Longitudinal changes in brain volume, cognitive function, and seizure outcomes in cryptogenic new-onset refractory...

To evaluate long-term structural, cognitive, functional, and seizure outcomes among survivors of cryptogenic new-onset refractory status epilepticus (C-NORSE) according to the timing of intravenous cyclophosphamide (IVCPA) initiation.

We examined seven consecutive patients with C-NORSE treated between 2012 and 2025. Of those, super-refractory status epilepticus (SRSE, n = 5) cases were stratified into SRSE-Early IVCPA (IVCPA initiated within 20 days after seizure onset) and SRSE-Late/No IVCPA (IVCPA initiated >20 days after onset or not administered); the refractory status epilepticus (RSE) group served as a reference. 4 of the 5 SRSE patients received IVCPA (3 cases were classified as early and 1 case as late). We assessed whole-brain volume change quantified on serial MRI, neurocognition by standardized tests, functional outcomes by mRS, and seizure outcomes during the acute phase, at discharge, and in the chronic phase (≥1 year) among groups.

The median follow-up was 5 years (range, 2-11 years). Whole-brain volume loss remained <10% in the RSE and SRSE-Early IVCPA groups, whereas marked medial temporal and diffuse brain atrophy developed in the two cases in the SRSE-Late/No IVCPA group, with whole-brain volume losses of 18.2% and 16.0%. Neurocognitive trajectories improved gradually in SRSE-Early IVCPA and showed severe chronic impairment in SRSE-Late/No IVCPA. Functional outcomes were excellent in SRSE-Early IVCPA and RSE but were poorer in SRSE-Late/No IVCPA. All patients developed drug-resistant epilepsy.

In this case series, earlier IVCPA initiation in patients with SRSE due to C-NORSE was potentially associated with less chronic brain atrophy and more favorable neurocognitive and functional trajectories. Future studies are warranted to determine whether early seizure control plus immunotherapy reduces the risk of chronic drug-resistant epilepsy and improves long-term cognition.