Can the Pupillary Light Reflex and Pupillary Unrest Be Used as Biomarkers of Parkinson's Disease? A Systematic Review...

Background/Objectives: The pathological changes preceding the onset of Parkinson's disease (PD) commence several decades before motor symptoms manifest, offering a potential window for identifying objective biomarkers for early diagnosis and disease monitoring. Among the primary non-motor features of PD is autonomic dysfunction; however, its precise assessment remains challenging, limiting its viability as a reliable biomarker. Both the pupillary light reflex (PLR) and pupillary unrest are regulated by autonomic pathways suggesting their potential as objective non-invasive indicators of the PD prodromal phase. This review systematically evaluates studies that compare PLR and pupillary unrest in individuals with PD and healthy controls to determine their utility as potential biomarkers of the disease. Methods: A systematic search strategy was designed to identify studies reporting PLR and pupillary unrest findings in PD patients. Searches were conducted across three databases (MEDLINE, Embase PsycINFO), supplemented by cross-referencing relevant studies found on Google Scholar. The literature search was last updated on 7 December 2020. Pupillometric parameters that permitted statistical synthesis included maximum constriction velocity (VMax), constriction amplitude (CAmp), and constriction latency (CL). Pooled incidence and effect sizes were determined using a random-effects model with an inverse variance DerSimonian-Laird estimator. The I² statistic was used to assess study heterogeneity. When meta-analysis was not feasible, a qualitative analysis was undertaken. Results: The initial search yielded 219 references. Following deduplication and exclusion of ineligible studies, 31 papers were selected for review. Pupillometric data from 11 studies were incorporated into the meta-analysis. Effect sizes for PD patients were significant for VMax -0.92, (p < 0.01), CAmp -0.58, (p < 0.05), and CL 0.46, (p < 0.05). Measures of pupillary unrest were elevated in PD patients compared to controls, but evidence was limited to two studies. Conclusions: Pupillary constriction in response to light is characterised by reduced speed and amplitude in PD, with effect sizes suggesting potential clinical applicability. However, evidence regarding baseline pupillary variability remains insufficient, underlining the necessity for further research. Pupillary metrics represent a promising avenue for early PD detection, though their clinical utility is constrained by methodological heterogeneity and variations in disease duration among studies.