis for both seizures and development, thus emphasizing research exploring effective treatments for ES.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Institutional Ethics Committee of the Tottori University Hospital (approval number: 22A108). Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

TO was responsible for the organization and coordination of the trial. YA was the chief investigator responsible for data analysis. HN was responsible for data analysis. SK, YN, HS, HM, KY, and YM designed the trial. All authors have contributed to the writing of the final manuscript and met the ICMJE authorship criteria.