Exploring retinal and functional markers of diabetic neuropathy

Diabetic peripheral neuropathy (DPN) is one of the most debilitating complications of diabetes. DPN is a major cause of foot ulceration and lower limb amputation. Early diagnosis and management is a key factor in reducing morbidity and mortality. Current techniques for clinical assessment of DPN are relatively insensitive for detecting early disease or involve invasive procedures such as skin biopsies. There is a need for less painful, non-invasive and safe evaluation methods. Eye care professionals already play an important role in the management of diabetic retinopathy; however recent studies have indicated that the eye may also be an important site for the diagnosis and monitoring of neuropathy. Corneal nerve morphology has been shown to be a promising marker of diabetic neuropathy occurring elsewhere in the body, and emerging evidence tentatively suggests that retinal anatomical markers and a range of functional visual indicators could similarly provide useful information regarding neural damage in diabetes – although this line of research is, as yet, less well established. This review outlines the growing body of evidence supporting a potential diagnostic role for retinal structure and visual functional markers in the diagnosis and monitoring of peripheral neuropathy in diabetes.

Functional status, postural stability and falls among older adults with glaucoma

Visual impairment is an important contributing factor in falls among older adults, which is one of the leading causes of injury and injury-related death in this population. Visual impairment is also associated with greater disability among older adults, including poorer health-related quality of life, increased frailty and reduced postural stability. The majority of this evidence, however, is based on measures of central visual function, rather than peripheral visual function. As such, there is comparatively limited research on the associations between peripheral visual function, disability and falls, and even fewer studies involving older adults with specific diseases which affect peripheral visual function, the most common of which is glaucoma. Glaucoma is one of the leading causes of irreversible vision loss among older adults, affecting around 3 per cent of adults aged over 60 years. The condition is characterised by retinal nerve fibre loss, primarily affecting peripheral visual function. Importantly, the number of older adults with glaucomatous visual impairment is projected to increase as the ageing population grows. The first component of the thesis examined the cross-sectional association between glaucomatous visual impairment and health-related quality of life (Study 1a), functional status (Study 1b) and postural stability (Study 1c) among older adults. A cohort of 74 community-dwelling adults with glaucoma (mean age 74.2 ± 5.9 years) was recruited and completed a baseline assessment. A number of visual function measures was assessed, including central visual function (visual acuity and contrast sensitivity), motion sensitivity, retinal nerve fibre analysis and monocular and binocular visual field measures (monocular 24-2 and binocular integrated visual fields (IVF): IVF-60 and IVF-120). The analyses focused on the associations between the outcomes measures and severity and location of visual field loss, as this is the primary visual function affected by glaucoma. In Study 1a, we examined the association between visual field loss and health-related quality of life, measured by the Short Form 36-item Health Survey (SF-36). Greater binocular visual field loss, on both IVF measures, was associated with lower SF-36 physical component scores, adjusted for age and gender (Pearson's r =|0.32| to |0.36|, p<0.001). Furthermore, inferior visual field loss was more strongly associated with the SF-36 physical component than superior field loss. No association was found between visual field loss and SF-36 mental component scores. The association between visual field loss and functional status was examined in Study 1b. Functional status outcomes measures included a physical activity questionnaire (Physical Activity Scale for the Elderly, PASE), performance tests (six-minute walk test, timed up and go test and lower leg strength) and an overall functional status score. Significant, but weak, correlations were found between binocular visual field loss and PASE and overall functional status scores, adjusted for age and gender (Pearson's r =|0.24| to |0.33|, p<0.05). Greater inferior visual field loss, independent of superior visual field loss, was significantly associated with poorer physical performance results and lower overall functional status scores. In Study 1c, we examined the association between visual field loss and postural stability, using a swaymeter device which recorded body movement during four conditions: eyes open and closed, on a firm and foam surface. Greater binocular visual field loss was associated with increased postural sway, both on firm and foam surfaces, independent of age and gender (Pearson’s r =|0.44| to |0.46|, p <0.001). Furthermore, inferior visual field was a stronger contributor to postural stability, more so than the superior visual field, particularly on the foam condition with the eyes open. Greater visual field loss was associated with a reduction in the visual contribution to postural sway, which underlies the observed association with postural sway. The second component of the thesis examined the association between severity and location of visual field loss and falls during a 12-month longitudinal follow-up. The number of falls was assessed prospectively using monthly fall calendars. Of the 71 participants who successfully completed the follow up (mean age 73.9 ± 5.7 years), 44% reported one or more falls, and around 20% reported two or more falls. After adjusting for age and gender, every 10 points missed on the IVF-120 increased the rate of falls by 25% (rate ratio 1.25, 95% confidence interval 1.08 - 1.44) or every 5dB reduction in IVF-60 increased the rate of falls by 47% (rate ratio 1.47, 95% confidence interval 1.16 - 1.87). Inferior visual field loss was a significant predictor of falls, more so than superior field loss, highlighting the importance of the inferior visual field area in safe and efficient navigation. Further analyses indicated that postural stability, more so than functional status, may be a potential mediating factor in the relationship between visual field loss and falls. Future research is required to confirm this causal pathway. In addition, the use of topical beta-blocker medications was not associated with an increased rate of falls in this cohort, compared with the use of other topical anti-glaucoma medications. In summary, greater binocular visual field loss among older adults with glaucoma was associated with poorer health-related quality of life in the physical domain, reduced functional status, greater postural instability and higher rates of falling. When the location of visual field loss was examined, inferior visual field loss was consistently more strongly associated with these outcomes than superior visual field loss. Insights gained from this research improve our understanding of the association between glaucomatous visual field loss and disability, and its link with falls among older adults. The clinical implications of this research include the need to include visual field screening in falls risk assessments among older adults and to raise awareness of these findings to eye care practitioners and adults with glaucoma. The findings also assist in developing further research to examine strategies to reduce disability and prevent falls among older adults with glaucoma to promote healthy ageing and independence for these individuals.

