A Remyelination Vulnerability Model of Trigeminal Neuralgia

Title: The Remyelination Vulnerability Model of Trigeminal Neuralgia Description: This manuscript introduces a novel mechanistic framework explaining the onset, localisation, and demographic patterns of trigeminal neuralgia (TN) through an integrated remyelination-based model. The Remyelination Vulnerability Model proposes that TN arises when mechanical microtrauma at the trigeminal root entry zone (TREZ) occurs in the context of impaired CNS remyelination—a process strongly dependent on androgen signalling and oligodendrocyte function. Classical vascular compression alone cannot account for the full range of clinical observations in TN. Up to 60% of asymptomatic individuals show neurovascular contact, and yet only a small minority develop TN. This model resolves this paradox by proposing that anatomical stressors (e.g., neurovascular compression, a flattened or low-volume Meckel’s cave, CSF buffering reduction) become pathogenic only when combined with hormonally mediated reductions in oligodendrocyte repair capacity. The model accounts for several features not adequately explained by existing theories: – Exclusive localisation of TN to the CNS myelin segment, not distal branches – Female predominance and strong association with peri-/post-menopause – Sudden onset despite longstanding compression – Recurrence after successful decompression – Bilateral or alternating TN – Early prodromal sensory changes (tingling, aching) preceding shocks By positioning TN as a condition of CNS remyelination failure triggered by mechanical stress, the framework provides a more coherent explanation of epidemiology, imaging findings, and clinical variability. It further suggests measurable biomarkers (free testosterone, SHBG, remyelination efficiency, Meckel’s cave morphology) and opens potential therapeutic directions involving hormonal optimisation and neuroprotective strategies.