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.

The post-illumination pupil response of melanopsin expressing intrinsically photosensitive retinal ganglion cells in diabetes

Purpose: This study investigates the clinical utility of the melanopsin expressing intrinsically photosensitive retinal ganglion cell (ipRGC) controlled post-illumination pupil response (PIPR) as a novel technique for documenting inner retinal function in patients with Type II diabetes without diabetic retinopathy. Methods: The post-illumination pupil response (PIPR) was measured in seven patients with Type II diabetes, normal retinal nerve fiber thickness and no diabetic retinopathy. A 488 nm and 610 nm, 7.15º diameter stimulus was presented in Maxwellian view to the right eye and the left consensual pupil light reflex was recorded. Results: The group data for the blue PIPR (488 nm) identified a trend of reduced ipRGC function in patients with diabetes with no retinopathy. The transient pupil constriction was lower on average in the diabetic group. The relationship between duration of diabetes and the blue PIPR amplitude was linear, suggesting that ipRGC function decreases with increasing diabetes duration. Conclusion: This is the first report to show that the ipRGC controlled post-illumination pupil response may have clinical applications as a non-invasive technique for determining progression of inner neuroretinal changes in patients with diabetes before they are ophthalmoscopically or anatomically evident. The lower transient pupil constriction amplitude indicates that outer retinal photoreceptor inputs to the pupil light reflex may also be affected in diabetes.

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.

Retinal nerve fibre layer thinning associated with diabetic peripheral neuropathy

Aims:  To investigate the relationship between retinal nerve fibre layer thickness and peripheral neuropathy in patients with Type 2 diabetes, particularly in those who are at higher risk of foot ulceration. Methods:  Global and sectoral retinal nerve fibre layer thicknesses were measured at 3.45 mm diameter around the optic nerve head using optical coherence tomography (OCT). The level of neuropathy was assessed in 106 participants (82 with Type 2 diabetes and 24 healthy controls) using the 0–10 neuropathy disability score. Participants were stratified into four neuropathy groups: none (0–2), mild (3–5), moderate (6–8), and severe (9–10). A neuropathy disability score ≥ 6 was used to define those at higher risk of foot ulceration. Multivariable regression analysis was performed to assess the effect of neuropathy disability scores, age, disease duration and retinopathy on RNFL thickness. Results:  Inferior (but not global or other sectoral) retinal nerve fibre layer thinning was associated with higher neuropathy disability scores (P = 0.03). The retinal nerve fibre layer was significantly thinner for the group with neuropathy disability scores ≥ 6 in the inferior quadrant (P < 0.005). Age, duration of disease and retinopathy levels did not significantly influence retinal nerve fibre layer thickness. Control participants did not show any significant differences in thickness measurements from the group with diabetes and no neuropathy (P > 0.24 for global and all sectors). Conclusions:  Inferior quadrant retinal nerve fibre layer thinning is associated with peripheral neuropathy in patients with Type 2 diabetes, and is more pronounced in those at higher risk of foot ulceration.

Visual function and CFH/ARMS2 risk genotypes in macular dystrophy due to maternally inherited diabetes and deafness

Maternally inherited diabetes and deafness (MIDD) is an autosomal dominant inherited syndrome caused by the mitochondrial DNA (mtDNA) nucleotide mutation A3243G. It affects various organs including the eye with external ophthalmoparesis, ptosis, and bilateral macular pattern dystrophy.1, 2 The prevalence of retinal involvement in MIDD is high, with 50% to 85% of patients exhibiting some macular changes.1 Those changes, however, can vary between patients and within families dramatically based on the percentage of retinal mtDNA mutations, making it difficult to give predictions on an individual’s visual prognosis...