Corneal confocal microscopy : a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy

OBJECTIVE: The accurate quantification of human diabetic neuropathy is important to define at-risk patients, anticipate deterioration, and assess new therapies. ---------- RESEARCH DESIGN AND METHODS: A total of 101 diabetic patients and 17 age-matched control subjects underwent neurological evaluation, neurophysiology tests, quantitative sensory testing, and evaluation of corneal sensation and corneal nerve morphology using corneal confocal microscopy (CCM). ---------- RESULTS: Corneal sensation decreased significantly (P = 0.0001) with increasing neuropathic severity and correlated with the neuropathy disability score (NDS) (r = 0.441, P < 0.0001). Corneal nerve fiber density (NFD) (P < 0.0001), nerve fiber length (NFL), (P < 0.0001), and nerve branch density (NBD) (P < 0.0001) decreased significantly with increasing neuropathic severity and correlated with NDS (NFD r = −0.475, P < 0.0001; NBD r = −0.511, P < 0.0001; and NFL r = −0.581, P < 0.0001). NBD and NFL demonstrated a significant and progressive reduction with worsening heat pain thresholds (P = 0.01). Receiver operating characteristic curve analysis for the diagnosis of neuropathy (NDS >3) defined an NFD of <27.8/mm2 with a sensitivity of 0.82 (95% CI 0.68–0.92) and specificity of 0.52 (0.40–0.64) and for detecting patients at risk of foot ulceration (NDS >6) defined a NFD cutoff of <20.8/mm2 with a sensitivity of 0.71 (0.42–0.92) and specificity of 0.64 (0.54–0.74). ---------- CONCLUSIONS: CCM is a noninvasive clinical technique that may be used to detect early nerve damage and stratify diabetic patients with increasing neuropathic severity. Established diabetic neuropathy leads to pain and foot ulceration. Detecting neuropathy early may allow intervention with treatments to slow or reverse this condition (1). Recent studies suggested that small unmyelinated C-fibers are damaged early in diabetic neuropathy (2–4) but can only be detected using invasive procedures such as sural nerve biopsy (4,5) or skin-punch biopsy (6–8). Our studies have shown that corneal confocal microscopy (CCM) can identify early small nerve fiber damage and accurately quantify the severity of diabetic neuropathy (9–11). We have also shown that CCM relates to intraepidermal nerve fiber loss (12) and a reduction in corneal sensitivity (13) and detects early nerve fiber regeneration after pancreas transplantation (14). Recently we have also shown that CCM detects nerve fiber damage in patients with Fabry disease (15) and idiopathic small fiber neuropathy (16) when results of electrophysiology tests and quantitative sensory testing (QST) are normal. In this study we assessed corneal sensitivity and corneal nerve morphology using CCM in diabetic patients stratified for the severity of diabetic neuropathy using neurological evaluation, electrophysiology tests, and QST. This enabled us to compare CCM and corneal esthesiometry with established tests of diabetic neuropathy and define their sensitivity and specificity to detect diabetic patients with early neuropathy and those at risk of foot ulceration.

