Rasmussen's encephalitis as a self-perpetuating neuroinflammation-network remodeling loop: A mechanistic framework for chronic disease progression.
Rasmussen's encephalitis (RE) is a rare and devastating immune-mediated epileptic encephalopathy characterized by drug-resistant seizures, progressive hemispheric atrophy, and irreversible neurological decline. Although T-cell-driven neuroinflammation and microglial activation are recognized pathological hallmarks, current models remain insufficient to explain the relentless chronic progression and the limited long-term efficacy of immunotherapies. Here, we propose an integrative neuroinflammation-network remodeling feedback framework to conceptualize RE as a self-sustaining immune-network disorder rather than a purely inflammatory disease. In this model, immune-mediated cytotoxicity, persistent activation of tissue-resident memory T cells, and glial dysregulation converge to disrupt synaptic homeostasis and large-scale network organization. Recurrent epileptic discharges and focal neuroinflammation synergistically compromise blood-brain barrier integrity, facilitating sustained immune infiltration and amplifying glial-driven inflammatory cascades. These processes, in turn, promote excitatory-inhibitory imbalance, pathological network synchronization, and progressive neuronal loss, reinforcing a vicious cycle of network instability and immune activation. This framework integrates immune mechanisms, glial-synaptic interactions, and network-level dysfunction into a unified pathogenic continuum. It thereby explains why interventions targeting only a single aspect, such as immunotherapy or surgical seizure control alone, consistently fail to halt disease progression. Importantly, it highlights the rationale for stage-specific, multi-target therapeutic strategies aimed at simultaneously modulating immune responses and restoring network stability. Beyond RE, this conceptual model provides a broader paradigm for understanding chronic epileptic and neuroimmune disorders driven by maladaptive immune-network coupling.