Dr Cirous Dehghani PhD
Dr Katie Edwards PhD
Dr Nicola Pritchard PhD
Professor Nathan Efron PhD DSc
Institute of Health and Biomedical Innovation, Queensland University of Technology
Diabetes is one of the most common diseases world-wide and can lead to serious complications including nephropathy, retinopathy and neuropathy. Diabetic peripheral neuropathy (DPN) is a debilitating and prevalent complication of diabetes and affects up to 50 per cent of patients with diabetes. DPN leads to numbness, loss of sensation, tingling, and pain or weakness that often affects patients’ feet and legs first, followed by their hands and arms. Lack of awareness of foot injury may lead to foot ulcers, which in advanced stages, can result in lower limb amputation.
Conventional measures of DPN such as skin or nerve biopsies, nerve electrophysiology and quantitative sensory tests have significant shortcomings. They are invasive and uncomfortable. They are unable to detect early, small nerve damage and repair, and they require specialised medical expertise and equipment.
It seems that lack of an early biomarker for nerve changes in diabetic neuropathy is one of the most notable obstacles of assessing treatment efficacy in clinical trials. There is an urgent need for a sensitive and reliable diagnostic marker for DPN.
|Figure 1. Laser-scanning confocal microscopy images of central corneal sub-basal nerve plexus (A) healthy participant, (B) diabetic participant without DPN and (C) diabetic participant with severe DPN
The LANDMark Study
The eye has been explored as a simple, non-invasive location for screening, diagnosis and follow-up of DPN. The LANDMark (Longitudinal Assessment of Neuropathy in Diabetes using novel ophthalmic MARKers) study is a two-site (Brisbane, Australia and Manchester, UK), four-year longitudinal observational study.
The LANDMark study has investigated the association between corneal confocal microscopy (CCM) (Figure 1), non-contact corneal aesthesiometry (NCCA), optical coherence tomography, and visual field perimetry and peripheral nerve morphology and function in individuals with type 1 and type 2 diabetes as well as healthy participants. The Brisbane site completed the four-year longitudinal study in July 2014 and the Manchester site is scheduled to finish this year.
The cross-sectional baseline findings of the LANDMark study were published in 2012 and demonstrated the utility of CCM and NCCA in diagnosis of DPN.1,2 The results also demonstrated reduced visual sensitivity within the central 30 degrees of visual field in participants with DPN.3
We have recently also published the four-year longitudinal outcomes, revealing that corneal nerve structure is relatively stable over time in non-neuropathic individuals.4 However, a significant linear decline of corneal nerve fibre density in neuropathic individuals was observed over four years with a decrease of approximately one nerve/mm2 per year (Figure 2). The observed decline was associated with age and duration of diabetes of the participants. The study also demonstrated that the corneal nerve parameters did change in a pattern comparable with some conventional measures of neuropathy.5
|Figure 2. Longitudinal course of corneal nerve fibre density over time in LANDMark study (Brisbane site). DPN-ve, diabetic participants without neuropathy; DPN+ve, diabetic participants with neuropathy.
In 2014, the US National Institutes of Health funded a multinational collaborative study, of which the Brisbane-based LANDMark study is a part, with the aim of assessing CCM as a surrogate endpoint for the identification and prediction of diabetic neuropathy in type 1 and type 2 diabetes.
This dataset will ultimately include five to seven years of follow-up on over 500 participants with diabetes from Australia, Canada, the USA and the UK. Through the approach of the multinational pooled dataset, this project will derive and validate specific CCM parameter cut-offs for the identification of DPN and the identification of individuals at future risk of DPN onset.
These results will permit application of corneal nerve assessment as a diagnostic marker for DPN in clinical practice and more importantly, in intervention trials for therapeutic agents for DPN.
- Edwards K et al. Utility of corneal confocal microscopy for assessing mild diabetic neuropathy: baseline findings of the LANDMark study. Clinical and Experimental Optometry 2012; 95: 3: 348-354.
- Pritchard N et al. Corneal sensitivity is related to established measures of diabetic peripheral neuropathy. Clinical and Experimental Optometry 2012; 95: 3: 355-361.
- Sampson GP et al. Visual sensitivity loss in the central 30° of visual field is associated with diabetic peripheral neuropathy. Diabetologia 2012; 55: 4: 1179-1185.
- Dehghani C et al. Morphometric stability of the corneal subbasal nerve plexus in healthy individuals: a 3-year longitudinal study using corneal confocal microscopy. Invest Ophthalmol Vis Sci 2014; 55: 5: 3195-3199.
- Dehghani C et al. Natural history of corneal nerve morphology in mild neuropathy associated with type 1 diabetes: development of a potential measure of diabetic peripheral neuropathy. Invest Ophthalmol Vis Sci 2014; 55: 12: 7982-7990.