A Bayesian model predicts the response of axons to molecular gradients

Axon guidance by molecular gradients plays a crucial role in wiring up the nervous system. However, the mechanisms axons use to detect gradients are largely unknown. We first develop a Bayesian “ideal observer” analysis of gradient detection by axons, based on the hypothesis that a principal constraint on gradient detection is intrinsic receptor binding noise. Second, from this model, we derive an equation predicting how the degree of response of an axon to a gradient should vary with gradient steepness and absolute concentration. Third, we confirm this prediction quantitatively by performing the first systematic experimental analysis of how axonal response varies with both these quantities. These experiments demonstrate a degree of sensitivity much higher than previously reported for any chemotacting system. Together, these results reveal both the quantitative constraints that must be satisfied for effective axonal guidance and the computational principles that may be used by the underlying signal transduction pathways, and allow predictions for the degree of response of axons to gradients in a wide variety of in vivo and in vitro settings.

Assessment of retinal structure and visual function in association with diabetic peripheral neuropathy

Diabetes is an increasingly prevalent disease worldwide. Providing early management of the complications can prevent morbidity and mortality in this population. Peripheral neuropathy, a significant complication of diabetes, is the major cause of foot ulceration and amputation in diabetes. Delay in attending to complication of the disease contributes to significant medical expenses for diabetic patients and the community. Early structural changes to the neural components of the retina have been demonstrated to occur prior to the clinically visible retinal vasculature complication of diabetic retinopathy. Additionally visual functionloss has been shown to exist before the ophthalmoscopic manifestations of vasculature damage. The purpose of this thesis was to evaluate the relationship between diabetic peripheral neuropathy and both retinal structure and visual function. The key question was whether diabetic peripheral neuropathy is the potential underlying factor responsible for retinal anatomical change and visual functional loss in people with diabetes. This study was conducted on a cohort with type 2 diabetes. Retinal nerve fibre layer thickness was assessed by means of Optical Coherence Tomography (OCT). Visual function was assessed using two different methods; Standard Automated Perimetry (SAP) and flicker perimetry were performed within the central 30 degrees of fixation. The level of diabetic peripheral neuropathy (DPN) was assessed using two techniques - Quantitative Sensory Testing and Neuropathy Disability Score (NDS). These techniques are known to be capable of detecting DPN at very early stages. NDS has also been shown as a gold standard for detecting 'risk of foot ulceration'. Findings reported in this thesis showed that RNFL thickness, particularly in the inferior quadrant, has a significant association with severity of DPN when the condition has been assessed using NDS. More specifically it was observed that inferior RNFL thickness has the ability to differentiate individuals who are at higher risk of foot ulceration from those who are at lower risk, indicating that RNFL thickness can predict late-staged DPN. Investigating the association between RNFL and QST did not show any meaningful interaction, which indicates that RNFL thickness for this cohort was not as predictive of neuropathy status as NDS. In both of these studies, control participants did not have different results from the type 2 cohort who did not DPN suggesting that RNFL thickness is not a marker for diagnosing DPN at early stages. The latter finding also indicated that diabetes per se, is unlikely to affect the RNFL thickness. Visual function as measured by SAP and flicker perimetry was found to be associated with severity of peripheral neuropathy as measured by NDS. These findings were also capable of differentiating individuals at higher risk of foot ulceration; however, visual function also proved not to be a maker for early diagnosis of DPN. It was found that neither SAP, nor flicker sensitivity have meaningful associations with DPN when neuropathy status was measured using QST. Importantly diabetic retinopathy did not explain any of the findings in these experiments. The work described here is valuable as no other research to date has investigated the association between diabetic peripheral neuropathy and either retinal structure or visual function.

