Intrinsically Photosensitive Retinal Ganglion Cell Dysfunction and Suprachiasmatic Nucleus -Mediated Circadian...

Circadian entraining input to the suprachiasmatic nucleus (SCN) is primarily from intrinsically photosensitive retinal ganglion cells (ipRGCs). While several retinal and optic nerve diseases are associated with ipRGC dysfunction, the role of ipRGC dysfunction in the context of SCN-mediated circadian disruption remains incompletely understood. We performed a systematic review of human studies examining relationships between ipRGC dysfunction and circadian effects. Databases were searched from inception until Apr 2026. Studies were independently assessed for risk of bias, screened, and data extracted by two reviewers. Due to high methodological variability, results were summarised qualitatively. GRADE was used to assess the certainty of evidence. 3,632 records were identified, of which 10 studies were included, 8 focused on ipRGC functional measures, and 2 on ipRGC structural measures. Across the 8 functional-measures studies, ipRGC dysfunction and impairment in one or more SCN-mediated circadian outcomes were consistently observed, and this association was independently corroborated in 6 of the 8 studies. Advanced glaucoma and diabetic retinopathy showed the greatest evidence of circadian disruption, including decreased melatonin excretion, delayed or altered dim-light melatonin onset, and failure to suppress melatonin with light exposure. Both ipRGC function and circadian regulation were preserved in mitochondrial optic neuropathies. Two additional studies showed strong links between post-illumination pupil response (PIPR) and melatonin-related circadian measures. In two post-mortem ipRGC structural measure studies, ipRGC density was reduced by 76.9% in severe diabetic retinopathy compared with controls, and age-related ipRGC dendritic atrophy was observed. Evidence in humans suggests a directionally consistent but very low-certainty relationship between SCN circadian disruption and ipRGC dysfunction, but the pattern and severity of disruption differ across disease states. PIPR has the potential to serve as a non-invasive marker of circadian disruption. The overall certainty of evidence is still very low, however, and requires larger, long-term studies with standardized circadian phenotyping.