Article: Complications Variables associated with corneal confocal microscopy parameters in healthy volunteers: implications for diabetic neuropathy screening T. Wu 1 *, A. Ahmed 1 *, V. Bril 2 , A. Orszag 1 , E. Ng 2 , P. Nwe 2 and B. A. Perkins 1 1 Division of Endocrinology and Metabolism and 2 Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada Accepted 30 March 2012 Abstract Aim Corneal confocal microscopy is a promising screening method for diabetic neuropathy. Although much research in this field has been accomplished, we aimed to determine and confirm the known clinical and eyewear variables associated with the parameters of corneal confocal microscopy specifically in healthy volunteers, in particular associations with corneal nerve fibre length. Methods Clinical characteristics, electrophysiological examination and a general clinical eye history were collected from 64 healthy volunteers. Corneal confocal microscopy was performed to determine corneal nerve fibre length, corneal nerve branch density, corneal nerve fibre density and tortuosity coefficient. Univariate and multivariate linear regression analysis was used to determine clinical variables associated with corneal nerve fibre length parameters. Results We observed that corneal nerve fibre length has a broad distribution in healthy volunteers (18 Æ 4 mm ⁄ mm 2 , 95% confidence interval, 12.3–25.7 mm ⁄ mm 2 ). Multivariate regression analysis demonstrated that HbA 1c was the only inde- pendent clinical factor to account for variations in corneal nerve fibre length, independent of age and status of contact lens wear. Conclusions This study does not provide convincing evidence that corneal nerve fibre length is independently associated with age or the wearing of contact lenses, and that these factors are therefore unlikely to hinder valid screening for polyneuropathies such as diabetic neuropathy. Furthermore, the strong inverse association of corneal nerve fibre length with glycaemic exposure may support the use of this parameter to detect subclinical pre-diabetic nerve injury. Diabet. Med. 29, e297–e303 (2012) Keywords corneal confocal microscopy, corneal nerve fibre length, healthy volunteers Introduction There is an urgent need to identify early biomarkers of diabetic sensorimotor polyneuropathy to detect and monitor nerve damage for the prevention of neuropathy-related sequelae [1]. Skin biopsy is generally accepted as a gold standard test to evaluate small intra-epidermal nerve fibres, but this technique has limitations related to invasiveness and cost, and has a diagnostic role currently limited to idiopathic small fibre painful neuropathy [2]. Substantial evidence exists to support the clinical evaluation of corneal nerve fibre morphology by corneal confocal microscopy (CCM) for identification of the severity of diabetic neuropathy [3–5]. Specifically, it has been shown to correlate with intra-epidermal nerve fibre density for neuropathy status and severity [6]. Corneal nerve fibre length (CNFL) has been suggested to be the optimal and most reliable parameter to detect nerve injury, as demonstrated by advan- tages in reproducibility [7,8] and concurrent validity [5] com- pared with other parameters of CCM. The non-invasive nature of CCM highlights its potential as a feasible objective clinical screening test for diabetic sensorimotor polyneuropathy that could be harmonized with screening for retinopathy performed by eye specialists. Given the important potential role of CCM in clinical screening and identification of diabetic sensorimotor poly- neuropathy [5], it is essential to identify the variables that may influence CNFL. Much fundamental work has been Correspondence to: B. A. Perkins, Endocrinology and Metabolism, University of Toronto, Toronto General Hospital 200 Elizabeth Street, Room EN-12–218, Toronto, Ontario, Canada M5G 2C4. E-mail: bruce.perkins@uhn.on.ca *These co-first authors contributed equally to the writing of the manuscript. DIABETICMedicine DOI: 10.1111/j.1464-5491.2012.03678.x ª 2012 The Authors. Diabetic Medicine ª 2012 Diabetes UK e297