Electrophysiological readout of ACTH-related neuroendocrine-immunomodulatory treatment response in infantile epileptic spasms syndrome: suppression of scalp ripple propagation networks.

Background: Adrenocorticotropic hormone (ACTH) is a first-line neuroendocrine-immunomodulatory therapy for infantile epileptic spasms syndrome (IESS), but noninvasive electrophysiological markers that objectively reflect treatment-related network changes remain limited. We investigated whether scalp putative ripple propagation network metrics provide markers of adrenocorticotropic hormone-related network response and early relapse risk. Methods: In this retrospective multicenter study, children receiving first-time ACTH therapy were included if paired pre- and post-treatment scalp electroencephalography (EEG) recordings and at least 6 months of follow-up were available. Five-minute artifact-free interictal slow-wave-sleep segments were analyzed. Putative ripple propagation networks were constructed using a time-delay-based method. The primary metrics were post-treatment total network connection strength (total NCS) and its reduction ratio, with ripple count and ripple-count reduction ratio used as rate-based comparators. Results: Sixty-one children were included; 27 achieved acute spasm freedom, and seven of these relapsed within 6 months. Baseline ripple count and network metrics did not distinguish subsequent responders from nonresponders. After adrenocorticotropic hormone therapy, acute responders showed marked suppression of putative ripple propagation network metrics, whereas nonresponders showed reduction in ripple count without comparable reductions in network metrics. Post-treatment total network connection strength and its reduction ratio differentiated acute responders from nonresponders, with areas under the curve (AUC) of 0.902 and 0.899, respectively. In exploratory analyses among acute responders, greater total network connection strength reduction was associated with sustained 6-month spasm freedom, although relapse-related estimates were limited by the small number of events. Conclusion: Scalp putative ripple propagation networks provide a noninvasive electrophysiological readout of ACTH-related network modulation in infantile epileptic spasms syndrome. In contrast to ripple count alone, network connection strength captured whether treatment was accompanied by disruption of propagating high-frequency activity. These findings suggest that total NCS and its reduction ratio may serve as candidate markers of adrenocorticotropic hormone-related neuroendocrine-immunomodulatory therapy response, while their relevance to relapse risk requires prospective validation.