INTRODUCTION: The treatment of infantile epileptic spasms syndrome (IESS) aims to achieve spasm control. Current first-line interventions include hormone therapy (adrenocorticotropic hormone [ACTH] and corticosteroids) and vigabatrin. Despite treatment, the response rate remains at around 40%, with some infants experiencing relapse after achieving initial spasm control. In certain cases, a second course of first-line therapy may be warranted. The objective of this study was to perform a secondary analysis of data from our previously published studies to elucidate factors influencing the efficacy of ACTH following its re-administration after the lack of response to the initial first-line treatment or relapse. METHODS: We conducted a retrospective analysis of clinical data from children with IESS who had experienced treatment failure or relapse following initial first-line therapy and who subsequently received ACTH at our institution as a second first-line treatment. We examined such variables as etiological classification, interval between treatments, age at first epileptic seizure, radiological findings, and changes in pharmacological treatment modalities, with the overall aim to assess the impact of these variables on the short-term response (disappearance of spasms for >
4 weeks and without hypsarrhythmia pattern) to the second administration of the first-line therapy. RESULTS: Among the 128 patients with IESS identified and included in the analysis, 50 (39.1%) achieved a short-term response. Comparative analysis indicated that responders had a shorter duration between the initial first-line therapy and the initiation of the second first-line treatment (median 1.00 [interquartile range {IQR} 0.00, 2.00] vs. 1.75 [IQR 0.50, 3.88] months), were younger at the time of the second first-line treatment (median 11 [IQR 8, 17] vs. 16 [IQR 10, 24] months, p = 0.008), and were less likely to present with additional seizure types during spasm episodes (12.0% vs. 28.2%, p = 0.030). A multifactorial regression model indicated that older age at first seizure and a short-term response to initial first-line treatment were associated with a higher likelihood of obtaining an initial response in the subsequent ACTH treatment (odds ratio [OR] 2.69, 95% confidence interval [CI] 1.39, 7.23, p = 0.014 and OR 5.41, 95% CI 1.48, 23.90, p = 0.016, respectively). Conversely, an older age at the time of the initial first-line treatment, an older age at the onset of epileptic spasms, and patients with congenital structural abnormalities without genetic abnormalities were less likely to achieve an initial response in subsequent ACTH treatment (OR 0.85, 95% CI 0.78, 0.92, p <
0.001
OR 0.43, 95% CI 0.16, 0.82, p = 0.032
and OR 0.18, 95% CI 0.04, 0.69, p = 0.016, respectively).. CONCLUSION: A second ACTH therapy regimen (second first-line treatment) may help some children with IESS who did not respond to the initial treatment or who subsequently relapsed, with one-third of patients responding in the short-term. Congenital anomalies without genetic abnormalities and older spasm onset age lessen the odds of response, while younger age at ACTH re-treatment could improve these. ACTH may be reconsidered after initial treatment response followed by relapse.