Primary Vascular Dysregulation in Normal-Tension Glaucoma: Pathophysiology and Management

Normal-tension glaucoma (NTG) is a progressive optic neuropathy occurring in the absence of elevated intraocular pressure (IOP), implying that mechanisms beyond mechanical stress drive axonal loss. Primary vascular dysregulation (PVD), a constitutional impairment of vascular tone regulation independent of structural disease, is increasingly recognized as a central pathogenetic contributor to NTG. This review examines the evidence linking PVD to NTG, explores underlying mechanisms, and evaluates current and emerging management strategies targeting vascular dysregulation. A comprehensive narrative review of peer-reviewed literature was conducted using PubMed, MEDLINE, EMBASE, and Cochrane databases from 1985 to March 2026. Search terms included: normal-tension glaucoma, primary vascular dysregulation, Flammer syndrome, ocular blood flow, endothelin-1, calcium channel blockers, optic nerve head ischemia, autoregulation, and neurovascular coupling. Studies including randomized controlled trials, prospective observational cohorts, case-control studies, systematic reviews, and seminal basic science investigations were selected for inclusion based on relevance and quality. PVD encompasses impaired autoregulation of optic nerve head (ONH) perfusion, elevated endothelin-1 (ET-1) levels with relative nitric oxide (NO) deficiency, defective neurovascular coupling, mitochondrial dysfunction, oxidative stress, exaggerated nocturnal hypotension, and autonomic nervous system imbalance. Clinically, PVD-associated NTG is characterized by optic disc haemorrhages, focal notch-type cupping, central and paracentral visual field defects, and progressive loss despite controlled IOP. Pharmacological strategies targeting vascular dysregulation, including calcium channel blockers (CCBs), magnesium supplementation, Ginkgo biloba extract (GBE), and endothelin receptor antagonists, have demonstrated clinical benefit in selected patient cohorts. Optimization of nocturnal systemic blood pressure, lifestyle modifications, and stress reduction are integral non-pharmacological components of management. PVD represents a clinically actionable pathophysiological entity in a significant proportion of NTG patients. Recognition of the PVD phenotype should prompt a multimodal management approach that integrates IOP reduction with strategies targeting ocular perfusion and vascular stability. Future well-powered randomized controlled trials in phenotypically defined PVD-NTG populations are needed to establish definitive therapeutic guidelines and to validate emerging neuroprotective strategies.