Corneal markers of diabetic neuropathy

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 non-invasive 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 non-contact 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.

Sustainability and urban settlements: urban metabolism as a framework for achieving sustainable development

Urban settlements, with their role as economic and governance nerve centres, are rapidly expanding in size and in consumption of resources, and consequently have significant impacts on the environment. The transition to an ‘eco-city’ - an urban settlement that adopts the goals and principles in the urban metabolism model - needs to occur to meet the challenges posed by a multitude of pressures including population growth, climate change and resource depletion. Thus, the adoption and integration of ‘sustainable development’ into the management of urban growth is one of the most critical governance issues for urban settlements. A framework in which sustainable development can be achieved is through the lenses of the established theoretical concept of ‘urban metabolism’. The key facet of the proposed ‘Integrated Urban Metabolism Framework’ is the provision of a platform whereby different fields can appreciate, absorb and learn from other areas, to increase the understanding of where each and every one of the pieces fit together in order to create a larger, holistic approach to the currently stagnant problem of unsustainable development.

Effects of enhanced somatosensory information on postural stability in older people and people with Parkinson’s disease

The somatosensory system plays an important role in balance control and age-related changes to this system have been implicated in falls. Parkinson’s disease (PD) is a chronic and progressive disease of the brain, characterized by postural instability and gait disturbance. Previous research has shown that deficiencies in somatosensory feedback may contribute to the poorer postural control demonstrated by PD individuals. However, few studies have comprehensively explored differences in somatosensory function and postural control between PD participants and healthy older individuals. The soles of the feet contain many cutaneous mechanoreceptors that provide important somatosensory information sources for postural control. Different types of insole devices have been developed to enhance this somatosensory information and improve postural stability, but these devices are often too complex and expensive to integrate into daily life. Textured insoles provide a more passive intervention that may be an inexpensive and accessible means to enhance the somatosensory input from the plantar surface of the feet. However, to date, there has been little work conducted to test the efficacy of enhanced somatosensory input induced by textured insoles in both healthy and PD populations during standing and walking. Therefore, the aims of this thesis were to determine: 1) whether textured insole surfaces can improve postural stability by enhancing somatosensory information in younger and older adults, 2) the differences between healthy older participants and PD participants for measures of physiological function and postural stability during standing and walking, 3) how changes in somatosensory information affect postural stability in both groups during standing and walking; and 4), whether textured insoles can improve postural stability in both groups during standing and walking. To address these aims, Study 1 recruited seven older individuals and ten healthy young controls to investigate the effects of two textured insole surfaces on postural stability while performing standing balance tests on a force plate. Participants were tested under three insole surface conditions: 1) barefoot; 2) standing on a hard textured insole surface; and 3), standing on a soft textured insole surface. Measurements derived from the centre of pressure displacement included the range of anterior-posterior and medial-lateral displacement, path length and the 90% confidence elliptical area (C90 area). Results of study 1 revealed a significant Group*Surface*Insole interaction for the four measures. Both textured insole surfaces reduced postural sway for the older group, especially in the eyes closed condition on the foam surface. However, participants reported that the soft textured insole surface was more comfortable and, hence, the soft textured insoles were adopted for Studies 2 and 3. For Study 2, 20 healthy older adults (controls) and 20 participants with Parkinson’s disease were recruited. Participants were evaluated using a series of physiological assessments that included touch sensitivity, vibratory perception, and pain and temperature threshold detection. Furthermore, nerve function and somatosensory evoked potentials tests were utilized to provide detailed information regarding peripheral nerve function for these participants. Standing balance and walking were assessed on different surfaces using a force plate and the 3D Vicon motion analysis system, respectively. Data derived from the force plate included the range of anterior-posterior and medial-lateral sway, while measures of stride length, stride period, cadence, double support time, stance phase, velocity and stride timing variability were reported for the walking assessment. The results of this study demonstrated that the PD group had decrements in somatosensory function compared to the healthy older control group. For electrodiagnosis, PD participants had poorer nerve function than controls, as evidenced by slower nerve conduction velocities and longer latencies in sural nerve and prolonged latency in the P37 somatosensory evoked potential. Furthermore, the PD group displayed more postural sway in both the anterior-posterior and medial-lateral directions relative to controls and these differences were increased when standing on a foam surface. With respect to the gait assessment, the PD group took shorter strides and had a reduced stride period compared with the control group. Furthermore, the PD group spent more time in the stance phase and had increased cadence and stride timing variability than the controls. Compared with walking on the firm surface, the two groups demonstrated different gait adaptations while walking on the uneven surface. Controls increased their stride length and stride period and decreased their cadence, which resulted in a consistent walking velocity on both surfaces. Conversely, while the PD patients also increased their stride period and decreased their cadence and stance period on the uneven surface, they did not increase their stride length and, hence walked slower on the uneven surface. In the PD group, there was a strong positive association between decreased somatosensory function and decreased clinical balance, as assessed by the Tinetti test. Poorer somatosensory function was also strongly positively correlated with the temporospatial gait parameters, especially shorter stride length. Study 3 evaluated the effects of manipulating the somatosensory information from the plantar surface of the feet using textured insoles in the same populations assessed in Study 2. For this study, participants performed the standing and walking balance tests under three footwear conditions: 1) barefoot; 2) with smooth insoles; and 3), with textured insoles. Standing balance and walking were evaluated using a force plate and a Vicon motion analysis system and the data were analysed in the same way outlined for Study 2. The findings showed that the smooth and textured insoles caused different effects on postural control during both the standing and walking trials. Both insoles decreased medial-lateral sway to the same level on the firm surface. The greatest benefits were observed in the PD group while wearing the textured insole. When standing under a more challenging condition on the foam surface with eyes closed, only the textured insole decreased medial-lateral sway in the PD group. With respect to the gait trials, both insoles increased walking velocity, stride length and stride time and decreased cadence, but these changes were more pronounced for the textured insoles. The effects of the textured insoles were evident under challenging conditions in the PD group and increased walking velocity and stride length, while decreasing cadence. Textured insoles were also effective in reducing the time spent in the double support and stance phases of the gait cycle and did not increase stride timing variability, as was the case for the smooth insoles for the PD group. The results of this study suggest that textured insoles, such as those evaluated in this research, may provide a low-cost means of improving postural stability in high-risk groups, such as people with PD, which may act as an important intervention to prevent falls.