Exploring retinal markers of diabetic neuropathy

Purpose To investigate the application of retinal nerve fibre layer (RNFL) thickness as a marker for severity of diabetic peripheral neuropathy (DPN) in people with Type 2 diabetes. Methods This was a cross-sectional study whereby 61 participants (mean age 61 [41-75 years], mean duration of diabetes 14 [1-40 years], 70% male) with Type 2 diabetes and DPN underwent optical coherence tomography (OCT) scans. Global and 4 quadrant (TSNI) RNFL thicknesses were measured at 3.45mm around the optic nerve head of one eye. Neuropathy disability score (NDS) was used to assess the severity of DPN on a 0 to 10 scale. Participants were divided into three age-matched groups representing mild (NDS=3-5), moderate (NDS=6-8) and severe (NDS=9-10) neuropathy. Two regression models were fitted for statistical analysis: 1) NDS scores as co-variate for global and quadrant RNFL thicknesses, 2) NDS groups as a factor for global RNFL thickness only. Results Mean (SD) RNFL thickness (µm) was 103(9) for mild neuropathy (n=34), 101(10) for moderate neuropathy (n=16) and 95(13) in the group with severe neuropathy (n=11). Global RNFL thickness and NDS scores were statistically significantly related (b=-1.20, p=0.048). When neuropathy was assessed across groups, a trend of thinner mean RNFL thickness was observed with increasing severity of neuropathy; however, this result was not statistically significant (F=2.86, p=0.065). TSNI quadrant analysis showed that mean RNFL thickness reduction in the inferior quadrant was 2.55 µm per 1 unit increase in NDS score (p=0.005). However, the regression coefficients were not statistically significant for RNFL thickness in the superior (b=-1.0, p=0.271), temporal (b=-0.90, p=0.238) and nasal (b=-0.99, p=0.205) quadrants. Conclusions RNFL thickness was reduced with increasing severity of DPN and the effect was most evident in the inferior quadrant. Measuring RNFL thickness using OCT may prove to be a useful, non-invasive technique for identifying severity of DPN and may also provide additional insight into common mechanisms for peripheral neuropathy and RNFL damage.

Retinal nerve fibre layer thickness is associated with higher risk of foot ulceration in diabetic peripheral neuropathy

Purpose To evaluate the association between retinal nerve fibre layer (RNFL) thickness and diabetic peripheral neuropathy in people with type 2 diabetes, and specifically those at higher risk of foot ulceration. Methods RNFL thicknesses was measured globally and in four quadrants (temporal, superior, nasal and inferior) at 3.45 mm diameter around the optic nerve head using optical coherence tomography (OCT). Severity of neuropathy was assessed using the Neuropathy Disability Score (NDS). Eighty-two participants with type 2 diabetes were stratified according to NDS scores (0-10) as: none, mild, moderate, and severe neuropathy. A control group was additionally included (n=17). Individuals with NDS≥ 6 (moderate and severe neuropathy) have been shown to be at higher risk of foot ulceration. A linear regression model was used to determine the association between RNFL and severity of neuropathy. Age, disease duration and diabetic retinopathy levels were fitted in the models. Independent t-test was employed for comparison between controls and the group without neuropathy, as well as for comparison between groups with higher and lower risk of foot ulceration. Analysis of variance was used to compare across all NDS groups. Results RNFL thickness was significantly associated with NDS in the inferior quadrant (b= -1.46, p=0.03). RNFL thicknesses globally and in superior, temporal and nasal quadrants did not show significant associations with NDS (all p>0.51). These findings were independent of the effect of age, disease duration and retinopathy. RNFL was thinner for the group with NDS ≥ 6 in all quadrants but was significant only inferiorly (p<0.005). RNFL for control participants was not significantly different from the group with diabetes and no neuropathy (superior p=0.07, global and all other quadrants: p>0.23). Mean RNFL thickness was not significantly different between the four NDS groups globally and in all quadrants (p=0.08 for inferior, P>0.14 for all other comparisons). Conclusions Retinal nerve fibre layer thinning is associated with neuropathy in people with type 2 diabetes. This relationship is strongest in the inferior retina and in individuals at higher risk of foot ulceration.

Melanopsin expressing intrinsically photosensitive Retinal Ganglion cells in retinal disease

Melanopsin containing intrinsically photosensitive Retinal Ganglion Cells (ipRGCs) are a class of photoreceptors with established roles in non-image forming processes. Their contributions to image forming vision may include the estimation of brightness. Animal models have been central for understanding the physiological mechanisms of ipRGC function and there is evidence of conservation of function across species. ipRGCs can be divided into 5 ganglion cell subtypes that show morphological and functional diversity. Research in humans has established that ipRGCs signal environmental irradiance to entrain the central body clock to the solar day for regulating circadian processes and sleep. In addition, ipRGCs mediate the pupil light reflex (PLR), making the PLR a readily accessible behavioural marker of ipRGC activity. Less is known about ipRGC function in retinal and optic nerve disease, with emerging research providing insight into their function in diabetes, retinitis pigmentosa, glaucoma and hereditary optic neuropathy. We briefly review the anatomical distributions, projections and basic physiological mechanisms of ipRGCs, their proposed and known functions in animals and humans with and without eye disease. We introduce a paradigm for differentiating inner and outer retinal inputs to the pupillary control pathway in retinal disease and apply this paradigm to patients with age-related macular degeneration (AMD). In these cases of patients with AMD, we provide the initial evidence that ipRGC function is altered, and that the dysfunction is more pronounced in advanced disease. Our perspective is that with refined pupillometry paradigms, the pupil light reflex can be extended to AMD assessment as a tool for the measurement of inner and outer retinal dysfunction.

