Elsevier

The Ocular Surface

Volume 9, Issue 1, January 2011, Pages 17-28
The Ocular Surface

Laboratory Science
James V. Jester, PhD, editor
Corneal Markers of Diabetic Neuropathy

https://doi.org/10.1016/S1542-0124(11)70006-4Get rights and content

Abstract

Diabetic neuropathy is a significant clinical problem that currently has no effective therapy, and in advanced cases, leads to foot ulceration and lower limb amputation. The accurate detection, characterization and quantification of this condition are important in order to define at-risk patients, anticipate deterioration, monitor progression, and assess new therapies. This review evaluates novel corneal methods of assessing diabetic neuropathy. Two new noninvasive corneal markers have emerged, and in cross-sectional studies have demonstrated their ability to stratify the severity of this disease. Corneal confocal microscopy allows quantification of corneal nerve parameters and noncontact corneal esthesiometry, the functional correlate of corneal structure, assesses the sensitivity of the cornea. Both these techniques are quick to perform, produce little or no discomfort for the patient, and are suitable for clinical settings. Each has advantages and disadvantages over traditional techniques for assessing diabetic neuropathy. Application of these new corneal markers for longitudinal evaluation of diabetic neuropathy has the potential to reduce dependence on more invasive, costly, and time-consuming assessments, such as skin biopsy.

Introduction

The eye is the only organ in the human body in which nerves can be observed directly and non-invasively. Specifically, rich nerve plexuses can be imaged at the subbasal layer of the corneal epithelium using corneal confocal microscopy and in the retina using optical coherence tomography. This paper reviews recent research into the utility of assessing the structure and function of the corneal subbasal nerve plexus as a marker of one the most common and debilitating complications of diabetes—peripheral neuropathy.

The American Diabetes Association reports mild to severe forms of nervous system damage in 60-70% of people with diabetes.1 This condition affects sensory, autonomic, and motor neurons of the peripheral nervous system. In advanced cases, it can lead to foot ulceration and lower limb amputation. In 2004, about 71,000 nontraumatic lower-limb amputations were performed in the U.S. with significant attributable health care costs,1 and the vast majority of these were due to late complications of diabetic neuropathy. The accurate detection, characterization, and quantification of this condition are important in order to define at-risk patients, anticipate deterioration, monitor progression, and assess new therapies.2

Recently, an international consensus group agreed to the following definition of confirmed diabetic sensorimotor polyneuropathy (DSPN): “The presence of an abnormality of nerve conduction and a symptom or symptoms or a sign or signs of neuropathy.”3 Common symptoms, usually in the feet or legs, include tingling, numbness, extreme sensitivity to touch, prickling, burning, and pain. These symptoms are usually worse at night.

Diabetic neuropathy may be the result of poor control of blood glucose levels. High levels of glucose in the blood (hyperglycemia) disrupt metabolism of nerves and reduce blood flow. This then causes accumulation of toxins, which damage nerve structure and function.4 Foot ulceration in people with neuropathy has an annual incidence in excess of 7% (compared with an incidence of less than 1% in those without neuropathy).5 Early detection or prediction of those at risk of foot ulceration is vital, as foot amputations are preceded by foot ulceration in 80% of cases.5

OUTLINE

  • I.

    Introduction

  • II.

    Traditional tests of diabetic neuropathy

    • A.

      Quantitative sensory testing

    • B.

      Electrophysiology

    • C.

      Nerve and skin biopsy

    • D.

      Magnetic resonance imaging

    • E.

      Monofilament test

    • F.

      Neuropad™

    • G.

      Heart rate variability

  • III.

    Corneal innervation

    • A.

      In vitro assessment of corneal nerve structure

    • B.

      In vivo assessment of corneal nerve structure

  • IV.

    Assessment of corneal sensitivity and corneal nerve function

  • V.

    Corneal dysfunction in diabetes

  • VI.

    Corneal tests as surrogate markers for neuropathy

  • VII.

    Summary and conclusions

Painful diabetic neuropathy affects approximately 30% of all diabetic patients,6, 7 and of those, 80% report the pain to be moderate or severe.6 It has a significant impact on quality of life and on health care costs.4 Individuals with painful diabetic peripheral neuropathy have been shown in a longitudinal study to have reduced quality of life and increased long-term costs compared to those with nonpainful neuropathy.8 Ollendorf et al, using a model based upon the incidence and cost of lower extremity amputations in diabetes, predicted potential savings of US$2-3 million over 3 years if foot ulceration could be prevented. 9 Ramsey et al estimated the attributable costs for a middle-aged diabetic male patient to be US$28,000 two years after a new foot ulcer.10 Risk factors associated with the development of neuropathy in diabetes include increased age, height and body mass index, duration of diabetes, hypertension, smoking, poor glycemic control, and abnormal lipid profile and albumin level.11, 12, 13, 14, 15, 16 Although these studies provide valuable information relating to factors associated with the development of diabetic neuropathy, they only define neuropathy using large nerve fiber dysfunction and shed no light on the pathological changes taking place in small nerve fiber damage or the degree to which changes in symptoms and signs correlate with small nerve fiber degeneration.