Global flash multifocal electroretinogram : early detection of local functional changes and its correlations with optical coherence tomography and visual field loss in diabetic eyes

Purpose: To investigate the correlations of the global flash multifocal electroretinogram (MOFO mfERG) with common clinical visual assessments – Humphrey perimetry and Stratus circumpapillary retinal nerve fiber layer (RNFL) thickness measurement in type II diabetic patients. Methods: Forty-two diabetic patients participated in the study: ten were free from diabetic retinopathy (DR) while the remainder suffered from mild to moderate non-proliferative diabetic retinopathy (NPDR). Fourteen age-matched controls were recruited for comparison. MOFO mfERG measurements were made under high and low contrast conditions. Humphrey central 30-2 perimetry and Stratus OCT circumpapillary RNFL thickness measurements were also performed. Correlations between local values of implicit time and amplitude of the mfERG components (direct component (DC) and induced component (IC)), and perimetric sensitivity and RNFL thickness were evaluated by mapping the localized responses for the three subject groups. Results: MOFO mfERG was superior to perimetry and RNFL assessments in showing differences between the diabetic groups (with and without DR) and the controls. All the MOFO mfERG amplitudes (except IC amplitude at high contrast) correlated better with perimetry findings (Pearson’s r ranged from 0.23 to 0.36, p<0.01) than did the mfERG implicit time at both high and low contrasts across all subject groups. No consistent correlation was found between the mfERG and RNFL assessments for any group or contrast conditions. The responses of the local MOFO mfERG correlated with local perimetric sensitivity but not with RNFL thickness. Conclusion: Early functional changes in the diabetic retina seem to occur before morphological changes in the RNFL.