Exploring Retinal Markers of Diabetic Neuropathy

Purpose : To investigate the application of retinal nerve fibre layer (RNFL) thickness as a marker for severity of diabetic peripheral neuropathy (DPN) in people with Type 2 diabetes. Methods : This was a cross-sectional study whereby 61 participants (mean age 61 [41-75 years], mean duration of diabetes 14 [1-40 years], 70% male) with Type 2 diabetes and DPN underwent optical coherence tomography (OCT) scans. Global and 4 quadrant (TSNI) RNFL thicknesses were measured at 3.45mm around the optic nerve head of one eye. Neuropathy disability score (NDS) was used to assess the severity of DPN on a 0 to 10 scale. Participants were divided into three age-matched groups representing mild (NDS=3-5), moderate (NDS=6-8) and severe (NDS=9-10) neuropathy. Two regression models were fitted for statistical analysis: 1) NDS scores as co-variate for global and quadrant RNFL thicknesses, 2) NDS groups as a factor for global RNFL thickness only. Results : Mean (SD) RNFL thickness (µm) was 103(9) for mild neuropathy (n=34), 101(10) for moderate neuropathy (n=16) and 95(13) in the group with severe neuropathy (n=11). Global RNFL thickness and NDS scores were statistically significantly related (b=-1.20, p=0.048). When neuropathy was assessed across groups, a trend of thinner mean RNFL thickness was observed with increasing severity of neuropathy; however, this result was not statistically significant (F=2.86, p=0.065). TSNI quadrant analysis showed that mean RNFL thickness reduction in the inferior quadrant was 2.55 µm per 1 unit increase in NDS score (p=0.005). However, the regression coefficients were not statistically significant for RNFL thickness in the superior (b=-1.0, p=0.271), temporal (b=-0.90, p=0.238) and nasal (b=-0.99, p=0.205) quadrants. Conclusions : RNFL thickness was reduced with increasing severity of DPN and the effect was most evident in the inferior quadrant. Measuring RNFL thickness using OCT may prove to be a useful, non-invasive technique for identifying severity of DPN and may also provide additional insight into common mechanisms for peripheral neuropathy and RNFL damage.

Retinal tissue thickness is reduced in diabetic peripheral neuropathy

Aim Retinal tissue integrity in relation to diabetic neuropathy is not known. The aim of this study was to investigate retinal tissue thickness in relation to diabetic peripheral neuropathy (DPN) with and without diabetic retinopathy (DR). Methods Full retinal thickness at the parafoveal and perifoveal macula and neuro-retinal thickness around the optic nerve head (ONH) and at the macula was examined using spectral domain optical coherence tomography. The eye on the hand-dominant side of 85 individuals with type 1 diabetes and 66 individuals with type 2 diabetes, with or without DR and DPN, were compared to the eyes (n=45) of age-matched non-diabetic controls. Diabetic neuropathy was defined as Neuropathy Disability Score (NDS) ≥3 on a scale of 0-10. A general linear model was used to examine the relationship between diabetic neuropathy and foveal, parafoveal and perifoveal retinal thickness and neuro-retinal thickness, in relation to DR status, age, gender, HbA1c levels and duration of diabetes. A p-value of <0.05 was considered statistically significant. Results Perifoveal retinal thickness is reduced with increasing severity of neuropathy, especially in the inferior hemisphere (p=0.004); this effect was not related to age (p=0.088). For every unit increase in NDS score, the inferior perifoveal retinal thickness reduced by 1.64 μm. Neuro-retinal thickness around the ONH decreased with increasing severity of neuropathy (p<0.014 for average and hemisphere thicknesses); for every unit increase in NDS, neuro-retinal thickness around the ONH reduced by 1.23 μm. Retinal thickness in the parafovea was increased in the absence of DR (p<0.017 for average and hemisphere thicknesses). Neuro-retinal thickness at the macula was inversely related to age alone (p<0.001). All retinal parameters, except the inferior perifovea, reduced with advancing age (p<0.007 for all). Conclusions Diabetic neuropathy is associated with changes in full retinal thickness and neuro-retinal layers. This may represent a second threat to vision integrity, in addition to the better-characterised retinopathy. This study provides new knowledge about the anatomical aspects of the retinal tissue in relation to neuropathy and retinopathy.

