Pulsed synchrony regulation of intraocular and cerebrospinal fluid pressure: a novel paradigm for glaucoma pathogenesis and treatment

Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons. While elevated intraocular pressure (IOP) is a core risk factor, the pathogenesis of normal-tension glaucoma (NTG) remains unclear, as static IOP is within the normal range. Based on circadian fluctuations of IOP and cerebrospinal fluid pressure (CSFP), and the pressure-dependent function of the ocular glymphatic system, we propose the "dynamic trans-lamina cribrosa pressure difference (TLCPD) imbalance" hypothesis. This hypothesis posits that optic nerve damage may stem from abnormal pulse synchrony between IOP and CSFP (phase mismatch, amplitude mismatch, or abnormal frequency) rather than static TLCPD elevation alone, pending further validation. Dynamic imbalance induces RGC injury through dual mechanisms: mechanical stress on the lamina cribrosa (collagen fiber rupture, astrocyte activation) and metabolic dysfunction (ocular glymphatic clearance impairment, toxic waste accumulation), which ultimately converge on the activation of the programmed axonal degeneration (PAD) pathway-a conserved final common effector of RGC axon loss. Phase mismatch is the core pathological pattern in NTG. In contrast, high-tension primary open-angle glaucoma (POAG) is characterized mainly by amplitude mismatch and abnormal frequency, with potential coexistence and mutual influence of these mechanisms. Verifiable clinical (24-h IOP-CSFP synchronous monitoring) and animal experiments are proposed. This hypothesis may help explain unresolved clinical phenomena, provides novel diagnostic markers (a transient peak in TLCPD) and therapeutic strategies (CSFP regulation, glymphatic function enhancement, modulation of the PAD pathway), and opens new avenues for personalized glaucoma management.