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Diabetes and the ocular surface


Dr Maria Markoulli
School of Optometry & Vision Science, UNSW

Jenny Wu


Diabetes mellitus (DM) is a metabolic disorder characterised by hyperglycaemia and is one of the most common systemic diseases in the world. It is projected that the prevalence of the disease in people aged 25 years or older in Australia will reach 2.9 million by 2025, increasing the financial strain on the health system.1 Diabetes is associated with premature mortality, macrovascular complications such as cardiovascular disease, and microvascular complications including nephropathy leading to kidney failure, potentially blinding diabetic retinopathy, and diabetic neuropathy.2,3

While the retinal complications of diabetes are well recognised by eye-care professionals, the effects on the ocular surface are poorly understood.

Diabetic keratopathy, for example, is estimated to affect between 47 and 64 per cent4 of people with diabetes during the course of their disease and can ultimately lead to neurotrophic ulcers and significant visual morbidity.5

Corneal denervation from chronic hyperglycaemia6-8 can lead to loss of corneal sensitivity.9,10 Epithelial fragility as a result of reduced epithelial adhesion to the underlying basement membrane,11,12 together with poor wound healing,13,14 increase the susceptibility to persistent epithelial erosions15 and corneal infection.11,16

Quality of life in people with diabetes can also be compromised with corneal neuropathy, which may lead to dry eye discomfort and significant visual impairment from loss of ocular surface integrity.11

It is not well understood how these ocular surface conditions relate to the duration of diabetes, the severity of the systemic disease such as peripheral neuropathy, or the timeline in which they occur.

Diabetic peripheral neuropathy, defined as the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes,17,18 can have a devastating effect on a patient’s quality of life. Painful neuropathy affects 30 per cent of people with diabetes, foot ulceration in seven per cent of patients with neuropathy, and lower limb amputation in advanced cases.11,19,20,21

Examination of nerve morphology in skin is via skin punch biopsy,22 which allows for objective and sensitive assessment of small nerve fibre damage but is invasive and non-repeatable.23 Nerve conduction,24 using biothesiometry which measures large nerve fibre function, is a sensitive, objective technique and is currently the ‘gold standard’ for diagnosis.

Non-invasive measurement

Unlike nerves elsewhere in the body, corneal nerves can be imaged in vivo and non-invasively with in vivo confocal microscopy (Figure 1).

Ph -150-Figure -1 - OL

Figure 1. In vivo confocal microscopy using the HRT II Corneal Rostock Module (Heidelberg Engineering, Dossenheim, Germany).  Image: Vinod Maseedupally

There is an emerging body of evidence showing that morphological changes in the corneal subbasal nerve plexus correlates with changes in the peripheral nerves, and may be a good surrogate measure for diabetic peripheral neuropathy (Figure 2).11,25,26

Ph 150 Figure 2 Comparison - OL

Figure 2. Central corneal nerve images, acquired with in vivo confocal microscopy

Edwards and colleagues27 conducted a five-year observational study measuring the change in corneal nerve morphology in people with diabetes using in vivo confocal microscopy. Participants with diabetic peripheral neuropathy were found to have significantly reduced corneal nerve fibre length and branch density compared to controls and participants with diabetes but without peripheral neuropathy.27

Significantly, a 2015 study reports that in vivo confocal microscopy can predict the onset of peripheral neuropathy in individuals with type 1 diabetes.28

Detection of those at risk

Optometrists and other eye-care practitioners routinely monitor corneal health and regularly screen people with diabetes for retinopathy. With the development of rapid automated analysis of corneal nerves in in vivo confocal microscopy,29 this technique may become more commonly available in clinical practice, with eye-care professionals playing an important role in the management of peripheral diabetic neuropathy through the detection of those at risk through the surrogate measure of corneal nerve density changes.

The underlying mechanisms relating to corneal neuropathy are multifactorial and not completely understood. Corneal nerves provide trophic support to the epithelial cells by releasing soluble mediators that stimulate epithelial cell growth, mitosis, differentiation and migration.6 These mediators include Substance P, Insulin-like Growth Factor-1 (IGF-1), calcitonin gene-related peptide, neuropeptide Y, and vasoactive-intestinal peptide.30

Epithelial cells, in turn, provide trophic support to corneal neurons by secreting growth factors (such as NGF) that promote neurite extension.6 In diabetes, there is thought to be a reduction in the concentration of these mediators, leading to a disruption in epithelial integrity, and a flow-on effect that causes further neuron loss and ultimately neurotrophic ulcers.10,31

An understanding of these underlying mechanisms may contribute to the development of treatments and preventative measures. For example, Substance P is a sensory neurotransmitter secreted by the trigeminal nerve. Substance P alone has no effect on epithelial migration; however, in conjunction with IGF-1 it has been shown to promote epithelial migration in a synergistic manner.32,33

Topical treatment with Substance P derivatives and IGF-1 have been shown to have good efficacy in healing epithelial defects and restoring ocular surface integrity in neurotrophic keratopathy, including diabetic keratopathy.5,34 Various studies have similarly demonstrated the ability of topical NGF to restore corneal sensitivity and ocular surface integrity after corneal neurotrophic keratitis.35,36

Early detection and treatment

Being able to elucidate the pathophysiology of diabetic corneal neuropathy through monitoring the subbasal nerve plexus in vivo and understanding the underlying mechanisms may lead to a better understanding of the processes that occur in peripheral neuropathy, and lead to earlier detection and treatment.

Optometrists and other eye-care practitioners play an important role in the management of diabetes through the early detection and management of microvascular complications including both retinopathy and corneal neuropathy.


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