Adaptive immune dysregulation drives new-onset refractory status epilepticus.

New-onset refractory status epilepticus (NORSE) is a life-threatening neurological condition that emerges abruptly in individuals without a prior history of epilepsy and is characterised by seizures that are refractory to standard antiseizure medications. NORSE is associated with high mortality and long-term neurological deficits, and autoimmune encephalitis (AIE) represents a major identifiable cause of NORSE. Growing evidence implicates immune-mediated mechanisms as central drivers of NORSE; however, existing studies have focused predominantly on innate immune dysregulation, including cytokine-driven neuroinflammation and microglial activation, whilst the role of adaptive immune mechanisms in AIE-mediated NORSE remains relatively underexplored. This review synthesises current evidence linking adaptive immune responses in NORSE pathogenesis, with particular emphasis on B and T lymphocytes in shaping neuroinflammation. B cell-mediated response is implicated in NORSE cases associated with AIE where autoantibodies such as anti-N-methyl-D-aspartate receptor (NMDAR) disrupt neuronal signalling and contribute to seizure generation. Beyond humoral immunity, T-cell subsets, for instance, cytotoxic T cells, contribute to neuronal damage through recognition of neuronal intracellular antigens. Emerging immunomodulatory therapies targeting adaptive immune components are also discussed, including monoclonal antibody therapies and innovative approaches inspired by conventional chimeric antigen receptor (CAR) T-cell technology. A deeper understanding of the complex interplay between innate and adaptive immune responses is essential to elucidate disease mechanisms and guide future development of more precise mechanism-based therapeutic strategies for NORSE.