Recently, two noninvasive corneal markers of diabetic neuropathy have emerged, and in cross-sectional studies have demonstrated their ability to detect early nerve fiber damage and stratify the severity of this disease. Corneal confocal microscopy (CCM) allows quantification of nerve structure in the cornea, while noncontact corneal esthesiometry (NCCE) assesses a presumed correlate measure of function—corneal sensitivity. The purpose of this review is to summarize our current understanding of these tests as potential markers of diabetic neuropathy. The application of these corneal tests compared to traditional methods will be described.

Section snippets

Traditional Tests of Diabetic Neuropathy

Assessment of peripheral neuropathy is an essential diagnostic procedure—it defines which types of nerves are predominantly affected and assists in management strategies. Evaluation and quantification may also encourage thought as to the cause of the condition. Conventional techniques such as nerve conduction studies and quantitative sensory testing, along with an assessment of neurological disability, offer a relatively robust means of defining neuropathic severity.17 However, these procedures

Corneal Innervation

The human cornea is richly innervated primarily by sensory nerve fibers originating from the ophthalmic division of the trigeminal nerve. Bundles of nerves enter the peripheral cornea in a radial fashion and lose their myelin sheath approximately 1 mm from the corneal limbus—this is essential for maintaining corneal transparency. The nerves in the stromal layers penetrate Bowman's layer and continue parallel to the corneal surface between Bowman's and the basal epithelial cell layer.34 In vitro

Assessment of Corneal Sensitivity and Corneal Nerve Function

Quantification of corneal nerve function by means of measuring corneal sensitivity has also contributed to our understanding of corneal innervation. Ocular surface sensations arise from nerves derived from the anterior ciliary branches of the ophthalmic division of the trigeminal nerve.57 Murphy and coworkers have described how corneal sensitivity can be measured using a novel noninvasive method, the noncontact corneal esthesiometer (NCCE).58, 59, 60 This instrument uses controlled pulses of

Corneal Dysfunction in Diabetes

In diabetes, deficiencies have been noted in all layers of the cornea. Individuals with diabetes have increased corneal thickness,65, 66 as well as alterations to cellular morphology and the basement membrane.67 These features invariably affect other parameters, such as reducing corneal sensitivity, 59, 68, 69, 70, 71, 72 tear secretion73 and cell density74 and increasing epithelial fragility (abnormal adhesion),75 as well as leading to abnormal hydration control76 and an increased risk of

Corneal Tests as Surrogate Markers for Neuropathy

Markers for a disease are ideally rapid, noninvasive, sensitive, specific for the disease, reproducible, affordable, and easy to use in a clinical setting. Corneal nerve parameters measured with CCM have been reported as potential surrogate markers for neuropathic damage and repair in diabetes.49, 54, 88, 89 Corneal sensitivity measured with NCCE is also being investigated as a corneal marker of diabetic neuropathy.47, 88, 90 Figure 3, Figure 4 show the mean corneal nerve fiber length and

Summary and Conclusions

Although CCM and NCCE are in their early stages of development, they show promise as potential markers of diabetic neuropathy. Application of these tests for longitudinal evaluation of diabetic neuropathy have several advantages, primarily reducing dependence on more invasive assessments, such as foot-punch biopsy, in this prevalent and clinically significant complication of diabetes. Further research is warranted to support the cross-sectional studies demonstrating the ability of CCM and NCCE

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  • Cited by (52)

    • The impact of diabetes on corneal nerve morphology and ocular surface integrity

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      Biopsy, however, is invasive and non-repeatable [83], and the procedure can place patients at risk of poor wound healing and infection [84]. The lack of a sensitive, non-invasive, and repeatable endpoint to measure changes in peripheral nerves is a major factor limiting clinical trials for the treatment of diabetic peripheral neuropathy [33,85,86]. Morphological changes in the corneal subbasal nerve plexus correlate with changes in the peripheral nerves and hence might provide an alternate measure for diabetic peripheral neuropathy [33,87–89].

    • Diagnostic capability of retinal thickness measures in diabetic peripheral neuropathy

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      Novel ophthalmic techniques such as corneal confocal microscopy and non-contact corneal aesthesiometry show promise in this regard. These techniques have been utilized in the identification of patients with minimal and more advanced diabetic DPN, and can grade the severity of DPN.4–6 More recently they have been proven to be comparable to intraepidermal nerve fiber density – the current gold standard for diagnosing patients with early DPN.6

    • Early vs. late intervention of high fat/low dose streptozotocin treated C57Bl/6J mice with enalapril, α-lipoic acid, menhaden oil or their combination: Effect on diabetic neuropathy related endpoints

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      The combination therapy also reduced diabetes induced blood glucose levels in both early and late intervention protocols. Loss of corneal nerves in the sub-epithelial layer as detected by non-invasive corneal confocal microscopy is being promoted as a means of early detection of diabetic peripheral neuropathy in humans as well as in pre-clinical studies (Davidson et al., 2012a; Malik et al., 2011; Papanas and Ziegler, 2013; Pritchard et al., 2011; Ziegler et al., 2014b). In this study we found that early intervention with mono-therapies and to a greater extent combination therapy was able to slow progression of loss of corneal nerves in the sub-epithelial layer as well as the corneal nerves penetrating the epithelium.

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    Supported by Juvenile Diabetes Research Foundation International (27-2007-878 and 8-2008-362) and National Health and Medical Research council (Australia) (497230).

    The authors have no proprietary or commercial interests in any concept or product discussed in this article.

    Single-copy reprint requests to: Nicola Pritchard (address below).

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