The relationship between Bayesian motor unit number estimation and histological measurements of motor neurons in wild-type and SOD1 G93A mice

Objective: To assess the relationship between Bayesian MUNE and histological motor neuron counts in wild-type mice and in an animal model of ALS. Methods: We performed Bayesian MUNE paired with histological counts of motor neurons in the lumbar spinal cord of wild-type mice and transgenic SOD1 G93A mice that show progressive weakness over time. We evaluated the number of acetylcholine endplates that were innervated by a presynaptic nerve. Results: In wild-type mice, the motor unit number in the gastrocnemius muscle estimated by Bayesian MUNE was approximately half the number of motor neurons in the region of the spinal cord that contains the cell bodies of the motor neurons supplying the hindlimb crural flexor muscles. In SOD1 G93A mice, motor neuron numbers declined over time. This was associated with motor endplate denervation at the end-stage of disease. Conclusion: The number of motor neurons in the spinal cord of wild-type mice is proportional to the number of motor units estimated by Bayesian MUNE. In SOD1 G93A mice, there is a lower number of estimated motor units compared to the number of spinal cord motor neurons at the end-stage of disease, and this is associated with disruption of the neuromuscular junction. Significance: Our finding that the Bayesian MUNE method gives estimates of motor unit numbers that are proportional to the numbers of motor neurons in the spinal cord supports the clinical use of Bayesian MUNE in monitoring motor unit loss in ALS patients. © 2012 International Federation of Clinical Neurophysiology.

Early inflammatory and myogenic responses to resistance exercise in the elderly

Introduction and Methods: This study compared changes in myokine and myogenic genes following resistance exercise (3 sets of 12 repetitions of maximal unilateral knee extension) in 20 elderly men (67.8 ± 1.0 years) and 15 elderly women (67.2 ± 1.5 years). Results: Monocyte chemotactic protein (MCP)-1, macrophage inhibitory protein (MIP)-1β, interleukin (IL)-6 and MyoD mRNA increased significantly (P < 0.05), whereas myogenin and myostatin mRNA decreased significantly after exercise in both groups. Macrophage-1 (Mac-1) and MCP-3 mRNA did not change significantly after exercise in either group. MIP-1β, Mac-1 and myostatin mRNA were significantly higher before and after exercise in men compared with women. In contrast, MCP-3 and myogenin mRNA were significantly higher before and after exercise in the women compared with the men. Conclusions: In elderly individuals, gender influences the mRNA expression of certain myokines and growth factors, both at rest and after resistance exercise. These differences may influence muscle regeneration following muscle injury

Utility of corneal confocal microscopy for assessing mild diabetic neuropathy: baseline findings of the LANDMark study

Background:  For those in the field of managing diabetic complications, the accurate diagnosis and monitoring of diabetic peripheral neuropathy (DPN) continues to be a challenge. Assessment of sub-basal corneal nerve morphology has recently shown promise as a novel ophthalmic marker for the detection of DPN. Methods:  Two hundred and thirty-one individuals with diabetes with predominantly mild or no neuropathy and 61 controls underwent evaluation of diabetic neuropathy symptom score, neuropathy disability score, testing with 10 g monofilament, quantitative sensory testing (warm, cold, vibration detection) and nerve conduction studies. Corneal nerve fibre length, branch density and tortuosity were measured using corneal confocal microscopy. Differences in corneal nerve morphology between individuals with and without DPN and controls were investigated using analysis of variance and correlations were determined between corneal morphology and established tests of, and risk factors for, DPN. Results:  Corneal nerve fibre length was significantly reduced in diabetic individuals with mild DPN compared with both controls (p < 0.001) and diabetic individuals without DPN (p = 0.012). Corneal nerve branch density was significantly reduced in individuals with mild DPN compared with controls (p = 0.032). Corneal nerve fibre tortuosity did not show significant differences. Corneal nerve fibre length and corneal nerve branch density showed modest correlations to most measures of neuropathy, with the strongest correlations to nerve conduction study parameters (r = 0.15 to 0.25). Corneal nerve fibre tortuosity showed only a weak correlation to the vibration detection threshold. Corneal nerve fibre length was inversely correlated to glycated haemoglobin (r = -0.24) and duration of diabetes (r = -0.20). Conclusion:  Assessment of corneal nerve morphology is a non-invasive, rapid test capable of showing differences between individuals with and without DPN. Corneal nerve fibre length shows the strongest associations with other diagnostic tests of neuropathy and with established risk factors for neuropathy.