From acute disturbance to chronic epilepsy.
| Disease stage/instability phase | Dominant processes | Neural contribution | Glial contribution | Tissue/Circuit consequence | Clinical or translational relevance |
|---|---|---|---|---|---|
| Stable/Compensated network | Balanced excitation and inhibition, preserved extracellular homeostasis, effective buffering and recovery mechanisms, restrained inflammatory tone, adaptive plasticity | Neurons maintain controlled firing, appropriate inhibitory restraint, and normal response to perturbation | Astrocytes, microglia, and other glial cells support potassium buffering, glutamate clearance, inflammatory restraint, metabolic coupling, and synaptic stability | Network remains resistant to hypersynchrony and can absorb transient perturbations without progressing to seizure-prone organization | Represents the physiological reference state and highlights the stabilizing systems that later therapies may seek to preserve or restore [9, 82, 184] |
| Early destabilization | Partial weakening of inhibitory restraint, impaired buffering, altered neurotransmitter clearance, inflammatory priming, reduced recovery efficiency | Increased responsiveness to perturbation, emerging excitability changes, less effective inhibitory containment, fluctuating thresholds for synchronized activity | Reduced astrocytic homeostatic efficiency, early microglial activation, beginning loss of inflammatory restraint, stress-sensitive glial signaling | Network appears partly compensated but becomes more vulnerable to recurrent excitation and less able to return fully to baseline after stress | Identifies a potentially intervention-sensitive phase in which compensatory mechanisms still exist but are becoming less reliable [178] |
| Acute seizure-associated disturbance | Intense neuronal firing, extracellular ionic disruption, neurotransmitter imbalance, calcium overload, acute glial activation, tissue stress signaling | Pathological discharge, hypersynchrony, recruitment of seizure-relevant ensembles, acute excitatory–inhibitory breakdown | Astrocytic buffering stress, microglial activation, inflammatory signaling, altered water and neurotransmitter regulation | Acute instability, local and distributed network disruption, cellular stress, and increased risk that seizure activity will leave a biological imprint | Clinically relevant for seizure termination, injury limitation, and prevention of secondary destabilizing cascades [37, 185, 186] |
| Epileptogenic transition | Sustained inflammatory signaling, danger-associated responses, blood–brain barrier dysfunction, maladaptive plasticity, incomplete recovery, repeated reactivation of destabilizing pathways | Persistent threshold lowering, altered synaptic responsiveness, impaired recovery, reinforcement of pro-excitatory circuit behavior | Chronic or repeated glial activation, inflammatory amplification, impaired homeostatic support, glia-mediated contribution to remodeling and persistent vulnerability | Acute disturbances become consolidated into more durable seizure-prone states with impaired resilience and increased susceptibility to recurrence | Represents a major translational target because it is the phase in which chronic epilepsy may be prevented or attenuated before remodeling becomes more fixed [169, 178] |
| Chronic remodeled epileptic network | Synaptic reorganization, mossy fiber sprouting where relevant, interneuron network alteration, rewiring after injury, persistent connectivity and synchrony changes | Neuronal networks become chronically permissive for recruitment, propagation, and recurrent pathological synchronization | Glial signaling, inflammatory persistence, extracellular matrix remodeling, metabolic and calcium-linked support of maladaptive circuit organization | Seizure-proneness becomes embedded in tissue and circuit architecture, allowing instability to persist even between overt seizures | Highlights why long-standing epilepsy often requires network-level and mechanism-guided therapies rather than acute suppression alone [37, 167, 169] |
MMN: Conceptualization, Writing—original draft, Writing—review & editing. The author read and approved the submitted version.
The author declares that there are no conflicts of interest.
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