Non-alcoholic fatty liver disease : can ultrasound assist in early diagnosis of prediabetes and delay progression to type2 diabetes mellitus

Non Alcoholic Fatty Liver Disease (NAFLD) is a condition that is frequently seen but seldom investigated. Until recently, NAFLD was considered benign, self-limiting and unworthy of further investigation. This opinion is based on retrospective studies with relatively small numbers and scant follow-up of histology data. (1) The prevalence for adults, in the USA is, 30%, and NAFLD is recognized as a common and increasing form of liver disease in the paediatric population (1). Australian data, from New South Wales, suggests the prevalence of NAFLD in “healthy” 15 year olds as being 10%.(2) Non-alcoholic fatty liver disease is a condition where fat progressively invades the liver parenchyma. The degree of infiltration ranges from simple steatosis (fat only) to steatohepatitis (fat and inflammation) steatohepatitis plus fibrosis (fat, inflammation and fibrosis) to cirrhosis (replacement of liver texture by scarred, fibrotic and non functioning tissue).Non-alcoholic fatty liver is diagnosed by exclusion rather than inclusion. None of the currently available diagnostic techniques -liver biopsy, liver function tests (LFT) or Imaging; ultrasound, Computerised tomography (CT) or Magnetic Resonance Imaging (MRI) are specific for non-alcoholic fatty liver. An association exists between NAFLD, Non Alcoholic Steatosis Hepatitis (NASH) and irreversible liver damage, cirrhosis and hepatoma. However, a more pervasive aspect of NAFLD is the association with Metabolic Syndrome. This Syndrome is categorised by increased insulin resistance (IR) and NAFLD is thought to be the hepatic representation. Those with NAFLD have an increased risk of death (3) and it is an independent predictor of atherosclerosis and cardiovascular disease (1). Liver biopsy is considered the gold standard for diagnosis, (4), and grading and staging, of non-alcoholic fatty liver disease. Fatty-liver is diagnosed when there is macrovesicular steatosis with displacement of the nucleus to the edge of the cell and at least 5% of the hepatocytes are seen to contain fat (4).Steatosis represents fat accumulation in liver tissue without inflammation. However, it is only called non-alcoholic fatty liver disease when alcohol - >20gms-30gms per day (5), has been excluded from the diet. Both non-alcoholic and alcoholic fatty liver are identical on histology. (4).LFT’s are indicative, not diagnostic. They indicate that a condition may be present but they are unable to diagnosis what the condition is. When a patient presents with raised fasting blood glucose, low HDL (high density lipoprotein), and elevated fasting triacylglycerols they are likely to have NAFLD. (6) Of the imaging techniques MRI is the least variable and the most reproducible. With CT scanning liver fat content can be semi quantitatively estimated. With increasing hepatic steatosis, liver attenuation values decrease by 1.6 Hounsfield units for every milligram of triglyceride deposited per gram of liver tissue (7). Ultrasound permits early detection of fatty liver, often in the preclinical stages before symptoms are present and serum alterations occur. Earlier, accurate reporting of this condition will allow appropriate intervention resulting in better patient health outcomes. References 1. Chalasami N. Does fat alone cause significant liver disease: It remains unclear whether simple steatosis is truly benign. American Gastroenterological Association Perspectives, February/March 2008 www.gastro.org/wmspage.cfm?parm1=5097 Viewed 20th October, 2008 2. Booth, M. George, J.Denney-Wilson, E: The population prevalence of adverse concentrations with adiposity of liver tests among Australian adolescents. Journal of Paediatrics and Child Health.2008 November 3. Catalano, D, Trovato, GM, Martines, GF, Randazzo, M, Tonzuso, A. Bright liver, body composition and insulin resistance changes with nutritional intervention: a follow-up study .Liver Int.2008; February 1280-9 4. Choudhury, J, Sanysl, A. Clinical aspects of Fatty Liver Disease. Semin in Liver Dis. 2004:24 (4):349-62 5. Dionysus Study Group. Drinking factors as cofactors of risk for alcohol induced liver change. Gut. 1997; 41 845-50 6. Preiss, D, Sattar, N. Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci.2008; 115 141-50 7. American Gastroenterological Association. Technical review on nonalcoholic fatty liver disease. Gastroenterology.2002; 123: 1705-25